CFR 2021 – Volume 7 by Radcliffe Cardiology

Volume 7 • 2021

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Volume 7 • 2021 Editor-in-Chief Andrew JS Coats

Monash University, Melbourne, Australia, and University of Warwick, Coventry, UK

Deputy Editor-in-Chief Giuseppe Rosano

IRCCS San Raffaele, Rome, Italy, and St George’s Hospitals NHS Trust, University of London, UK

Associate Editor Cristiana Vitale

Department of Medical Sciences, IRCCS San Raffaele, Rome, Italy

Section Editors Case Reports and Clinical Cases

Advanced Heart Failure

Emerging Technologies

University of Split, Split, Croatia

Columbia University Irving Medical Center, New York, NY, US

Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia

Cardiogenic Shock

Critical Care Cardiology

University of Copenhagen, Copenhagen, Denmark

Vanderbilt University, Nashville, TN, US

Josip A Borovac

Ersilia M DeFilippis

Acute Heart Failure

Ovidiu Chioncel

University of Medicine Carol Davila, Bucharest, Romania

Finn Gustafsson

Digital Health

Sean Lal

Maurizio Volterrani

IRCCS San Raffaele Pisana, Rome, Italy

Aniket S Rali

Editorial Board William T Abraham

Frank Edelmann

Ohio State University College of Medicine, Columbus, OH, US

Charité University Medicine, Berlin, Germany

Ali Ahmed

St Bartholomew’s Hospital, UK; King’s College London, London, UK

Fozia Ahmed

University of Melbourne, Australia

Amod Amritphale

Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Washington DC VA Medical Center, Washington DC, US Manchester University NHS Foundation Trust, Manchester, UK University of South Alabama, Mobile, AL, US

John J Atherton

Royal Brisbane and Women’s Hospital, Brisbane, Australia

Julia Grapsa

David L Hare

Sivadasanpillai Harikrishnan

Theresa A McDonagh

King’s College Hospital, London, UK

Kenneth McDonald

St Vincent’s University Hospital, Dublin, Ireland

Ileana L Piña

Wayne State University, Detroit, MI, US

Kian Keong Poh

National University Heart Center, Singapore

Amina Rakisheva

Loreena Hill

Scientific Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan

Tiny Jaarsma

Cardiovascular Clinic Santa Maria, University of Antioquia, Medellín, Colombia

School of Nursing and Midwifery, Queen’s University Belfast, Belfast, Northern Ireland

Clara Saldarriaga

Feras Bader

Linköping University, Linköping, Sweden

Michael Böhm

Torrens University, Wakefield Campus, Adelaide, Australia

University of Saarland, Homburg, Germany

Centre for Heart Diseases, Faculty of Health Sciences, Wrocław Medical University, Wrocław, Poland

Eugene Braunwald

Dipak Kotecha

University of Birmingham, Birmingham, UK

School of Nursing and Midwifery, Queen’s University Belfast, Belfast, Northern Ireland

Javed Butler

Farrer Park Hospital, Singapore

Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

Harvard Medical School, Boston, MA, US University of Mississippi Medical Center, Jackson, MS, US

Vijay Chopra

Heart Failure Programme and Research, Max Super Specialty Hospital, New Delhi, India

Alain Cohen-Solal

Paris Diderot University, Paris, France

Kevin Damman

Ewa Jankowska

Bernard Kwok

Ekaterini Lambrinou

Cyprus University of Technology, Limassol, Cyprus

Lars H Lund

Karolinska Insitutet and Karolinska University Hospital, Stockholm, Sweden

Alexander Lyon

Royal Brompton Hospital, London, UK

Francesco Maisano

University of Groningen, University Medical Center Groningen, Groningen, Netherlands

University Hospital, Zurich, Switzerland

Carmine De Pasquale

Mamas A Mamas

Flinders University, Adelaide, Australia

University of Keele, Keele, Staffordshire, UK

Simon Stewart

David Thompson

Izabella Uchmanowicz

Wroclaw Medical University, Poland

Harriette Van Spall

McMaster University, Hamilton, Canada

Raymond Wong

National University Heart Centre, National University Hospital, Singapore

Yuhui Zhang

Fuwai Hospital and National Center for Cardiovascular Diseases, Beijing, China

Shelley Zieroth

Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada

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Volume 7 • 2021

Editorial Publishing Director Leiah Norcott | Managing Editor Agnieszka Topolska Head of Print Design Tatiana Losinska | Production Editors Aashni Shah, Bettina Vine Editorial Coordinator Calum White | Peer Review Editor Nicola Parsons Contact agnieszka.topolska@radcliffe-group.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2021 All rights reserved • ISSN: 2057-7540 • eISSN: 2057-7559

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Volume 7 • 2021

Aims and Scope

• Cardiac Failure Review is an international, English language,

peer-reviewed, open access journal that publishes articles continuously on www.CFRjournal.com. • Cardiac Failure Review aims to assist time-pressured physicians to stay abreast of key advances and opinions in heart failure. • Cardiac Failure Review publishes balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Cardiac Failure Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format

• Cardiac Failure Review publishes review articles, original research,

expert opinion pieces, guest editorials and letters to the editor. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Editorial Board.

Abstracting and Indexing

Cardiac Failure Review is abstracted, indexed and listed in PubMed, Crossref, Scopus, Google Scholar and Directory of Open Access Journals. All articles are published in full on PubMed Central a month after publication. Radcliffe Group is an STM member publisher.

Editorial Expertise

Cardiac Failure Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by the Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of editors and technical editors.

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The journal follows guidance from the International Committee of Medical Journal Editors and the Committee on Publication Ethics. We expect all parties involved in the journal’s publication to follow these guidelines. All authors must declare any conflicts of interest.

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Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for noncommercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/ by-nc/4.0/legalcode). Radcliffe Medical Media retains all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publisher. To support open access publication costs, Radcliffe charges an Article Publication Charge (APC) to authors upon acceptance of an unsolicited paper as follows: £1,050 UK | €1,200 Eurozone | $1,369 all other countries. Waivers are available, as specified in the ‘Instructions to authors’ section on www.CFRjournal.com.

Peer Review

• On submission, all articles are assessed by the Editor-in-Chief • • • •

to determine their suitability for inclusion. Suitable manuscripts are sent for double-blind peer review. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. Once a manuscript has been amended in accordance with the reviewers’ comments, it is assessed to ensure it meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval.

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Cardiac Failure Review is an online publication. Articles are published continuously on www.CFRjournal.com. The journal is free to read online and PDF downloads are available for registered users.

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Online

Submissions and Instructions to Authors

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the Editorial Board and Managing Editor. Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. Instructions to authors and additional submission details are available at www.CFRjournal.com. Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Agnieszka Topolska, agnieszka.topolska@radcliffe-group.com. Articles may be submitted directly at www.editorialmanager.com/cfr.

All published manuscripts are free to read at www.CFRjournal.com. They are also available at www.radcliffecardiology.com, along with articles from the other journals in Radcliffe Cardiology’s cardiovascular portfolio – Arrhythmia & Electrophysiology Review, European Cardiology Review, Interventional Cardiology and US Cardiology Review.

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All articles included in Cardiac Failure Review are available as reprints. Please contact the Promotional Sales Director, David Bradbury david.bradbury@radcliffe-group.com.

Contents Viscoelastic Haemostatic Assays in Cardiovascular Critical Care

Aniket S Rali, Ahmed M Salem, Melat Gebre, Taylor M Garies, Siva Taduru and Arthur W Bracey Jr DOI: https://doi.org/10.15420/cfr.2020.22

Pulmonary Embolism and Heart Failure: A Reappraisal Mattia Arrigo and Lars Christian Huber DOI: https://doi.org/10.15420/cfr.2020.26

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Chris Wai Hang Lo, Yue Fei and Bernard Man Yung Cheung DOI: https://doi.org/10.15420/cfr.2020.19

Representation of Women Physicians in Heart Failure Clinical Practice Ersilia M DeFilippis, Yasbanoo Moayedi and Nosheen Reza DOI: https://doi.org/10.15420/cfr.2020.31

Rationale for and Practical Use of Sacubitril/Valsartan in the Patient’s Journey with Heart Failure and Reduced Ejection Fraction Mauro Gori, James L Januzzi, Emilia D’Elia, Ferdinando L Lorini and Michele Senni DOI: https://doi.org/10.15420/cfr.2020.25

CardioMEMS Implantation Using Gadolinium-based Contrast Agent: A Case Report Aniket S Rali, Lynne W Stevenson and Sandip K Zalawadiya DOI: https://doi.org/10.15420/cfr.2021.03

Digital Health: Implications for Heart Failure Management Arvind Singhal and Martin R Cowie DOI: https://doi.org/10.15420/cfr.2020.28

Fatal Enterovirus-related Myocarditis in a Patient with Devic’s Syndrome Treated with Rituximab

Ava Diarra, Guillaume Gantois, Mouna Lazrek, Basile Verdier, Vincent Elsermans, Hélène Zephir, Benjamin Longère, Xristos Gkizas, Céline Goeminne, Gilles Lemesle, Francis Juthier, Johana Bene, David Launay, Romain Dubois, Sandrine Morell-Dubois, Fanny Vuotto and Anne-Laure Piton DOI: https://doi.org/10.15420/cfr.2020.33

Hyperkalaemia in Heart Failure

Umar Ismail, Kiran Sidhu and Shelley Zieroth DOI: https://doi.org/10.15420/cfr.2020.29

The Future of Telemedicine in the Management of Heart Failure Patients

José Silva-Cardoso, José Ramón González Juanatey, Josep Comin-Colet, José Maria Sousa, Ana Cavalheiro and Emília Moreira DOI: https://doi.org/10.15420/cfr.2020.32

Evaluation and Management of Heart Block After Transcatheter Aortic Valve Replacement Anthony J Mazzella, Sameer Arora, Michael J Hendrickson, Mason Sanders, John P Vavalle and Anil K Gehi DOI: https://doi.org/10.15420/cfr.2021.05

How to Implant His Bundle and Left Bundle Pacing Leads: Tips and Pearls Shunmuga Sundaram Ponnusamy and Pugazhendhi Vijayaraman DOI: https://doi.org/10.15420/cfr.2021.04

Unknown Risks of Transplantation in Adults with Congenital Heart Disease

Aniket S Rali, Angela Weingarten, Emily Sandhaus, Richa Gupta, Allman Rollins, David Bichell, Nhue Do, D Marshall Brinkley, Kelly H Schlendorf, Daniel Freno, Keki Balsara and Jonathan N Menachem DOI: https://doi.org/10.15420/cfr.2021.09

Effect of Statin Intensity on the Progression of Cardiac Allograft Vasculopathy

Tracey M Ellimuttil, Kimberly Harrison, Allman T Rollins, Irene D Feurer, Scott A Rega, Jennifer Gray and Jonathan N Menachem DOI: https://doi.org/10.15420/cfr.2021.07

Left Ventricular Systolic Dysfunction Due to Atrial Fibrillation: Clinical and Echocardiographic Predictors Erez Marcusohn, Ofer Kobo, Maria Postnikov, Danny Epstein, Yoram Agmon, Lior Gepstein, Yaron Hellman and Robert Zukermann DOI: https://doi.org/10.15420/cfr.2021.17

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Contents Cardiac Sarcoidosis: When and How to Treat Inflammation

Gerard T Giblin, Laura Murphy, Garrick C Stewart, Akshay S Desai, Marcelo F Di Carli, Ron Blankstein, Michael M Givertz, Usha B Tedrow, William H Sauer, Gary M Hunninghake, Paul F Dellaripa, Sanjay Divakaran and Neal K Lakdawala DOI: https://doi.org/10.15420/cfr.2021.16

The Gap to Fill: Rationale for Rapid Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy for Heart Failure with Reduced Ejection Fraction Nicholas K Brownell, Boback Ziaeian and Gregg C Fonarow DOI: https://doi.org/10.15420/cfr.2021.18

Carbohydrate Antigen 125: A Biomarker at the Crossroads of Congestion and Inflammation in Heart Failure Marko Kumric, Tina Ticinovic Kurir, Josko Bozic, Duska Glavas, Tina Saric, Bjørnar Marcelius, Domenico D’Amario and Josip A Borovac DOI: https://doi.org/10.15420/cfr.2021.22

Adjunctive Techniques for Repair of Ischaemic Mitral Regurgitation Sigrid L Johannesen, Colin M Barker and Melissa M Levack DOI: https://doi.org/10.15420/cfr.2021.06

Isolated Left Ventricular Apical Hypoplasia Abhishek Dattani and Rachana Prasad DOI: https://doi.org/10.15420/cfr.2021.24

Surgical Management

Viscoelastic Haemostatic Assays in Cardiovascular Critical Care Aniket S Rali ,1 Ahmed M Salem ,2 Melat Gebre ,3 Taylor M Garies ,4 Siva Taduru5 and Arthur W Bracey Jr6 1. Division of Cardiovascular Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, US; 2. Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas, US; 3. Department of Anaesthesiology, Emory University School of Medicine, Atlanta, Georgia, US; 4. Department of Nursing, Vanderbilt University Medical Centre, Nashville, Tennessee, US; 5. Department of Cardiovascular Diseases, University of Kansas Medical Centre, Kansas City, Kansas, US; 6. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, US

Abstract

The initiation and management of anticoagulation is a fundamental practice for a wide variety of indications in cardiovascular critical care, including the management of patients with acute MI, stroke prevention in patients with AF or mechanical valves, as well as the prevention of device thrombosis and thromboembolic events with the use of mechanical circulatory support and ventricular assist devices. The frequent use of antiplatelet and anticoagulation therapy, in addition to the presence of concomitant conditions that may lead to a propensity to bleed, such as renal and liver dysfunction, present unique challenges. The use of viscoelastic haemostatic assays provides an additional tool allowing clinicians to strike a delicate balance of attaining adequate anticoagulation while minimising the risk of bleeding complications. In this review, the authors discuss the role that viscoelastic haemostatic assay plays in cardiac populations (including cardiac surgery, heart transplantation, extracorporeal membrane oxygenation, acute coronary syndrome and left ventricular assist devices), and identify areas in need of further study.

Keywords

Critical care cardiology, thromboelastography, viscoelastic haemostatic assays, rotational thromboelastometry Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: ASR and AMS are joint first authors. Received: 7 September 2020 Accepted: 30 October 2020 Citation: Cardiac Failure Review 2021;7:e01. DOI: https://doi.org/10.15420/cfr.2020.22 Correspondence: Aniket S Rali, 1215 21st Avenue South, Nashville, TN 37232-8802, US. E: aniket.rali@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Since its inception, cardiovascular critical care has witnessed an increase in the complexity of its patient population and the therapies available. The initiation and management of anticoagulation is a fundamental practice for a wide variety of indications, including the management of patients with acute MI, stroke prevention in patients with AF or mechanical valves, as well as the prevention of device thrombosis and thromboembolic events with the use of mechanical circulatory support and ventricular assist devices. Management of peri- and postoperative cardiovascular patients also mandates an ability to adequately assess for and to pivot between optimal haemostatic conditions to anticoagulation states suitable to mitigate blood loss. The frequent use of antiplatelet and anticoagulation therapy, in addition to the presence of concomitant conditions that may lead to a propensity to bleed, such as renal and liver dysfunction, present unique challenges requiring a heavy reliance on testing that allows the cardiac intensivist to strike a delicate balance to avoid thrombotic and bleeding events.1 Common (or conventional) coagulation tests (CCTs) include prothrombin time/international normalised ratio (PT/INR), activated partial thromboplastin time (aPTT), platelet count, D-dimer and fibrinogen levels. While these parameters are important and widely used in the management

of cardiovascular patients, CCTs are performed on platelet-poor plasma and are run in artificial states where the various blood elements are separated to allow for facility in performing assays, and these limitations should be recognised. CCTs cannot measure interactions between clotting factors, tissue factor and platelets. INR and PTT have the greatest utility in assessing patients being managed with anticoagulant therapy. Several studies have questioned the usefulness and reliability of CCTs to assess coagulopathy and to guide haemostatic interventions, especially in the setting of perioperative bleeding.2,3 In certain patient categories (e.g. liver disease) where a complex balanced coagulopathy exists, these may be poor predictors of bleeding risk. Modest elevations of INR in the 1.3–1.8 range have been shown to be poor predictors of both bleeding and response to plasma therapy. While CCTs may identify patients at increased risk of bleeding due to thrombocytopenia, they do not provide data on qualitative platelet dysfunction, as may be seen, for example, with the use of antiplatelet agents or in uraemia. Bleeding time has grown out of favour for this purpose due to its operator dependence and lack of sensitivity.1,4 CCTs, thus, reflect a static evaluation of the coagulation cascade with clot formation as the endpoint rather than assessing the coagulation system as a whole. They have been shown to correlate poorly as predictors of clinical bleeding and transfusion requirements, fail to detect the effects of antiplatelet therapy or novel anticoagulation agents,

Viscoelastic Haemostatic Assays in Cardiovascular Critical Care Figure 1: Schematic of Viscoelastic Testing

Table 1: Evaluated Parameters of Thromboelastography Versus Rotational Thromboelastometry Testing

ROTEM: pin rotates 4.75° every 6 seconds (cup is stationary)

Cup

Clot phase Initiation

Pin Whole blood clotted at 37°C

TEG: cup rotates 4.45° every 10 seconds (pin is stationary) Schematic of viscoelastic testing with a specimen of whole blood in a cup heated to 37°C. With thromboelastography (TEG), the cup oscillates with the pin remaining stationary, whereas with rotational thromboelastometry (ROTEM), the pin oscillates while the cup remains stationary. Measurement of pin synchronisation with the cup reflects the stages of clot formation. Source: Salem et al. 2019.13 Reproduced with permission from The Korean Neurocritical Care Society under a Creative Commons (CC BY-NC) licence.

Figure 2: Thromboelastography Parameters

Measurement

Time from start to 2 mm clot length Kinetics Time from 2 mm to 20 mm clot length Angle of propagation from 2 mm to 20 mm clot formation Strength Amplitude measured at peak clot strength Calculated from maximum amplitude Lysis/stability Percentage of loss of amplitude at fixed time after maximum amplitude

TEG

ROTEM

Reaction time

Clot time

Clot formation time

Clot formation time Alpha angle

Alpha angle

Maximum amplitude G Lysis at 30 min, estimated percentage of lysis

Maximum clot firmness Maximum clot elasticity Lysis index at 30 min, maximum lysis

G = shear elastic modulus parameter; ROTEM = rotational thromboelastometry; TEG = thromboelastography.

neurointensivists to elucidate different coagulopathy profiles among patients with intracerebral haemorrhage, subarachnoid haemorrhage and traumatic brain injury.13 More recently, it has been used with increasing frequency in the medical intensive care unit as a means of assessing the coagulopathy of coronavirus disease 2019 (COVID-19).14,15 Some studies have shown utility in predicting clinical course. For example, Mortus et al. showed elevated thromboses rates in patients with abnormal TEG parameters, and Wright et al. showed fibrinolysis shutdown, as demonstrated by elevated D-dimer, and complete failure of clot lysis at 30 minutes on TEG predicted venous thromboembolic events.15,16 In recent years, there has been a growing body of evidence supporting its use in critically ill cardiovascular patients. In this paper, we will review the fundamentals of VHA, its use and limitations, as well as identifying areas in need of future study in this patient population.

Thrombelastography recording with measurement parameters. Source: Salem et al. 2019.13 Reproduced with permission from The Korean Neurocritical Care Society under a Creative Commons (CC BY-NC) licence.

do not describe platelet function or fibrinolysis, and lack accuracy in detecting deficiencies in coagulation factors.5,6 The limitations of CCTs, including the timeliness of reporting results, have led to the increased utilisation of viscoelastic haemostatic assays (VHAs), which depict a coagulation profile representative of the cell-based theory of haemostasis (i.e. initiation, amplification, propagation and termination through fibrinolysis).5 Its use in trauma patients (when compared with CCT) has allowed clinicians to better predict the need for massive transfusions, as well as mortality, and there has been a reported mortality benefit to thromboelastography (TEG)-directed haemostatic resuscitation in this population among patients requiring massive transfusions compared with those resuscitated with CCTs.7–10 A clinical benefit was also found in the haemostatic resuscitation of cirrhotic patients with non-variceal and variceal gastrointestinal bleeding, with a significant reduction in the number of transfused blood products when this was guided by TEG.11,12 TEG-guided blood product transfusion also demonstrated a lower rebleeding rate among cirrhotic patients with variceal bleed at 6 weeks.12 Its use in neurocritical care has allowed

Overview of Viscoelastic Haemostatic Assay and its Interpretation

VHAs are performed through placing whole blood mixed with an activator (typically kaolin) and warmed to approximate body temperature (i.e. 37°C) in an oscillating cup with a suspended pin, which then transduces changes in viscosity determined by the tension in the pin. Changes in tension during clot formation and breakdown are plotted against time, and the resulting data provide a description of the coagulation and fibrinolytic profile of the sample tested (Figure 1). TEG is the VHA most commonly used in North America, with TEM/rotational thromboelastometry (TEM/ ROTEM) presenting an alternative means of performing this test where the pin oscillates rather than the cup containing blood. TEG and ROTEM measure different phases of the coagulation cascade. Measurements obtained from TEG include the time to initiate clot formation (reaction time; R), the rate of clot formation (kinetics; alpha angle), maximum clot strength (maximum amplitude; MA) and clot stability (fibrinolysis at 30 minutes; Figure 2 and Table 1). ClotPro (Enicor, now acquired by Haemonetics Corporation, Boston, MA, US) is another VHA that uses thromboelastography with elastic motion. Similar to conventional thromboelastometry systems, the surfaces of the ClotPro cup and pin experience a relative movement, driven by an elastic

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Viscoelastic Haemostatic Assays in Cardiovascular Critical Care element rotating the cup while the pin is stationary. The rotation of the cup is detected by a high-sensitivity electronic sensor. The ClotPro device comes with active tip technology, which eliminates manual reagent handling and improves standardisation. Both ROTEM and ClotPro include multiple panel assays that help us evaluate various aspects of coagulation cascade. For example, ROTEM assays include EXTEM, for evaluating the extrinsic pathway, INTEM, for the intrinsic pathway, FIBTEM, for evaluation of fibrinogen contribution to clot formation, and HEPTEM and APTEM for evaluation of heparin effect or thrombolysis reversal. HEPTEM and INTEM can be used together to demonstrate heparin-induced coagulopathy by evaluating clotting time on both the assays. FIBTEM and EXTEM used in conjunction can differentiate hypofibrinogenaemia and thrombocytopenia. EXTEM and APTEM when used in conjunction can diagnose fibrinolysis.

Figure 3: Baylor St Luke’s Medical Centre Transfusion Algorithm

Quantra is a new VHA based on sonic estimation of elasticity via resonance sonorheometry technology.17 It is based on the principle that as the blood coagulates over time and increases its stiffness, the resonance frequency increases. These parameters are plotted over time. It evaluates the viscoelastic properties of whole blood by means of the following functional parameters: CT, CT with heparinase, clot stiffness, fibrinogen contribution to clot stiffness, platelet contribution to clot stiffness and CT ratio.

Baylor St Luke’s Medical Centre (BSLMC) transfusion algorithm based on abnormal coagulation testing in bleeding cardiovascular surgery patients. ACT = activated clotting time; INR = international normalised ratio; MA = maximum amplitude; PLT = platelets; PTT = partial thromboplastin time; TEG = thromboelastography.

Sonoclot is a device that assesses viscoelastic properties for the blood using a sensitive electronic microviscometer that uses an oscillating suspended probe in the whole blood. It assesses haemostatic processes by assessing clot initiation by activated clotting time (ACT), fibrin propagation by clot rate and clot retraction using platelet function number. The platelet function number quantifies the quality of the clot retraction. Results will have values between 0 (no platelet function) and 5 (strong platelet function). An example of a CCT- and TEG-guided transfusion algorithm implemented at the Baylor St Luke’s Medical Center (Houston, TX, US) cardiovascular intensive care unit is shown in Figure 3.

Limitations of Viscoelastic Haemostatic Assay

There are a few limitations to the use of TEG in cardiac patients, most notably its inability to reliably detect the presence of single antiplatelet therapy or warfarin.18,19 It may, however, detect the presence of combination antiplatelet therapy use. A variation of TEG, TEG with platelet mapping (Haemonetics Corporation) and ROTEM delta (Instrumentation Laboratory) with platelet assays, are specific VHAs that have been shown to correlate with platelet aggregometry, and are able to detect platelet dysfunction due to antiplatelet therapy and other coagulopathies.17,20 This test is discussed in further detail below in the subsection titled VHA in ACS. It is also noteworthy that VHA testing is an in vitro assessment of coagulation, and thus does not factor in the role of vascular endothelium to coagulation; likely an important contributing factor in patients with cardiovascular disease. This test is also an inherently poor predictor of platelet adhesion and bleeding diathesis related to von Willebrand disease. Newer modifications of VHA (specifically ROTEM) with ristocetin have helped overcome this limitation; however, detection of mild-tomoderate von Willebrand disease is best done with other diagnostic systems.21 The coagulopathy induced by hypothermia during surgery, particularly cardiac surgery, is not detected by TEG, where the blood is warmed to a normal temperature at the time of testing; however, temperature adaptation can help overcome some of these challenges.22–24 The same limitations apply to CCT.

BSLMC operating room transfusion algorithm

Protamine

PLT < 102K

Microvascular bleeding by observation of surgical field

ACT > baseline

TEG MA < 48 and/or

Platelet transfusion

Coagulation and platelet tests

INR > 1.6

All normal

PTT > 57

Surgical re-exploration of chest

Fibrinogen < 144

and/or Plasma transfusion

Cryoprecipitate transfusion

There is a need for multiple daily calibrations of these devices, performed by trained personnel and using standardised techniques, adequate maintenance and quality control, as well as standardisation of sample collection and testing to reduce interlaboratory variability. The newer generation of VHA, such as TEG-6, ROTEM sigma and Quantra, have cartridge-based automated test preparation without the need for manual pipetting and reagent mixing, which helps drive standardisation and reduces interpersonal and interlaboratory variability.

Viscoelastic Haemostatic Assay in Specific Cardiac Populations Viscoelastic Haemostatic Assay in Cardiac Surgery

Cardiopulmonary bypass used in cardiac surgery causes several derangements in the haemostatic system.25 These derangements may lead to intraoperative and postoperative bleeding, mediastinal reexploration, and transfusion of allogeneic blood products, all of which contribute to significant morbidity and mortality.26–28 Preprocedural factors, including dual antiplatelet therapy, oral anticoagulants that decrease thrombin production and hypofibrinogenaemia, also increase the risk of bleeding in cardiac surgery patients.29–31 Hence, timely diagnosis and treatment of any bleeding diathesis is imperative.32–34 Conventionally the decision to transfuse haemostatic blood products has been guided by clinical judgement or CCT. However, none of the standard laboratory coagulation tests were developed to predict bleeding risks or to guide coagulation management in surgical patients.35 A meta-analysis by Bolliger et al. evaluated 12 studies (two matched case–control, three retrospective cohort and seven randomised controlled trials) examining the role of TEG and ROTEM in the management of cardiac surgery patients.36 They found that TEG- or ROTEM-based transfusion triggers reduced the rates of blood component transfusions in cardiac surgery patients. Furthermore, there was a significant reduction in bleeding and surgical re-exploration after cardiac surgery. A more contemporary meta-analysis by Meco et al. confirmed that VHA reduces blood component transfusions while also decreasing postoperative bleeding at 12 and 24 hours, and re-do sternotomies that were not due to surgical causes in cardiac surgery patients.37 Another meta-analysis by Dias et al. evaluated seven elective cardiac surgery randomised controlled trials. In the elective surgery meta-analysis, they showed reduced platelets, plasma transfusion, operating room length of

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Viscoelastic Haemostatic Assays in Cardiovascular Critical Care stay, intensive care unit length of stay and bleeding rate.38 Hence, TEGand ROTEM-guided transfusion protocols find themselves a 1C recommendation in the European Society of Anaesthesiology guidelines on the management of perioperative bleeding.39 Only a handful of TEG or ROTEM studies in cardiac surgery patients have reported mortality outcomes.40–42 Mortality was noted to be lower in the interventional arm in one of the studies, while two others did not show a mortality improvement with the use of VHA.42,43 Various factors may have influenced mortality outcomes in these studies, including patients’ baseline perioperative mortality risks (very low or very high), or analyses of only those patients that experienced bleeding. Furthermore, the primary aim of viscoelastic testing is to guide haemostatic interventions, which only indirectly affect mortality. The use of VHA to predict bleeding in patients with symptomatic, severe aortic stenosis undergoing transcatheter aortic valve implantation was explored in a study of 54 consecutive patients by Rymuza et al. using TEG VHA testing.44 Samples drawn prior to the procedure were not predictive of bleeding complications. Receiver operating characteristic curve analysis of samples drawn at the end of the procedure showed significant specificity and sensitivity of bleeding complications; however, namely R, alpha angle and MA. After multivariate logistic regression analysis, MA was found to be an independent predictor of bleeding after transcatheter aortic valve implantation, both as a contiguous variable (OR 0.95 per 1 mm increment) and with a cut-off of ≤46.6 mm.

Viscoelastic Haemostatic Assay in Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) was first clinically employed in limited facilities in the 1970s, but in recent years the number of centres offering ECMO has increased dramatically.45,46 As the availability of ECMO has become widespread, the indications for its use have also expanded beyond cardiac failure and acute severe respiratory failure.47 Exposure of the patient’s blood to the various surfaces of extracorporeal circulation causes an inflammatory response, which triggers a systemic inflammatory response syndrome-like cascade, leading to an increased risk of both haemorrhagic and thrombotic complications.48 The rates of life-threatening haemorrhage and thrombosis in ECMO are reported to be between 10% and 33%, making anticoagulation and its monitoring a critical aspect of delivering ECMO support.49 Despite the widespread use of ECMO, there is significant variability among centres regarding anticoagulation monitoring, and currently no consensus exists for anticoagulation during ECMO. Unfractionated heparin is the anticoagulant of choice at most ECMO centres, and a survey of 121 international ECMO centres showed ACT to be the preferred (97%) method of anticoagulation monitoring.49 In addition to ACT, aPTT was used in 94% of patients at various intervals ranging from every 4–5 hours to >12 hours apart; routine or occasional antithrombin III (82%), anti-factor Xa (65%) and TEG (43%) testing during ECMO were also reported among surveyed centres.49 Among these various tests, TEG alone provides a comprehensive survey of haemostatic cascade, as discussed above. Heparin’s impact on aPTT results is blunted by acute phase reactants; for example, alpha-2-macroglobulin and factor VIII. This may lead to an overdose of heparin when assessing anticoagulation with aPTT results only. Panigada et al. conducted a retrospective study of 32 patients treated with ECMO for severe respiratory failure to evaluate the prevalence of a TEG R >90 minutes (‘flat line’) reversible with heparinase

during ECMO.50 They frequently observed a marked heparin effect on the TEG tracing despite an aPTT ratio (1.5–2.0) and ACT within the therapeutic anticoagulation range. These findings raise the concern that patients on ECMO may be excessively anticoagulated when utilising aPTT- and ACTbased protocols to guide heparin therapy. In a follow-up study, Panigada et al. evaluated the safety and efficacy of TEG-driven heparin titration in ECMO patients.51 In a multicentre, randomised controlled trial, 42 patients with acute respiratory failure on veno-venous ECMO were randomised to either a TEG-based protocol (target 16–24 minutes of the R parameter, TEG group) or a standard of care aPTT-based protocol (target 1.5–2 of aPTT ratio, aPTT group) to guide heparin dosing. They found that heparin dosing was lower in the TEG group compared with the aPTT (p=0.03), while the number of haemorrhagic or thrombotic events and transfusions given were not statistically different between the two groups. However, there was a tendency for less bleeding from surgical sites and overall less bleeding in the TEG group. Overall, TEG R-based heparin dosing for patients on ECMO appears to be safe, feasible and preferred over conventional aPTT-based dosing. In a small prospective observational study, Nair et al. studied ROTEM and platelet aggregometry, and suggested that ROTEM-guided coagulation management could avoid bleeding and possibly improve patient care.52 There is increasing interest in VHA testing in the management of patients on ECMO. However, there remains a paucity of high-quality evidence, thereby necessitating larger trials to determine the superiority of VHA testing compared with CCTs in this arena.

Viscoelastic Haemostatic Assay in Acute Coronary Syndrome

The most prominent event that defines acute coronary syndrome (ACS) is the formation of an intra-arterial thrombus, usually resulting from activation of platelets and fibrinogen at the ruptured plaque. A global haemostasis test, such as TEG, may show promise as a surrogate marker of the thrombus formation process and to aid in the diagnosis of ACS. Zhou et al. investigated its use for this purpose in a study of 142 patients with ACS, and found that the shear elastic modulus parameter (G), which is a computer-generated value reflecting complete strength of the clot and is calculated from the amplitude (A) with the formula: G = (5,000 × A) / (100 − A), is an independent diagnostic indicator of ACS (OR 2.6; 95% CI [2.035–3.322]) in this cohort of patients.53 The optimal cut-off value for the diagnosis of ACS was 10.55 dyne/cm2, while the sensitivity was 66.2% and the specificity was 92.4%. Current guidelines recommend treatment with dual antiplatelet therapy for 6–12 months in all patients presenting with ACS or undergoing percutaneous coronary intervention and implantation of drug-eluting stents.54,55 The combination of aspirin and a P2Y12 inhibitor (such as clopidogrel, ticagrelor or prasugrel) is prescribed in these patients to prevent thrombotic events and adverse cardiovascular events.56 While the addition of P2Y12 inhibition to aspirin has significantly improved cardiovascular outcomes in patients presenting with ACS, platelet inhibitory responses to clopidogrel are subject to significant interindividual variability.57 Individual testing for clopidogrel hyporesponsiveness may be desirable, but is not routinely performed, because current gold standard tests for platelet reactivity, impedance aggregometry, light transmittance aggregometry and vasodilatorstimulated phosphoprotein phosphorylation assessment using flow cytometry, are time-consuming, require significant technical skill and are expensive.58,59

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Surgical Management As discussed above, whole blood clot strength measured by TEG is not sensitive to platelet reactivity. Hence, the standard TEG has been modified to allow assessment of the contribution of P2Y12 receptor inhibitor by the addition of adenosine diphosphate (ADP), and the effects of aspirin by the addition of arachidonic acid (AA).60,61 This modification is referred to as platelet mapping, and is further modified to calculate the area under the curve at 15 minutes of the ADP trace.62 This modified TEG has been well validated to rapidly detect changes in platelet activity in response to loading doses of aspirin and clopidogrel.63–67 It has also been shown to correlate well with Accumetrics Verify-Now rapid platelet function analyser (r2=0.54, p<0.0001) and vasodilator-stimulated phosphoprotein phosphorylation (r2=0.26, p=0.001) to assess the response to clopidogrel in patients presenting with ACS.62 Reduced clopidogrel platelet inhibition and high residual platelet reactivity has been shown to lead to adverse outcomes in patients undergoing percutaneous coronary intervention for stable angina, unstable angina and ST segment elevation MI.68–71 AA- or ADP-induced platelet–fibrin clot strength (MAAA or MAADP) is indicative of the net residual platelet reactivity after treatment with aspirin or clopidogrel, respectively. A recently published post hoc analysis of a prospective, single-centre cohort study including 447 patients with ACS showed that the relative platelet inhibition rate (AA% or ADP%) independently predicted the risk of 6-month ischaemic events.72 Furthermore, high MAAA (HR 3.963; 95% CI [1.152–13.632]; p=0.029) and high MAADP (HR 5.185; 95% CI [2.228– 12.062]; p<0.001) were independent predictors of ischaemic events, and an even higher risk rendered when they coexisted (HR 7.870; 95% CI [3.462–17.899]; p<0.001).

Viscoelastic Haemostatic Assay in Left Ventricular Assist Devices

Left ventricular assist devices (LVADs) improve survival and quality of life in end-stage heart failure patients who are refractory to medical therapy.73 This has led to a steady increase in their utilisation in recent years, with current annual implant rates exceeding 2,500/year.74 However, overall outcomes in these patients are significantly affected by two known complications of LVADs; namely, bleeding and pump thrombosis.75–77 The reported incidence of device thrombosis is around 8.4% at 3 months postimplantation, with an overall incidence of 12.3% at 24 months.75 The consequences of this complication can be severe, and include pump failure-induced cardiogenic shock, stroke and even death. The 6-month mortality associated with thrombotic complications in LVAD patients is high and reaches 48%.75 The prothrombotic milieu in LVAD patients is driven by a persistent high inflammatory state and endothelial activation leading to activation of clotting factors, as well as persistent platelet activation.78 Hence, pharmacological anticoagulation management after implant commonly includes a vitamin K antagonist in addition to a platelet inhibitor to decrease thrombotic and embolic risk. Current recommendations include warfarin dosed to an INR goal of 2.0–3.0 and an antiplatelet therapy, such as aspirin (81–325 mg daily).79 Adequate anticoagulation in LVAD patients is usually monitored through serial measurements of INR, and there exists limited data on the role of VHA in this patient population. A single-centre retrospective analysis of 98 patients with durable mechanical circulatory support devices (31 Heartware LVADs, 25 HeartMate II [HM II] LVADs, 35 total artificial hearts [TAHs] and 7 biventricular assist devices) found the TEG-based coagulation index to be the single most statistically significant parameter used to optimally

anticoagulate patients.80 The coagulation index is calculated using the reaction time, kinetics, alpha and MA values from a kaolin-activated TEG assay. In this study, a significantly higher coagulation index was observed among the patients that had thromboembolic events as compared with those who did not (mean for TAH3.12 versus 1.12, HM II 2.79 versus 1.74, Heartware 2.79 versus 1.70 and for biventricular assist device 2.79 versus 1.72). The authors of this study proposed that patients with HM II and Heartware devices should be maintained at a coagulation index value ≤1.5, whereas those with TAH devices should be maintained at a coagulation index ≤1.2 to minimise their risk of thromboembolic events. Furthermore, individualised INR goals should be set for patients based on what INR levels correspond to these coagulation index targets. These findings are consistent with another prior study involving patients with 99 SynCardia TAH.81 A more recent retrospective study by Xia et al. evaluated the role of TEG in predicting and defining pump thrombosis in HM II patients.82 A significant mean change in coagulation index of 0.71 (95% CI [0.1–1.32]; p=0.02) over a 24-month post-implantation follow-up period was noted in patients with suspected pump thrombosis compared with patients without. This change first became significant at 6 months. While the mean change in coagulation index significantly decreased over time in the group without pump thrombosis (−2.84; 95% CI [−5.21, −0.47]; p=0.02), it was not significantly different in the group with pump thrombosis (−1.72, 95% CI [−4.22, 0.78]; p=0.18). These findings make a case for routine TEG monitoring, specifically using mean changes in coagulation index, for evaluating pump thrombosis in HM II patients. Tarzia et al. reported a case of ROTEM-guided administration of recombinant activated factor VII for refractory bleeding after implantation of a biventricular assist device.83 Further prospective studies are required to validate these findings.

Viscoelastic Haemostatic Assay in Heart Transplants

Postoperative bleeding is one of the most common complications after cardiac surgery owing to the extracorporeal circulation, and contributes to significant morbidity and mortality. A single-centre observational prospective study of 49 cardiac transplant patients noted that the mean blood transfusion was 6.39 ± 5.33 units, fresh frozen plasma 4.9 ± 5.4 units and platelets 6.47 ± 9.61 units.84 Patients requiring ≥6 blood units were significantly more likely to require continuous renal replacement therapy (50% versus 12.5%; p=0.01) and had higher intensive care unit mortality (33.3% versus 4%; p=0.01). Crabbe et al. reported a case of ROTEM-guided targeted haemostatic therapy in a heart transplant recipient who developed coagulopathy after therapeutic plasma exchange. Since VHAs offer better differential diagnosis of bleeding in the perioperative setting, they offer guidance for targeted haemostatic correction, as demonstrated by Crabbe et al.85 The key to prevention of major bleeding requiring massive transfusion in cardiac transplantation patients is adequate preoperative evaluation and analysis of bleeding or thrombotic tendencies and drugs that affect haemostasis. Although there is a paucity of literature on the utilisation of VHA testing in cardiac transplantation, it offers a promising strategy to guide individualised transfusion goals in this patient population.

Viscoelastic Haemostatic Assay in Direct Oral Anticoagulants

Direct oral anticoagulants (DOACs) are being used increasingly in patients with non-valvular AF for stroke prophylaxis, as well as venous

Surgical Management thromboembolism prophylaxis and treatment. VHA have been used to assess the presence of DOACs in patients with acute bleeding events. Studies have shown prolongation of ROTEM clotting times and TEG Rs in the presence of DOACs.86–88 INTEM-CT is more prolonged compared with EXTEM clotting time, whereas maximum clot firmness is unaffected in the presence of DOACs.87,89 ROTEM and ClotPro have commercially available assays to detect direct thrombin inhibitors using their EcaTEM and Eca-Test assays, respectively. ClotPro has a commercially available Russell’s viper venom test assay to detect direct factor Xa inhibitors, while ROTEM modifications have been studied to evaluate activity of direct factor Xa inhibitors.90 There is also an investigational DOAC assay for the TEG 6s system that has been shown to have high sensitivity and specificity.90,91 VHA testing is promising in the setting of DOACs for their detection; however, there are no large clinical trials to demonstrate their utility in the role of assessing hard clinical endpoints.

Future Directions and Call for Further Areas of Study

There currently exists a paucity of data on the use of VHA in the setting of heart transplantation to guide transfusion strategies in this patient population. In the setting of ACS, further studies to validate the use of VHA as a diagnostic and prognostic aid are merited. As previously discussed, the use of TEG in patients with LVAD has revealed coagulation index to be an important parameter when determining the optimal degree of anticoagulation in this patient population. Further prospective studies examining the use of this parameter to guide anticoagulation against the incidence of thrombotic and bleeding events in patients with LVADs are required. Furthermore, the authors were unable to identify studies where VHA was utilised to assess the degree of platelet inhibition in this subset of patients. While there exists a significant amount of data on the use of VHA with ECMO, there are currently three other types of temporary (or percutaneous) 1. Masud F. The Urgency and Impact of Cardiovascular Critical Care. Methodist Debakey Cardiovasc J 2018;14:75–6. http:// dx.doi.org/10.14797/mdcj-14-2-75; PMID: 29977463. 2. Haas T, Fries D, Tanaka KA, et al. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence? Br J Aesth 2015;114:217–24. https://doi.org/10.1093/ bja/aeu303; PMID: 25204698. 3. Dzik WH. Predicting hemorrhage using preoperative coagulation screening assays. Curr Hematol Rep 2004;3:324– 30. https://www.ncbi.nlm.nih.gov/pubmed/15341698; PMID: 15431698. 4. Collyer TC, Gray DJ, Sandhu R, et al. Assessment of platelet inhibition secondary to clopidogrel and aspirin therapy in preoperative acute surgical patients measured by Thrombelastography® Platelet Mapping™. Br J Anaesth 2009;102:492–8. https://doi.org/10.1093/bja/aep039; PMID: 19286767. 5. Sankarankutty A, Nascimento B, Teodoro da Luz L, et al. TEG® and ROTEM® in trauma: similar test but different results? World J Emerg Surg 2012;7(Suppl 1):S3. https://doi. org/10.1186/1749-7922-7-S1-S3; PMID: 23531394. 6. Walsh M, Fritz S, Hake D, et al. Targeted thromboelastographic (TEG) blood component and pharmacologic hemostatic therapy in traumatic and acquired coagulopathy. Curr Drug Targets 2016;17:954–70. https://doi.org/10.2174/1389450117666160310153211; PMID: 26960340. 7. Holcomb JB, Minei KM, Scerbo ML, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department. Ann Surg 2012;476–86. https://doi.org/10.1097/SLA.0b013e3182658180; PMID: 22868371. 8. Gonzalez E, Moore EE, Moore HB, et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg

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MCS devices; namely, the intra-aortic balloon pump, Impella devices and the TandemHeart.92 Anticoagulation with the use of an intra-aortic balloon pump is intended to reduce the risk of device thrombosis, thromboembolism or limb ischaemia. Current evidence on this is sparse, with some data suggesting that it may be safe to not anticoagulate when using intra-aortic balloon pump counter pulsation.93 The decision on whether or not to anticoagulate in this context should be tailored to the individual patient, on balance of the risks and benefits. VHA shows promise as a tool to guide such decisions; however, the authors were unable to identify any studies examining this. Impella and TandemHeart devices mandate anticoagulation to prevent device thrombosis.92,94 The prevalence of major bleeding complications among these patient populations is highly variable, with reports of up to 54% prevalence with Impella use and 59% with TandemHeart use.95 The authors could not identify any studies that incorporate the use of VHA in the management of anticoagulation in these settings, which may guide clinicians in identifying those that are at a heightened risk for complications.

Conclusion

CCTs have long been used to guide the anticoagulation status of critically ill and perioperative cardiovascular patients; however, they present many limitations. VHA overcomes many of these limitations, and although it has been in use for >60 years, its use in this patient population remains relatively nascent. It has been shown to reduce the need for blood component transfusions, as well as postoperative bleeding and mediastinal re-exploration when used to guide transfusions in the surgical setting. In the ECMO population, its use has been associated with lower doses of unfractionated heparin use when compared with CCT-guided protocols, with no associated increase in the incidence of thromboembolic events and a trend towards fewer bleeding events. Due to its properties in defining the patient’s overall haemostatic profile, VHA shows promise in many other applications within cardiovascular critical care. There is a need for further studies exploring the use of VHA in this arena.

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Surgical Management 79. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013;32:157–87. https://doi. org/10.1016/j.healun.2012.09.013; PMID: 23352391. 80. Volod O, Lam LD, Lin G, et al. Role of thromboelastography platelet mapping and international normalized ratio in defining “normocoagulability” during anticoagulation for mechanical circulatory support devices. ASAIO J 2017;63:24– 31. https://doi.org/10.1097/MAT.0000000000000445; PMID: 27660902. 81. Copeland J, Copeland H, Nolan P, et al. Results with an anticoagulation protocol in 99 SynCardia total artificial heart recipients. ASAIO J. 2013;59:216–20. https://doi.org/10.1097/ MAT.0b013e318288a390; PMID: 23644607. 82. Xia R, Varnado S, Graviss EA, et al. Role of thromboelastography in predicting and defining pump thrombosis in left ventricular assist device patients. Thromb Res 2020;192:29–35. https://doi.org/10.1016/j.thromres. 2020.03.016; PMID: 32447105. 83. Tarzia V, Buratto E, Bortolussi G, et al. The danger of using a sledgehammer to crack a nut: ROTEM-guided administration of recombinant activated factor VII in a patient with refractory bleeding post-ventricular assist device implantation. Artif Organs 2015;39:248–53. https://doi. org/10.1111/aor.12355; PMID: 25065398. 84. Diaz-Martin A, Escoresca-Ortega AM, Hernandez-Caballero C,

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Therapy

Clinical Characteristics of De Novo Heart Failure and Acute Decompensated Chronic Heart Failure: Are They Distinctive Phenotypes That Contribute to Different Outcomes? Wilson Matthew Raffaello ,1 Joshua Henrina ,2 Ian Huang ,1,3 Michael Anthonius Lim ,1 Leonardo Paskah Suciadi ,2 Bambang Budi Siswanto 4 and Raymond Pranata 1 1. Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Indonesia; 2. Siloam Heart Institute, Siloam Hospitals Kebon Jeruk, Jakarta, Indonesia; 3. Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin General Hospital, Bandung, Indonesia; 4. Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia, National Cardiovascular Center Harapan Kita, Jakarta, Indonesia

Abstract

Heart failure is currently one of the leading causes of morbidity and mortality. Patients with heart failure often present with acute symptoms and may have a poor prognosis. Recent evidence shows differences in clinical characteristics and outcomes between de novo heart failure (DNHF) and acute decompensated chronic heart failure (ADCHF). Based on a better understanding of the distinct pathophysiology of these two conditions, new strategies may be considered to treat heart failure patients and improve outcomes. In this review, the authors elaborate distinctions regarding the clinical characteristics and outcomes of DNHF and ADCHF and their respective pathophysiology. Future clinical trials of therapies should address the potentially different phenotypes between DNHF and ADCHF if meaningful discoveries are to be made.

Keywords

Cardiac failure, new onset, heart failure, paradigm, therapy, medication, phenotype Disclosure: The authors have no conflicts of interest to declare. Acknowledgments: WMR and JH are equal first authors. Received: 29 July 2020 Accepted: 23 October 2020 Citation: Cardiac Failure Review 2021;7:e02. DOI: https://doi.org/10.15420/cfr.2020.20 Correspondence: Raymond Pranata, Faculty of Medicine, Universitas Pelita Harapan, Jl. Jend. Sudirman No. 20, Tangerang, Banten 15810, Indonesia. E: raymond_pranata@hotmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) remains a leading source of morbidity, mortality and economic burden worldwide.1–4 Despite numerous therapeutic breakthroughs provided by landmark clinical trials in stable chronic HF (CHF), there has been little progress over the past two decades in the treatment of acute HF (AHF).5 Therefore, a new paradigm is needed based on better characterisation of AHF for novel clinical discoveries.6–8

size-fits-all treatment for AHF should be abandoned, and a better understanding of this heterogeneous syndrome in terms of classification is needed. Accordingly, in this review we briefly explain the importance of distinguishing DNHF from ADCHF, which provides a better appreciation of risk factors, prognostication and treatment implications for these two distinct clinical entities.

Several classifications of HF have been proposed. Based on its temporal course, HF may be classified into CHF and AHF, with latter having two forms: de novo AHF (DNHF), defined as acutely worsened heart function without known underlying heart disease, and acutely decompensated HF (ADCHF), defined as the sudden or gradual onset of symptoms of cardiac failure with known pre-existing cardiomyopathy and a continuum of the natural history of CHF.9–13 Nonetheless, this dichotomisation has only been used for epidemiological purposes.6–8

De Novo Heart Failure Versus Acute Decompensated Chronic Heart Failure

Interestingly, data extracted from the ASCEND-HF trial provides additional information regarding AHF (DNHF and ADCHF).5 Early diagnosis of HF (≤1 month) before hospitalisation is an independent variable indicating better dyspnoea relief and improved post-hospitalisation mortality in AHF compared with CHF patients. This finding may have an effect on future research regarding treatments and outcomes.5 Thus, the notion of a one-

AHF presents as a clinical syndrome. Many classifications have been proposed based on the history of HF, the specific underlying aetiology or precipitating factors, dominant signs and symptoms and major haemodynamic changes, including systolic blood pressure, at presentation (Figure 1). A previous meta-analysis of 15 cohort studies involving 38,320 subjects found that acute coronary syndrome (ACS) and infection were the most common precipitating factors of DNHF and ADCHF, respectively.14 Hypertensive heart disease (HHD) was more frequent in DNHF than in ADCHF. Conversely, comorbidities, such as hypertension, diabetes, ischaemic heart disease, chronic obstructive pulmonary disease, AF and a history of stroke or transient ischaemic attack, were more

De Novo HF Versus ADCHF Figure 1: Mechanism of De Novo Heart Failure New onset or undiagnosed cardiac dysfunction Disrupted coronary blood flow

Myocardial ischaemia

Acute valvular incompetence

Pericardial tamponade

Arrhythmia

Others: • Toxic • Inflammation

Acute haemodynamic derangement De novo heart failure

common in the ADCHF patient group.14,15 Patients with ADCHF also tend to be older and are more likely to have a history of MI, percutaneous coronary intervention, coronary artery bypass grafting and infections.14 Importantly, patients with ADCHF were more likely to be hospitalised in the internal medicine department (Table 1).16 Commensurate with the worse baseline health status of ADCHF patients, laboratory findings revealed lower haemoglobin, higher serum creatinine, lower estimated glomerular filtration rate, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and a Charlson comorbidity index in the ADCHF compared with DNHF population. More importantly, mortality at 3 months and 1 year was significantly lower in the former group.14 A strong association has been found between mortality and chronicity of HF, highlighting the importance of AHF categorisation.16–19 Several studies have demonstrated a possible association between left ventricular ejection fraction (LVEF) and HF outcome.20 A multicentre Koreanbased registry reported outcomes for DNHF and ADCHF patients according to LVEF stratification.21 Interestingly, although mortality rates were higher in the DNHF group, there was no difference in mortality rates in the DNHF group among patients with HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF). In contrast, in the ADCHF group, HFrEF was associated with higher mortality than HFmrEF and HFpEF.21 The authors of that study postulated that because of the chronic nature of the condition and complication by comorbidities, the ADCHF group did not have a chance to recuperate after acute events.21 In addition, the association between chronicity in HF and long-term mortality is well established, because HF is a progressive disease. Other notable differences between DNHF and ADCHF are electrocardiographic abnormalities. Based on multicentre European cohorts of AHF, although there was no difference in the prevalence of right bundle branch block (RBBB) between DNHF and ADCHF groups, RBBB was prognostically crucial in DNHF and significantly predicted mortality, even after adjusting for traditional factors.22 In contrast, left bundle branch block and intraventricular conduction delay (IVCD) were more common in the ADCHF group. Nevertheless, only IVCD predicted mortality in the ADCHF group, and this relationship remained significant after adjustment.22

Clinical Characteristics of Acute Decompensated Chronic Heart Failure

As demonstrated in several clinical trials, the natural course of ADCHF is inseparable from that of CHF, but ADCHF and DNHF have different characteristics and outcomes.5,16,21,23–25

There are several notable findings in ADCHF patients: they usually present with signs and symptoms of volume overload and congestion (dyspnoea, orthopnoea, ascites and lower limb oedema) and are associated with higher comorbidity and mortality rates.10 Moreover, ADCHF presents as more profound left ventricular (LV) dysfunction and congestion, as indicated by higher NT-proBNP concentrations, which are associated with worse outcomes.26 Other notable findings in ADCHF patients are pulmonary and systemic vascular congestion associated with a higher end-diastolic pressure–volume relationship.10,27–29 CHF may also cause persistent haemodynamic changes and chronic metabolic derangement, contributing to higher mortality in ADCHF than DNHF.10,14,17 These findings were well demonstrated in a Danish study, in which hospitalisation with CHF was correlated with higher mortality rates and LV dysfunction was a potent predictor of mortality.30 As demonstrated in several studies, patients with ADCHF tend to be older and may have multiple comorbidities, such as diabetes, hypertension, AF, chronic kidney disease and a history of MI. These factors contribute to poorer vital organ function, as reflected by lower serum cholesterol and protein concentrations, higher urea and creatinine concentrations and increased systemic inflammatory markers, which, in turn, contributes to the higher mortality rate.14,28,31,32

Mechanism Underlying ADCHF

Volume expansion in CHF is a short-term compensatory mechanism to maintain adequate tissue perfusion and is regulated by the neurohormonal response. Nonetheless, this compensatory mechanism becomes maladaptive in the long term.16 Eventually, this altered mechanism leads to fluid accumulation, which results in fluid overload and congestion in the organs. Mitigation of volume overload by diuretics and vasodilators further activates this compensatory mechanism, ultimately leading to further decompensation as the cycle continues.33–35 In addition to fluid accumulation, redistribution of fluid may play an essential role in ADCHF. Sympathetic stimulation caused by dysregulated neurohormonal responses to tissue hypoxia may induce transient vasoconstriction in the splanchnic and peripheral venous circulation, resulting in displacement of fluid into the pulmonary circulation, which contributes to acute episodes of decompensation (Figure 2).36–38 As the cycle continues, a series of decompensation episodes leads to declining function in HF. The exact mechanism behind the deterioration of heart function remains unknown. However, it may be related to the

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De Novo HF Versus ADCHF Table 1: Differences Between Acute Decompensated Chronic Heart Failure and De Novo Heart Failure Acute Decompensated Chronic Heart Failure

De Novo Heart Failure

Patient characteristics

Older population, worse baseline status and laboratory findings Known history of underlying heart failure

No history of heart failure

Comorbidities

IHD, COPD, AF, diabetes, stroke/TIA History of CABG and PCI more frequent

Less frequent

Trigger events

Medication (poor compliance, resistance), infections, diet (excessive sodium intake), cardiovascular complications, interventions (surgery), drugs (alcohol, digitalis)

Cardiac ischaemia or valvular incompetence (acute MI, acute mitral regurgitation), inflammatory (viral myocarditis) and toxic (drug-induced) insults

Clinical presentation

Dyspnoea, orthopnoea, lower limb oedema, ascites, weight gain

Cardiogenic shock and acute pulmonary oedema

Main pathophysiology

Pulmonary and systemic vascular congestion caused by LV dysfunction, maladaptive neurohumoral activation, fluid overload and redistribution

Acute haemodynamic derangement caused by LV systolic dysfunction

Mortality

Higher mortality rates

Lower mortality rates compared with ADCHF patients

Source: Kurmani et al.,9 Xanthopoulos et al.,10 Hummel et al.,13 Pranata et al.14 and Younis et al.16 CABG = coronary artery bypass grafting; COPD = chronic obstructive pulmonary disease; IHD = ischaemic heart disease; LV = left ventricular; PCI = percutaneous coronary intervention; TIA = transient ischaemic attack.

pathophysiology of ADCHF, which consists of two phases, the initiation and amplification phases. The initiation phase is related to several insults that may trigger decompensation of HF, followed by the amplification phase, which induces neurohormonal activation as a host compensatory mechanism for impaired oxygen supply and demand and haemodynamic disturbance. Activation of the inflammatory response may trigger pathological cardiac remodelling, worsening cardiac function, decreasing cardiac output and worsening renal function.39,40 Acute episodes of HF are well known to increase mortality rates, as demonstrated in several studies. The exact mechanism is unknown, but the number of hospitalisations in HF patients is associated with increased mortality rates.41,42 One study hypothesised that as acute decompensation episodes occur, cardiac function will never return to prehospital levels because myocardial damage has occurred.43 This hypothesis has been demonstrated in another study that showed an acceleration in the pathological remodelling of the myocardium, indicated by a transient elevation in troponin I and markers of extracellular matrix turnover (i.e. matrix metalloproteinase 2, tissue matrix metalloproteinase 1 and procollagen type III N-terminal peptides), as the decompensation episode occurs.44 Complex haemodynamic and metabolism changes and maladaptive adrenergic responses play an important role in ADCHF, because these disturbances pertain to the underlying CHF status. Persistent stimulation of β-adrenoceptors in CHF results in the downregulation of these receptors, leading to myocyte contractile dysfunction and increased apoptosis through intrinsic and extrinsic pathways. Modulation of intracellular calcium concentrations, reactive oxygen species (ROS), activation of Fas and tumour necrosis factor (TNF) receptors and initiation of the caspase pathway may result in myocyte apoptosis, direct cardiac dysfunction and decreased cardiac function. Interestingly, altered Ca2+ handling leads to impaired excitation–contraction coupling in the myocyte.43,45–47 Ultimately, LV dysfunction leads to right-sided heart dysfunction, causing severe systemic congestion, including intestinal congestion, major organ dysfunction and adverse metabolic changes that may lead to malnutrition and cachexia and increased mortality.10,48,49 Moreover, impaired oxygen delivery to the peripheral tissue in CHF patients, which is counterbalanced by the maladaptive mechanism described above, causes fluid retention and accumulation in tissues.50,51 Intestinal congestion leads to intestinal oedema, which ultimately

Figure 2: Pathophysiology of Acute Decompensated Chronic Heart Failure Pre-existing ↓ cardiac dysfunction

Impaired tissue oxygen delivery Inflammatory cytokine Venous return

Neurohormonal activation

Splanchnic vasoconstriction

Fluid redistribution

Renal dysfunction

Fluid accumulation

Organ congestion

impairs nutrient absorption and contributes to malnutrition in CHF patients.17,48 Intestinal congestion, demonstrated by increased gut wall thickness, may contribute to iron deficiency in HF patients that is associated with decreased aerobic performance, increased fatigue and unfavourable outcomes.52–55 A poorly functioning gastrointestinal tract due to oedema, combined with hepcidin dysregulation in HF patients and the intolerable side-effects of oral iron administration, may reduce oral iron uptake.54,56–58 Recent studies show that IV iron administration has a more favourable outcome than oral iron therapy or placebo.59,60 IV ferric carboxymaltose is widely used because of large-scale trials that have been undertaken and have demonstrated the safety of the drug.58 Therefore, current guidelines suggest iron replenishment therapy must be considered in iron-deficient HF patients to improve outcomes, functional status and quality of life.58,61 Intestinal oedema often causes a phenomenon called malnutrition– inflammation complex syndrome, which predisposes to a higher level of circulating endotoxaemia caused by the translocation of lipopolysaccharide from the oedematous intestine, combined with poor nutritional status, which contributes to lower neutralisation and binding

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De Novo HF Versus ADCHF of the lipopolysaccharide. The result of this process is a chronic, persistent inflammatory response.31,62

atrial pressure, catecholamine release and β-adrenoceptor activation, resulting in myocardial injury and tissue hypoperfusion.43,71,72

Conversely, obesity paradoxically confers protective effects on CHF patients. Nevertheless, the intricacies of the mechanisms involved have not been fully elucidated as yet, and cannot be explained alone by the cachexia that is caused by HF.63 Renal impairment is a strong predictor of mortality in HF and is more profound in ADCHF than DNHF.64 Several factors may contribute to worsening kidney function, such as kidney hypoperfusion, a higher incidence of chronic kidney disease, renal venous congestion and higher levels of inflammatory cytokines (interleukin [IL]-6) and comorbidities.65–67

Elevated inflammatory cytokines and responses further exacerbate haemodynamic abnormalities and may directly affect the myocardium through various mechanisms. Intestinal congestion further leads to translocation of endotoxin, also known as lipopolysaccharide, and may induce TNF-α and other inflammatory cytokines. Several effects are associated with increases in TNF-α, such as LV dysfunction and remodelling through the ROS pathway, increased intracellular caspase apoptosis signalling and calcium dysregulation, resulting in impaired contractile proteins in myocytes and the induction of cardiac cell death, as well as the development of anorexia and cachexia, which lead to malnutrition and low protein utilisation.71,73,74 IL-6 is a well-known inflammatory marker, released as an inflammatory response from damaged tissue, which, in this case, is the myocyte. However, an extended sustained release of IL-6 may lead to maladaptive hypertrophy and a decrease myocyte contractile function, which depresses cardiac function.75–77 Other effects seen following the sustained release of IL-6 are endothelial dysfunction, a decreased diuretic response, activation of the neurohumoral response and a reduction in the glomerular filtration rate, which further exacerbates the cardiorenal syndrome, mediating the adverse effects of angiotensin II and promoting sodium retention by activating renal epithelial sodium channels.78–80

From the treatment perspective, diuretic resistance is of concern in ADCHF patients. Although the precise mechanism remains unknown, several factors have been proposed to explain the ineffective response to diuretic therapy. Diuretic resistance may originate from impaired drug absorption resulting from a congested intestine, which consequently reduces the rate of drug absorption and prolongs the time until the therapeutic threshold is reached.68,69 A decrease in kidney blood flow in advanced kidney disease in CHF patients, combined with the use of nonsteroidal anti-inflammatory drugs, may further reduce the delivery of diuretics. Endogenous accumulation of anions may compete with the diuretics at their binding sites, resulting in reduced secretion of the diuretic.69 Post-diuretic salt retention is a compensatory mechanism that often occurs after the urinary concentration of sodium is reduced with short-acting diuretics, and, combined with non-compliance with a saltrestricted diet, may negate the effects of diuretics such that a negative sodium balance may not be achieved. The long-term use of loop diuretics may also attenuate their natriuretic effects, as demonstrated in animal studies.69 This mechanism is known as a braking phenomenon and is caused by structural changes in the distal convoluted tubules that lead to increases in sodium reabsorption.69 CHF patients who were hospitalised for non-fatal HF are at the highest risk of dying within 1 month of discharge, with the risk progressively decreasing over time. Interestingly, this is also seen in HF patients hospitalised for other diseases. Furthermore, second and third hospitalisations due to HF confer a 30% cumulative incremental risk of death, which plateaus after four or more hospitalisations.42 Similarly, worsening HF is associated with high early and later mortality, with the risk of the latter being comparable to the risk of death due to MI and stroke.70 The long-term prognosis for ADCHF patients is dismal, with 58% and 48% higher 1- and 10-year mortality risks, respectively, than DNHF patients.16 Together, these findings indicate that although ADCHF patients may survive hospitalisation events due to cardiac or non-cardiac diseases, they may not reach their previous baseline clinical status, which is reflected by their increased mortality. Therefore, key preventive strategies should be identified and implemented to mitigate this excess mortality risk.

Inflammatory Processes in ADCHF

Higher proinflammatory cytokine concentrations are seen in ADCHF compared with DNHF, reflected by higher IL-6 concentrations in the ADCHF group, causing a more pronounced inflammatory response. The profound inflammatory response may be caused by a complex mechanism involving interactions between venous dilatation caused by a rise in right

Thus, higher inflammatory and metabolic burden caused by a complex interaction between the haemodynamic disturbance, organ dysfunction and fluid accumulation may contribute to the higher mortality in ADCHF than DNHF.17

Clinical Implications: Risk Stratification, Therapeutic Management and Design of Clinical Trials

Currently, the initial therapy for HF is based on a clinical assessment of congestion (wet versus dry) and/or peripheral hypoperfusion (warm versus cold), leading to four classification options. Although most patients with AHF admitted to hospital present with signs and symptoms of congestion, diuretics and vasodilators have been the mainstay of therapy unless systolic blood pressure is <90 mmHg, in which case inotropic agents and vasopressors may be considered.61 Understanding the plethora of differences between DNHF and ADCHF has far-reaching public health and clinical consequences. First, there are differences in risk factors between these two groups, and so different preventive and curative strategies for AHF events should be used. In DNHF, hypertensive heart disease is prevalent. Therefore, health promotion of lifestyle modifications and a healthier diet for hypertensive individuals identified through screening, complemented with optimal guideline-directed medical therapy (GDMT), are crucial for modifying this risk factor.81 A study from Korea showed that, compared with ADCHF patients, DNHF patients had more pronounced prognostic implications of adherence to GDMT.82 Early initiation of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy reduced the rate of rehospitalisation (HR 0.57; 95% CI [0.34–0.95]), mortality (HR 0.41; 95% CI [0.24–0.69]) and the composite endpoint (HR 0.52; 95% CI [0.36–0.77]).82 Moreover, AHF events are precipitated mainly by acute coronary syndrome, specifically ST-elevation MI.14 Thus, mitigating cardiac injury through rapid

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De Novo HF Versus ADCHF reperfusion and myocardial protection strategies is crucial in preventing lifelong ventricular dysfunction.83 Indeed, this transient but life-threatening STEMI event was demonstrated in the ASCEND-HF analysis, which showed that 30-day mortality was higher in the DNHF than ADCHF group, although 1- and 10-year mortality was lower in the DNHF group.5 In contrast, ADCHF patients were sicker and complicated with many comorbidities, which rendered them more vulnerable to infection.5 Understandably, infection was the most common precipitator of HF in this group. Respiratory infection accounts for the majority of decompensation in HF patients (>50%).14,84 Thus, it seems rational to prevent infection by vaccination. Indeed, a large Danish cohort study demonstrated that influenza vaccination reduced the risk of all-cause and cardiovascular deaths in HF patients.84 Similarly, pneumococcal vaccination is putatively useful in preventing the precipitation of acute decompensation episodes in ADCHF patients. Nonetheless, investigations with more extensive clinical trials are needed.85 Optimal GDMT is equally important for CHF patients to prevent acute decompensation episodes. CHF is associated with excessive neurohormonal activation and maladaptive compensation, which can be halted by several agents.86 Renin–angiotensin system (RAS) blockers and β-blockers have been shown to improve quality of life and commensurately decrease morbidity and mortality.87 In addition, newer agents can be added to the armamentarium, including angiotensin receptor–neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 (SGLT-2) inhibitors, which are oral antidiabetic drugs.88,89 Consequently, managing chronic heart failure patients has become more complex, and this particularly reflected by studies showing that many cardiologists fail to uptitrate drug doses to reach guideline-recommended doses.90 Moreover, in the acute setting (i.e. ADCHF), rapid in-hospital decongestion through IV therapy is the rule to reduce morbidity.91,92 Other than for symptom relief, adequate reduction in congestion is equally important for reducing subsequent hospitalisations.93 When a patient’s haemodynamic status has stabilised, ARNI can be started. In the PIONEERHF study, ADCHF patients who received ARNI had lower NT-proBNP 1. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Fail 2014;1:4–25. https://doi.org/10.1002/ehf2.12005; PMID: 28834669. 2. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol 2011;8:30–41. https:// doi.org/10.1038/nrcardio.2010.165; PMID: 21060326. 3. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602. 4. Lesyuk W, Kriza C, Kolominsky-Rabas P. Cost-of-illness studies in heart failure: a systematic review 2004–16. BMC Cardiovasc Disord 2018;18:74. https://doi.org/10.1186/s12872018-0815-3; PMID: 29716540. 5. Greene SJ, Hernandez AF, Dunning A, et al. Hospitalization for recently diagnosed versus worsening chronic heart failure: from the ASCEND-HF trial. JACC Cardiovasc Interv 2017;69:3029–39. https://doi.org/10.1016/j.jacc.2017.04.043; PMID: 28641792. 6. Adams KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209–16. https://doi.org/10.1016/j.

concentrations than those who received enalapril.94 More importantly, there was no significant difference in side-effect rates between these two agents. In addition, the distinction between DNHF and ADCHF is essential in terms of risk stratification. The risk stratification for in-hospital mortality of acutely decompensated HF patients has been established in a study using registry-based data, which simplified AHF scenarios into a single entity.95 Thus, further research that prognostically evaluates the inhospital mortality of AHF subjects would benefit from classifying AHF into two distinct groups. Finally, to improve the clinical outcomes and quality of care for DNHF and ADCHF patients, future clinical trials should address the underlying differences between the two conditions by providing a dichotomisation between DNHF and ADCHF.14 No real treatment progress for AHF patients over the past several decades may be the result of combining these two different entities.5,49 Indeed, the importance of classification in HF can be seen in previous clinical trials. By classifying CHF on the basis of ejection fraction, pharmacological breakthroughs for this disease can be better appreciated: there are many drugs available to modify the course of HFrEF, leading to direct and indirect improvements in quality of life, morbidity and mortality of CHF patients.89,96–98 In contrast, no meaningful development has been made in the treatment of patients with HFpEF.89,99,100 Similarly, compared with AHF patients with a previous HF diagnosis, a diagnosis of AHF and HF ≤1 month before hospitalisation was independently associated with more significant early dyspnoea relief and improved post-discharge survival.5 Therefore, consideration should be given to distinguishing de novo or recently diagnosed HF from ADCHF when designing future acute HF trials.5

Conclusion

AHF is a cardiovascular emergency syndrome leading to mortality, morbidity and economic burden worldwide. Nevertheless, evidencebased and effective treatment options remain limited. Thus, innovative solutions are sorely needed. Future clinical trials of therapy should address the potentially different phenotypes between DNHF and ADCHF if meaningful discoveries are to be made.

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Treatment

Pulmonary Embolism and Heart Failure: A Reappraisal Mattia Arrigo

and Lars Christian Huber

Department of Internal Medicine, Triemli Hospital Zurich, Zurich, Switzerland

Abstract

Acute heart failure and acute pulmonary embolism share many features, including epidemiological aspects, clinical presentation, risk factors and pathobiological mechanisms. As such, it is not surprising that diagnosis and management of these common conditions might be challenging for the treating physician, in particular when both are concomitantly present. While helpful guidelines have been elaborated for both acute heart failure and pulmonary embolism, not many studies have been published on the coexistence of these diseases. With a special focus on diagnostic tools and therapeutic options, the authors review the available literature and, when evidence is lacking, present their own approach to the management of dyspnoeic patients with acute heart failure and pulmonary embolism.

Keywords

Pulmonary embolism, heart failure, right ventricular dysfunction, triage, anticoagulation, thrombolysis, circulatory support Disclosure: The authors have no conflicts of interest to declare. Received: 19 October 2020 Accepted: 30 October 2020 Citation: Cardiac Failure Review 2021;7:e03. DOI: https://doi.org/10.15420/cfr.2020.26 Correspondence: Lars C Huber, Department of Internal Medicine, Triemli Hospital Zurich, Birmensdorferstrasse 497, 8063 Zurich, Switzerland. E: lars.huber@zuerich.ch Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Dyspnoea is one of the leading symptoms in patients presenting to the emergency department. It is estimated that more than 50% of hospitalised patients and up to one-third of ambulatory outpatient present – at least to some degree – with dyspnoea.1 Its prevalence increases with age and, in many patients, more than one aetiology of dyspnoea is present.2. The incidence of pulmonary embolism (PE) and heart failure (HF) also increases with age and, not surprisingly, both conditions are among the most frequent causes of dyspnoea leading to hospitalisation, relevant morbidity and mortality.3 PE and acute HF not only have similar clinical presentations but also share many risk factors and pathophysiological mechanisms.4 For that reason, the diagnosis of coexisting PE and HF in dyspnoeic patients is challenging. The identification of one of these might lead to premature exclusion of the other and, as such, a diagnosis of concomitant PE and HF may be delayed, missed or not even considered by the treating physician.4 Furthermore, one condition may aggravate the other and the coexistence of both conditions has major therapeutic implications and detrimental effects on survival.5 In this paper, we summarise the pathophysiologic interactions of PE and HF, describe our diagnostic algorithm for PE in patients with HF and, based on the most recent recommendations on the treatment of PE and acute HF (AHF), we propose our therapeutic approach to patients with concomitant PE and AHF.5–8

Case Presentation

A 79-year-old woman with HF with preserved ejection fraction (HFpEF) presented to the emergency department reporting a sudden increase of

breathlessness and chest discomfort over the last few hours. Arterial blood pressure was 160/95 mmHg, the pulse was regular with a heart rate of 115 BPM. The peripheral oxygen saturation (SpO2) was 88% by breathing ambient air (94% with 4 l/min of oxygen) and the respiratory rate 32/min. The physical examination was remarkable for pitting oedema on both legs, distended jugular veins and bilateral pulmonary crackles. Extremities were warm and appear well perfused. The ECG showed sinus rhythm; no repolarisation abnormalities were present. Levels for high-sensitivity troponin were mildly elevated without relevant changes after 1 hour. The patient was treated with loop diuretics for AHF without relevant improvement of symptoms. The junior physician on night shift duty suspected the presence of concomitant PE and called his senior to discuss how to further manage this patient.

Pathophysiology Cardiovascular Disease and the Risk of Pulmonary Embolism

Arterial hypertension, dyslipidaemia, diabetes, obesity, tobacco use, unhealthy diet, stress and oestrogen therapy have major detrimental effects on endothelial function, inflammation and hypercoagulability, and may promote the occurrence of both atherothrombosis (leading to MI and HF) and venous thrombosis (leading to PE).9 A large registry study showed that previous MI significantly increases the risk of PE.10 The higher the burden of coronary artery disease, the higher the risk of experiencing PE.11 Patients with HF have a nearly doubled incidence and mortality of PE than those without HF – this risk increases as the cardiac function declines.12,13 A left ventricular ejection fraction (LVEF) <20% is independently associated with a 38-fold risk of a venous thromboembolism compared to patients without HF.14

Pulmonary Embolism and Heart Failure Figure 1: Stroke Volume and Afterload

Table 1: Diagnostic Scores PERC Rule

Wells’ Score

Geneva Score (Revised)

Previous venous thromboembolism

Trauma, immobilisation or recent surgery

100%

Stroke volume

Left ventricle 90%

History

Malignancy

80%

Right ventricle 70%

+10

+20

+30

Change in afterload (mmHg) Stroke volume of the left and right ventricles in relation to changes in afterload. BL = baseline. Source: Arrigo et al. 2019.21

Among patients with PE, patients with coexisting HF have less frequently identified triggers, such as recent surgery or active malignancy, and present less commonly with signs of deep venous thrombosis. Conversely, these patients are older and are more likely to have AF (32% versus 7%) and respiratory impairment (i.e. hypoxaemia and hypercapnia).13 Whether AF increases per se the risk of PE or whether it is merely a marker of comorbidities and severe cardiac disease remains a matter of debate.15,16 Since the prevalence of right atrial thrombi, potentially causing PE, in patients with AF has been described as low (<1%) compared to left atrial thrombi (9%), we question the clinical relevance of this association.17

PE Precipitating HF

PE may induce a rapid increase in pulmonary pressures and acutely precipitate HF by causing right ventricular dysfunction (acute cor pulmonale). The elevation of pulmonary pressure following PE is observed only when more than half of the pulmonary vasculature is obstructed by thrombotic material.18–20 This is because distension and recruitment of additional pulmonary capillaries might decrease vascular resistance and compensate for circulatory changes. When thrombotic occlusion extends to more than 50% of the lung vessels, pressure elevation occurs. An unconditioned right ventricle (RV) can tolerate a mean pulmonary arterial pressure of up to ~40 mmHg. If the RV is exposed to higher pressures, it can either tolerate it (then an antecedent adaption of the RV secondary to a pre-existing elevation of pulmonary pressure must be assumed) or its function is impaired. The normal RV function is an interplay between preload, contractility, afterload, ventricular interdependence and heart rhythm.21 A massive and rapid increase in RV afterload as observed in the context of PE induces RV dilation and a reduction in RV contractility, leading to a drop in RV stroke volume (Figure 1), change in ventricular interdependence and an increase in systemic congestion.21 As a consequence of the

Age

Hormone use

Pulmonary embolism is the most likely diagnosis

x x

Clinical Presentation Clinical signs and symptoms of deep vein thrombosis

Tachycardia

Haemoptysis

Hypoxaemia

PERC = Pulmonary Embolism Rule-out Criteria.

reduced RV function and altered interdependence, left ventricular preload is impaired, which may cause a reduction in left ventricular stroke volume and hypotension. Increased RV wall tension, arterial hypotension and impaired oxygenation may precipitate RV ischaemia and arrhythmias, which further deteriorate cardiac function and cause profound haemodynamic instability and shock.5,22 In summary, PE and HF have similar clinical presentations and share many risk factors and pathophysiological mechanism. Patients with cardiac disease, such as coronary artery disease, AF and, in particular, HF, display a higher risk for PE. On the other hand, PE may precipitate RV and left ventricle (LV) dysfunction and induce AHF or shock.

Diagnosis

The diagnostic process for the presence of PE in patients with HF includes clinical gestalt, the use of designated scores, laboratory markers and CT pulmonary angiography (CTPA). Our own algorithm to approach this topic is summarised in Figure 2.

Clinical Gestalt, Scores and D-dimers

Every diagnostic process begins with the formulation of a pretest probability by integrating all clinical information obtained. In this context, it should be emphasised that the result of any medical test that was ordered to confirm or to rule out a given disease is useless if not seen in the light of pretest probability.23 For example, paroxysmal nocturnal dyspnoea, auscultation of a third heart sound and radiological evidence for pulmonary venous congestion with interstitial oedema might result in such a high suspicion for the presence of AHF that the additional information obtained by measurement of cardiac biomarkers (i.e. natriuretic peptides) lowers – not increases – the diagnostic yield.24,25 For the semi-quantitative estimation of pretest probabilities in patients with suspected PE, several scores have been developed, of which the Geneva and the Wells score are probably the most popular ones.26 These scores have proven to be useful tools to estimate probabilities for the presence of PE in a clinical setting. However, these tools are limited by the

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Pulmonary Embolism and Heart Failure fact that both scores have been designed to lead to a further testing cascade, either by measurement of D-dimers (in cases of low pretest probability) or by CTPA (in cases of moderate or high probability). Moreover, the pretest probability for the presence of PE estimated by experienced clinicians is non-inferior or even superior to the probability calculated by one of these scoring systems.27,28 This difference might become more accentuated in the setting of a coexisting condition – such as AHF – for which no validated scores exist. Therefore, in patients with signs and symptoms of AHF and suspected PE, we advocate to use clinical gestalt to estimate the pretest probability for PE. In this specific situation, congestive HF should be strongly considered as an additional persistent risk factor to develop venous thromboembolism. In case of a low pretest probability, the Pulmonary Embolism Rule-out Criteria (PERC) rule should then be employed as initial scoring system. The PERC rule, with a sensitivity >97%, allows to rule out PE without additional testing.29 Because there are many overlapping variables between specific scoring systems (Table 1), we discourage the use of the Wells or Geneva score followed by the PERC score.30 When the pretest probability for PE is estimated to be low and at least one PERC criterion is abnormal or when the pretest probability is moderate, D-dimers should be measured (Figure 2). In case of elevated age-adjusted D-dimers or when pretest probability is high, CTPA should be performed next (Figure 2). To our knowledge, no studies have examined the predictive value of scoring systems or have evaluated distinct cut-off levels of D-dimers in the context of PE and AHF. However, a negative PERC score or normal age-adapted levels of D-dimers appear to safely rule out PE even when accompanied by other conditions.29

CT Pulmonary Angiography

CTPA is, to date, arguably the gold standard to diagnose PE (European Society of Cardiology [ESC] guidelines class I indication). Here, we want to emphasise two points. First, according to Bayesian probabilities, in patients with high pretest probability for the presence of PE, up to 8% of chest imaging might yield false negative results.31 This might be particularly true in patients with acute right-sided HF caused by tumour microemboli, which, in contrast to paraneoplastic venous thromboembolism, might be too small to be detected by imaging methods. Hence, it remains controversial whether patients with a negative CTPA and a high clinical probability should be further investigated.6 Second, patients with acute right HF and subsequently elevated central venous pressure and venous congestion commonly experience worsening renal function. In fact, venous congestion, more than reduced cardiac output, is the best haemodynamic predictor for a reduced glomerular filtration rate.32,33 Conversely, however, the risk of inducing post-contrast acute kidney injury is overestimated.34 Acute contrast-induced nephropathy is defined as the iatrogenic worsening of kidney function following the administration of IV radiocontrast – it usually shows a mild course with spontaneous return to baseline renal function without longterm compromise. As such, in patients with moderate to high probability for PE, we advocate not withholding CTPA as one of the most important diagnostic cornerstones.

Cardiac Biomarkers and Echocardiography for Risk Stratification

The latest guideline paper from the American College of Chest Physicians proposes a pragmatic approach to the use of both echocardiography and cardiac biomarkers and, in particular, suggests

Figure 2: Diagnostic Algorithm Clinical gestalt

Low probability of PE (<15%)

Moderate probability of PE (<15–35%)

High probability of PE (<35%)

PERC rule

Normal

≥1 Abnormal

Age-adjusted D-dimer

Normal

CTPA

Elevated

Normal

Positive

No PE

No further testing for PE Consider alternative diagnosis

Treatment (Figure 3)

Diagnostic algorithm for suspected pulmonary embolism in patients with heart failure. The clinical gestalt includes all information available from the history, physical examination, chest X-ray and ECG to estimate the pre-test probability of pulmonary embolism (PE).55 The PERC rule includes age <50 years, heart rate <100 BPM, peripheral oxygen saturation ≥95%, absence of unilateral leg swelling, absence of haemoptysis, absence of recent trauma or surgery, no prior venous thromboembolism and no hormone use. If one or more variables are abnormal, PE cannot be ruled out and further testing is recommended.29 The use of age-adjusted D-dimer cut-off is recommended. For patients aged <50 years, we use 500 µg/l. For patients aged 50 years or more, we use age (years) × 10 (i.e. 65 [years] × 10 = 650 µg/l).56 CTPA: CT pulmonary angiography; PE = pulmonary embolism. PERC = Pulmonary Embolism Rule-out Criteria. Source: Kline et al. 2008,29 Huber et al. 201056 and Righini et al 2014.57

not to use these diagnostic tools routinely in all patients with PE or in all patients with a non-low-risk profile.35 Cardiac biomarkers, such as high-sensitivity troponins and natriuretic peptides, are associated with higher risk of PE-related death but, since they are frequently elevated (in ~50–60% of patients with PE), they have a low positive predictive value and do usually not alter treatment decisions.6 In the clinical setting of concomitant acute PE and HF, the diagnostic yield of cardiac biomarkers is even further reduced. Because they have an excellent negative predictive value, natriuretic peptides and high-sensitivity troponins are of major use when found at normal levels. This, however, is an unlikely scenario in patients presenting with both PE and HF. Routine echocardiography for the assessment of RV function is not recommended for the diagnostic workup of haemodynamically stable patients with PE.6 Indeed, echocardiographic evidence of RV dysfunction (e.g. RV:LV ratio ≥1.0, tricuspid annullar plane systolic excursion <16 mm) is common (prevalence of ~25% in unselected patients with PE) and associated with worse short-term outcome, but displays low positive predictive value for PE-related death.36 Conversely, in stable patients with concomitant (including acute) HF, echocardiography should be performed at admission or during the index

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Pulmonary Embolism and Heart Failure

Early management (<1 hour)

Triage (<15 minutes)

Figure 3: Management Algorithm Evaluation of cardiopulmonary distress (BP, HR, RR, SpO2, signs of hypoperfusion) and PESI score

Cardiopulmonary unstable or PESI III–V

Res. Area ICU/CCU

Diagnosis

Support

Treatment

TTE

Optimise oxygenation

Consider thrombolysis

Lung ultrasound

Optimise preload Restore pressure

Consider other options if thrombolysis not feasible

Improve contractility

Anticoagulation

Cardiopulmonary stable and PESI I–II

ED Normal ward

Diagnosis TTE

Support

Treatment

Search for other precipitants of AHF

Optimise oxygenation

Anticoagulation

Search for other precipitants of AHF

Evaluate clinical response to treatment

Re-evaluation and patient allocation

Evaluate clinical response to treatment

Improvement

Deterioration

Improvement

Deterioration

Optimise diuretics Start oral HF treatment Consider switch to DOAC/VKA Consider discharge Plan follow-up

Transfer to ICU/CCU ‘Pathway unstable’

Consider transfer to normal ward ‘Pathway stable’

Consider MCS (i.e. ECLS) Consider palliative care

Management algorithm for pulmonary embolism in patients with heart failure. BP = blood pressure; CCU = cardiac care unit; DOAC = direct anticoagulant; ECLS = extracorporeal life support; ED = emergency department; EKOS = ultrasound-enhanced thrombolysis; HF = heart failure; HR = heart rate; ICU = intensive care unit; MCS = mechanical circulatory support; PESI = pulmonary embolism severity index; Res. = resuscitation; = RR = respiratory rate; SpO2 = peripheral oxygen saturation; TTE = transthoracic echocardiography; VKA = vitamin K antagonist.

hospitalisation to diagnose the underlying cardiac pathology that may require specific treatments and/or initiation of a neuro-humoral blockade (such as beta-blockers or renin–angiotensin–aldosterone system inhibitors).3,37 In patients with suspected or confirmed PE and haemodynamic instability, echocardiography should be immediately performed (ESC guidelines class I indication). Indeed, in unstable patients with suspected PE, the presence or absence of echocardiographic signs of acute cor pulmonale may rule in or rule out PE as a cause of haemodynamic instability and accelerate the diagnostic process and treatment delivery.6

Management

The management of patients with concomitant PE and HF/AHF may be challenging.5,21 The spectrum of disease may vary from oligo- or asymptomatic presentations to critical illness with profound cardiopulmonary instability. Therefore, the first minutes should be dedicated to triage, i.e. assessment of the cardiopulmonary distress based on the acquisition of the vital signs (blood pressure, heart rate, respiratory rate and peripheral oxygen saturation), the estimation of the perfusion state (search for signs of peripheral hypoperfusion, such as cold, mottled skin, altered mental state and oliguria), and the determination of the PESI score (Figure 3 and Table 2).5,21 Cardiac arrest, obstructive shock (systolic blood pressure <90 mmHg and signs of peripheral hypoperfusion), and persistent hypotension (systolic blood pressure <90 mmHg or requiring vasopressors) define haemodynamic instability.6

Low-risk Patients without Cardiopulmonary Instability

Low-risk patients presenting with cardiopulmonary stability and PESI I–II (Figure 3, left side) can be managed in a regular emergency department or a normal ward.

The management should consist of three parts delivered simultaneously. First, the diagnostic process should be refined by searching for other precipitating factors of AHF (e.g. myocardial ischaemia, arrhythmia, infection, uncontrolled hypertension and noncompliance) and performing a transthoracic echocardiogram (TTE) to better understand the underlying cardiac pathology leading to AHF and assess the presence of cardiac sequelae of PE (e.g. RV dysfunction and pulmonary hypertension).38,39 The additional information derived from the finalised diagnostic process may allow the optimisation of the treatment directly tailored to the underlying precipitating factor and cardiac pathology.40 Second, oxygenation should be optimised by delivering supplemental oxygen through a nasal cannula or face mask (target SpO2 >94%).5,8 In addition to relieving symptoms, supplemental oxygen reduces precapillary pulmonary vasoconstriction and RV afterload. Conversely, positive pressure noninvasive ventilation should be used with caution to avoid negative effects on the RV. Pulmonary and systemic congestion should be treated with loop diuretics (and/or vasodilators in selected cases presenting with elevated systolic blood pressure).3,41 Third, anticoagulation should be started as soon as the diagnosis of PE is made or suspected in case of intermediate or high probability (ESC guidelines class I indication).6 In selected patients, oral anticoagulation with direct oral anticoagulants (DOAC) can be used. However, for the majority of patients with PE and AHF, we prefer to start with unfractionated heparin (bolus followed by continuous infusion) then switch to DOAC or vitamin K antagonists (VKA) after a few days. Indeed, in patients with AHF, the bioavailability of oral drugs may be reduced because of gastrointestinal congestion and the renal elimination of DOACs may be impaired if renal function deteriorates because of venous congestion.

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Pulmonary Embolism and Heart Failure Table 2: Pulmonary Embolism Severity Index Prognostic Score Variable

Points

PESI score PESI class

Age (years)

___ points

0–65

Male sex

+10 points

66–85

History of heart failure

+10 points

86–105

III

History of lung disease

+10 points

106–125

History of cancer

+30 points

>125

Systolic blood pressure <100 mmHg

+30 points

Heart rate ≥110/minute

+20 points

Respiratory rate ≥30/minute

+20 points

Oxygen saturation <90%

+20 points

Temperature <36°C

+20 points

Altered mental status

+60 points

Total

___ points

The clinical response to the initial treatment should be continuously reevaluated to determine further treatment and patient allocation.42 In case of improvement, diuretics should be further tailored until euvolaemia is achieved; the oral HF therapies should be started or uptitrated and the anticoagulation should be switched to DOAC/VKA.3,37,41 Before hospital discharge, patients should be instructed and a follow-up plan should be organised. For deteriorating patients, a transfer to the intensive care unit (ICU) or cardiac care unit (CCU) should be considered (see below).

High-risk Patients or With Cardiopulmonary Instability

Patients with either cardiopulmonary instability or with PESI III–V should be managed in the resuscitation area or in the ICU/CCU.5,8,22 In an analogy to the treatment of stable patients, the management of unstable or severely ill patients should consist of three parts delivered simultaneously. First, the role of additional diagnostic modalities, such as TTE and lung ultrasound, is particularly important in unstable patients to better understand and characterise the underlying cardiac and pulmonary conditions and to optimise cardiopulmonary support. Special attention should be given to signs of RV dysfunction (e.g. RV fractional area change, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity and McConnell’s sign), signs of pulmonary and systemic congestion (pulmonary pressure and inferior vena cava diameter), left ventricular systolic and diastolic function, and concomitant valve pathologies. The lung ultrasound may assist differentiation of the cause of hypoxia (pulmonary oedema versus PE).43,44 Second, cardiopulmonary support should include the optimisation of the oxygenation by delivering supplemental oxygen through a nasal cannula or face mask (target SpO2 >94%).5,8 As mentioned above, positive pressure noninvasive/invasive ventilation should be used with caution to avoid negative effects on the RV function. Haemodynamic support should start with optimisation of the preload but we want to add a note of caution here: while some patients presenting with shock may display intravascular fluid depletion and will be fluid responsive, most patients present with systemic congestion and additional fluid loading may worsen organ function.5,21,32

The key step in the management of RV dysfunction is the restoration of the perfusion pressure by adding a vasopressor (i.e. norepinephrine).5,21 Norepinephrine increases the mean arterial pressure, improves coronary perfusion, reduces RV ischaemia without negative effects on RV afterload (pulmonary resistance is not affected by norepinephrine).45 If haemodynamic stability is not restored after optimisation of the preload and vasopressor support and significant RV dysfunction is shown by echocardiography, treatment with a positive inotropic drug to increase myocardial contractility is recommended.5,21 The choice of inotropic drug should be based on the differences in pharmacodynamics and pharmacokinetics.46 Catecholamines (e.g. dobutamine) offer the advantage of a rapid onset of effect (within minutes) but increase myocardial oxygen demand, which can precipitate myocardial ischaemia. Phosphodiesterase III inhibitors (e.g. milrinone) and the calcium-sensitiser levosimendan require longer (hours) to achieve the maximal effect, have a longer duration of effect of hours to days and display strong vasodilatory properties (both substances reduce pulmonary and systemic pressures).47 Levosimendan, in contrast to catecholamines and phosphodiesterase III inhibitors, does not increase myocardial oxygen consumption. The third part of the treatment of patients with PE and cardiopulmonary instability should be reperfusion strategies. Systemic thrombolysis should be considered in all patients presenting with severe haemodynamic instability or shock caused by PE (ESC guidelines class I indication).6 In this setting, thrombolysis compared to heparin has shown to reduce total mortality, PE-related mortality and PE recurrence, but is associated with a ~10% rate of severe bleedings and a ~2% rate of intracranial haemorrhage.48 It is unclear whether thrombolysis has an impact on symptoms, functional capacity and the development of chronic thrombo-embolic pulmonary hypertension (CTEPH: see below); In our institution, we use alteplase (10 mg as an IV bolus, followed by 90 mg over 2 hours). In patients with a body weight of <65 kg, the maximal dose is 1.5 mg/kg. Of note, unfractionated heparin is not to be withheld during continuous infusion of alteplase. In high-risk patients who are not in shock or in patients with contraindications for systemic thrombolysis, other options to rapidly reduce the RV afterload might be considered. One option is the use of ultrasound-enhanced, catheter-directed low-dose thrombolysis. However, most knowledge about this technique is derived from registries and case series, and one small randomised trial showing a larger decrease in the RV/LV ratio at 24 hours.49 Surgical pulmonary embolectomy is performed with cardiopulmonary bypass with removal or suction of the fresh clots through incision of the main pulmonary arteries. It provides similar success to systemic thrombolysis and should be considered when systemic thrombolysis is contraindicated (ESC guidelines class I indication). The re-evaluation of the clinical response to the initial treatment is of crucial importance in unstable patients to timely evaluate the need for mechanical circulatory support, such as extracorporeal life support (ECLS) by the mean of venous–arterial extracorporeal membrane oxygenation (va-ECMO) device.5,21 If clinical improvement is observed, a reduction in cardiopulmonary support should be attempted and, when cardiopulmonary stability is achieved, transfer to a normal ward should be considered.

Long-term Management

The patency restoration of the pulmonary arterial bed occurs within the first weeks to few months in the majority of patients with PE.50,51 However, persistent dyspnoea or poor physical performance months to years after acute PE is frequently reported, particularly in patients with coexisting HF.52 Functional impairment frequently does not correlate with a

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Pulmonary Embolism and Heart Failure Figure 4: Risk Factors of Venous Thromboembolism Venous thromboembolism risk factors

Identifiable risk factors

Major

Minor

Major transient (reversible)

Major persistent (irreversible)

Minor transient (reversible)

Minor persistent (irreversible)

Example: major surgery

Example: active malignancy

Examples: long-haul flight; oestrogen therapy; trauma with fractures

Examples: heart failure; inflammatory disease; lower leg paralysis; family historyof venous thromboembolism; obesity

Recurrence rate at 1 year: 0%

Recurrence rate at 1 year: 3.8%

Recurrence rate at 1 year: 7.1%

Recurrence rate at 1 year: 10.7%

No identifiable risk factor

Recurrence rate at 1 year: 10%

Venous thromboembolism categorised according to risk factors. The most recent classification of venous thromboembolism is dichotomised into identifiable or non-identifiable risk factors. Identifiable risk factors can be further categorised into major or minor risk factors, both of which can be reversible (transient) or irreversible (persistent). All groups with the exception of ‘transient major risk factors’ (green box) have an elevated risk of annual recurrence: 3.8% (persistent major); 7.1% (transient minor); 10.7% (persistent minor); and 10% (no identifiable risk factor).53 Since only few patients with a persistent major risk factor (i.e. cancer) were analysed in these studies, recurrence rate in this cohort of patients might be underestimated.57 These data have major implications in the decision of the optimal duration of anticoagulant therapy. Source: Prins et al. 201853 and Albertsen et al. 2018.58

echocardiography or pulmonary function test, both of which are usually within normal limits.52 In a few PE patients, thrombi become persistent and organised and, in some cases, this may result in the rare but life-threatening condition of CTEPH.6 The hallmark of CTEPH is fibrotic transformation of pulmonary thrombus causing fixed obstruction of some pulmonary arteries and overflow of the other – open – pulmonary arteries, with consecutive microvascular remodelling and the development of pulmonary hypertension. A detailed discussion of diagnosis and treatment of CTPEH is beyond the scope of this article. We want to emphasise that diagnosing CTEPH is difficult, in particular in patients with other causes of dyspnoea such as HF. Because this condition is rare, we discourage systematic screening with echocardiography in all patients with PE, in particular when asymptomatic. However, in HF patients with recent PE undergoing regular echocardiographic follow-ups, new-onset or worsening of pulmonary hypertension after at least 3 months of anticoagulation therapy may indicate the development of CTPEH and further investigations by right-heart catheter and/or lung scintigraphy are indicated. The duration of anticoagulation should be defined after assessment of the risk factors for the development of venous thromboembolism (VTE) (Figure 4). Former classification of VTE using terms as ‘provoked’, ‘unprovoked’ or ‘idiopathic’ VTE should no longer be used since these terms have not proven to be helpful to guide choice and duration of anticoagulation treatment. Of note, except for VTE occurring in the context of a major transient risk factor (e.g. major surgery), in which the risk of recurrence approaches 0% and, as such, can be excluded, all categories have a similar risk of recurrence.53 In other words, the absolute recurrence risk for patients with identifiable risk factors is, in the long term, the same as in patients without identifiable risk factors.

These data support the pathophysiological concept of a final common pathway, by which single risk factors contribute to rather than explain an underlying thrombophilic diathesis. It should further be emphasised that the cumulative incidence of recurrent VTE is continuously increasing over time and a substantial proportion of these recurrent events has fatal outcome resulting in death. In the light of these considerations, anticoagulation for at least 3 months is recommended in all patients with PE (ESC guidelines class I recommendation) and, except for patients with a major transient risk factor, anticoagulation without a predefined date to stop should be the preferred treatment option for patients with VTE in most situations (ESC guidelines class I/IIa recommendation). In patients with cancer, we prefer to use low-molecular-weight heparin or apixaban for those with gastrointestinal involvement and apixaban or edoxaban for people with non-gastrointestinal cancer.54,55

Conclusion

PE and AHF share many features, including epidemiological aspects, clinical presentation, risk factors and pathobiological mechanisms. Diagnosis and management of these common entities might be challenging for the treating physician, in particular when both conditions are concomitantly present. The diagnostic approach of HF patients with suspected PE should consider pretest probabilities using clinical gestalt and validated scores. Additional testing (D-dimers and/or CTPA) is employed when needed. Patients with PE and HF should be triaged according to haemodynamic stability. Management should include cardiopulmonary support with special attention to the detrimental effect of PE on RV function, and antithrombotic treatment. Further studies designed to define the best diagnostic and therapeutic approach in this distinct population of patients are needed.

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Pulmonary Embolism and Heart Failure 1. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea. Am J Resp Crit Care 2012;185:435–52. https://doi.org/10.1164/ rccm.201111-2042ST; PMID: 22336677. 2. Mulrow CD, Lucey CR, Farnett LE. Discriminating causes of dyspnea through clinical examination. J Gen Intern Med 1993;8:383–92 https://doi.org/10.1007/BF02600079; PMID: 8410400. 3. Arrigo M, Jessup M, Mullens W, et al. Acute heart failure. Nat Rev Dis Primers 2020;6:16. https://doi.org/10.1038/s41572020-0151-7; PMID: 32139695. 4. Piazza G, Goldhaber SZ. Pulmonary embolism in heart failure. Circulation 2008;118:1598–601. https://doi.org/10.1161/ CIRCULATIONAHA.108.803965; PMID: 18838576. 5. Harjola V, Mebazaa A, Čelutkienė J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016;18:226–41 https://doi.org/10.1002/ejhf.478; PMID: 26995592. 6. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2019;41:543– 603 https://doi.org/10.1093/eurheartj/ehz405; PMID: 31504429. 7. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/ eurheartj/ehw128; PMID: 27206819. 8. Mebazaa A, Yilmaz MB, Levy P, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergenc. Eur J Heart Fail 2015;17:544–58. https://doi.org/10.1002/ejhf.289; PMID: 25999021. 9. Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation 2010;121:2146–50. https://doi.org/10.1161/ CIRCULATIONAHA.110.951236; PMID: 20479165. 10. Sørensen HT, Horvath-Puho E, Lash TL, et al. Heart disease may be a risk factor for pulmonary embolism without peripheral deep venous thrombosis. Circulation 2011;124:1435–41. https://doi.org/10.1161/ CIRCULATIONAHA.111.025627; PMID: 21900083. 11. Cavallari I, Morrow DA, Creager MA, et al. Frequency, predictors, and impact of combined antiplatelet therapy on venous thromboembolism in patients with symptomatic atherosclerosis. Circulation 2018;137:684–92. https://doi. org/10.1161/CIRCULATIONAHA.117.031062; PMID: 29084737. 12. Beemath A, Stein PD, Skaf E, et al. Risk of venous thromboembolism in patients hospitalized with heart failure. Am J Cardiol 2006;98:793–5. https://doi.org/10.1016/j. amjcard.2006.03.064; PMID: 16950187. 13. Monreal M, Muñoz-Torrero JFS, Naraine VS, et al. Pulmonary embolism in patients with chronic obstructive pulmonary disease or congestive heart failure. Am J Med 2006;119:851–8. https://doi.org/10.1016/j.amjmed.2005.11.035; PMID: 17000216. 14. Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001;54:810–6. https://doi.org/10.1016/S08954356(00)00373-5; PMID: 11470390. 15. Yetkin E, Cuglan B, Turhan H, et al. Ignored identity of agedependent increase in pulmonary embolism. Chest 2019;156:1271–2. https://doi.org/10.1016/j.chest.2019.07.033; PMID: 31812196. 16. Pauley E, Orgel R, Rossi JS, et al. Response. Chest 2019;156:1272–3. https://doi.org/10.1016/j. chest.2019.08.2174; PMID: 31812197. 17. Cresti A, García-Fernández MA, Miracapillo G, et al. Frequency and significance of right atrial appendage thrombi in patients with persistent atrial fibrillation or atrial flutter. J Am Soc Echocardiog 2014;27:1200–7. https://doi. org/10.1016/j.echo.2014.08.008; PMID: 25240491. 18. McIntyre KM, Sasahara AA. The ratio of pulmonary arterial pressure to pulmonary vascular obstruction: index of preembolic cardiopulmonary status. Chest 1977;71:692–7. https://doi.org/10.1378/chest.71.6.692; PMID: 862439. 19. McIntyre KM, Sasahara AA. The hemodynamic response to

pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol 1971;28:288–94. https://doi.org/10.1016/0002-9149(71)90116-0; PMID: 5155756. 20. Alpert JS, Haynes FW, Dalen JE, et al. Experimental pulmonary embolism: effect on pulmonary blood volume and vascular compliance. Circulation 1974;49:152–7. https:// doi.org/10.1161/01.CIR.49.1.152; PMID: 4808835. 21. Arrigo M, Huber LC, Winnik S, et al. Right ventricular failure: pathophysiology, diagnosis and treatment. Cardiac Fail Rev 2019;5:140–6. https://doi.org/10.15420/cfr.2019.15.2; PMID: 31768270. 22. Chioncel O, Parissis J, Mebazaa A, et al. Epidemiology, pathophysiology and contemporary management of cardiogenic shock – a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2020;22:1315–41. https://doi.org/10.1002/ ejhf.1922; PMID: 32469155. 23. Sox HC, Higgins MC, Owens DK. Medical decision making. Chichester: Wiley-Blackwell; 2013. https://doi. org/10.1002/9781118341544. 24. McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure. Circulation 2002;106:416–22. https://doi. org/10.1161/01.CIR.0000025242.79963.4C . PMID: 12135939. 25. Simel DL, Rennie D. The Rational Clinical Examination: EvidenceBased Clinical Diagnosis. McGraw-Hill Education, 2009. 26. Stüssi-Helbling M, Arrigo M, Huber LC. Pearls and myths in the evaluation of patients with suspected acute pulmonary embolism. Am J Medicine 2019;132:685–91. https://doi. org/10.1016/j.amjmed.2019.01.011; PMID: 30710540. 27. Lucassen W, Geersing G-J, Erkens PMG, et al. Clinical decision rules for excluding pulmonary embolism: a metaanalysis. Ann Intern Med 2011;155:448. https://doi. org/10.7326/0003-4819-155-7-201110040-00007; PMID: 21969343. 28. Penaloza A, Verschuren F, Meyer G, et al. Comparison of the unstructured clinician gestalt, the Wells score, and the revised Geneva score to estimate pretest probability for suspected pulmonary embolism. Ann Emerg Med 2013;62:117124.e2. https://doi.org/10.1016/j.annemergmed.2012.11.002; PMID: 23433653. 29. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost 2008;6:772–80. https://doi. org/10.1111/j.1538-7836.2008.02944.x; PMID: 18318689. 30. Theunissen J, Scholing C, Hasselt W van, et al. A retrospective analysis of the combined use of PERC rule and Wells score to exclude pulmonary embolism in the emergency department. Emerg Med J 2016;33:696–701. https://doi.org/10.1136/emermed-2016-205687; PMID: 27287004. 31. Belzile D, Jacquet S, Bertoletti L, et al. Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a metaanalysis of the management outcome studies. J Thromb Haemost 2018;16:1107–20. https://doi.org/10.1111/jth.14021; PMID: 29645405. 32. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous Congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009;53:589–96. https://doi.org/10.1016/j.jacc.2008.05.068; PMID: 19215833. 33. Aelst LNLV, Arrigo M, Placido R, et al. Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion. Eur J Heart Fail 2017;20:738–47. https://doi. org/10.1002/ejhf.1050; PMID: 29251818. 34. Timal RJ, Kooiman J, Sijpkens YWJ, et al. Effect of no prehydration vs sodium bicarbonate prehydration prior to contrast-enhanced computed tomography in the prevention of postcontrast acute kidney injury in adults with chronic kidney disease: the Kompas randomized clinical trial. JAMA Intern Med 2020;180:533. https://doi.org/10.1001/ jamainternmed.2019.7428; PMID: 32065601. 35. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease. Chest 2016;149:315–52. https://doi. org/10.1016/j.chest.2015.11.026; PMID: 26867832. 36. Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011;15:R103. https://doi.org/10.1186/cc10119; PMID: 21443777. 37. Gayat E, Arrigo M, Littnerova S, et al. Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study. Eur J Heart Fail 2017;20:345–54. https://doi.org/10.1002/ejhf.932; PMID: 28849606. 38. Arrigo M, Gayat E, Parenica J, et al. Precipitating factors and

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90-day outcome of acute heart failure: a report from the intercontinental GREAT registry. Eur J Heart Fail 2016;19:201– 8. https://doi.org/10.1002/ejhf.682; PMID: 27790819. 39. Arrigo M, Tolppanen H, Sadoune M, et al. Effect of precipitating factors of acute heart failure on readmission and long-term mortality. ESC Heart Fail 2016;3:115–21. https:// doi.org/10.1002/ehf2.12083; PMID: 27812386. 40. Arrigo M, Nijst P, Rudiger A. Optimising heart failure therapies in the acute setting. Cardiac Fail Rev 2018;4:1. https://doi.org/10.15420/cfr.2017:21:1; PMID: 29892475. 41. Mullens W, Damman K, Harjola V-P, et al. The use of diuretics in heart failure with congestion – a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:137– 55. https://doi.org/10.1002/ejhf.1369; PMID: 30600580. 42. Arrigo M, Parissis JT, Akiyama E, et al. Understanding acute heart failure: pathophysiology and diagnosis. Eur Heart J Suppl 2016;18(suppl G):G11–8 https://doi.org/10.1093/ eurheartj/suw044. 43. McConnell MV, Solomon SD, Rayan ME, et al. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469–73. https://doi.org/10.1016/S0002-9149(96)00339-6; PMID: 8752195. 44. Picano E, Pellikka PA. Ultrasound of extravascular lung water: a new standard for pulmonary congestion. Eur Heart J 2016;37:2097–104. https://doi.org/10.1093/eurheartj/ehw164; PMID: 27174289. 45. Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984;60:132–5. https://doi. org/10.1097/00000542-198402000-00009; PMID: 6198941. 46. Arrigo M, Mebazaa A. Understanding the differences among inotropes. Intensive Care Med 2015;41:912–5. https://doi. org/10.1007/s00134-015-3659-7; PMID: 25605474. 47. Ishihara S, Gayat E, Sato N, et al. Similar hemodynamic decongestion with vasodilators and inotropes: systematic review, meta-analysis, and meta-regression of 35 studies on acute heart failure. Clin Res Cardiol 2016;105:971–80. https://doi.org/10.1007/s00392-0161009-6; PMID: 27314418. 48. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2014;36:605–14. https://doi.org/10.1093/eurheartj/ehu218; PMID: 24917641. 49. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479–86. https://doi. org/10.1161/CIRCULATIONAHA.113.005544; PMID: 24226805. 50. Dalen JE, Banas JS, Brooks HL, et al. Resolution rate of acute pulmonary embolism in man. N Engl J Med 1969;280:1194–9. https://doi.org/10.1056/ NEJM196905292802202; PMID: 5767460. 51. Tow DE, Wagner HN. Recovery of pulmonary arterial blood flow in patients with pulmonary embolism. N Engl J Med 1967;276:1053–9. https://doi.org/10.1056/ NEJM196705112761902; PMID: 6025661. 52. Klok FA, Hulle T van der, den Exter PL, et al. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014;28:221–6. https://doi. org/10.1016/j.blre.2014.07.003; PMID: 25168205. 53. Prins MH, Lensing AWA, Prandoni P, et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018;2:788–96. https://doi.org/10.1182/ bloodadvances.2018017160; PMID: 29632234. 54. Raskob GE, Es N van, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615–24. https://doi.org/10.1056/ NEJMoa1711948; PMID: 29231094. 55. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382(17):1599–607. https://doi. org/10.1056/NEJMoa1915103; PMID: 32223112. 56. Huber LC, Müller V. Acute pulmonary embolism. N Engl J Med 2010;363:1973–4. https://doi.org/10.1056/NEJMc1009061; PMID: 21067401. 57. Righini M, Es JV, Exter PLD, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUSTPE study. JAMA 2014;311:1117–24. https://doi.org/10.1001/ jama.2014.2135; PMID: 24643601. 58. Albertsen IE, Nielsen PB, Søgaard M, et al. Risk of recurrent venous thromboembolism: a Danish nationwide cohort study. Am J Med 2018;131:1067–74.e4. https://doi. org/10.1016/j.amjmed.2018.04.042; PMID: 30266273.

Treatment

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Chris Wai Hang Lo ,1 Yue Fei

and Bernard Man Yung Cheung

1,2,3

1. Division of Clinical Pharmacology and Therapeutics, Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; 2. State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong, China; 3. Institute of Cardiovascular Science and Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.

Abstract

Type 2 diabetes is among the most prevalent chronic diseases worldwide and the prevention of associated cardiovascular complications is an important treatment goal. Sodium–glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are second-line options after metformin, while cardiovascular outcome trials have been conducted to establish the cardiovascular safety of these antidiabetic drug classes. SGLT2 inhibitors have been shown to have the best overall mortality, renal and cardiovascular outcomes. Reduction in hospitalisation for heart failure is particularly consistent. GLP-1 receptor agonists have also showed some benefits, especially in stroke prevention. DPP-4 inhibitors showed neutral effects on cardiovascular outcomes, but may increase the incidence of heart failure. Favourable outcomes observed in trials of SGLT2 inhibitors mean that these should be the preferred second-line option. DPP-4 inhibitors are useful for patients with diabetes at low cardiovascular risk.

Keywords

Antidiabetic drug, sodium–glucose co-transporter 2 inhibitor, glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase-4 inhibitor, type 2 diabetes, cardiovascular outcome, heart failure, stroke, mortality, renal outcomes Disclosure: The authors have no conflicts of interest to declare. Received: 19 July 2020 Accepted: 11 November 2020 Citation: Cardiac Failure Review 2021;7:e04. DOI: https://doi.org/10.15420/cfr.2020.19 Correspondence: Bernard Cheung, University Department of Medicine, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, China. E: mycheung@hku.hk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Type 2 diabetes (T2D) is becoming increasingly prevalent across the world. Its cardiovascular complications are major causes of mortality and use of medical resources.1 Prevention of cardiovascular diseases is, therefore, an important goal of the treatment of T2D. Metformin is the first-line therapy, according to the European Society of Cardiology, the American Diabetes Association (ADA) and the International Diabetes Federation.2–4 After metformin, three new antidiabetic drug classes have emerged as second-line therapy options. Sodium–glucose co-transporter 2 (SGLT2) inhibitors exert hypoglycaemic effects by inhibiting glucose reabsorption at the proximal convoluted tubules, causing glycosuria, natriuresis and volume contraction (Figure 1).5 Besides SGLT2 inhibition, incretin-based therapies have also been used in recent years for the treatment of T2D (Figure 2). Incretins are gut-derived hormones that send a signal to the pancreas after the ingestion of food.6,7 There are two main incretin hormones: glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP, also known as glucose-dependent insulinotropic polypeptide). Both are secreted by enteroendocrine cells in the intestines and stimulate pancreatic beta-cells to secrete insulin.7 GLP1 additionally inhibits glucagon release by pancreatic alpha-cells and delays gastric emptying.6 GIP, on the other hand, also stimulates glucagon production, yet fails to stimulate insulin secretion in people with diabetes.7 Therefore, it has not been developed as a therapeutic agent. The plasma half-life of GLP-1 is short, so GLP-1 receptor agonists (RAs) have modifications in the peptide to prolong half-life.6 As these incretin

hormones are degraded by dipeptidyl peptidase-4 (DPP-4), DPP-4 inhibitors can amplify their pharmacological actions.8 Both of these two incretin-based therapies improve postprandial glucose control.6,8 Among the three drug classes, the preferred second-line treatment remains unclear (Table 1). However, the thiazolidinediones are not favoured as second-line drugs. Indeed, pioglitazone-induced heart failure (HF) and the withdrawal of rosiglitazone because of cardiovascular concerns eventually led to a change in the policy of regulatory authorities.9,10 The US Food and Drug Administration and the European Medicines Agency now require all new antidiabetic drugs to undergo large cardiovascular outcome trials (CVOTs) to confirm cardiovascular safety and benefits. As a result of this requirement, multiple CVOTs have been published in recent years (Table 2). Some trials have shown cardiovascular benefits for GLP-1 RAs and SGLT2 inhibitors, which have been confirmed in meta-analyses.11-18 However, their effects on particular outcomes remain inconsistent in trials.15,19,20 This may be a result of limitations in statistical power and differences in patient characteristics and the drugs used. In the absence of adequately powered head-to-head trials, superiority amongst the three antidiabetic drug classes cannot be established. Network meta-analyses (NMAs) can evaluate comparative risks or benefits using indirect evidence. Our 2019 NMA included 14 trials and a total of 121,047 patients.17 First, we found that both SGLT2 inhibitors and GLP-1 RAs

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Figure 1: Postulated Mechanisms of SGLT2 Inhibitors Ischaemic stroke prevention – neutral

Myocardial Na+/H+ exchanger 3 SGLT2 inhibitors

↑Thrombus formation

Promote ↑Blood viscosity

Glycosuria

Natriuresis

↑Uric acid excretion

↓Body weight

↓HbA1c ↑Tubuloglomerular feedback

↓Adipose tissue Inflammation ↑Lipolysis ↑Ketone bodies Use as cardiac fuel

↓Oxidative stress (at renal tubules)

Afferent arteriolar vasoconstriction

↓Na+/H+ exchanger 1

↓Blood pressure

↓Left ventricular preload

↓Sympathetic tone ↓Arterial stiffness ↓Oxidative stress

Volume contraction (at interstitial fluid)

↓Fluid retention by renin–angiotensin– aldosterone system

↓Left ventricular afterload Heart failure benefits

↓Glomerular hyperfiltration ↓Albuminuria

↓Ischaemic injury

Cardiovascular benefits

Renal benefits

Green lines = beneficial mechanisms; red line = harmful mechanism. SGLT2 = sodium–glucose co-transporter 2.

significantly reduced major adverse cardiovascular events (MACE), hospitalisation for HF and renal composite outcome compared to placebo. Second, SGLT2 inhibitors were shown to have the greatest cardiovascular and all-cause mortality benefits amongst all three new antidiabetic drug classes. Third, the GLP-1 RA class was the only one that showed reductions in nonfatal stroke events. Finally, the risks of cardiovascular and renal outcomes in DPP-4 inhibitors were found to be neutral when compared to placebo and inferior to the other two drug classes.

SGLT2 Inhibitors

The EMPA-REG OUTCOME and CANVAS studies have shown favourable all-cause mortality and cardiovascular outcomes.11,12 Meta-analyses of CVOTs confirmed the cardiovascular benefits.17,18 Three studies from landmark CVOTs further stratified patients according to baseline characteristics.21,22,23 The benefits of SGLT2 inhibitors were more apparent in patients with a history of HF and reduced ejection fraction.22,23 However, baseline risk was higher in this group of patients, possibly accounting for

higher absolute risk reductions in cardiovascular outcomes. The DECLARETIMI 58 trial enrolled a majority of patients who did not have established atherosclerotic cardiovascular disease (ASCVD), and did not show significant reduction in MACE.19 This may imply the cardioprotection offered by SGLT2 inhibitors is less evident in such a group of patients .18 However, analysis from the EMPA-REG OUTCOME trial reported consistent benefits regardless of baseline risks and prior history.21 Neither of these trials was designed to investigate HF outcomes, but they illustrated the value in identifying patient subgroups that benefit most from SGLT2 inhibitor treatment. SGLT2 inhibitors are postulated to induce selective volume contraction.24 Thus, there is a selective reduction of interstitial fluid in contrast to traditional diuretics.24 Therefore, intravascular volume depletion and fluid retention by the renin–angiotensin–aldosterone system (RAAS) in the long run are limited.25 SGLT2 inhibitors also inhibit myocardial Na+/H+ exchanger (NHE) 1,5 which has been hypothesised to attenuate cardiac

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Figure 2: Incretin Physiology and Mechanisms of Action of DPP-4 Inhibitors and GLP-1 Receptor Agonists ↑ Nitric oxide production/coronary flow ↓ Endothelial dysfunction

↑ Nitric oxide synthase ↓ Oxidative stress

Food ingestion

↓ Vascular cell adhesion molecule-1

↓ Atherosclerosis

↓ Reactive oxygen species

↓ Neuroinflammation

↓Stroke

↓ Blood pressure ↓ Left ventricular dysfunction ↓ Arterial stiffness Protect cardiac progenitor cells Intestines

GLP-1 receptor agonists ↑Gut hormones/ peptide release

Cardiovascular effects

Incretin actions (GLP-1/GIP)

Degraded GLP-1/GIP

DPP-4 inhibitors

Degraded SDF-1/neuropeptide Y/substance P

For GLP-1 only: ↑ Insulin secretion (from β cells) ↓ Glucagon secretion (from α cells) ↓ Gastric emptying SDF-1/neuropeptide Y/substance P

↓ Postprandial glucose levels

↑Sympathetic activity ↑β-receptor activation

↑ Heart failure ↑ Cardiac fibrosis ↑ Myocardial apoptosis

Green lines = beneficial mechanisms; red lines = harmful mechanisms; dotted lines= degradation pathways. Dipeptidyl peptidase-4; GIP = gastric inhibitory polypeptide; GLP = glucagon-like peptide; SDF = stromal-cell-derived factor.

hypertrophy and HF development.26 Natriuresis is reported to improve left ventricular (LV) preload conditions, which could be potentiated by additional NHE-3 inhibition at the proximal tubules. 5,27 Furthermore, SGLT2 inhibitors reduce sympathetic tone and blood pressure (BP), which would improve afterload. 5,28,29 SGLT2 inhibitors are therefore particularly useful for diabetic patients with HF.3 Moreover, attenuation in endothelial dysfunction and arterial stiffness by reducing oxidative stress has also been reported, bringing potential benefits in vascular diseases.29,30 Dapagliflozin and empagliflozin have also shown anti-fibrotic effects in rats and human cardiac fibroblasts.31,32 Importantly, SGLT2 inhibitors induce weight loss and increase HDL levels in trials.11,12,26 They also increase lipolysis and reduce inflammation in adipose tissues.33 The switch from utilisation of glucose to ketones is also believed to be beneficial, especially for cardiac metabolism.5 All of these mechanisms may help to explain the cardiovascular benefits observed.11,12 The DAPA-HF and the EMPEROR-Reduced (NCT03057977) trials showed statistically significant reductions in HF hospitalisation, regardless of history of diabetes.34 However, the change in mortality did not reach statistical significance in EMPEROR-Reduced.35 The cardioprotective mechanisms independent of glucose lowering are still not fully understood. The EMPA-HEART trial showed reduction in LV mass and systolic BP in HF with reduced ejection fraction (HFrEF) patients, although the effects on N-terminal pro-B-type natriuretic peptide (NT-proBNP) was insignificant.36 The EMPERIAL trials (NCT03448419 and NCT03448406) reported no significant improvements in exercise capacity measured by 6-minute walking distance. Improvements in quality of life scores were

found in patients with HFrEF but not in those with HF with preserved ejection fraction. Results from on-going EMPA-KIDNEY (NCT03594110), DELIVER (NCT0319213), SMARTEST (NCT03982381), as well as the recently terminated SCORED (NCT03315143) and SOLOIST-WHF (NCT03521934) trials will further elucidate the cardioprotective effects and identify patients who may benefit most from treatment with SGLT2 inhibitors. SGLT2 inhibitors have shown clear-cut renal benefits in the CREDENCE and DAPA-CKD (NCT03036150) trials, which have also been confirmed in meta-analyses.17,37 The natriuresis induced by SGLT2 inhibitors stimulates tubuloglomerular feedback and vasoconstriction in afferent arterioles, thus reducing glomerular hyperfiltration and albuminuria.26,38,39 Concomitant use of RAAS inhibitors is reported to have synergistic effects on renal tubules, slowing down the progression of chronic kidney disease (CKD).40 The aforementioned shift in metabolic energetics is believed to inhibit oxidative stress and ischaemic injury, not only in myocardium but also in renal tubules.29,38 Reduction in BP and body weight as well as increase in uric acid excretion are all postulated as renoprotective mechanisms.39 The benefits of SGLT2 inhibitors are not always apparent. The effect of SGLT2 inhibitors on stroke events appears to be neutral or even slightly harmful. The EMPA-REG OUTCOME trial detected slight elevations in nonfatal stroke events.11 In a subgroup analysis of the CANVAS trial, the results showed protective effects against haemorrhagic stroke, yet neutral effects on ischaemic stroke (HR 0.95; 95% CI [0.74–1.22]).41 BP reduction may account for the prevention of haemorrhagic stroke.42

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Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Table 1: Current Recommendations on Antidiabetic Drugs Organisation and Year of Publication

First-line Option(s)

Second-line Option(s) – On Metformin Monotherapy

European Society of Cardiology 20192

ASCVD/high CV risk SGLT2 inhibitors*† or GLP-1 RAs* Without ASCVD/low CV risk Metformin

ASCVD/high CV Risk SGLT2 inhibitors*† or GLP-1 RAs* Without ASCVD/low CV Risk DPP-4 inhibitors/GLP-1 RAs/SGLT2 inhibitors/TZDs

American Diabetes Association 20203

Metformin

High risk/established ASCVD GLP-1 RAs* (preferred)/SGLT2 inhibitors*† High risk/established CKD/HF SGLT2 inhibitors*† (preferred)/GLP-1 RAs* Without established or risk factors for ASCVD/CKD/HF DPP-4 inhibitors/GLP-1 RAs/SGLT2 inhibitors/TZDs/SUs

International Diabetes Association 20174

Metformin

SUs (except glibenclamide/glyburide)/DPP-4 inhibitors/SGLT2 inhibitors Weight loss prioritised GLP-1 RAs

National Institute for Health and Care Excellence 2015 (updated 2019)64

Metformin

DPP-4 Inhibitors/pioglitazone/sulphonylureas/SGLT2 inhibitors

*With proven cardiovascular benefits, indication of reducing cardiovascular events. †Only if estimated glomerular filtration rate is adequate. ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; GLP-1 RAs = glucagon-like peptide 1 receptor agonists; HF = heart failure; SGLT2 = sodium–glucose co-transporter 2; SU = sulphonylurea; TZDs = thiazolidinediones.

However, elevated haematocrit was also observed in the EMPA-REG OUTCOME trial, which might predispose to ischaemic strokes.11,42,43 Although haemoconcentration improves cardiovascular outcomes, the higher blood viscosity may trigger thrombus formation.27,42–44 Although weight loss should protect against ischaemic stroke, compensatory changes may limit weight loss in the long term.33 Although a harmful effect on stroke has not been confirmed, the protective effect on haemorrhagic stroke may mask the effect on ischaemia if both types of stroke are included as a composite endpoint.16–18 Population-wide observational studies may help to evaluate the long-term risk of ischaemic strokes during SGLT2 inhibitor therapy. Overall, SGLT2 inhibitors have demonstrated the most favourable cardiovascular and all-cause mortality outcomes. Indirect evidence showed overall superiority over DPP-4 inhibitors, which appears to be a class effect.16,17 However, superiority between GLP-1 RAs and SGLT2 inhibitors varies across different outcomes. SGLT2 inhibitors are superior in terms of mortality outcomes, yet protection against MACE was similar among GLP-1 RAs and SGLT2 inhibitors.16,17 Also, mortality benefits did not reach statistical significance in the CREDENCE and DECLARE-TIMI 58 trials.19,37 The CREDENCE trial was prematurely terminated because of overwhelming renal and cardiovascular benefits. A shortened follow-up period limited the power of the study to detect changes in mortality, if present. Besides the CREDENCE trial, other non-empagliflozin trials also failed to show significant changes.12,19 Trials of non-empagliflozin SGLT2 inhibitors investigating mortality endpoints are needed to fill in the evidence gap. The combination of RAAS and SGLT2 inhibitors should be advocated as concomitant inhibition appears to achieve better cardiovascular and renal outcomes.40

GLP-1 Receptor Agonists

The LEADER, HARMONY OUTCOMES and EXSCEL trials demonstrated the cardiovascular safety of GLP-1 RAs.13–15 Meta-analyses have reported favourable cardiovascular safety profiles for GLP-1 RAs, especially in MACE and nonfatal stroke events.16,17,45 Improvements in the composite kidney outcome were also detected.45 However, the benefits were less clear-cut in comparison with SGLT2 inhibitors and somewhat conflicting across trials. Discrepancies in mortality-related outcomes could be due to differences in follow-up periods and study population. Intraclass differences and variations in pharmacokinetics are also possible explanations.

Liraglutide, a long-acting GLP-1 RA, yielded favourable results in the LEADER trial.13 In addition to glycaemic control, slowing of atherosclerosis and anti-inflammatory actions also account for the benefits of GLP-1 agonism. The interaction between GLP-1 RAs and cardiac GLP-1 receptors has been suggested to improve myocardial ischaemia and protect cardiac progenitor cells.46 They also exert protective effects independent of GLP-1 receptors.6 Liraglutide has been reported to induce endothelial nitric oxide synthase via AMP-activated protein kinase signalling.6 Nitric oxide production improves coronary artery flow and endothelial dysfunction. Besides, GLP-1 RAs inhibit mitochondrial oxidative damage and attenuate reactive oxygen species production.47 Liraglutide has also been shown to suppress vascular cell adhesion molecule-1 expression in the endothelium.6 It also improves arterial stiffness and LV function, while reducing NT-proBNP levels, a biomarker for LV dysfunction.48 Vasodilatory and antioxidant actions could account for some of the antiatherogenic effects in GLP-1 RAs, therefore this drug class may be preferable in diabetic patients with predominant ASCVD risk.3 However, different results were found in studies of exenatide.15,20 Intravenous exenatide in patients after coronary artery bypass grafting surgery did not offer additional cardiovascular benefits compared to parenteral insulin.20 Differences have been suggested to be related to different immunogenicity profiles and signalling pathways in exendin-4 and GLP-1 based agonists.46 Exendin-4 based agonists are postulated to be more immunogenic and cause injection site reactions, leading to higher drug discontinuation rate and diminished benefits in the EXSCEL trial.15,46 Given the conflicting evidence, CVOTs were conducted to study GLP-1 RAs with different populations and formulations. The FREEDOMCVO and REWIND trials included injection-free GLP-1 RA with osmotic mini-pump and patients without established cardiovascular background respectively, whereas the PIONEER 6 study investigated oral semaglutide.49–51 Mortality outcomes in some of these trials are encouraging, yet the results are inconsistent.49,51 GLP-1 RAs uniquely reduced nonfatal stroke events in the LEADER and SUSTAIN-6 trials.13,52 The effects were confirmed in our latest NMA (OR 0.88; 95% CI [0.77–0.99]).17 GLP-1 RAs are reported to be neuroprotective because of the ability to cross the blood-brain barrier and actions on neuroinflammation pathways.47 Besides atherosclerosis, oxidative stress is considered to be

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Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Table 2: Completed and On-going CVOTs of New Antidiabetic Drugs Trial

Treatment (Daily Dose Unless Specified)

Number of Patients (Antidiabetic Drug/Placebo)

Inclusion Criteria/Patient Characteristics

Primary Endpoints

SGLT2 inhibitors EMPA-REG OUTCOME11

Empagliflozin (10/25 mg) versus placebo

7,020 (4,687/2,333)

Adult patients with T2D and established CVD

A composite of death from CV causes, nonfatal MI (silent MI excluded) or nonfatal stroke

CANVAS12,41

Canagliflozin (300/100 mg) versus placebo

4,330 (2,888/1,442)

T2D patients >30 years with a history of symptomatic ASCVD or 50 years with >two CVD risk factors

A composite of death from CV causes, nonfatal MI or nonfatal stroke

CANVAS-R12,41

Canagliflozin (300/100 mg) versus placebo

5,812 (2,907/2,905)

T2D patients >30 years with a history of symptomatic ASCVD or 50 years with >2 CVD risk factors

A composite of death from CV causes, nonfatal MI, or nonfatal stroke

DECLARE-TIMI 5819

Dapagliflozin (10 mg) versus placebo

17,160 (8,582/8,578)

T2D patients with multiple risk factors for ASCVD (10,186) or established ASCVD (6,974)

MACE (CV death, MI, or ischemic stroke)

CREDENCE37

Canagliflozin (100 mg) versus placebo

4,401 (2,202/2,199)

CKD patients (eGFR 30–90 ml/ min/1.73 m2 and urinary ACR 300–5,000 mg/g), including 60% of patients with eGFR within 30–60 ml/min/1.73m2

A composite of end-stage kidney disease, doubling of serum creatinine levels from baseline, or death from renal or CV disease

DAPA-HF34

Dapagliflozin (10 mg) versus placebo

4,744 (2,373/2,371)

Adults with an ejection fraction ≤40%, and NYHA class II,III or IV symptoms

Composite of worsening heart failure or death from CV causes

VERTIS-CV65

Ertugliflozin (5/15 mg) versus placebo

8,238*

T2D patients with evidence or a history of atherosclerosis involving the coronary, cerebral or peripheral vascular systems

Time to first occurrence of MACE (composite of CV death, nonfatal MI or nonfatal stroke)

DAPA-CKD (NCT03036150; terminated prematurely)

Dapagliflozin (10/5 mg) versus placebo

4,304

Adults with eGFR 25–75 ml/ min/1.73m2 and albuminuria for 3 months (urinary ACR 200–5,000 mg/g)

Time to the first occurrence of ≥50% sustained decline in eGFR, end-stage renal disease, CV or renal death

EMPEROR-Reduced (NCT03057977)

Empagliflozin (10 mg) versus placebo

3,730*

Patients with chronic heart failure (NYHA class II–IV) and reduced ejection fraction and elevated NT-proBNP levels

Time to first event of CV death or hospitalisation for heart failure

EMPA-HEART36

Empagliflozin (10 mg) versus placebo

97 (49/48)

T2D patients 40–80 years with known coronary artery disease (history of previous MI or previous coronary revascularisation)

Change in left ventricular mass from baseline to 6 months

EMPA-KIDNEY (NCT03594110)

Empagliflozin‡ versus placebo

6,000†

Adults with CKD at risk of progression (eGFR 20–45 ml/ min/1.73m2 or 45–90 ml/min/1.73m2 with urinary ACR ≥200 mg/g)

Time to first occurrence of kidney disease progression or CV death

DELIVER (NCT03619213)

Dapagliflozin (10 mg) versus placebo

6,100†

Patients ≥40 years with heart failure (NYHA class II–IV) at enrolment, elevated NT-proBNP levels and LVEF >40%

Time to the first occurrence of CV death, hospitalisation for heart failure and urgent heart failure visit

SMARTEST (NCT03982381)

Dapagliflozin (10 mg) versus metformin (1000–3000 mg)

4,300†

Adults with T2D who are drug naïve or receiving oral monotherapy for glycaemic control

Time to first occurrence of death, MI, stroke, heart failure, diabetic nephropathy, retinopathy or foot ulcer

SCORED (NCT03315143; Sotagliflozin‡ versus placebo prematurely terminated because of COVID-19)

10,558*

T2D patients >18 years with ≥one major CV risk factor, or >55 years with ≥two minor CV risk factors

Time to first MACE (CV death, nonfatal MI, nonfatal stroke) or hospitalisation for heart failure

SOLOIST-WHF (NCT03521934; Sotagliflozin‡ versus placebo prematurely terminated because of COVID-19)

4,000†

T2D patients with worsening heart failure (prior diagnosis for >3 months) and brain natriuretic peptide ≥150 pg/ml (≥450 pg/ml for AF patients)

Cardiovascular death or hospitalisation for heart failure, time to occurrence for patients with LVEF <50%

Ongoing Trials

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Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes Table 2: Cont. GLP-1 RAs LEADER13

Liraglutide (1.8 mg injection or maximum tolerated dose) versus placebo

HARMONY OUTCOMES14

9,340 (4,668/4,672)

T2D patients >50 years with established CVD (6,764), CKD stage 3 or higher (2,307) or >60 years with >one CVD risk factor

First occurrence of death from CV causes, nonfatal MI (silent included), or nonfatal stroke

Albiglutide (30–50 mg injection 9,463 (4,731/4,732) weekly depending on tolerability) versus placebo

T2D (HbA1c >7.0%) patients >40 years, with established disease of coronary, cerebrovascular or peripheral arterial circulation

First occurrence of death from CV causes, MI, and stroke

EXSCEL15

Exenatide (2 mg injection weekly) 10,782 (5,394/5,388) versus placebo

Patients with T2D at any level of CV risk, including 70% with known CVD

First occurrence of death from CV causes, nonfatal MI, or nonfatal stroke

REWIND50

Dulaglutide (1.5 mg injection weekly) versus placebo

9,901 (4,949/4,952)

T2D patients >50 years, who had either previous CV event or CV risk factors

First occurrence of nonfatal MI, nonfatal stroke, and death from CV or unknown causes

PIONEER 651

Semaglutide (14 mg oral daily) versus placebo

3,183 (1,591/1,592)

Patients ≥50 years with established CV or CKD, or ≥60 years with CV risk factors only

First occurrence of MACE, a composite of death from CV causes (including undetermined causes), nonfatal MI, or nonfatal stroke

SUSTAIN-652

Semaglutide (0.5/1.0 mg injection 3,297 (1,648/1,649) weekly) versus placebo

Patients ≥50 years with established CV or CKD, or ≥60 years with ≥one CV risk factor

First occurrence of CV death, nonfatal MI, or nonfatal stroke

ELIXA66

Lixisenatide (10–20 µg injection daily) versus placebo

6,068 (3,034/3,034)

T2D patients with an acute coronary syndrome event within 180 days before screening

First occurrence of death from CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina

Semaglutide (0.24–2.4 mg injection weekly) versus placebo

17,500†

Patients ≥45 years with BMI ≥27 kg/m2 and established CVD (MI/stroke/PAD/revascularisation or amputation due to atherosclerotic disease)

Time to first occurrence of CV death, nonfatal MI, or nonfatal stroke

SAVOR-TIMI 5357

Saxagliptin (5/2.5 mg depending on eGFR) versus placebo

16,492 (8,280/8,212)

T2D patients who either had a history of established CVD or multiple risk factors for vascular disease

A composite of CV death, nonfatal MI, or nonfatal ischaemic stroke

EXAMINE58

Alogliptin (25/12.5/6.25 mg depending on eGFR) versus placebo

5,380 (2,701/2,679)

T2D patients with an ACS event within 15–90 days before randomisation

Composite MAC consisting CV death, nonfatal acute MI, or nonfatal ischaemic stroke

CARMELINA59

Linagliptin (5 mg) versus placebo 6,979 (3,494/3,485)

T2D adults with high CV and renal risk

Time to first occurrence of CV death, nonfatal MI, or nonfatal stroke

TECOS67

Sitagliptin (100/50 mg depending 14,523 (7,257/7,266) on eGFR) versus placebo

T2D patients >50 years, with established CVD

First confirmed event of CV death, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina

Ongoing Trials SELECT (NCT03574597)

DPP-4 inhibitors

*Number of patients in each cohort not specified. †Estimated enrolment number. ‡Daily dose not specified. ACS = acute coronary syndrome; ACR = albumin-to-creatinine ratio; ASCVD = atherosclerotic cardiovascular diseases; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; COVID-19 = coronavirus disease 2019; CVOT = cardiovascular outcome trial; DPP-4 = dipeptidyl peptidase-4; eGFR = estimated glomerular filtration rate; GLP-1 RAs = glucagon-like peptide 1 receptor agonists; LVEF = left ventricular ejection fraction; MACE = major adverse cardiovascular events; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PAD = peripheral arterial disease; SGLT2 = sodium–glucose co-transporter 2; T2D = type 2 diabetes.

responsible for stroke development.53 GLP-1 RAs reduce oxidative stress and reactive oxygen species production via p-AKT/endothelial nitric oxide synthase and nuclear factor-κ B p65 pathways.47 CVOTs are being conducted in order to expand the indication of GLP-1 RAs from ASCVD prevention in diabetes to a broader patient population. Results from the FIGHT trial did not support the use of liraglutide in HF patients, which is not surprising given less clear-cut HF benefits in NMA compared to SGLT2 inhibitors.17,54 The on-going EGRABIS1 (NCT02829502) and Lirabolic (NCT04057261) trials also aim to explore the effects of GLP-1

RAs on cardiometabolic markers, such as mean cerebral flow velocity, as well as BP and lipid profiles. Together with the SLIM LIVER (NCT04216589) study in non-alcoholic fatty liver disease patients, these trials will clarify the neuroprotective and cardioprotective mechanisms of GLP-1 RAs independent of glucose levels. This might provide the scientific basis for the benefits of this drug class in the prevention of vascular diseases.

DPP-4 Inhibitors

DPP-4 inhibitors did not show cardiovascular benefits in meta-analyses by other researchers and ourselves.16,17,55 A previous meta-analysis concluded

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Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes significant reductions in MACE, but the inclusion of trials with shorter follow-up periods may limit the robustness of the conclusions. Elevated hospitalisation for HF incidence remains a concern, as reported in the SAVOR-TIMI 53 trial.55–57 However, in the EXAMINE and the latest CARMELINA trials, HF incidences were neutral.58,59 DPP-4 inhibitors have been reported to inhibit degradation of endogenous peptides other than GLP-1, including stromal-cell-derived factor (SDF) 1, neuropeptide Y and substance P (Figure 2).60 Potentiation of these peptides results in sympathetic activation via cyclic AMP signalling and beta-receptor activation, which may contribute to HF development and cardiac fibrosis. Elevated SDF-1 and substance P levels are also suggested to induce apoptosis of the myocardium.60 In the SAVOR-TIMI 53 trial, attenuated HF elevation was detected when beta-blockers were used concomitantly.58,60 This might imply that chronic sympathetic activation might underlie the inferiority of DPP-4 inhibitors. Notably, most patients enrolled in trials with neutral HF outcomes have concomitant prescriptions for RAAS inhibitors, which could ameliorate the tendency of DPP-4 inhibitors to worsen HF.58,59 Combination therapy may counteract the detrimental effects of DPP-4 inhibitors, thus masking the harmful effects. In real life, patient with diabetes are often receiving a RAAS blocker. This makes the drug class useful even in dialysis patients.8 Nevertheless, DPP-4 inhibitors should be used with caution in patients with HF or at risk of HF.

Clinical Implications

Observational studies have been conducted to provide insights into the clinical roles of the new antidiabetic drugs.61,62 A retrospective cohort study has demonstrated beneficial safety profiles over sulphonylureas, whereas O’Brien et al. reported similar improvements in cardiovascular outcomes across the three drug classes.61,62 However, it must be noted that selection bias could be prominent in observational studies, as the number of patients included in the study was significantly higher for those receiving DPP-4 inhibitors (28,898) than for SGLT2 inhibitors (5,677) or GLP-1 RAs (11,351).62 The lack of patients enrolled in specific groups also make the use of propensity score matching difficult. Nevertheless, these 1. Morrish NJ, Wang SL, Stevens LK, et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44:S14–21. https://doi. org/10.1007/pl00002934; PMID: 11587045. 2. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486; PMID: 31497854. 3. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2020. Diabetes Care 2020;43:S98–S110. https://doi.org/10.2337/dc20-S009; PMID: 31862752. 4. International Diabetes Federation. Recommendations For Managing Type 2 Diabetes In Primary Care. IDF, 2017. https:// www.idf.org/e-library/guidelines/128-idf-clinical-practicerecommendations-for-managing-type-2-diabetes-in-primarycare.html (accessed 11 December 2020). 5. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018;61:2108–17. https://doi.org/10.1007/s00125018-4670-7; PMID: 30132036. 6. Sposito AC, Berwanger O, de Carvalho LSF, et al. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Cardiovasc Diabetol 2018;17:157. https://doi.org/10.1186/ s12933-018-0800-2; PMID: 30545359. 7. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013;17:819–37. https://doi.org/10.1016/j.cmet.2013.04.008; PMID: 23684623. 8. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review.

10. 11.

12.

13.

14.

15.

studies are still valuable because head-to-head randomised controlled trials are lacking. Population-wide observational studies provide a good and generalisable estimation of clinical effects with modest confidence, thus defining the clinical roles of each antidiabetic drug class more clearly. Choosing an antidiabetic drug class with proven cardiovascular and mortality benefits is now advocated in guidelines.3,4,63 SGLT2 inhibitors and GLP-1 RAs should be recommended as second-line treatment options after metformin, echoing recommendations by the ADA and the American College of Cardiology.3,63 The choice between SGLT2 inhibitors and GLP-1 RAs should be tailor-made according to patient characteristics. SGLT2 inhibitors offered more overall mortality benefits. They should be considered superior in most patients, including those with HF and CKD.3 However, ischaemia prevention is superior for GLP-1 RAs, thus making them preferable in patients with predominant ASCVD risk.3 Differences in routes of administration and adverse effect profiles may also play a role in prescription decisions. Most GLP-1 RAs are available as subcutaneous injections, which are inconvenient. Oral semaglutide might make this class attractive to use, but it is expensive. On-going trials, including headto-head trials, are required to address comparative safety and efficacy, as well as possible intraclass differences.

Conclusion

Current evidence confirmed the cardiovascular safety of the three new antidiabetic drug classes, but it is important to appreciate the differences among them. SGLT2 inhibitors show superiority in mortality and cardiovascular events, mainly driven by hospitalisation for HF, and renal events. GLP-1 RAs can reduce nonfatal stroke and MACE, yet inconsistent evidence suggests possible intraclass differences. Both drug classes should now be considered as the preferred second-line treatment in T2D patients after metformin according to patient characteristics. In terms of cardiovascular and renal outcomes, DPP-4 inhibitors have not demonstrated benefits in comparison with placebo and have been proven to be inferior to GLP-1 RAs and SGLT2 inhibitors. In this new era, antidiabetic drugs no longer just control blood glucose, but should also address the cardiovascular risks of T2D patients.

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16. Fei Y, Tsoi MF, Kumana CR, et al. Network meta-analysis of cardiovascular outcomes in randomized controlled trials of new antidiabetic drugs. Int J Cardiol 2018;254:291–6. https:// doi.org/10.1016/j.ijcard.2017.12.039; PMID: 29277321. 17. Fei Y, Tsoi MF, Cheung BMY. Cardiovascular outcomes in trials of new antidiabetic drug classes: a network metaanalysis. Cardiovasc Diabetol 2019;18:112. https://doi. org/10.1186/s12933-019-0916-z; PMID: 31462224. 18. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. https://doi.org/10.1016/S01406736(18)32590-X; PMID: 30424892. 19. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389; PMID: 30415602. 20. Besch G, Perrotti A, Salomon du Mont L, et al. Impact of intravenous exenatide infusion for perioperative blood glucose control on myocardial ischemia-reperfusion injuries after coronary artery bypass graft surgery: sub study of the phase II/III ExSTRESS randomized trial. Cardiovasc Diabetol 2018;17:140. https://doi.org/10.1186/s12933-018-0784-y; PMID: 30384842. 21. Fitchett D, Butler J, van de Borne P, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J 2018;39:363–70. https://doi.org/10.1093/eurheartj/ehx511; PMID: 29020355. 22. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes diabetes mellitus. Circulation 2019;139:2528–36. https:// doi.org/10.1161/CIRCULATIONAHA.119.040130; PMID: 30882238. 23. Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: Results from the CANVAS program. Circulation 2018;138:458–68. https://doi. org/10.1161/CIRCULATIONAHA.118.034222; PMID: 29526832. 24. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018;20:479–87. https://doi.org/10.1111/dom.13126; PMID: 29024278. 25. Schork A, Saynisch J, Vosseler A, et al. Effect of SGLT2 inhibitors on body composition, fluid status and reninangiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 2019;18:46. https://doi.org/10.1186/s12933019-0852-y; PMID: 30953516. 26. Packer M, Anker SD, Butler J, et al. Effects of sodiumglucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025–9. https://doi. org/10.1001/jamacardio.2017.2275; PMID: 28768320. 27. Santos-Ferreira D, Gonçalves-Teixeira P, Fontes-Carvalho R. SGLT-2 inhibitors in heart failure and type-2 diabetes: hitting two birds with one stone? Cardiology 2020;145:311–20. https://doi.org/10.1159/000504694; PMID: 31865310. 28. Briasoulis A, Al Dhaybi O, Bakris GL. SGLT2 inhibitors and mechanisms of hypertension. Curr Cardiol Rep 2018;20:1. https://doi.org/10.1007/s11886-018-0943-5; PMID: 29349558. 29. Kaplan A, Abidi E, El-Yazbi A, et al. Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev 2018;23:419–37. https://doi.org/10.1007/s10741-0179665-9; PMID: 29322280. 30. Pulakazhi Venu VK, El-Daly M, Saifeddine M, et al. Minimizing hyperglycemia-induced vascular endothelial dysfunction by inhibiting endothelial sodium-glucose cotransporter 2 and attenuating oxidative stress: implications for treating individuals with type 2 diabetes. Can J Diabetes 2019;43:510–4. https://doi.org/10.1016/j. jcjd.2019.01.005; PMID: 30930073. 31. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 2017;104:298–310. https://doi. org/10.1016/j.freeradbiomed.2017.01.035; PMID: 28132924. 32. Kang S, Verma S, Hassanabad AF, et al. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results. Can J Cardiol 2020;36:543–53. https://doi.org/10.1016/j.cjca.2019.08.033; PMID: 31837891. 33. Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs 2019;79:219–30. https:// doi.org/10.1007/s40265-019-1057-0; PMID: 30701480. 34. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/ NEJMoa1911303; PMID: 31535829. 35. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020 Oct 8;383(15):1413-1424. https://doi.org/10.1056/ NEJMoa2022190. PMID: 32865377. 36. Verma S, Mazer CD, Yan AT, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial. Circulation 2019;140:1693–702. https://doi.org/10.1161/ CIRCULATIONAHA.119.042375; PMID: 31434508. 37. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744; PMID: 30990260. 38. de Albuquerque Rocha N, Neeland IJ, McCullough PA, et al.

Effects of sodium glucose co-transporter 2 inhibitors on the kidney. Diab Vasc Dis Res 2018;15:375–86. https://doi. org/10.1177/1479164118783756; PMID: 29963920. 39. Georgianos PI, Divani M, Eleftheriadis T, et al. SGLT-2 inhibitors in diabetic kidney disease: what lies behind their renoprotective properties? Curr Med Chem 2019;26:5564–78. https://doi.org/10.2174/0929867325666180524114033; PMID: 29792136. 40. Zou H, Zhou B, Xu G. SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease. Cardiovasc Diabetol 2017;16:65. https://doi.org/10.1186/s12933017-0547-1; PMID: 28511711. 41. Zhou Z, Lindley RI, Rådholm K, et al. Canagliflozin and stroke in type 2 diabetes mellitus. Stroke 2019;50:396–404. https://doi.org/10.1161/STROKEAHA.118.023009; PMID: 30591006. 42. Imprialos KP, Boutari C, Stavropoulos K, et al. Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality? J Neurol Neurosurg Psychiatry 2017;88:249–53. https://doi.org/10.1136/jnnp-2016-314704; PMID: 27895093. 43. Jin YZ, Zheng DH, Duan ZY, et al. Relationship between hematocrit level and cardiovascular risk factors in a community-based population. J Clin Lab Anal 2015;29:289– 93. https://doi.org/10.1002/jcla.21767; PMID: 24849556. 44. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018;41:356–63. https://doi.org/10.2337/dc171096; PMID: 29203583. 45. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/ S2213-8587(19)30249-9. PMID: 31422062. 46. Caruso I, Cignarelli A, Giorgino F. Heterogeneity and similarities in GLP-1 receptor agonist cardiovascular outcomes trials. Trends Endocrinol Metab 2019;30:578–89. https://doi.org/10.1016/j.tem.2019.07.004; PMID: 31401015. 47. Oh YS, Jun HS. Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci 2017;19:26. https://doi.org/10.3390/ijms19010026; PMID: 29271910. 48. Lambadiari V, Pavlidis G, Kousathana F, et al. Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes. Cardiovasc Diabetol 2018;17:8. https://doi.org/10.1186/s12933-017-0646-z; PMID: 29310645. 49. Intarcia Therapeutics. Intarcia announces successful cardiovascular safety results in phase 3 FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetes. PR Newswire 6 May 2016. https://www.prnewswire.com/ news-releases/intarcia-announces-successfulcardiovascular-safety-results-in-phase-3-freedom-cvo-trialfor-itca-650-an-investigational-therapy-for-type-2diabetes-300264245.html (accessed 20 January 2021). 50. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–30. https://doi.org/10.1016/S01406736(19)31149-3; PMID: 31189511. 51. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841–51. https://doi. org/10.1056/NEJMoa1901118; PMID: 31185157. 52. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. https://doi.org/10.1056/ NEJMoa1607141; PMID: 27633186. 53. Allen CL, Bayraktutan U. Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 2009;4:461– 70. https://doi.org/10.1111/j.1747-4949.2009.00387.x;

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PMID: 19930058. 54. Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: A randomized clinical trial. JAMA 2016;316:500–8. https://doi.org/10.1001/ jama.2016.10260; PMID: 27483064. 55. Rehman MB, Tudrej BV, Soustre J, et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: metaanalysis of placebo-controlled randomized clinical trials. Diabetes Metab 2017;43:48–58. https://doi.org/10.1016/j. diabet.2016.09.005; PMID: 27745828. 56. Monami M, Ahrén B, Dicembrini I, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a metaanalysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112–20. https://doi.org/10.1111/dom.12000; PMID: 22925682. 57. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317–26. https://doi. org/10.1056/NEJMoa1307684; PMID: 23992601. 58. Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 2015;385:2067–76. https://doi.org/10.1016/S0140-6736(14)62225-X; PMID: 25765696. 59. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 2019;321:69–79. https://doi.org/10.1001/jama.2018.18269; PMID: 30418475. 60. Packer M. Do DPP-4 inhibitors cause heart failure events by promoting adrenergically mediated cardiotoxicity? Clues from laboratory models and clinical trials. Circ Res 2018;122:928–32. https://doi.org/10.1161/ CIRCRESAHA.118.312673; PMID: 29436388. 61. Elharram M, Moura CS, Abrahamowicz M, et al. Novel glucose lowering agents are associated with a lower risk of cardiovascular and adverse events in type 2 diabetes: a population based analysis. Int J Cardiol 2020;310:147–54. https://doi.org/10.1016/j.ijcard.2020.03.025; PMID: 32303419. 62. O’Brien MJ, Karam SL, Wallia A, et al. Association of secondline antidiabetic medications with cardiovascular events among insured adults with type 2 diabetes. JAMA Netw Open 2018;1:e186125. https://doi.org/10.1001/ jamanetworkopen.2018.6125; PMID: 30646315. 63. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol 2018;72:3200–23. https://doi.org/10.1016/j.jacc.2018.09.020; PMID: 30497881. 64. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. London: NICE, 2015. https:// www.nice.org.uk/guidance/ng28 (accessed 11 December 2020). 65. Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial (VERTISCV). Am Heart J 2018;206:11–23. https://doi.org/10.1016/j. ahj.2018.08.016; PMID: 30290289. 66. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. https://doi.org/10.1056/ NEJMoa1509225; PMID: 26630143. 67. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–42. https://doi.org/10.1056/ NEJMoa1501352; PMID: 26052984.

Women in Heart Failure

Representation of Women Physicians in Heart Failure Clinical Practice Ersilia M DeFilippis ,1 Yasbanoo Moayedi2 and Nosheen Reza

1. Division of Cardiology, Columbia University Irving Medical Center, New York, NY, US; 2. Ted Rogers Centre of Excellence for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Canada; 3. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, US

Abstract

Women have been integral in the development of advanced heart failure (HF) and transplantation as a clinical subspecialty of cardiovascular medicine. However, women remain underrepresented in leadership positions, senior academic ranks and as researchers in HF. In recent years, there have been accelerating efforts to examine sex differences in the clinical and research domains of HF. The purpose of this review is to discuss the representation of women in HF training programmes and clinical practice, the demographics of HF clinicians compared with other cardiology subspecialties, the persistent sex disparities in HF practice and research environments and potential strategies to promote equity and inclusion for women in the field.

Keywords

Women, heart failure, heart transplantation, sex, leadership, sponsorship, mentorship Disclosure: The authors have no conflicts of interest to declare. Funding: NR is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (No. KL2TR001879). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Acknowledgement: The authors acknowledge Jaime Abreu, Ana Lybecker and Jeanne Leonard of the Heart Failure Society of America for their assistance in obtaining the data reported in this manuscript. Received: 4 December 2020 Accepted: 15 January 2021 Citation: Cardiac Failure Review 2021;7:e05. DOI: https://doi.org/10.15420/cfr.2020.31 Correspondence: Nosheen Reza, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 South Tower, Room 11-145, 3400 Civic Center Boulevard, Philadelphia, PA 19104, US. E: nosheen.reza@pennmedicine.upenn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

While women comprise nearly 50% of US medical school graduates and more than 40% of internal medicine resident physicians, the field of cardiology remains male dominated, with little change in the percentage of women cardiologists over the past 20 years.1 Currently, around one in five general cardiology fellows is a woman. This is comparable to the representation of women in surgical subspecialties, such as thoracic surgery (21%), neurosurgery (17%) and orthopaedic surgery (15%), and highlights the failures to recruit and retain women trainees in cardiovascular medicine, termed the ‘residency to fellowship cliff’.2,3 Beyond the postgraduate medical training period, the percentage of women cardiologists in practice drops to 12.6%.1 Women also hold disproportionately fewer leadership positions within cardiovascular medicine.4 Compared with men, women are significantly less likely to achieve senior academic ranks.5 In a recent analysis of the careers of women physicians in academic medical centres, women were less likely than men to be promoted to associate or full professor or to be appointed as department chairs, and there were no significant changes in these likelihoods over the 35-year study period.6 Unfortunately, the percentage of women cardiologists who experience discrimination in the workplace has not demonstrably decreased in the past two decades. According to serial American College of Cardiology (ACC) Professional Life Surveys, approximately 60–70% of women reported discrimination in professional settings both in 1996 and in 2015.7 This is a significant

deterrent for women considering careers in cardiology, and it has secondary impacts on the demographics of the field of heart failure (HF). Within the subspecialty of advanced HF and transplant cardiology (AHFTC), women have played integral roles in the field’s founding, recognition and development. Yet as with other cardiology subspecialties, women face persistent challenges with respect to achieving pay equity, career advancement and leadership.8 In this review, we discuss the historical representation of women in HF clinical practice, the landscape of women in AHFTC training programmes, factors contributing to sex disparities in clinical practice and HF research, enduring challenges and potential strategies to promote the career development of women in HF.

Historical Landscape of Women in Heart Failure

Dr Sharon Hunt is one of the pioneers of the field of advanced HF and cardiac transplantation and is often referred to as the matriarch of heart transplantation.9 Her work at Stanford as a fellow and as faculty during the growth of adult cardiac transplantation in the US set the stage for the inauguration of the field as a subspecialty of cardiology.9 Her clinical and research careers focused on improving the survival of patients after heart transplantation and reducing adverse effects of immunosuppression. In 1976, she reported in Circulation on the outcomes of 109 individuals undergoing heart transplantation at Stanford between January 1968 and August 1976.10 This visionary work was one of the earliest reports

Women in HF Clinical Practice Figure 1: Timeline of Key Events and Roles of Women in Advanced Heart Failure and Transplant Cardiology Dr Mariell Jessup chairs writing group for 2009 ACC/AHA Guidelines for the Practice Guideline: Focused Update Diagnosis and Management of Heart Failure in Adults

Dr Sharon Hunt named Chair of inaugural ACC/AHA Guidelines for the Evaluation of Chronic Heart Failure in the Adult 2001

2009

Heart Failure Society of America advocates for establishment of advanced HF subspeciality

Dr Margaret Billingham installed as first woman president of the International Society for Heart and Lung Transplantation

80 accredited AHFTC training programmes in the US, with 26% of AHFTC trainees being women

Dr JoAnn Lindenfeld installed as first women president of the Heart Failure Society of America

2004

2019

2015

1990 2008 AHFTC subspeciality approved by ABIM with pathway for board certification

1995

2017 Dr Mary Norine Walsh installed as President of the ACC

Dr Sharon Hunt calls for specialised training in HF/transplant cardiology 2003 1970s–1980s Dr Sharon Hunt and Dr Hannah Valantine perform pioneering research on cardiac transplantation

Dr Lynne Stevenson publishes haemodynamic profile classification of patients with HF

2013 Dr Mariell Jessup named President of the American Heart Association

ABIM = American Board of Internal Medicine; ACC = American College of Cardiology; AHA = American Heart Association; AHFTC = advanced heart failure and transplant cardiology; HF = heart failure.

suggesting that cardiac transplantation could prolong survival and return patients to improved functional status.10 Dr Hunt was also a leader in major cardiovascular professional societies. She was the Chair of the inaugural ACC/American Heart Association (AHA) Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, published in 2001, and served as President of the International Society for Heart and Lung Transplantation from 1995 to 1996.9 Equally important in the field of advanced HF and cardiac transplantation in the 1980s was another trailblazing female clinical investigator, Dr Hannah Valantine. At Stanford, she led innovative research in applying Doppler and M-mode echocardiography to the detection of allograft rejection.11 She was mentored by Dr Hunt, and the two women closely collaborated to advance the science of long-term immunosuppression, cardiac allograft vasculopathy and more.12–15 Dr Valantine was promoted to full professor at Stanford in 2000 and became the inaugural Senior Associate Dean for Diversity and Leadership in 2004.16 She became nationally recognised for her revolutionary success in promoting diversity in the workforce, and was recruited to the National Institutes of Health (NIH) in 2014 as the inaugural Chief Officer for Scientific Workforce Diversity and as a tenured investigator in the National Heart, Lung, and Blood Institute. There, Dr Valantine established novel programmes, such as the Distinguished Scholars Program and the NIH Equity Committee that served to dramatically increase the representation of women, and of African–American/black and Hispanic tenure-track principal investigators, and of women in NIH leadership positions. In addition to each of their remarkable professional legacies, both Dr Hunt and Dr Valantine have inspired generations of clinicians and investigators, many of whom have been women who have subsequently led the field of HF and cardiac transplantation as it continued to evolve in the 1990s.

In 1995, Dr Hunt and others published recommendations on training HF and transplantation in the Journal of the American College of Cardiology. As part of this first Core Cardiology Training Symposium, she and other taskforce members created perhaps the earliest call for a subspecialty in HF and transplantation.17 Dr Hunt wrote: “For trainees who wish to devote a substantial portion of their career to transplant-related research and patient management, further training beyond other clinical requirements for cardiology training should be required. Although there are currently very few formal training programs in transplant cardiology, a number of centers to provide such training, and an outline of the important aspects can be drawn”.17 The taskforce encouraged such training to occur at centres with established programmes in clinical cardiac transplantation with at least 20 transplant procedures annually. Members emphasised that programmes should be staffed by board-certified cardiologists with expertise in cardiac transplantation, and should require 1 year of training in all phases of pre- and post-transplant clinical management.17 Beginning in 2004, the Heart Failure Society of America (HFSA) built on Dr Hunt’s efforts from the prior decade and began to advocate for the need for a subspecialty focused on advanced HF.18 The HFSA also encouraged other professional societies, such as the ACC, to support its advocacy efforts. The society posited that, in light of an expanding population of individuals with HF, specialists would be uniquely positioned to provide excellence in care for complex patients. In September 2008, the American Board of Medical Specialties approved a proposal by the American Board of Internal Medicine (ABIM) to establish the

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

Women in HF Clinical Practice Figure 2: Proportion of Women in Advanced Heart Failure and Transplant Cardiology Training Programmes in the US from 2011 to 2019 36

Women (%)

24 21

11 8

2011/12

2012/13

9 9

2013/14

18 12

2014/15

2015/16

General cardiology

2016/17

12 8

2017/18

2018/19

Interventional

Data obtained from the American Board of Internal Medicine. Legend corresponds to subspecialty cardiology training programmes. EP = electrophysiology; HF = heart failure.

subspecialty of Advanced Heart Failure and Transplant Cardiology and a pathway for board certification.19 Since that time, the field of advanced HF has grown significantly and has become a subspecialty that is attractive to women.

Factors Contributing to the Increased Representation of Women in Heart Failure

Dr Hunt postulated that women may be more highly represented in HF for a few reasons, including the enduring presence of women role models and mentors and support for the inclusion of women from the time of the field’s inception.20 It is perhaps the only subspecialty within cardiology that was largely spurred by women and one in which women have played key roles in its development (Figure 1). Dr Hunt also speculated that women have been successful in HF careers because of their proclivity for collaborative work, a particularly important skill for a multidisciplinary field, such as advanced HF and cardiac transplantation. The field developed with the partnership and leadership of women, and therefore, was not perceived as being “exclusive to male colleagues”.20 Dr Hunt, Dr Valantine and many other renowned and highly accomplished women have advanced the field and served as role models, mentors and sponsors for both women and men.

Women in Contemporary Heart Failure Training and Practice

In the US, there are currently 80 accredited advanced HF programmes in 35 states. The ABIM regularly collects data by sex of first-year fellows in Accreditation Council for Graduate Medical Education-accredited training programmes. From 2011 to 2019, the percentage of women in general cardiology fellowship training programmes has increased from 21% to 25%. For women in AHFTC programmes, the percentage is between 26% and 36% (Figure 2). This is significantly higher than that of women in more procedural subspecialties, such as clinical cardiac electrophysiology and interventional cardiology, similar to the trends observed in the demographics of board-certified cardiologists.21 As of December 2016, there were 939 cardiologists who were ABIM board certified in AHFTC; of these, 239 (25.5%) were women.1 Notably, this is

compared to only 4.9% women among board-certified interventional cardiologists, 8.6% among board-certified electrophysiologists and 12.5% among board-certified clinical cardiologists.1 In Europe, interest in AHFTC has also continued to grow. According to the European Society of Cardiology (ESC) membership database, as of December 2018, 33.7% of ESC members were women and 33.8% of members of the Heart Failure Association of the ESC were women.22 At the ESC Heart Failure Congress in recent years, the proportion of women attendees has been consistently higher than that of men among the younger age groups. Similar trends have also been seen in the distribution of men and women taking the Heart Failure Association Certification exam in Europe, suggesting increasing interest in HF as a subspecialty among young women cardiologists.22 Within the HFSA, data show that 59% of active members, as of November 2020, were women (J Leonard, Personal Communication, 20 November 2020). However, only 29% of the women members are physicians and 9% are trainees. Of the women members, 32% are early career (0–5 years after training), 26% mid-career and 36% established career (6% did not indicate a career level).

Women in Leadership Positions in Heart Failure

Despite the relatively higher proportions of women in HF, their representation in professional society leadership positions remains low. The AHA was founded in 1924, and Dr Helen Taussig served as its first woman president in 1965. Among subsequent women AHA presidents was Dr Mariell Jessup (President 2013–2014), who was also instrumental in achieving formal recognition for AHFTC as a certified subspecialty.23 Additionally, she chaired the writing group for the 2009 Focused Update: ACC Foundation/ AHA Guidelines for the Practice Guideline: Focused Update Diagnosis and Management of Heart Failure in Adults, served as vice chair of the writing committee for the 2013 ACC Foundation/AHA Guideline for the Management of Heart Failure and vice chair of the writing committee for the 2017 ACC Foundation/AHA/HFSA Focused Update of the 2013 ACC Foundation/AHA Guideline for the Management of Heart Failure.24–26

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Women in HF Clinical Practice Figure 3: Strategies for Increasing Representation and Experience of Women in Heart Failure

Recruitment

• Mentorship throughout training stages • Targeted outreach • Promote benefits of an advanced HF career • Increase trainee exposure to advanced HF careers • Bias mitigation with standardised selection criteria

Opportunity

• Peer reviewers, editorial boards, selection committees, advisory boards • Government, industry, philanthropy funding • Professional networks and collaborations • Specialised training in basic, translational, clinical implementation research leadership

Promotion

• Transparency in benchmarking and promotion processes • Consideration of traditionally unrewarded educational and service activities • Recognition of gender disparities in the process • Coaching, mentoring, sponsoring structures • Family-friendly and flexible policies and timelines

Leadership

• Institutional roles • Professional societies and organisations • Training programmes • HF/transplant/VAD programmes • Steering committees

HF = heart failure; VAD = ventricular assist device.

Since the founding of the ACC in 1949, there have been 68 organisational presidents; four of these have been women.27 Of these women, one, Dr Mary Norine Walsh (President 2017–2018), practices in advanced HF and cardiac transplantation. In Canada, HF clinician, Dr Heather Ross, has served as President of both the Canadian Society of Transplantation (2004–2005) and the Canadian Cardiovascular Society (2015–2016).28,29 The Heart Failure Association of the ESC was launched in 2004 and has not been led by a woman to date.30 Since 1996, there have been 15 presidents of the HFSA. The first woman HFSA President, Dr JoAnn Lindenfeld, was inaugurated in 2014, nearly 10 years after the organisation’s founding. Dr Biykem Bozkurt (President 2019–2020) and Dr Nancy Albert (President 2020–2021) are the organisation’s second and third women presidents, respectively. Similarly, from 1981 to 2020, there have been 37 presidents of the International Society for Heart and Lung Transplantation. Of these, only five (13.5%) have been women.31 One of these five women, Dr Maryl R Johnson, also served as President of the American Society of Transplantation (2010–2011).32

Women and Discrimination in Heart Failure Clinical Practice and Research

Despite the demographics of women in HF clinical practice, women still perceive sex-based imbalances with regard to salary, leadership positions and academic promotions.8 In 2019, Moayedi and colleagues surveyed 236 international HF cardiologists to determine factors that influenced their career choices.8 Among both women and men, the three most important factors attracting respondents to careers in HF cardiology included patient complexity and continuity of care, clinical diversity and evolving technology. There were no differences in rank order by sex of the respondent.8 Participants emphasised an increased need for sponsorship, increased support for maternity leave and income transparency to attract and maintain women in HF.8

Regarding academic rank, more men than women had achieved the rank of professor with no differences at the assistant or associate professor levels.33 While this is a potentially biased sample of those who responded to a voluntary survey, these findings are consistent with disparities observed in academic medicine, at least in the US, more broadly.6 Women also remain underrepresented as clinical trialists in cardiology and in HF. We previously reviewed the publications referenced in Class I recommendations in both US and European guidelines for management of HF, as well as all HF clinical trials published from 2001 to 2016 with more than 400 participants.34 The overall proportions of women as first authors in the referenced publications in the US and European guidelines were 18% and 16%, respectively, and, as senior authors, were 13% and 12%. Of the examined clinical trials, 16% of publications had a woman as first or senior author, and the median number of women authors per trial was one. Overall proportions of women as first or senior authors of HF clinical trial publications did not increase over the 15-year study period. Industry-funded trials had fewer women authors per trial; it has been previously demonstrated that women receive fewer total dollars from financial relationships with pharmaceutical and device companies compared with men.35 In addition, we found an association between the number of women authors of HF clinical trials with the enrolment of women participants.34 Outreach initiatives and dedicated efforts are needed to increase support for women HF researchers and site investigators, as well as collaborations with industry, which may also help stimulate increased representation of women in HF clinical trials. Another recent systematic review of 403 HF randomised controlled trials published in high impact journals from 2000 to 2019 found that women only represented 15.6% of lead authors, 12.9% of senior authors and 11.4% of corresponding authors.36 Notably, there were no significant changes in

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Women in HF Clinical Practice the representation of women as lead authors over time. Women were less likely to be lead authors in multicentre trials, those conducted in North America or Europe or had men as senior authors.36

Reconciling Sex Disparities in Heart Failure Practice and Research

These data highlight the critical need to sustainably increase and advance diversity, equity and inclusion in the field of AHFTC. In 2019, Dr Nancy Sweitzer proposed a valuable multipronged thematic framework to address these issues.33 AHFTC can be an emotionally demanding specialty that frequently encompasses advanced and critical illness, death and dying. This can be burdensome to both men and women, but can be exacerbated by lack of institutional support or mentorship, which may disproportionately affect women. As Sweitzer writes: “workplace discrimination is not merely an issue of numbers”, and culture change must be implemented to reduce workplace harassment and microaggressions.33 While equal hiring, remuneration and representation of women in HF is paramount, we also need to strive for policies that lead to lasting behavioural, cultural and structural changes. These actions are especially important to advance women’s research careers and include 1. Mehta LS, Fisher K, Rzeszut AK, et al. Current demographic status of cardiologists in the United States. JAMA Cardiol 2019;4:1029–33. https://doi.org/10.1001/ jamacardio.2019.3247; PMID: 31509160. 2. DeFilippis EM, Lau ES, Wei J, et al. Where are the women in academic cardiology? Lancet 2018;392:2152–3. https://doi. org/10.1016/S0140-6736(18)32618-7; PMID: 30496087. 3. Douglas PS, Williams KA, Walsh MN. Diversity matters. J Am Coll Cardiol 2017;70:1525–9. https://doi.org/10.1016/j. jacc.2017.08.003; PMID: 28911516. 4. Sanghavi M. Women in cardiology: introspection into the under-representation. Circ Cardiovasc Qual Outcomes 2014;7:188–90. https://doi.org/10.1161/CIRCOUTCOMES. 113.000449; PMID: 24347662. 5. Blumenthal DM, Olenski AR, Yeh RW, et al. Sex differences in faculty rank among academic cardiologists in the United States. Circulation 2017;135:506–17. https://doi.org/10.1161/ CIRCULATIONAHA.116.023520; PMID: 28153987. 6. Richter KP, Clark L, Wick JA, et al. Women physicians and promotion in academic medicine. N Engl J Med 2020;383:2148–57. https://doi.org/10.1056/NEJMsa1916935; PMID: 33252871. 7. Lewis SJ, Mehta LS, Douglas PS, et al. Changes in the professional lives of cardiologists over 2 decades. J Am Coll Cardiol 2017;69:452–62. https://doi.org/10.1016/j. jacc.2016.11.027; PMID: 28012614. 8. Moayedi Y, Hershman SG, Ross HJ, et al. Perceived generational, geographic, and sex-based differences in choosing a career in advanced heart failure: an international survey. Circ Heart Fail 2019;12:e005754. https://doi. org/10.1161/CIRCHEARTFAILURE.118.005754; PMID: 31296097. 9. Walsh MN. Women as leaders in cardiovascular medicine. Clin Cardiol 2018;41:269–73. https://doi.org/10.1002/ clc.22920; PMID: 29485719. 10. Hunt SA, Rider AK, Stinson EB, et al. Does cardiac transplantation prolong life and improve its quality? An updated report. Circulation 1976;54(Suppl 6):III56–60. PMID: 45827. 11. Valantine HA, Fowler MB, Hunt SA, et al. Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation 1987;76:V86–92. PMID: 3311461. 12. Cantin B, Giannetti N, Parekh H, et al. Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection. Clin Transplant 2002;16:196–201. https://doi. org/10.1034/j.1399-0012.2002.01122.x; PMID: 12010143. 13. Deng MC, Bell S, Huie P, et al. Cardiac allograft vascular disease. Relationship to microvascular cell surface markers and inflammatory cell phenotypes on endomyocardial biopsy. Circulation 1995;91:1647–54. https://doi.org/10.1161/01. cir.91.6.1647; PMID: 7882470.

the diversification of manuscript and grant reviewers, journal editorial boards and steering and leadership committees.37 Equally important strategies include the implementation of family-friendly policies, flexible work structures and support for adequate and equitable parental leaves. Additionally, sponsorship is necessary for creating diverse professional networks and workplace paradigms that value and reward mutual respect, teamwork and collaboration (Figure 3).

Conclusion

Since its inception, the field of advanced HF and cardiac transplantation has had pioneering women cardiologists at its helm. These women have helped to define the subspecialty and served as role models, mentors and sponsors for many generations of female and male HF physicians. The relatively increased representation of women in HF training programmes and clinical practice may uniquely position us to provide guidance to other subspecialties with respect to the recruitment and promotion of women. However, the small numbers of women in leadership positions in clinical practice, academics and research, and enduring disparities, highlight that many opportunities for improvement remain, and undoubtedly women in HF will continue to lead the way.

14. Gao SZ, Schroeder JS, Alderman EL, et al. Prevalence of accelerated coronary artery disease in heart transplant survivors. Comparison of cyclosporine and azathioprine regimens. Circulation 1989;80:III100–5. PMID: 2805287. 15. Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med 2010;362:1890–1900. https:// doi.org/10.1056/NEJMoa0912965; PMID: 20413602. 16. Stanford. Hannah Valantine. 2020. https://profiles.stanford. edu/hannah-valantine?tab=bio (accessed 28 November 2020). 17. Hunt S, Bristow MR, Kubo SH, et al. Guidelines for training in adult cardiovascular medicine. Core Cardiology Training Symposium (COCATS). Task Force 8: training in Heart Failure and Transplantation. J Am Coll Cardiol 1995;25:29–31. https:// doi.org/10.1016/0735-1097(95)96222-k; PMID: 7798519. 18. Konstam MA, Executive Council of the Heart Failure Society of America. Heart failure training: a call for an integrative, patient-focused approach to an emerging cardiology subspecialty. J Am Coll Cardiol 2004;44:1361–2. https://doi. org/10.1016/j.jacc.2004.06.055; PMID: 15464313. 19. Konstam MA, Jessup M, Francis GS, et al. Advanced heart failure and transplant cardiology: a subspecialty is born. J Am Coll Cardiol 2009;53:834–6. https://doi.org/10.1016/j. jacc.2009.01.009; PMID: 19264238. 20. Hunt SA. Women Leaders in cardiac transplantation: a historical and personal perspective. Circulation 2019;139:1005–6. https://doi.org/10.1161/ CIRCULATIONAHA.118.038631; PMID: 30779643. 21. American Board of Internal Medicine. Percentage of firstyear fellows by gender and type of medical school attended. 2021. https://www.abim.org/about/statistics-data/ resident-fellow-workforce-data/first-year-fellows-by-gendertype-of-medical-school-attended.aspx (accessed 16 October 2020). 22. Crespo-Leiro MG. Heart failure is taking center stage. Circ Heart Fail 2019;12:e006025. https://doi.org/10.1161/ CIRCHEARTFAILURE.119.006025; PMID: 31296095. 23. Patterson K. Mariell Jessup: shaping a subspecialty. Circ Res 2017;120:613–6. https://doi.org/10.1161/CIRCRESAHA. 117.310656; PMID: 28209791. 24. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:1977–2016. https://doi.org/10.1161/CIRCULATIONAHA.109.192064; PMID: 19324967. 25. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of

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the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239. https://doi.org/10.1016/j. jacc.2013.05.019; PMID: 23747642. 26. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–61. https://doi. org/10.1161/CIR.0000000000000509; PMID: 28455343. 27. American College of Cardiology. Our History. 2020. https:// www.acc.org/about-acc/our-history (accessed 10 November 2020). 28. Canadian Cardiovascular Society. Executive and Council. 2020. https://www.ccs.ca/en/about-us/executive-and-council (accessed 10 November 2020). 29. Canadian Society of Transplantation. CST Past Presidents. 2021. https://www.cst-transplant.ca/past-presidents.html (accessed 12 January 2021). 30. European Society of Cardiology. HFA Board 2020–2022. 2021. https://www.escardio.org/Sub-specialty-communities/ Heart-Failure-Association-of-the-ESC-(HFA)/About/Board (accessed 12 January 2021). 31. The International Society for Heart and Lung Transplantation. Past Presidents. 2020. https://ishlt.org/ governance/board-of-directors/past-presidents (accessed 12 January 2021). 32. American Society of Transplantation. Past Presidents. 2020. https://www.myast.org/about-ast/history/past-presidents (accessed 12 January 2021). 33. Sweitzer NK. Choosing a career in heart failure. Circ Heart Fail 2019;12:e006139. https://doi.org/10.1161/ CIRCHEARTFAILURE.119.006139; PMID: 31296098. 34. Reza N, Tahhan AS, Mahmud N, et al. Representation of women authors in international heart failure guidelines and contemporary clinical trials. Circ Heart Fail 2020;13:e006605. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006605; PMID: 32757645. 35. Rose SL, Sanghani RM, Schmidt C, et al. Gender differences in physicians’ financial ties to industry: a study of national disclosure data. PLoS One 2015;10:e0129197. https://doi. org/10.1371/journal.pone.0129197; PMID: 26067810. 36. Whitelaw S, Thabane L, Mamas MA, et al. Characteristics of heart failure trials associated with under-representation of women as lead authors. J Am Coll Cardiol 2020;76:1919–30. https://doi.org/10.1016/j.jacc.2020.08.062; PMID: 33092727. 37. Reza N, DeFilippis EM, Michos ED. The cascading effects of COVID-19 on women in cardiology. Circulation 2021;143:615– 7. https://doi.org/10.1161/CIRCULATIONAHA.120.049792; PMID: 3301678.

Therapy

Rationale for and Practical Use of Sacubitril/Valsartan in the Patient’s Journey with Heart Failure and Reduced Ejection Fraction Mauro Gori,1 James L Januzzi,2 Emilia D’Elia,1 Ferdinando L Lorini3 and Michele Senni1 1. Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy; 2. Cardiology Division, Massachusetts General Hospital, Boston, MA, US; 3. Intensive Care Department, Papa Giovanni XXIII Hospital, Bergamo, Italy

Abstract

Sacubitril with valsartan (sacubitril/valsartan) is a relatively novel compound that has become a milestone in the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) in the last decade. Contemporary data suggest that sacubitril/valsartan is associated with improved outcomes compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and has a greater beneficial effect on myocardial reverse remodelling. Additionally, two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting, thus enabling a continuum of use in the patient’s journey with HFrEF. This article summarises available data on the effectiveness and tolerability of sacubitril/valsartan in patients with HFrEF, and provides the clinician with practical insights to facilitate the use of this drug in every setting, with an emphasis on acute HF, hypotension, electrolyte imbalance and renal insufficiency.

Keywords

Sacubitril/valsartan, management, acute heart failure, chronic heart failure, reverse remodelling Disclosure: JLJ has received grant support and consulting income from Novartis Pharmaceuticals. MS has received consulting income from Novartis Pharmaceuticals. All other authors have no conflicts of interest to declare. Received: 2 October 2020 Accepted: 11 November 2020 Citation: Cardiac Failure Review 2021;7:e06. DOI: https://doi.org/10.15420/cfr.2020.25 Correspondence: Michele Senni, Cardiovascular Department, Division of Cardiology, ASST Papa Giovanni XXIII, Bergamo, Piazza OMS, 1-24127 Bergamo, Italy. E: msenni@asst-pg23.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a highly prevalent disease in the community, with poor prognosis.1 Epidemiologically, approximately 50% of symptomatic HF patients have HF with reduced ejection fraction (HFrEF). The prevalence of HF has been estimated to increase by 46% by the year 2030, with the correspondingly large direct medical costs.2,3 Unfortunately, recent Medicare data suggest that 16.4% of patients with HF have had a potentially preventable readmission, implying that there is an opportunity to improve patient outcome, particularly for those with HFrEF, which can be treated with angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNis), mineralocorticoid receptor antagonists (MRAs), β-blockers and cardiac resynchronisation therapy to reduce risk.4 According to the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, guideline-directed medical therapies (GDMT) for HFrEF were strikingly under-utilised. Notably, fewer than 30% of patients received GDMT at target doses, and only 1% were receiving ACEi/ARB/ ARNi/β-blocker/MRA at target.5 Similar data were derived from both outpatient and inpatient registries.6 Additionally, of the GDMT, the ARNi sacubitril with valsartan (sacubitril/ valsartan) was prescribed in only 13% of eligible patients, and at a target dose in 30% of these, even though the CHAMP-HF registry was published in 2018 and, hence, afterwards, the utilisation of GDMT and appropriate dosing of sacubitril/valsartan in clinical practice might have improved. Of

note, there is a growing body of data on the efficacy and superiority of this compound, compared with other renin–angiotensin–aldosterone system (RAAS) blockers, which would clearly justify efforts to preferentially implement sacubitril/valsartan therapy in the treatment of HFrEF patients.7–14

Range of Use of Sacubitril/Valsartan in HFrEF Patients

In the last few years, several studies have been published on the range of use of sacubitril/valsartan in the various settings of HFrEF.15,16 Importantly, these data derive not only from the landmark trial on the use of sacubitril/ valsartan in HFrEF, the PARADIGM-HF, but also from studies, such as the TITRATION trial, on the possible modalities of titration of sacubitril/ valsartan in clinical practice, the PIONEER and TRANSITION studies, which deal with the important topic of initiating sacubitril/valsartan in the acute HF setting, as well as the PRIME study, PROVE-HF and EVALUATE-HF studies, which provided insights into the reverse remodelling effect of sacubitril/valsartan (Table 1 and Figure 1 ).17–37 This plethora of data justifies the continuum of use of sacubitril/valsartan across the outpatient and inpatient settings, in the so-called ‘patient journey’, especially considering sacubitril/valsartan is not only beneficial but also cost-effective, according to three analyses recently published.38–41 This article will focus on this growing and convincing body of data and on the practical use of sacubitril/valsartan.

Sacubitril/Valsartan: Milestone in HFrEF Treatment Table 1: Studies on the Continuum of Use of Sacubitril/Valsartan in the Setting of Heart Failure with Reduced Ejection Fraction Trial, Setting

Design and Study Period

Patients Inclusion Criteria (n)

PARADIGM-HF,32 ambulatory

• Multicentre, prospective,

8,442

randomised clinical trial of S/V (target dose 97/103 mg twice daily) compared with enalapril. • An open-label run-in with S/V preceded a randomisation period

Results: Primary Endpoint

Other Results

• NHYA II–IV • EF ≤35% • Elevated natriuretic peptides • Randomised to S/V or

After a median follow up of 27 months, 20% reduction in composite of CV death and hospitalisation for HF with S/V

Reduction of CVD (20%), HF hospitalisation (21%), all-cause mortality (16%) Reduction of sudden cardiac death (20%), all-cause and HF readmissions at 30 and 60 days, reducation of worsening HF More beneficial in different geographic regions and different age groups regardless of LVEF, recent hospitalisation and lower doses Mitigation of the risk of hyperkalaemia and renal failure Improvement of QOL, glycaemic control and delay of the time of insulin initiation

enalapril

TITRATION,33 ambulatory

• Multicentre, prospective,

498

• NHYA II–IV • EF ≤35%

77.8% of patients reached the optimal dosage of S/V with a rapid titration, 84.3% of patients with a slow titration

Safety was equal for both regimens More gradual initiation/uptitration maximised attainment of target dose in the low-dose ACEi/ARB group

PRIME HF,43 ambulatory

• Multicentre, prospective,

118

• HFrEF (EF <35%) • Chronic functional mitral

Decrease in effective regurgitant orifice area was significantly greater with S/V

Changes in regurgitant volume, LVESV, LVEDV and incomplete mitral leaflet closure area greater with S/V

• HFrEF (EF <40%) • Stable patients in optimal

Change in aortic characteristic impedance not significantly different

Significant changes in NT-proBNP and various structural parameters at 12 weeks, demonstrating rapid reverse remodelling with S/V. Better QOL with S/V

Significant reduction of NT-proBNP with S/V, which correlated with reverse remodelling (changes in LVDVI, LVSVI, LAVI, E/e′, LVEF) evaluated in a core laboratory

Results were consistent in those with low NT-proBNP, those not reaching target dose of S/V, those with new-onset HF and/or those not taking an ACEi/ARB at enrolment

S/V versus enalapril was associated with a 47% versus 25% reduction in NT-proBNP in the period for acute HF (SBP ≥100 from baseline to the mean mmHg, no need for intensification of IV diuretics of weeks 4 and 8 or use of IV vasodilators for 6 h.

Safety of S/V in acute HF patients and also in patients with new-onset HF Significant reduction in repeat HF hospitalisations (exploratory clinical outcome)

EVALUATE-HF,35 ambulatory

PROVE-HF, ambulatory

randomised clinical trial of S/V. An open-label run-in with S/V preceded a randomisation period of uptitration: condensed regimen in 3 weeks versus a conservative regimen in 6 weeks • Study period: 16 weeks randomised clinical trial of S/V compared with valsartan • Study period: 12 months

• Multicentre, prospective,

randomised clinical trial of S/V compared with enalapril • Study period: 12 weeks

• Multicentre, prospective,

open-label, clinical trial of S/V • Study period: 12 months

regurgitation secondary to LVD • Stable patients in optimal medical therapy for HF • Randomised to S/V or valsartan 464

medical therapy for HF

• Randomised to S/V or enalapril

794

• HFrEF (EF <35%) • Stable patients on optimal medical therapy for HF

PIONEER-HF,36 in-hospital

• Multicentre, prospective,

887

• NHYA II–IV • EF ≤35% • Stable patients hospitalised

TRANSITION,37 in-hospital

• Multicentre, prospective,

1,002

• HFrEF • Hospitalisation for acute

randomised clinical trial of S/V compared with enalapril • Study period: 8 weeks

randomised clinical trial comparing the initiation of S/V in-hospital versus ≤2 weeks after discharge • Study period: 10 weeks

decompensated HF, after being haemodynamically stabilised

Percentage of patients S/V was safe and well-tolerated in acute HF achieving the target dose patients and also in patients with new-onset of S/V 200 mg twice daily HF at 10 weeks after randomisation was similar in the predischarge and the post-discharge groups

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CV = cardiovascular; CVD = cardiovascular disease; EF = ejection fraction; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LAVI = left atrial volume index; LVD = left ventricular dysfunction; LVDVI = left ventricular diastolic volume index; LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; LVSVI = left ventricular systolic volume index; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; QOL = quality of life; SBP = systolic blood pressure; S/V = sacubitril/valsartan.

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Sacubitril/Valsartan: Milestone in HFrEF Treatment Figure 1: Clinical Trials of Sacubitril/Valsartan in the Patient’s Journey with Heart Failure with Reduced Ejection Fraction

PIONEER TRANSITION HFrEF patient

PRIME EVALUATE-HF PROVE-HF

PARADIGM-HF TITRATION

Once the patient with heart failure with reduced ejection fraction (HFrEF) is admitted to hospital (red arrow), the PIONEER trial shows a significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) associated with the use of sacubitril/valsartan (S/V) in the acute setting; moreover, a significant reduction in heart failure (HF) re-hospitalisation is documented.36 After discharge (yellow arrow), the TRANSITION trial shows that S/V is safe and well-tolerated in acute HFrEF patients after hemodynamic stabilisation during the vulnerable phase.37 In the ambulatory setting (light green arrow), the PRIME, EVALUATE-HF and PROVE-HF trials document a beneficial effect of S/V on NT-proBNP and reverse remodelling.30,34,35 In stable HFrEF patients at home (dark green arrow), the PARADIGM-HF trial shows a 20% reduction in cardiovascular death and HF hospitalisation with S/V compared with enalapril.32 The TITRATION trial, moreover, documents a well-tolerated rapid titration of the optimal dosage of S/V in the majority of patients.33

Studies in the Ambulatory Setting PARADIGM-HF Trial

TITRATION Study

The PARADIGM-HF trial was a large (n=8,442) multicentre, prospective, randomised clinical trial of sacubitril/valsartan (target dose, 97/103 mg twice daily) compared with enalapril in patients with left ventricular ejection fraction (LVEF) ≤40%.32 After a median follow up of 27 months the trial was stopped early due to overwhelming clinical benefit of sacubitril/ valsartan, with a significant reduction in the risk of cardiovascular death (including sudden cardiac death), and in HF hospitalisation; and the good safety profile. Although sacubitril/valsartan was associated with symptomatic hypotension more frequently than enalapril, more participants assigned to enalapril discontinued study medication due to adverse effects. Furthermore, even if the dose of sacubitril/valsartan was downtitrated from target because of hypotension, patients still had better outcomes compared with those on enalapril. Based on the PARADIGM-HF trial results, sacubitril/valsartan is approved for use in patients with symptomatic HFrEF. However, limited information was provided from the PARADIGM-HF trial on how to initiate sacubitril/valsartan in clinical practice, when sacubitril/valsartan should be initiated (outpatient versus inpatient setting), whether sacubitril/valsartan can provide any meaningful and clinically relevant benefit on remodelling, and how the drug affects those not represented in the PARADIGM-HF trial (i.e. those with new-onset HF, those naïve to RAAS inhibition, those with lower concentrations of N-terminal pro-B-type natriuretic peptide [NT-proBNP] and those unable to be initially titrated to target dose). The results from several recently completed studies summarised in this article provide additional supporting evidence on the use of sacubitril/valsartan in HFrEF patients.

The TITRATION study was designed and conducted to provide guidance on how to initiate and uptitrate sacubitril/valsartan in those with chronic HFrEF. TITRATION enrolled 498 patients not previously on treatment, or with variable pre-treatment with ACEi/ARBs.33,42 Patients were randomised to one of two blinded arms: uptitration condensed, which included the uptitration of sacubitril/valsartan from 50 mg twice daily to 200 mg twice daily in 3 weeks including the run-in phase; and a conservative arm in which the titration from 50 mg twice daily to 200 mg twice daily was performed in 6 weeks, including the run-in phase. Treatment success, defined as tolerability of the drug, was achieved in 77.8% of the patients in the uptitration condensed arm, and in 84.3% of the conservative arm (p=0.078). TITRATION found that patients not on previous treatment with ACEi/ARBs or those on low doses of either may reach and maintain target doses of sacubitril/valsartan when the titration is more gradual. Additionally, in patients initially intolerant to the sacubitril/valsartan dose, a downtitration could be useful, allowing, eventually, for the target dose to be reached. In summary, the TITRATION study demonstrates that sacubitril/valsartan may be titrated quickly, in 3 weeks, in most patients, except in ACEi/ARBnaïve patients or in those on a low background dose of ACEi/ARBs.

PRIME Study

This study was designed to provide evidence of a beneficial effect of sacubitril/valsartan on remodelling in HFrEF patients. In the PRIME study, the researchers conducted a double-blind trial of 118 patients with HFrEF and chronic functional mitral regurgitation secondary to left ventricular

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Sacubitril/Valsartan: Milestone in HFrEF Treatment dysfunction (LVD) who were taking GDMT.43 Patients were assigned to valsartan or sacubitril/valsartan. Compared with the valsartan group, the sacubitril/valsartan had a greater remodelling benefit as manifested by: a greater reduction of effective regurgitant orifice area (−0.058 cm2 for S/V versus −0.018 cm2 for valsartan; p=0.032), which was the primary outcome of the study; and a greater decrease in regurgitant volume (mean difference, −7.3 ml; 95% CI [−12.6, −1.9]). Decrease in LV end-diastolic volume index was greater in the sacubitril/valsartan group (mean difference, −7 ml/m2; 95% CI [−13.8, −0.2]), while there were no significant differences in other left ventricular metrics, in incomplete mitral leaflet closure area, or in changes in blood pressure. In summary, PRIME is a small study showing for the first time the reverse remodelling effect of sacubitril/valsartan in HFrEF with functional mitral regurgitation.

PROVE-HF Study

In the PARADIGM-HF trial, reduction in NT-proBNP concentration was tightly associated with improved outcome of patients treated with sacubitril/valsartan. Given that NT-proBNP reduction during GDMT has previously been linked to reversal of cardiac remodelling, the PROVE-HF sought to further examine this question. PROVE-HF was an open-label study of 794 patients with chronic HFrEF assigned to sacubitril/valsartan and evaluated on echocardiography prior to treatment, at 6 months, and at 12 months.34 NT-proBNP concentration was measured at each study visit. Following study completion, echocardiograms were transmitted to a core laboratory where they were interpreted following completion of all study procedures in a temporally and clinically blinded fashion. The study demonstrated a significant 37% reduction in NT-proBNP after initiation of sacubitril/valsartan; reduction in NT-proBNP was strongly associated with reverse cardiac remodelling. For example, from a baseline LVEF of 28%, by 12 months LVEF increased an average of 9.4%; many patients had even more dramatic improvement.34 In a similar fashion, there were decreases in indexed LV and left atrial (LA) volumes, LV mass index, and improvement in diastolic function as reflected in reduction of E/e′ ratio. Results were consistent between those with new-onset HF and/or those not taking an ACEi or ARB at enrolment (n=118 at baseline), or those not achieving the target sacubitril/valsartan dose (n=264). In summary, the PROVE-HF study is more proof of the cardiac reverse remodelling process associated with sacubitril/valsartan, and of the significant reduction in NT-proBNP related to ARNi.

EVALUATE-HF Study

In EVALUATE-HF, the researchers assessed whether a change in aortic characteristic impedance might pathophysiologically contribute to the superiority of sacubitril/valsartan compared with enalapril in patients with HFrEF. They randomly assigned 464 patients with HF and LVEF ≤40% to sacubitril/valsartan or enalapril.35 At 12 weeks, the sacubitril/valsartan group had a decrease in aortic characteristic impedance (primary outcome) and the enalapril group had an increase in this parameter, but the difference was not statistically significant. However, the sacubitril/ valsartan group had a significantly greater reduction in NT-proBNP, and greater reduction of several echocardiographic parameters, such as LV end-diastolic or systolic volume index, LA volume index, and mitral E/e′ ratio compared with the enalapril group (secondary endpoints). Additionally, the investigators demonstrated a significant improvement in the overall summary score of the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ), an exploratory secondary endpoint. These data

suggest a clear remodelling benefit even after 3 months of treatment with sacubitril/valsartan compared with standard care. In summary, the EVALUATE-HF study, although demonstrating a nonsignificant improvement in aortic impedance with sacubitril/valsartan compared with enalapril, does demonstrate greater cardiac reverse remodelling and improvement in quality of life with sacubitril/valsartan (secondary endpoints).

Studies in the In-hospital Setting PIONEER Study

Given that the PARADIGM-HF trial had excluded patients with acute decompensated HF, the PIONEER study was designed specifically to assess whether the superiority of sacubitril/valsartan versus enalapril was confirmed also in the acute setting.36 The enrolment of this trial was started as soon as the patients were haemodynamically stable during an inpatient HF admission. Haemodynamic stabilisation was defined as systolic blood pressure (SBP) ≥100 mmHg, no need for intensification of IV diuretics or the use of IV vasodilators 6 hours before randomisation. Patients were not allowed to have had IV inotropes in the previous 24 hours. In PIONEER, 881 patients were enrolled. One-third of patients had de novo HF, and 52% were not on an ACEi/ARB. Dosing was started with the lowest dose (24/26 mg sacubitril/valsartan twice daily or enalapril 2.5 mg twice daily) if blood pressure was between 100 and 120 mmHg. The median time to randomisation was 68 hours, and 25% were randomised in the first 48 hours. Then, based on blood pressure thresholds that changed through the trial, the dose was allowed to be uptitrated to the target (97/103 mg twice daily for sacubitril/valsartan versus 10 mg twice daily for enalapril). A total of 60% of the population reached the target dose of enalapril by 8 weeks, and approximately 55% reached the sacubitril/valsartan target dose. Across the 8-week study period, sacubitril/valsartan treatment was associated with statistically significant NT-proBNP reduction compared with enalapril (47% versus 25%), which was the primary outcome of the study. There were no statistically significant differences in rates of symptomatic hypotension, worsening renal function, angioedema events, or hyperkalaemia between the two study arms (secondary outcome). Additionally, analysis of an exploratory clinical composite outcome (composite of deaths, rehospitalisation for HF, implantation of an LV assist device, or listing for transplantation), showed a statistically significant 46% RR reduction in favour of sacubitril/valsartan, entirely driven by a 44% reduction in repeat HF hospitalisations. In summary, in the PIONEER study, the superiority of sacubitril/valsartan versus ACEi was confirmed also in the acute setting.

TRANSITION Study

TRANSITION was another study aiming to evaluate sacubitril/valsartan safety and efficacy in patients stabilised after hospitalisation for acute HF.37,44 The researchers randomly assigned 1,002 patients who were hospitalised for acute decompensated HFrEF to sacubitril/valsartan, after haemodynamic stabilisation. Patients were initiated on sacubitril/valsartan while still in the hospital or soon after discharge. Of the cohort, 29% were newly diagnosed with HFrEF and 24% had not previously taken ACEi/ARB. The primary endpoint, the proportion of patients achieving the sacubitril/ valsartan target dose 97/103 mg twice daily at 10 weeks after randomisation, was achieved in 45% of the predischarge group and in 50.4% of the post-discharge group (RR ratio 0.893; 95% CI [0.783–1.019]). In addition, 86.4% of the predischarge group and 88.8% of the

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Sacubitril/Valsartan: Milestone in HFrEF Treatment post‑discharge group maintained any dose for at least 2 weeks before week 10 after randomisation (RR ratio 0.973; 95% CI [0.929–1.02]). Study drug discontinuation occurred in 4.5% of the predischarge group and in 3.5% of the post-discharge group (RR ratio 1.287; 95% CI [0.692–2.395]). Rates of adverse events, serious adverse events, and death did not significantly differ between the groups. Death rates were low and no deaths were related to the study drug, according to the researchers.

Table 2: Standard Cautions and Contraindications for Sacubitril/Valsartan Therapy Cautions and Contraindications Chronic HFrEF S/V should not be given in conjunction with ACEi/ARB because of the risk of renal impairment and hyperkalaemia In patients receiving ACEi, it should be discontinued for at least 36 h prior to S/V to reduce the risk of angioedema

In summary, TRANSITION, similarly to the PIONEER study, showed the feasibility and safety of initiating sacubitril/valsartan in the acute HFrEF setting, even in new-onset patients. Given that the hospitalisation setting represents a pivotal moment in the clinical course of HFrEF and is associated with opportunities to fine-tune GDMT, data from these two trials provide reassuring information, and support ARNi initiation in this setting.

Renal function, potassium, blood pressure and possibly natriuretic peptides should be monitored during introduction and titration Starting dose of S/V is one 24 mg/26 mg tablet twice daily unless the patient is frankly hypertensive and/or is taking a large dose of ACEi/ ARB prior to ARNi The drug is not started in those with SBP <100 mmHg In the absence of obvious congestion, in the case of high dose of loop diuretic, empirically lower the loop diuretic dose to mitigate risk for symptomatic hypotension

Sacubitril/Valsartan Therapy in Context

A common issue that arises for the clinician is the uncertainty about whether ACEi/ARB therapy is sufficient in their apparently stable patients with HFrEF. The studies summarised in this article,32–37,42–44 and the three meta-analyses, provide strong evidence for the superiority of sacubitril/ valsartan, compared with conventional RAAS inhibition, in the outpatient setting.38–41,43,45–48 Importantly, the benefit of sacubitril/valsartan over enalapril was consistent, regardless of background therapy.27 Given that HF decompensation is the best clinical indicator of insufficiency of current HF treatment, available evidence prompts the substitution of an ACEi/ARB with sacubitril/valsartan also in this setting. Initiation during hospitalisation might allow for better titration and easier treatment of side-effects. The question of whether it might be better to start with an ARNi or an MRA in a de novo setting, would theoretically need formal testing. Of note, sacubitril/valsartan seemed to partially mitigate the risk of hyperkalaemia when the patient was already taking MRA, and long-term renal function seemed protected to a larger extent by sacubitril/valsartan compared with RAAS inhibitors.14 These data on renal protection with sacubitril/valsartan were consistent across the spectrum of LVEF.10,49–51 At the same time, recent data suggest that another class of drugs, the sodium–glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i), should be added to the treatment for HFrEF.52,53 Whether ARNi/SGLT2i therapies should be implemented simultaneously or sequentially is unknown. However, there are promising data showing benefits in patients already taking ARNi who were randomised to dapagliflozin in the DAPA-HF trial.54 Additionally, it has been suggested that combining ARNi, SGLT2i, MRA and β-blocker therapy will lead to a significantly better prognosis in HFrEF.55 Finally, the use of sacubitril/valsartan in patients with higher LVEF, such as HF with preserved ejection fraction (HFpEF), is somewhat controversial. The PARAGON-HF study did show a borderline reduction in the combined primary endpoint of incident cardiovascular death or HF hospitalisation (p=0.059),56 and sensitivity analyses of this trial and of other HFpEF studies have shown that patients with LVEF between 40 and 55% might gain significant benefit from therapies such as ARNi.56,57 Thus, it might be worthwhile to distinguish the ‘curable’ HFpEF (i.e. with LVEF ≤55%), for which ARNi might prove to be effective through the antagonism of many pathophysiologic mechanisms of HFpEF, from HFpEF with LVEF >55%, which is normally associated with a significant burden of comorbidities, and which is, thus, not treatable to date.58–61

The dose of S/V should be doubled every 2–4 weeks until the optimal dose of one 97 mg/103 mg tablet twice daily is reached, based on the patient’s tolerability Acute HFrEF

In a patient already taking an ACEi, suspending the ACEi and initiating an ARB early on will facilitate the switch to ARNi Best time to initiate sacubitril/valsartan in acute HFrEF may be when the patient is not yet ‘dry’, in order to avoid hypotension Start at 24 mg/26 mg twice daily, with intention to ultimately titrate the dose to 97 mg/103 mg twice daily after discharge If patients experience tolerability problems, a dose adjustment of concomitantly administered drugs or temporary dose reduction or interruption of S/V is recommended When initiating therapy, pay more attention to patients with a tendency to hypotension, with chronic renal failure, with previous episodes of hyperkalaemia, and those who are elderly, due to the higher occurrence of side-effects

ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNi = angiotensin receptor neprilysin inhibitor; HFrEF = heart failure with reduced ejection fraction; SBP = systolic blood pressure; S/V = sacubitril/valsartan.

Practicalities of Sacubitril/Valsartan Use in HFrEF Patients

The patient with HF is characterised not only by advanced age but also by the presence of comorbidities, such as renal failure, hypotension and hyperkalaemia, which can represent a serious obstacle to the correct and effective implementation of GDMT. Nonetheless, the initiation and titration of sacubitril/valsartan is worthwhile, in order to promote reverse cardiac remodelling, improve symptoms and hopefully reduce the risk of cardiovascular events. Clinicians contemplating the use of sacubitril/valsartan should consider several important steps. These include clear discussions with patients about the need for changing their treatment, and the steps needed to do so; inclusion of colleagues, such as advanced practitioners and other para-medical specialists, to assist in titration and follow-up and involvement of non-specialists in the decision-making and follow-up process.

Education

Shared decision-making and education are crucial when contemplating the use of sacubitril/valsartan, for several reasons. The therapy may be more costly than relatively inexpensive generic ACEis/ARBs and patients will need to understand the benefits of taking sacubitril/valsartan to reduce uncertainty. In those with acute HF, patients may also be unhappy

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Sacubitril/Valsartan: Milestone in HFrEF Treatment Figure 2: Response to Tolerability Problems in the Use of Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction Patients Hypotension

X X X X X

Renal impairment

Ca blockers α-blockers Nitrates Diuretics S/V

Volume X Diuretics X S/V

discharge.33,42 It is critically important that at the time of discharge the patient has at least 30 days’ worth of sacubitril/valsartan and that insurance coverage has been confirmed, if applicable.

Hyperkalaemia

Low-potassium diet Potassium binders X MRAs X S/V

HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; S/V = sacubitril/valsartan.

about changing from medications they may have been taking for a long period of time; once again, a clear discussion about the advantages of sacubitril/valsartan relative to older GDMT is important. Patients should be taught about how the ARNi is initiated, and warned that hospital visits will be required to titrate the therapy. Education should be provided regarding the potential for hypotension and how to manage it, and patients should be warned about the very small risk of angioedema.

Initiation and Titration

Standard cautions and contraindications for sacubitril/valsartan are listed in Table 2. If a patient is eligible for ARNi therapy, certain considerations are important prior to initiating and titrating sacubitril/valsartan. If a patient is receiving an ACEi, the drug should be discontinued for at least 36 hours to reduce the risk of angioedema. In the patient with chronic HFrEF, the generally recommended starting dose of sacubitril/valsartan is one 24 mg/26 mg tablet twice daily unless the patient is frankly hypertensive and/or is taking a large dose of ACEi/ARB prior to ARNi initiation. In the absence of obvious congestion, for those patients taking a high dose of loop diuretic, clinicians may choose to empirically lower the loop diuretic dose to mitigate risk of symptomatic hypotension. Reducing (or even discontinuing) the loop diuretic may be possible as the drug is titrated further. The dose of sacubitril/valsartan should be doubled every 2–4 weeks until the optimal dose of one 97 mg/103 mg tablet twice daily is reached, based on patient tolerability.26 This titration may be performed by members of the care team, including physicians, nurses, or pharmacists. It is reasonable to include monitoring of electrolytes, kidney function and possibly natriuretic peptides as sacubitril/valsartan is introduced and increased. In patients with acute HFrEF, the indications, cautions, and contraindications for sacubitril/valsartan are similar. As with chronic HFrEF, if a patient is taking an ACEi, it must be discontinued 36 hours before ARNi initiation. If clinicians recognise that a patient taking an ACEi is likely to initiate sacubitril/valsartan later in their hospital course, suspending the ACEi and initiating an ARB early on will facilitate the switch to ARNi. In the PIONEER study, patients with acute HFrEF were started on sacubitril/ valsartan at a time when their diuretic dose was stable and was not being intensified.36 Given the rapid and significant effects on filling pressures, the best time to initiate sacubitril/valsartan in acute HFrEF may be at a time when the patient is not yet ‘dry’, in order to avoid hypotension. In acute HFrEF, it is suggested to start at 24 mg/26 mg twice daily, with intention to ultimately titrate the dose to 97/103 mg twice daily after

If patients experience tolerability problems (SBP ≤95 mmHg, symptomatic hypotension , hyperkalaemia, renal dysfunction), a dose adjustment of concomitantly administered drugs (e.g. reduction of furosemide during the starting of sacubitril/valsartan) or temporary dose reduction or interruption of sacubitril/valsartan are recommended (Figure 2).28 When initiating therapy, it is necessary to pay more attention to patients with a tendency to hypotension, with chronic renal failure, with previous episodes of hyperkalaemia, and those who are elderly, because these are the patients in whom the appearance of side-effects is more frequent.

Special Circumstances

Renal Impairment • No dose adjustment of sacubitril/valsartan is required in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60–90 ml/min/1.73 m2). • In patients with moderate renal impairment (eGFR 30–60 ml/min/1.73 m2), an initial dose of sacubitril/valsartan 24/26 mg twice daily should be considered. • In patients with severe renal impairment (eGFR <30 ml/min/1.73 m2), sacubitril/valsartan should be used with caution and a starting dose 24/26 mg twice daily is recommended, given that in this patient setting clinical experience is very limited. • In patients with end-stage renal disease the use of sacubitril/ valsartan is not recommended because there is no clinical experience.

The use of sacubitril/valsartan may be associated with a decrease in renal function, especially if dehydration or concomitant use of non-steroidal anti-inflammatory drugs is present. Dose reduction should be considered in patients who develop a clinically significant decrease in renal function. Evaluation of patients with HF should always include examination of renal function, given that patients with mild–moderate renal impairment are more at risk of developing hypotension.

Hypotension

Treatment with sacubitril/valsartan should be initiated in patients with SBP ≥100 mmHg. Given that cases of symptomatic hypotension have been reported in patients treated with sacubitril/valsartan in clinical trials, especially in patients ≥65 years of age, in patients with renal disease, and in patients with low SBP (<112 mmHg), when starting therapy or during titration of the sacubitril/valsartan dose, blood pressure should be routinely monitored. Routine assessment of blood pressure is done for all vasoactive therapies commonly used for the condition of HF. If hypotension occurs, a temporary dose reduction or withdrawal of sacubitril/valsartan is recommended. A dosage adjustment of diuretics, concomitant antihypertensives, α-blocker drugs used for the treatment of prostatic hypertrophy and for other causes of hypotension (e.g. hypovolemia) should also be considered.

Hyperkalaemia

Treatment with sacubitril/valsartan should not be started if the serum potassium level is >5.4 mmol. Given that sacubitril/valsartan may be associated with an increased risk of hyperkalaemia, monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes, hypoaldosteronism, or are on a highpotassium diet or treated with MRAs. If patients experience clinically

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Sacubitril/Valsartan: Milestone in HFrEF Treatment relevant hyperkalaemia, teaching about low potassium diets is the first step. If hyperkalaemia persists, the dose adjustment of the concomitant medication or temporary dose reduction or withdrawal is recommended. The use of potassium-binding agents to facilitate use of sacubitril/ valsartan may also be considered.

Conclusion

Clinical practice guidelines for HFrEF recommend that patients be stable on an optimal dose of ACEi/ARB before sacubitril/valsartan implementation, whereas the regulatory labelling for sacubitril/valsartan in the EU and US is more liberal.62,63 In fact, it does not require any specific dose of ACEi/ARBs or even prior ACEi/ARB treatment at all. In 1. Owan T, Hodge D, Herges R, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251–9. https://doi.org/10.1056/ NEJMoa052256; PMID: 16855265. 2. Heidenreich PA, Albert NM, Allen L, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602. 3. Benjamin EJ, Blaha MJ, Chiuve SE, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2017 update: a report from the American Heart Association. Circulation 2017;135:e146–603. https://doi.org/10.1161/ CIR.0000000000000491; PMID: 28122885. 4. Grosu A, Senni M, Iacovoni A, et al. Cardiac resynchronization in combination with beta blocker treatment in advanced chronic heart failure (CARIBE-HF): the results of the CARIBE-HF study. Acta Cardiol 201;66:573–80. https://doi.org/10.1080/AC.66.5.2131081; PMID: 22032050. 5. Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry. J Am Coll Cardiol 2018;72:351–66. https://doi. org/10.1016/j.jacc.2018.04.070; PMID: 30025570. 6. Psotka MA, Ammon SE, Fiuzat M, et al. Heart failure sitebased research in the United States: results of the Heart Failure Society of America Research Network Survey. JACC Heart Fail 2019;7:431–8. https://doi.org/10.1016/j. jchf.2019.02.008; PMID: 30981742. 7. Claggett B, Packer M, McMurray JJ, et al. Estimating the long-term treatment benefits of sacubitril-valsartan. N Engl J Med 2015;373:2289–90. https://doi.org/10.1056/ NEJMc1509753; PMID: 26630151. 8. Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36:1990–97. https://doi.org/10.1093/eurheartj/ ehv186; PMID: 26022006. 9. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576–84. https://doi. org/10.1093/eurheartj/ehv330; PMID: 26231885. 10. Damman K, Gori M, Claggett B, et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail 2018;6:489–98. https://doi.org/10.1016/j.jchf.2018.02.004; PMID: 29655829. 11. Kristensen SL, Martinez F, Jhund PS, et al. Geographic variations in the PARADIGM-HF heart failure trial. Eur Heart J 2016;37:3167–74. https://doi.org/10.1093/eurheartj/ehw226; PMID: 27354044. 12. Solomon SD, Claggett B, Desai AS, et al. Influence of ejection fraction on outcomes and efficacy of sacubitril/ valsartan (LCZ696) in heart failure with reduced ejection fraction: the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial. Circ Heart Fail 2016;9:e002744. https://doi.org/10.1161/CIRCHEARTFAILURE.115.002744; PMID: 26915374. 13. Simpson J, Jhund PS, Silva Cardoso J, et al. Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol 2015;66:2059–71. https://doi.org/10.1016/j.jacc.2015.08.878; PMID: 26541915. 14. Kristensen SL, Preiss D, Jhund PS, et al. Risk related to prediabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from Prospective Comparison of ARNI with ACEI to Determine Impact on

light of recent data from studies subsequent to PARADIGM-HF, it seems compelling and obvious that initiation of sacubitril/valsartan is preferred regardless of pretreatment with ACEi/ARB, as conceded by consensus documents published by the American College of Cardiology and European Society of Cardiology.64,65 Eligibility for treatment would largely follow the regulatory labelling for sacubitril/valsartan, namely symptomatic HFrEF without contraindication, the inclusion criterion used in the PROVE-HF study. Besides clear benefit in ACEi/ARB-naïve patients, the results from PROVE-HF suggest that more nuanced means to identify eligible patients should be avoided: for example, prescribing ARNi only for those with elevated NT-proBNP or only for those who might tolerate maximum doses is not advisable.34

Global Mortality and Morbidity in Heart Failure Trial. Circ Heart Fail 2016;9:e002560. https://doi.org/10.1161/ CIRCHEARTFAILURE.115.002560; PMID: 26754626. 15. Gori M, Volterrani M, Piepoli M, et al. Angiotensin receptorneprilysin inhibitor (ARNi): clinical studies on a new class of drugs. Int J Cardiol 2017;226:136–40. https://doi.org/10.1016/j. ijcard.2016.06.083; PMID: 27378659. 16. Gori M, Senni M. Sacubitril/valsartan (LCZ696) for the treatment of heart failure. Expert Rev Cardiovasc Ther 2016;14:145–53. https://doi.org/10.1586/14779072.2016.11288 27; PMID: 26642078. 17. McMurray J, Packer M, Desai A, et al. A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. Eur Heart J 2015;36:434–9. https://doi. org/10.1093/eurheartj/ehu455; PMID: 25416329. 18. Solomon SD, Claggett B, Packer M, et al. Efficacy of sacubitril/valsartan relative to a prior decompensation: the PARADIGM-HF trial. JACC Heart Fail 2016;4:816–22. https:// doi.org/10.1016/j.jchf.2016.05.002; PMID: 27395349. 19. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol 2016;68:241–8. https://doi.org/10.1016/j.jacc.2016.04.047; PMID: 27417000. 20. Okumura N, Jhund PS, Gong J, et al. Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Circulation 2016;133:2254–62. https://doi.org/10.1161/ CIRCULATIONAHA.115.020729; PMID: 27143684. 21. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–61. https://doi.org/10.1161/ CIRCULATIONAHA.114.013748; PMID: 25403646. 22. Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/ valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol 2017;2:79–85. https:// doi.org/10.1001/jamacardio.2016.4733; PMID: 27842179. 23. Böhm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 2017;38:1132–43. https://doi. org/10.1093/eurheartj/ehw570; PMID: 28158398. 24. Desai AS, Solomon S, Claggett B, et al. Factors associated with noncompletion during the run-in period before randomization and influence on the estimated benefit of LCZ696 in the PARADIGM-HF Trial. Circ Heart Fail 2016;9:e002735. https://doi.org/10.1161/ CIRCHEARTFAILURE.115.002735; PMID: 27296397. 25. Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in n-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol 2016;68:2425–36. https://doi.org/10.1016/j.jacc.2016.09.931; PMID: 27908347. 26. Vardeny O, Claggett B, Packer M, et al. Efficacy of sacubitril/ valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail 2016;18:1228–34. https://doi.org/10.1002/ ejhf.580; PMID: 27283779. 27. Okumura N, Jhund PS, Gong J, et al. Effects of sacubitril/ valsartan in the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) according to background therapy. Circ Heart Fail 2016;9:e003212. https://doi. org/10.1161/CIRCHEARTFAILURE.116.003212; PMID: 27618854.

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28. Gori M, Senni M, Metra M. High-sensitive cardiac troponin for prediction of clinical heart failure: are we ready for prime time? Circulation 2017; 135:1506–8. https://doi. org/10.1161/CIRCULATIONAHA.117.027681; PMID: 28416522. 29. Chandra A, Lewis EF, Claggett BL, et al. Effects of sacubitril/ valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2018; 3:498–505. https://doi.org/10.1001/jamacardio.2018.0398; PMID: 29617523. 30. Lewis EF, Claggett BL, McMurray JJV, et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail 2017;10:e003430. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003430; PMID: 28784687. 31. Seferovic JP, Claggett B, Seidelmann SB, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5:333–40. https://doi.org/10.1016/S2213-8587(17)300876; PMID: 28330649. 32. McMurray J, Packer M, Desai A, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371: 993–1004. https://doi.org/10.1056/ NEJMoa1409077; PMID: 25176015. 33. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/ valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 2016;18:1193–202. https://doi. org/10.1002/ejhf.548; PMID: 27170530. 34. Januzzi J, Prescott M, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1085–95. https:// doi.org/10.1001/jama.2019.12821; PMID: 31475295. 35. Desai A, Solomon S, Shah A, et al. Effect of sacubitrilvalsartan versus enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2019;322:1077–84. https://doi.org/10.1001/ jama.2019.12843; PMID: 31475296. 36. Velazquez E, Morrow D, DeVore A, et al. Angiotensinneprilysin inhibition in acute decompensated heart failure. N Engl J Med 2018;380:539–48. https://doi.org/10.1056/ NEJMoa1812851; PMID: 30415601. 37. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019; 21:998–1007. https://doi.org/10.1002/ejhf.1498; PMID: 31134724. 38. Senni M. Monografia Entresto® (sacubitril/valsartan). InFocus 2019;XXII(7):1–44. https://springerhealthcare.it/issue/annoxxii-n-7-settembre-2019 (accessed 30 March 2021). 39. King JB, Shah RU, Bress AP, et al. Cost-effectiveness of sacubitril-valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail 2016;4:392–402. https:// doi.org/10.1016/j.jchf.2016.02.007; PMID: 27039128. 40. Sandhu AT, Ollendorf DA, Chapman RH, et al. Costeffectiveness of sacubitril-valsartan in patients who have heart failure with reduced ejection fraction. Ann Intern Med 2017;166:607–8. https://doi.org/10.7326/L17-0044; PMID: 28418550. 41. Gaziano TA, Fonarow GC, Claggett B, et al. Costeffectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol 2016; 1: 666–72. https://doi.org/10.1001/ jamacardio.2016.1747; PMID: 27438344. 42. Senni M, McMurray JJV, Wachter R, et al. Impact of systolic

Sacubitril/Valsartan: Milestone in HFrEF Treatment blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail 2018;20:491–500. https:// doi.org/10.1002/ejhf.1054; PMID: 29164797. 43. Kang DH, Park SJ, Shin SH, et al. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation 2019;139:1354–65. https://doi.org/10.1161/ CIRCULATIONAHA.118.037077; PMID: 30586756. 44. Senni M, Wachter R, Witte KK, et al. Initiation of sacubitril/ valsartan shortly after hospitalisation for acutely decompensated heart failure in patients with newly diagnosed (de novo) HF: a subgroup analysis of the TRANSITION study. Eur J Heart Fail 2020;22:303–12. https:// doi.org/10.1002/ejhf.1670; PMID: 31820537. 45. Solomon SD, Claggett B, McMurray JJ, et al. Combined neprilysin and renin-angiotensin system inhibition in heart failure with reduced ejection fraction: a meta-analysis. Eur J Heart Fail 2016;18:1238–43. https://doi.org/10.1002/ejhf.603; PMID: 27364182. 46. Wang Y, Zhou R, Lu C, et al. Effects of the angiotensinreceptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc 2019;8:e012272. https://doi. org/10.1161/JAHA.119.012272; PMID: 31240976. 47. Burnett H, Earley A, Voors AA, et al. Thirty years of evidence on the efficacy of drug treatments for chronic heart failure with reduced ejection fraction: a network meta-analysis. Circ Heart Fail 2017;10(1):e003529. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003529; PMID: 28087688. 48. Sciatti E, Senni M, Lombardi CM, et al. Sacubitril/valsartan: from a large clinical trial to clinical practice. J Cardiovasc Med (Hagerstown) 2018;19:473–9. https://doi.org/10.2459/ JCM.0000000000000687; PMID: 29917003. 49. Packer M, Claggett B, Lefkowitz MP, et al. Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2018;6:547–54. https://doi.org/10.1016/S2213-8587(18)301001; PMID: 29661699. 50. Voors AA, Gori M, Liu LC, et al. Renal effects of the

angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2015; 17:510–17. https://doi.org/10.1002/ejhf.232; PMID: 25657064. 51. Mc Causland FR, Lefkowitz MP, Claggett B, et al. Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. Circulation 2020; 142:1236–45. https://doi.org/10.1161/ CIRCULATIONAHA.120.047643; PMID: 32845715. 52. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1002/ ejhf.1548; PMID: 31309699. 53. Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413– 24. https://doi.org/10.1056/NEJMoa2022190; PMID: 32865377. 54. Solomon SD, Jhund PS, Claggett BL, et al. Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF Trial. JACC Heart Fail 2020;8:811–18. https://doi.org/10.1016/j.jchf.2020.04.008; PMID: 32653447. 55. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020;396:121–8. https:// doi.org/10.1016/S0140-6736(20)30748-0; PMID: 32446323. 56. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensinneprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794. 57. Solomon SD, Vaduganathan ML, Claggett B, et al. Sacubitril/ valsartan across the spectrum of ejection fraction in heart failure. Circulation 2020;141:352–61. https://doi.org/10.1161/ CIRCULATIONAHA.119.044586; PMID: 31736342. 58. Quarta G, Gori M, Iorio A, et al. Cardiac magnetic resonance in heart failure with preserved ejection fraction: myocyte, interstitium, microvascular, and metabolic abnormalities. Eur J Heart Fail 2020;22:1065–75. https://doi.org/10.1002/

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ejhf.1961; PMID: 32654354. 59. D’Elia E, Vaduganathan M, Gori M, et al. Role of biomarkers in cardiac structure phenotyping in heart failure with preserved ejection fraction: critical appraisal and practical use. Eur J Heart Fail 2015;17:1231–9. https://doi.org/10.1002/ ejhf.430; PMID: 26493383. 60. Gori M, D’Elia E, Senni M. Sacubitril/valsartan therapeutic strategy in HFpEF: clinical insights and perspectives. Int J Cardiol 2019;281:158–65. https://doi.org/10.1016/j. ijcard.2018.06.060; PMID: 30420146. 61. Böhm M, Bewarder Y, Kindermann I. Ejection fraction in heart failure revisited: where does the evidence start? Eur Heart J 2020;41:2363–5. https://doi.org/10.1093/eurheartj/ ehaa281; PMID: 32350518. 62. Yancy C, Jessup M, Butler J, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–61. https://doi. org/10.1161/CIR.0000000000000509; PMID: 28455343. 63. Ponikowski P, Voors A, Anker S, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; 37:2129–200. https://doi. org/10.1093/eurheartj/ehw128; PMID: 27206819. 64. Seferovic P, Ponikowski P, Anker S, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:1169–86. https://doi.org/10.1002/ejhf.1531. https://doi. org/10.1002/ejhf.1531; PMID: 31129923. 65. Hollenberg SM, Warner Stevenson L, Ahmad T, et al. 2019 ACC expert consensus decision pathway on risk assessment, management, and clinical trajectory of patients hospitalized with heart failure: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2019;74:1966–11. https://doi.org/10.1016/j. jacc.2019.08.001; PMID: 31526538.

Digital Health

CardioMEMS Implantation Using Gadolinium-based Contrast Agent: A Case Report Aniket S Rali , Lynne W Stevenson

and Sandip K Zalawadiya

Section of Advanced Heart Failure and Transplant Cardiology, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, US

Abstract

A 57-year-old woman with New York Heart Association Class III heart failure requiring multiple hospitalisations over the previous year presented for CardioMEMS implantation. Because of the patient’s allergy history of anaphylaxis to iodine-based contrast agent she underwent the device implantation with gadolinium-based contrast agent (Magnevist), which was successful.

Keywords

Implantable devices, CardioMEMS, heart failure, pulmonary artery Disclosure: LWS provides unpaid consultation regarding ambulatory haemodynamic monitoring but has no financial relationships with industry. All other authors have no conflicts of interest to declare. Received: 4 February 2021 Accepted: 23 February 2021 Citation: Cardiac Failure Review 2021;7:e07. DOI: https://doi.org/10.15420/cfr.2021.03 Correspondence: Sandip K Zalawadiya, 1215 21st Avenue South, Room 5209, MCE South Tower, 5th Floor, Nashville, TN 37232-8802, US. E: sandip.k.zalawadiya@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

CardioMEMS is a wireless implantable pulmonary artery pressure monitoring device that has been shown to reduce heart failure hospitalisations in New York Heart Association (NYHA) Class III patients regardless of left ventricular ejection fraction.1,2 Since its approval in 2014 by the Food and Drug Administration, more than 5,500 devices have been implanted in the US.3 Implantation of the CardioMEMS device is an outpatient procedure including a right heart catheterisation to measure simultaneous right heart, pulmonary artery and pulmonary capillary wedge pressures and a limited pulmonary arteriogram using an iodinebased contrast agent (IBCA) to locate an appropriate target branch of pulmonary artery for device implantation. Use of IBCAs exposes patients with advanced chronic kidney disease or iodine contrast allergy to significant risks, and a history of prior anaphylactic reaction virtually precludes their safe use. We report a patient with history of anaphylaxis from IBCA in whom substitution of a gadolinium-based contrast agent (GBCA) allowed safe implantation of the CardioMEMS device.

Case Report

A 57-year old woman with NYHA Class III heart failure with history of diabetes, hyperlipidaemia and hypertension presented with ischaemic heart failure with an ejection fraction of 40%. During the previous year she had three hospitalisations for decompensated heart failure and continued to struggle with volume management on outpatient basis; hence, she was referred for CardioMEMS implantation. Her allergy history included anaphylactic reaction to both shellfish and iodinated dye. On the day of the procedure, the patient’s serum creatinine was 1.13 mg/dl with an estimated glomerular filtration rate (eGFR) of 50 ml/min/1.73m2.

Because of concern for recurrence of her allergic reaction even if pretreatment was given, we opted to trial GBCA (Magnevist) for limited pulmonary angiogram. We used 7 ml (0.09 ml/kg or 0.045 mmol/kg) of the contrast agent to obtain images (Figure 1). To facilitate pulmonary artery opacification, the contrast material was injected with balloon tip of the Swan-Ganz catheter inflated. Once a suitable sized branch vessel was identified, the CardioMEMS device was successfully deployed and calibrated in the room (Figure 2). The patient tolerated the procedure without any complications and was discharged home in stable condition.

Discussion

We describe, to our knowledge, the first successful deployment of CardioMEMS device using GBCA in a patient with history of anaphylactic reaction to IBCAs. Retrospective studies estimate the incidence of IBCArelated allergic reactions between 0.7% and 1.0 %, and the incidence of severe allergic reaction is estimated at 0.01%.4 Women and patients with history of asthma and autoimmune disorders generally have higher risk of IBCA-related allergic reaction, particularly in the setting of positive family history or known personal history of an allergy to shellfish.5 In patients with non-severe reactions, pre-medications with glucocorticoids and antihistamines are recommended, although their efficacy is uncertain.5,6 Recommendations for patients with history of anaphylactoid reactions generally include avoidance of repeated exposure to IBCAs. Consequently, such patients may be denied access to implanted devices such as CardioMEMS and denial of their benefit to improve quality of life and decrease heart failure hospitalisations. Several studies have evaluated the role of non-iodinated contrast materials such as those based on gadolinium and carbon dioxide in a

CardioMEMS Implantation Using Gadolinium-based Contrast Agent Figure 1: Pulmonary Angiography With Magnevist Injection

Figure 2: Post-CardioMEMS Implantation Angiography

variety of clinical scenarios.7 A review of gadolinium chelates for non-MRI applications found Magnevist to be the most extensively studied GBCA; a dose of 0.3–0.4 mmol/kg of ideal body weight has been recommended.8 It is worth noting that GBCAs used at doses higher than 0.4 mmol/kg have been associated with an increased risk of contrast-induced nephropathy and should be avoided among those with advanced renal disease (eGFR <30 ml/min/1.73 m2) or acute renal failure.9 However, in patients with severe allergic reactions to IBCAs such as our patient, GBCA may offer an attractive alternative to safely perform the implant procedure. Historically, one of the major concerns with GBCAs have been the risk of nephrogenic skin fibrosis, especially when eGFR is <30 ml/min/1.73 m2. However, contemporary evidence suggests this risk to be low (<1%) with newer generations of GBCAs.10

In our patient, using a much smaller dose of 0.045 mmol/kg, we were able to obtain good quality images and perform successful device implantation. In addition, our patient required no pre-medication and experienced no intra- or post-procedural complications.

1. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S01406736(11)60101-3; PMID: 21315441. 2. Shavelle DM, Desai AS, Abraham WT, et al. Lower rates of heart failure and all-cause hospitalizations during pulmonary artery pressure-guided therapy for ambulatory heart failure: one-year outcomes from the CardioMEMS post-approval study. Circ Heart Fail 2020;13:e006863. https://doi. org/10.1161/CIRCHEARTFAILURE.119.006863; PMID: 32757642. 3. Vaduganathan M, DeFilippis EM, Fonarow GC, et al. Postmarketing adverse events related to the CardioMEMS HF system. JAMA Cardiol 2017;2:1277–9. https://doi. org/10.1001/jamacardio.2017.3791; PMID: 28975249. 4. Pradubpongsa P, Dhana N, Jongjarearnprasert K, et al. Adverse reactions to iodinated contrast media: prevalence,

Conclusion

This is the first report to describe successful use of GBCA in performing limited pulmonary angiography to implant the CardioMEMS device. In heart failure patients with history of severe reactions to IBCA and without severe renal dysfunction, the use of GBCA may offer safe alternative to guide implantation of the implantable haemodynamic monitoring system and could be considered when visualisation of a limited vascular area is required for implantation of other devices.

risk factors and outcome – the results of a 3-year period. Asian Pac J Allergy Immunol 2013;31:299–306. https://doi. org/10.12932/AP0297.31.4.2013; PMID: 24383973. 5. Rosado IA, Doña Diaz I, Cabañas RM, et al. Clinical practice guidelines for diagnosis and management of hypersensitivity reactions to contrast media. J Investig Allergol Clin Immunol 2016;26:144–55. https://doi.org/10.18176/ jiaci.0058; PMID: 27326981. 6. Torres MJ, Gomez F, Doña A, et al. Diagnostic evaluation of patients with nonimmediate cutaneous hypersensitivity reactions to iodinated contrast media. Allergy 2012;67:929– 35. https://doi.org/10.1111/j.1398-9995.2012.02840.x; PMID: 22583135. 7. Spinosa DJ, Matsumoto AH, Angle JF, et al. Gadoliniumbased contrast and carbon dioxide angiography to evaluate renal transplants for vascular causes of renal insufficiency and accelerated hypertension. J Vasc Interv Radiol 1998;9:909–16. https://doi.org/10.1016/S1051-

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

0443(98)70421-X; PMID: 9840034. 8. Strunk HM and H Schild. Actual clinical use of gadoliniumchelates for non-MRI applications. Eur Radiol 2004;14:1055– 62. https://doi.org/10.1007/s00330-004-2260-1; PMID: 14872279. 9. Boyden TF and Gurm HS. Does gadolinium-based angiography protect against contrast-induced nephropathy?: a systematic review of the literature. Catheter Cardiovasc Interv 2008;71:687–93. https://doi.org/10.1002/ccd.21459; PMID: 18360867. 10. Amet S, Launay-Vacher V, Clément O, et al. Incidence of nephrogenic systemic fibrosis in patients undergoing dialysis after contrast-enhanced magnetic resonance imaging with gadolinium-based contrast agents: the Prospective Fibrose Nephrogenique Systemique study. Invest Radiol 2014;49:109–15. https://doi.org/10.1097/ RLI.0000000000000000; PMID: 24169070.

Digital Health

Digital Health: Implications for Heart Failure Management Arvind Singhal

and Martin R Cowie

1,2

1. Royal Brompton Hospital, London, UK; 2. School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK

Abstract

Digital health encompasses the use of information and communications technology and the use of advanced computing sciences in healthcare. This review covers the application of digital health in heart failure patients, focusing on teleconsultation, remote monitoring and apps and wearables, looking at how these technologies can be used to support care and improve outcomes. Interest in and use of these technologies, particularly teleconsultation, have been accelerated by the coronavirus disease 2019 pandemic. Remote monitoring of heart failure patients, to identify those patients at high risk of hospitalisation and to support clinical stability, has been studied with mixed results. Remote monitoring of pulmonary artery pressure has a consistent effect on reducing hospitalisation rates for patients with moderately severe symptoms and multiparameter monitoring shows promise for the future. Wearable devices and apps are increasingly used by patients for health and lifestyle support. Some wearable technologies have shown promise in AF detection, and others may be useful in supporting self-care and guiding prognosis, but more evidence is required to guide their optimal use. Support for patients and clinicians wishing to use these technologies is important, along with consideration of data validity and privacy and appropriate recording of decision-making.

Keywords

Digital health, e-health, m-health, cardiology, heart failure, telemedicine, wearables, machine learning, apps, COVID-19 Disclosure: The salary of AS is funded by a fellowship from Abbott. MRC has provided consultancy advice to Medtronic, Abbott, Boston Scientific, We-Health, AstraZeneca and Bayer related to digital health, and research funds to his institution from Bayer, Boston Scientific, Medtronic and Abbott. Received: 9 November 2020 Accepted: 29 December 2020 Citation: Cardiac Failure Review 2021;7:e08. DOI: https://doi.org/10.15420/cfr.2020.28 Correspondence: MR Cowie, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, Strand, London WC2R 2LS, UK. E: martin.cowie@kcl.ac.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Digital health is defined by the WHO as “a broad umbrella term encompassing eHealth, as well as emerging areas, such as the use of advanced computing sciences in ‘big data’, genomics and artificial intelligence”, and it defines eHealth as “the use of information and communications technology in support of health and health-related fields” (Figure 1 and Table 1).1 Cardiologists have been integrating basic forms of digital health into their practice for decades, from telephone consultations to electronic health records (EHRs). The traditional model of heart failure (HF) outpatient care, with scheduled face-to-face visits often many months apart, was largely unchanged by digital technology; remote monitoring (RM) and teleconsultation were the exception rather than the rule. The coronavirus disease 2019 (COVID-19) pandemic necessitated a rapid and dramatic change to this approach, with government stay-at-home orders, shielding guidelines and health service reorganisation strongly discouraging face-to-face appointments. The focus of service delivery rapidly shifted to teleconsultation, with an increase in RM where this was possible (Figure 2). This short review discusses a variety of digital technologies that increasingly play a role in HF management for both healthcare professionals and patients.

The Digital Landscape

The smartphone is now a portable, powerful personal computer and communications device sitting in most people’s pocket. Smartphone

penetration ranges from 80% of adults in high-income countries, such as the US, UK, France and Germany, to 60% in China and 37% in India.2 A review by the cardiologist Eric Topol identified several key priorities in digital transformation in healthcare, including increased use of telemedicine, smartphone apps and sensors and wearables for diagnostic and RM purposes.3 Artificial intelligence and machine learning techniques were also identified as likely to play an increasing role in image interpretation and pattern recognition, clinical decision support, disease and treatment monitoring and more rapid discovery of new therapeutics. However, several barriers exist to the widespread implementation of digital health programmes, as identified in the EU e-Health action plan 2012–2020 (Table 2).4 The European Society of Cardiology (ESC) e-Cardiology Working Group proposed several solutions to tackle some of these issues, including redesign of workflows and assurance of interoperability of services.5 A particular challenge is that patient groups with the greatest healthcare need, such as the elderly or those with low incomes, may have the least access to digital technologies, creating a so-called digital divide. Lack of health literacy (the ability of patients to understand and use written healthcare information) and digital literacy (the ability to use information and communication technologies to find, evaluate, create and communicate information) must be tackled within the healthcare workforce and the general population if the digital revolution is to succeed at scale.6

Digital Health: Implications For HF Management Figure 1: Domains of Digital Health and eHealth Digital health eHealth

Big data Telemedicine

Clinical information systems

Genomics

Wearables and sensors

Mobile apps

mHealth

ePrescribing

Referral networks

Integrated networks

Artificial intelligence

Source: WHO 20191 and Cowie et al. 2016.63

Table 1: Definitions Term

Definition

Digital health

A broad umbrella term encompassing e-Health (which includes m-Health), as well as emerging areas, such as the use of advanced computing sciences in big data, genomics and artificial intelligence.1

eHealth

The use of information and communications technology in support of health and health-related fields.1

mHealth

Medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants and other wireless devices.64

Telehealth

Delivery of health care services, where patients and providers are separated by distance.65 Often used interchangeably with telemedicine.

Teleconsultation

The use of information and communications technology to consult with patients or other providers separated by distance.

Remote monitoring

A subset of telehealth that facilitates patient monitoring as well as the timely transfer of patient-generated data from patient to care team and back to the patient.66

Teleconsultation

Teleconsultation is used in this article to mean the use of information and communications technology to consult with patients at a distance, although teleconsultation can also refer to communication between healthcare professionals. Teleconsultation had been identified as a possible solution to overburdened outpatient departments before the COVID-19 pandemic.7 Nevertheless, it has not been widely used in cardiology outpatient services until recently. A recent Organisation for Economic Co-operation and Development (OECD) report into telemedicine found that teleconsultations represented just 0.1–0.2% of the number of face-to-face consultations in selected OECD countries.8 A lack of clear reimbursement mechanisms was cited as the most frequent barrier to adopting telemedicine services. In March 2020, many healthcare organisations across Europe and the US rapidly moved to teleconsultation for routine outpatient appointments to minimise the risk of COVID-19 transmission to patients and staff, and

reimbursement mechanisms were amended to incentivise this. For example, in the US, temporary measures allowed telehealth services to be billed as if they were in-person services for patients enrolled in Medicare or Medicaid.9 State medical licensure within the US was also a barrier to providing teleconsultations for patients who lived in different states to the healthcare professional; typically physicians are only licensed to practise in the state in which they work, whereas telehealth consultations were deemed to take place in the patient’s location. To tackle this issue during COVID-19, most states issued waivers to allow telehealth provided by out-of-state physicians.10 Video consultations have been well received in primary care but have so far had limited evaluation in HF care.11,12 A small study in selected HF patients found video consultations to be broadly acceptable but challenges included establishing a good connection, communication difficulties due to latency and connection degradation and inability to conduct physical examinations.13 Another small study of video consultations in HF patients explored examinations in more detail. Although in all appointments a basic form of examination was possible, communicating instructions to patients and carers was particularly challenging for clinicians.14

Remote Monitoring for Decompensation of Heart Failure

HF is a long-term condition with episodic deterioration (decompensation).15 Decompensation is a critical event; European registry data show that hospitalisation carries a 24% risk of death within 1 year.16 Improvement in disease monitoring – identifying when patients may be deteriorating and when intervention may restabilise the syndrome – has obvious attractions. Traditional periodic clinical assessment suffers from the limitation that early signs of decompensation are unlikely to coincide with a clinic appointment and patients tend to seek professional advice only when their symptoms are advanced.17 Self-monitoring, where patients track their symptoms, weight and other physiological variables (such as blood pressure), has been a mainstay of HF management for several years.15 However, it relies on patients being motivated, having access to technology (such as scales and automatic sphygmomanometers), and having access to clinical advice, often through a HF nurse telephone service. Unfortunately, many HF patients lack the requisite knowledge for effective self-care, so effective interaction with clinicians – at the right time – is crucial for self-monitoring to translate into improved outcomes.18,19 RM is the use of telecommunication technologies to monitor patient status at a distance. Structured telephone support (STS) offers a basic level of RM. Patients are called by a member of the HF team to discuss symptoms, drug therapy, compliance with lifestyle measures and they may be asked to provide measurements such as weight and blood pressure or pulse rate. The evidence for STS is mixed, but a 2015 metaanalysis reported a marginal mortality benefit (risk ratio [RR] 0.87 for allcause mortality; 95% CI [0.77–0.98]) and reduction in HF hospitalisations (RR 0.85; 95% CI [0.77–0.93]), but no effect on all-cause hospitalisations.20 STS is relatively labour-intensive and costs vary according to the intensity of monitoring. Non-invasive standalone systems involve the regular transmission of physiological data to HF teams. Teams may either review this data regularly or be alerted when a variable is outside a specified range.21 The exact choice of measurements transmitted varies between different systems. The evidence base is mixed, with randomised trials failing to show consistent benefit.

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Digital Health: Implications For HF Management Table 2: Barriers and Solutions to the Large-scale Deployment of Digital Health-based Care in Cardiology Barriers4

Solutions5

Stakeholder resistance to adopt digital care

• Lack of awareness of, and confidence among patients, citizens

• Patient digital health education programmes. • Redesign contemporary workflow models.

Legal, ethical and technical barriers

• Lack of inter-operability between digital solutions. • Assure interoperability of digital health services. • Lack of legal clarity for health and wellbeing mobile applications • European-wide digital health certification programmes. and the lack of transparency regarding the use of data collected • Assure compliance to digital health directives.

Lack of reimbursement

• Inadequate or fragmented legal frameworks for reimbursement. • Encourage economical evaluations of digital health-based care. • High start-up costs. • Inform health insurance industry and policy makers. • Limited large-scale evidence of cost-effectiveness. • Stimulate digital health-related knowledge and experience

and healthcare professionals. • Regional differences in accessing ICT services, including limited access in deprived areas.

by such applications.

sharing.

ICT = Information and communications technology.

One randomised trial of telemonitoring in 1,571 HF patients with New York Heart Association (NYHA) Class II–III symptoms and a HF hospitalisation in the preceding 12 months compared a wireless system, transmitting daily readings of weight, blood pressure, oxygen saturations, heart rate and a health status questionnaire, with usual care.22 The composite outcome of all-cause mortality and percentage days hospitalised was reduced (RR 0.8; 95% CI [0.65–1.00]), although crucially this study excluded patients with depression or NYHA Class I or IV. A meta-analysis of smaller randomised telemonitoring trials showed a small mortality benefit (RR 0.80 for all-cause mortality; 95% CI [0.68–0.94]).20 However the heterogeneity of interventions, health service structures, patients studied and definitions of ‘usual care’ make it difficult to make specific recommendations based on these data. The ESC and American College of Cardiology HF guidelines, written before the COVID-19 pandemic, do not recommend routine use of RM (Table 3), but during the COVID-19 pandemic RM of chronic conditions was recommended by many organisations, including the Centers for Disease Control and Prevention, in order to maintain continuity of care in the absence of face-to-face contact.15,23,24

Invasive Device Remote Monitoring

Patients with symptomatic HF with severely reduced ejection fraction may have an implantable cardiac device such as an ICD or CRT as part of their HF management.15,23 Such devices require regular checks to monitor device performance, longevity and detection of arrhythmia, but most modern devices can wirelessly connect with home monitors that transmit relevant data and alerts, allowing a device check to be performed remotely.25 Home monitoring is safe and effective for routine device checks, with earlier detection of arrhythmia and technical issues.26 Centres using home monitoring of implanted devices have reported reduced face-to-face contact.27 Implantable devices can also collect physiological data that may correlate with HF status. Intrathoracic impedance correlates well with pulmonary fluid content, but device-based impedance alerts resulted in a 79% increase in HF hospitalisation in one randomised trial, due to the low specificity of alerts when measuring impedance alone, and perhaps also the anxiety triggered by an audible alert from the device.28,29 Multiparametric monitoring, incorporating intrathoracic impedance with other variables such as heart rate, heart rate variability, physical activity and heart sounds, has shown more potential. Routine remote multiparametric monitoring of 1,650 patients with an implantable device at

Figure 2: Challenges Posed to Heart Failure Care by COVID-19 and Digital Health Solutions Distancing between heart failure specialist and patient

• Teleconsultation • Remote monitoring • Increased use of apps and wearables

Distancing between healthcare professionals

Distancing between researchers and trial participants

• Electronic health records and transfer of health information • Virtual multidisciplinary meetings • Virtual referrals for clinical advice

• Electronic remote consent • Web-based or app-based patient-reported outcome data collection • Use of wearables for physiological data collection

nine English hospitals over an average of 2.8 years failed to show an improvement over usual care in a randomised trial, but this study depended on human interpretation of the data trends.30 Using similar parameters, the HeartLogic (Boston Scientific) algorithm was able to identify HF decompensation with a sensitivity of 70% and an unexplained alert rate of only 1.47 per patient-year, with a median lead time of 34 days before the HF event.31 There is currently no specific evidence-based intervention to a HeartLogic alert, and it is therefore currently unclear whether the algorithm improves hospitalisation or mortality when used in routine practice. The MANAGE-HF randomised trial is due to report these outcomes in 2025 (NCT03237858). Implantable haemodynamic monitors have shown promise at preventing HF hospitalisation. Pulmonary artery pressure (PAP) increases in response to increasing intracardiac pressure or fluid volume, with rises in pressure typically preceding symptoms by some weeks.32 A randomised trial showed that remote daily PAP monitoring, (via a CardioMEMS device; Abbott) and titration of medications in response to rises in pressure, reduced subsequent HF hospitalisation by 30% in NYHA Class III patients who had been admitted for HF in the previous year.33 Data from NYHA Class III patients outside the US confirm this benefit.34,35 The GUIDE HF study (NCT03387813) is examining the impact in a broader spectrum of patients, including those with milder symptoms.

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Digital Health: Implications For HF Management Table 3: Existing Guidelines on Remote Monitoring for Heart Failure Events (Pre-COVID-19) ESC: 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure15 Recommendations for exercise, multidisciplinary management and monitoring of patients with heart failure: • Monitoring of pulmonary artery pressures using a wireless implantable haemodynamic monitoring system (CardioMems) may be considered in symptomatic patients with HF with previous HF hospitalisation in order to reduce the risk of recurrent HF hospitalisation. (Class IIb, level B). • Multiparameter monitoring based on ICD (IN-TIME approach) may be considered in symptomatic patients with HFrEF (LVEF≤35%) in order to improve clinical outcomes. (Class IIb, level B). HFA of the ESC: Clinical practice update on heart failure 201966 Telemedicine: • Home telemonitoring using an approach that is similar to the one used in TIM-HF2 (Telemedical Interventional Management in Heart Failure II) may be considered for patients with HF in order to reduce the risk recurrent CV and HF hospitalisations and CV death. ACCF/AHA: 2013 ACCF/AHA Guideline for the Management of Heart Failure23 Systems of care to promote care coordination for patients with chronic HF: • The quality of evidence is mixed for specific components of HF clinical management interventions, such as home-based care, disease management, and remote telemonitoring programmes. • Overall, very few specific interventions have been consistently identified and successfully applied in clinical practice. AHA: Using Remote Patient Monitoring Technologies for Better Cardiovascular Disease Outcomes (2019)67 HF: • Although recent systematic reviews and meta-analyses have shown a positive effect on HF-related admissions and mortality rates and all-cause mortality rates, the bulk of the literature consists of low-quality and inconsistent evidence about the beneficial effect of remote monitoring. ACCF = American College of Cardiology Foundation; AHA = American Heart Association; COVID-19 = coronavirus disease 2019; CV = cardiovascular; ESC = European Society of Cardiology; HF = heart failure; HFA = Heart Failure Association; HFrEF = heart failure with reduced ejection fraction; IN-TIME = INfluence of Home Monitoring on The clinical Management of heart failurE patients with impaired left ventricular function; LVEF = left ventricular ejection fraction.

Apps and Wearables

While RM systems are generally ‘prescribed’ by clinicians and often reimbursed by healthcare systems or insurance companies, apps and wearables are largely marketed directly to consumers as tools for health and lifestyle maintenance. The last decade has seen a rapid proliferation of health apps. In 2017 it was estimated that 325,000 health apps were available on smartphones.36 Despite this, very few of them have been designed specifically for HF patients; a 2019 review identified 10 apps focused on HF self-care available on the Apple App Store and Google Play store.37 Four of these were developed by scientific societies (including the American Heart Association and the Swiss Federation of Cardiology) and they were predominantly aimed at patient education, symptom tracking and prompting users to seek early care for symptoms in order to address low health literacy and poor understanding of self‑care in HF patients.38,39 However, few HF apps have been evaluated in randomised controlled trials, and those that have been are not yet commercially available. Without good quality evidence and clear app standards it is challenging for clinicians to know what to recommend, though there is a growing understanding of the importance of assessment and regulation in this field. Governments and organisations have adopted their own regulatory approaches to apps. For example, the Catalan government has created a public library of accredited health apps with the ICT Social Health

Foundation, while other independent organisations such as the Organisation for the Review of Care and Health Apps work with health service providers internationally to assess healthcare apps. The National Institute for Health and Care Excellence in England has developed an evidence standards framework for digital health technologies, which provides a path to reimbursement for technologies that demonstrate effectiveness and value.40 Consumer wearables are devices that record and transmit physiological signals that can be worn, such as activity trackers and smartwatches, and these are becoming increasingly popular. Some products now offer irregular pulse detection, lead-1 ECG, blood pressure and oxygen saturation monitoring capabilities. These devices are, therefore, potentially useful tools in HF self-care and even RM, but patients bringing physiological data to clinicians poses several new dilemmas:

• Are the data valid? • How should clinicians use the data in managing HF patients? • How are data regulated and incorporated into electronic health records?

Validity

Activity monitors using accelerometry, often in the form of a wristband/ watch, are the most common form of wearable device. Most modern devices show high accuracy in measuring step count in controlled conditions, but devices were found to be less accurate at low ambulation speeds, which is of relevance to HF patients.41,42 Wearable heart rate monitors use photoplethysmography (PPG), which is the illumination of a capillary bed and measurement of pulsatile changes in light absorption.43 Performance of PPG-based devices degrades with exertion, and a study of HF patients using Fitbit and Apple Watch showed poor accuracy in measuring dynamic heart rate changes.44,45 PPG is, therefore, best used for measuring resting heart rate. Analysis of PPG waveforms, however, can detect irregular pulses and therefore potentially be used for AF screening46 – the presence of AF has therapeutic implications in HF patients, such as decisions regarding rate or rhythm control, and potential need for lifelong anticoagulation. PPG alone cannot differentiate between AF and other causes of irregular pulse, but can be combined with ECG patch recording for confirmation in patients with an irregular pulse.47 Such an approach was used in the Apple Heart Study, a large-scale AF screening study using a PPG-based smartwatch algorithm.48 In patients who had an irregular pulse notification and agreed to apply and send back an ECG patch recording, 34% had confirmed AF during the subsequent 2-week recording period and 77% of irregular pulse notifications with simultaneous recording were confirmed to be AF, with atrial ectopy making up the majority of the remainder.48 Newer versions of the Apple Watch can also generate a lead 1 ECG. The HEARTLINE study, recruiting 150,000 patients aged over 65, is investigating whether the irregular pulse detection algorithm and ECG feature leads to a reduction in stroke and death in a real-world setting (NCT04276441). Although theoretically PPG could be used to detect paroxysmal tachycardias, it is less well studied, and no PPG-based technologies are licensed outside of AF detection.49 In addition to PPG and ECG features, miniature wrist oscillometric sphygmomanometers can now be incorporated into a smartwatch for blood pressure monitoring; the first such device to be licensed showed high accuracy when compared with manual blood pressure measurement at rest.50

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Digital Health: Implications For HF Management Using Data From Wearables in Heart Failure Patients

Physical activity is an important prognostic parameter in HF. Six-minute walk test performance is a strong predictor of subsequent cardiac death in HF patients but is rarely used outside of research as it is cumbersome to measure.51 Activity monitoring could provide a simple, objective measure of functional limitation. A retrospective study of 189 American patients with self-reported HF showed a significant negative association between physical activity and mortality, and a prospective Japanese study of 170 HF patients showed a step count of <4,889 steps/day was a stronger predictor of mortality than VO2 max (peak oxygen consumption, an important marker of cardiopulmonary fitness) on exercise testing.52,53 However, prospective evidence of using activity monitors to guide therapy, for example instead of NYHA Class, is lacking. Activity monitors could be used to monitor and encourage adherence to exercise therapy in HF, but evidence from large randomised controlled trials in HF patients is lacking. Patient acceptability of wearables, including a watch or other wrist-worn device, is also likely to be variable.54,55

Regulation and Integration

Two key questions arise from wearable devices and apps: are they medical devices and who is responsible for the data generated? The EU Medical Device Regulation in Europe and the Food and Drug Administration in the US regulate medical devices in those geographies. Technologies such as apps and wearables fall under their remit if they are intended for medical purposes (i.e. for the diagnosis, prevention, monitoring or treatment of disease), make claims of health benefit, or pose potential risk of harm to patients.56 Therefore, health technology companies are often careful to avoid medical claims and often market devices as ‘health and wellness’ products rather than tools for disease management. As the information collected on users becomes more identifiable and medically relevant it can become subject to data protection regulations. In the EU, the General Data Protection Regulation regulates data that can be used to directly or indirectly identify a person, and applies to all companies processing the personal data of subjects residing in the EU. Privacy policies of many medical apps and wearables fail to meet these standards set for data storage, access, control and processing; this is an essential requirement before clinicians can recommend these products.57 Incorporating wearable data into electronic health records currently requires manual input in most cases. Improvements in automatic upload of validated data may remove a barrier to clinicians using these data in clinical decision-making.

Machine Learning

Machine learning involves computers training themselves on large sample datasets to build predictive mathematical models. Most implanted devices can only provide short daily samples of data, but non-invasive monitors linked with smartphones can transmit continuously and allow for larger, richer datasets for analysis. The LINK-HF study investigated the use of a multisensor patch continuously measuring ECG signals, thoracic impedance, body temperature and accelerometry in 100 HF patients. Data were uploaded to the cloud via a smartphone, and machine learning was used to create a personalised baseline for patients. A prognostic machine learning algorithm was able to predict impending decompensation with a sensitivity of 88% and a specificity of 86% a median of 6.5 days before the HF event.58 Further research is required to determine whether such algorithms can be used to trigger an appropriate intervention that can help restabilise the HF syndrome, and thus prevent the need for HF hospitalisation.

Other investigational products are taking a similar approach. The µCor patch (Zoll), equipped with an ECG monitor and radiofrequency transmitter measuring pulmonary fluid content, is under investigation for its ability to predict HF events (NCT03476187), and a smart-textile vest with multiple electrodes measuring similar parameters to HeartLogic (heart rate, heart rate variability, respiratory rate and thoracic impedance) is also being studied (NCT03719079). Machine learning algorithms may pick up subtle ECG changes not detectable by human observers. They have shown promise in predicting future episodes of AF from sinus rhythm ECGs and even at identifying left ventricular systolic dysfunction from ECGs.59 A recent study from the Mayo Clinic in the US retrospectively analysed the ECGs of 1,606 patients without known left ventricular systolic dysfunction (LVSD) who had a subsequent echocardiogram within 30 days. A machine learning algorithm was able to predict LVSD (defined as an ejection fraction <35%) with a sensitivity and specificity of 74% and 87% respectively.60 The area under the receiver operating characteristic curve was 0.89, outperforming N-terminal pro-brain natriuretic peptide (0.80) at predicting LVSD. Such algorithms are not yet in clinical practice, and would need to be certified as a medical device before they would be able to be used, but they may form part of decision and diagnostic aids in the near future. Machine learning analysis of cardiac imaging is a rapidly advancing field, with encouraging early results in image acquisition, interpretation in echocardiography and MRI.61 As systems are able incorporate these data with electronic health records, the resulting rich datasets offer the potential of precision medicine and diagnostics, and improved access to key diagnostic testing.

Sustainability of New Technology

The COVID-19 pandemic has resulted in a rapid disruption and digital transformation of HF services, with greatly increased use of telehealth. The extent to which these changes will be sustained after social distancing measures are relaxed will depend on evidence of patient outcomes, patient and clinician acceptability, and use of healthcare resources during the pandemic, which is currently lacking. However, it is unlikely that healthcare practice will return to a state of business as usual. Teleconsultation is associated with a significant start-up cost for equipment, training and software licences, but many organisations have made substantial investments during the pandemic, thus overcoming a major barrier for on-going use. RM technologies need more detailed health technology assessments to judge their clinical and costeffectiveness in different healthcare settings; use of the CardioMEMS device outside the US will depend on how it is priced and whether this remains cost-effective in a post-COVID world.

Conclusion

As citizens become digitally empowered, patients will increasingly be able to use technology to manage their own health and disease. Self-management of type 1 diabetes using blood glucose sensors has meant that physician contact is the exception rather than the rule for wellcontrolled patients with that condition, and self-management of blood pressure in hypertension is effective and increasingly common.62 Such a model would certainly be attractive in HF, but further research is needed to determine which physiological data and interventions can be used to reduce the risk of major HF decompensation events such as hospitalisation, or even to reduce mortality. PAP monitoring systems are effective at reducing HF hospitalisations, but demonstrating cost-effectiveness will be

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Digital Health: Implications For HF Management essential for widespread adoption outside of the US setting. Reimbursement mechanisms are a key driver and enabler for change, but often trail behind innovation. The COVID-19 pandemic has forced 1. WHO. WHO guideline: Recommendations on digital interventions for health system strengthening. Geneva: WHO, 2019. https:// www.who.int/reproductivehealth/publications/digitalinterventions-health-system-strengthening/en/ (accessed 19 January 2021). 2. Newzoo. Newzoo Global Mobile Market Report 2019. Newzoo, 2019 https://newzoo.com/insights/trend-reports/newzooglobal-mobile-market-report-2019-light-version (accessed 19 January 2021). 3. NHS Health Education England. The Topol review: Preparing the healthcare workforce to deliver the digital future. Health Education England; 2019. https://topol.hee.nhs.uk (accessed 19 January 2021). 4. European Commission. eHealth Action Plan 2012-2020: Innovative healthcare for the 21st century. Brussels: European Commission, 2012. https://ec.europa.eu/digital-singlemarket/en/news/ehealth-action-plan-2012-2020-innovativehealthcare-21st-century (accessed 19 January 2021). 5. Frederix I, Caiani EG, Dendale P, et al. ESC e-Cardiology Working Group position paper: overcoming challenges in digital health implementation in cardiovascular medicine. Eur J Prev Cardiol 2019;26:1166–77. https://doi. org/10.1177/2047487319832394; PMID: 30917695. 6. American Library Association Digital literacy. ALA, 2021. https://literacy.ala.org/digital-literacy (accessed 19 January 2021). 7. Royal College of Physicians. Outpatients: The future – adding value through sustainability. London: RCP, 2018. https://www. rcplondon.ac.uk/projects/outputs/outpatients-future-addingvalue-through-sustainability (accessed 19 January 2021). 8. Cravo Oliveira Hashiguchi T. Bringing health care to the patient: An overview of the use of telemedicine in OECD countries. Paris: OECD, 2020. https://doi.org/10.1787/8e56ede7-en. 9. U.S. Department of Health & Human Services. Telehealth: delivering care safely during COVID-19. Washington, DC: HHS, 2020. https://www.hhs.gov/coronavirus/telehealth/ index.html (accessed 19 January 2021). 10. Federation of State Medical Boards. U.S. states and territories modifying requirements for telehealth in response to COVID-19. FSMB, 2021. https://www.fsmb.org/siteassets/advocacy/pdf/ states-waiving-licensure-requirements-for-telehealth-inresponse-to-covid-19.pdf (accessed 19 January 2021). 11. Thiyagarajan A, Grant C, Griffiths F, et al. Exploring patients’ and clinicans’ experiences of video consultations in primary care: a systematic scoping review. BJGP Open 2020;4:bjgpopen20X101020. https://doi.org/10.3399/ bjgpopen20X101020; PMID: 32184212. 12. Donaghy E, Atherton H, Hammersley V, et al. Acceptability, benefits, and challenges of video consulting: a qualitative study in primary care. Br J Gen Pract 2019;69:e58–94. https://doi.org/10.3399/bjgp19X704141; PMID: 31160368. 13. Shaw SE, Seuren LM, Wherton J, et al. Video consultations between patients and clinicians in diabetes, cancer, and heart failure services: linguistic ethnographic study of videomediated interaction. J Med Internet Res 2020;22:e18378. https://doi.org/10.2196/18378; PMID: 32391799. 14. Seuren LM, Wherton J, Greenhalgh T, et al. Physical examinations via video for patients with heart failure: qualitative study using conversation analysis. J Med Internet Res 2020;22:e16694. https://doi.org/10.2196/16694; PMID: 32130133. 15. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129–200. https:// doi.org/10.1093/eurheartj/ehw128; PMID: 27206819. 16. Crespo-Leiro MG, Anker SD, Maggioni AP, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613–25. https://doi. org/10.1002/ejhf.566; PMID: 27324686. 17. Schiff GD, Fung S, Speroff T. Decompensated heart failure: symptoms, patterns of onset and contributing factors. Am J Med 2003;114:625–30. https://doi.org/10.1016/s00029343(03)00132-3; PMID: 12798449. 18. Rogers A, Addington-Hall J, Abery A, et al. Knowledge and communication difficulties for patients with chronic heart failure: qualitative study. BMJ 2000;321:605–7. https://doi. org/10.1136/bmj.321.7261.605; PMID: 10977838. 19. Clark AM, Freydberg CN, McAlister FA, et al. Patient and informal caregivers’ knowledge of heart failure: necessary but insufficient for effective self-care. Eur J Heart Fail 2009;11:617–21. https://doi.org/10.1093/eurjhf/hfp058; PMID: 19414477.

healthcare systems to re-evaluate reimbursement for digital technologies and has broken down many of the barriers to more widespread adoption of digital approaches to HF diagnosis and care.

20. Inglis SC, Clark RA, Dierckx Ret al. Structured telephone support or non-invasive telemonitoring for patients with heart failure. Cochrane Database Syst Rev 2015;10:CD007228. https://doi.org/10.1002/14651858.CD007228.pub3; PMID: 26517969. 21. Riley JP, Cowie MR. Telemonitoring in heart failure. Heart 2009;95:1964–8. https://doi.org/10.1136/hrt.2007.139378; PMID: 19923337. 22. Koehler F, Koehler K, Deckward O, et al. Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallelgroup, unmasked trial. Lancet 2018;392:1047–57. https://doi. org/10.1016/S0140-6736(18)31880-4; PMID: 30153985. 23. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2013;128:e240–327. https://doi.org/10.1161/ CIR.0b013e31829e8776; PMID: 23741058. 24. Centers for Disease Control and Prevention. Using telehealth to expand access to essential health services during the COVID-19 pandemic. Atlanta, GA: CDC, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/telehealth. html (accessed 19 January 2021). 25. Wilkoff BL, Auricchio A, Brugada J, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical considerations. Heart Rhythm 2008;5:907–25. https://doi. org/10.1016/j.hrthm.2008.04.013; PMID: 18551743. 26. Varma N, Epstein AE, Irimpen A, et al. Efficacy and safety of automatic remote monitoring for implantable cardioverterdefibrillator follow-up: the Lumos-T safely reduces routine office device follow-up (TRUST) trial. Circulation 2010;122:325–32. https://doi.org/10.1161/ CIRCULATIONAHA.110.937409; PMID: 20625110. 27. Hernández-Madrid A, Lewalter T, Proclemer A, et al. Remote monitoring of cardiac implantable electronic devices in Europe: results of the European Heart Rhythm Association survey. Europace 2014;16:129–32. https://doi.org/10.1093/ europace/eut414; PMID: 24344325. 28. Abraham WT. Intrathoracic impedance monitoring for early detection of impending heart failure decompensation. Congest Heart Fail 2007;13:113–5. https://doi. org/10.1111/j.1527-5299.2007.06255.x; PMID: 17392616. 29. Van Veldhuisen DJ, Braunschweig F, Conraads V, et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure. Circulation 2011;124:1719–26. https://doi.org/10.1161/ CIRCULATIONAHA.111.043042; PMID: 21931078. 30. Morgan JM, Kitt S, Gill J, et al. Remote management of heart failure using implantable electronic devices. Eur Heart J 2017;38:2352–60. https://doi.org/10.1093/eurheartj/ ehx227; PMID: 28575235. 31. Boehmer JP, Hariharan R, Devecchi FG, et al. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE Study. JACC Heart Fail 2017;:216–25. https://doi.org/10.1016/j. jchf.2016.12.011; PMID: 28254128. 32. Adamson PB, Gold MR, Bennett T, et al. Continuous hemodynamic monitoring in patients with mild to moderate heart failure: results of the Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic Heart Failure (REDUCEhf) trial. Congest Heart Fail 2011;17:248–54. https://doi.org/10.1111/j.1751-7133.2011. 00247.x; PMID: 21906250. 33. Abraham WT, Stevenson LW, Bourge RC, et al. Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet 2016;387:453– 61. https://doi.org/10.1016/S0140-6736(15)00723-0; PMID: 26560249. 34. Angermann CE, Assmus B, Anker SD, et al. Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). Eur J Heart Fail 2020;22:1891–901. https://doi.org/10.1002/ejhf.1943; PMID: 32592227. 35. Cowie MR, de Groote P, McKenzie S, et al. Rationale and design of the CardioMEMS Post-Market Multinational Clinical Study: COAST. ESC Heart Fail 2020;7:865–72. https://doi. org/10.1002/ehf2.12646; PMID: 32031758 36. US Food & Drug Administration. Device software functions including mobile medical applications. Washington, DC: FDA, 2019. https://www.fda.gov/medical-devices/digital-

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health-center-excellence/device-software-functionsincluding-mobile-medical-applications (accessed 19 January 2021). 37. Mortara A, Vaira L, Palmieri V, et al. Would you prescribe mobile health apps for heart failure self-care? An integrated review of commercially available mobile technology for heart failure patients. Card Fail Rev 2020;6:e13. https://doi. org/10.15420/cfr.2019.11; PMID: 32537246. 38. Cajita MI, Cajita TR, Han HR. Health literacy and heart failure: a systematic review. J Cardiovasc Nurs 2016;31:121– 30. https://doi.org/10.1097/JCN.0000000000000229; PMID: 25569150. 39. Clark AM, Freydberg CN, McAlister FA, et al. Patient and informal caregivers’ knowledge of heart failure: necessary but insufficient for effective self-care. Eur J Heart Fail 2009;11:617–21. https://doi.org/10.1093/eurjhf/hfp058; PMID: 19414477. 40. Evidence standards framework for digital health technologies. National Institute for Health and Care Excellence (2021). https://www.nice.org.uk/about/what-wedo/our-programmes/evidence-standards-framework-fordigital-health-technologies (accessed 23 April 2021). 41. Kooiman TJM, Dontje ML, Sprenger SR, et al. Reliability and validity of ten consumer activity trackers. BMC Sports Sci Med Rehabil 2015;7:24. https://doi.org/10.1186/s13102-015-0018-5; PMID: 26464801. 42. Allen J. Photoplethysmography and its application in clinical physiological measurement. Physiol Meas 2007;28:R1–39. https://doi.org/10.1088/0967-3334/28/3/R01; PMID: 17322588. 43. Feehan LM, Geldman J, Sayre EC, et al. Accuracy of Fitbit devices: systematic review and narrative syntheses of quantitative data. JMIR Mhealth Uhealth 2018;6:e10527. https://doi.org/10.2196/10527; PMID: 30093371. 44. Cadmus-Bertram L, Gangnon R, Wirkus EJ, et al. The accuracy of heart rate monitoring by some wrist-worn activity trackers. Ann Intern Med 2017;166:610–2. https://doi. org/10.7326/L16-0353; PMID: 28395305. 45. Moayedi Y, Abdulmajeed R, Duero Posada J, et al. Assessing the use of wrist-worn devices in patients with heart failure: feasibility study. JMIR Cardio 2017;1:e8. https:// doi.org/10.2196/cardio.8301; PMID: 31758789. 46. Paradkar N, Chowdhury SR. Cardiac arrhythmia detection using photoplethysmography. Annu Int Conf IEEE Eng Med Biol Soc 2017;2017:113–6. https://doi.org/10.1109/ EMBC.2017.8036775; PMID: 29059823. 47. Chan PH, Wong CK, Poh YC, et al. Diagnostic performance of a smartphone-based photoplethysmographic application for atrial fibrillation screening in a primary care setting. J Am Heart Assoc 2016;5:e003428. https://doi.org/10.1161/ JAHA.116.003428; PMID: 27444506. 48. Perez M V., Mahaffey KW, Hedlin H, et al. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med. 2019;381:1909–17. https://doi.org/10.1056/ NEJMoa1901183; PMID: 31722151. 49. Ip JE. Wearable devices for cardiac rhythm diagnosis and management. JAMA 2019;321:337–8. https://doi.org/10.1001/ jama.2018.20437; PMID: 30633301. 50. Kuwabara M, Harada K, Hishiki Y, Kario K. Validation of two watch-type wearable blood pressure monitors according to the ANSI/AAMI/ISO81060-2:2013 guidelines: Omron HEM6410T-ZM and HEM-6410T-ZL. J Clin Hypertens (Greenwich) 2019;2:853–8. https://doi.org/10.1111/jch.13499; PMID: 30803128. 51. Rostagno C, Olivo G, Comeglio M, et al. Prognostic values of 6-minute walk corridor test in patients with mild to moderate heart failure: comparison with other methods of functional evaluation. Eur J Heart Fail 2003;5:247–52. https:// doi.org/10.1016/s1388-9842(02)00244-1; PMID: 12798821. 52. Loprinzi PD. The effects of free-living physical activity on mortality after congestive heart failure diagnosis. Int J Cardiol 2016;203:598–9. https://doi.org/10.1016/j.ijcard.2015.11.017; PMID: 26574935. 53. Izawa KP, Watanabe S, Oka K, et al. Usefulness of step counts to predict mortality in Japanese patients with heart failure. Am J Cardiol 2013;111:1767–71. https://doi.org/10.1016/j. amjcard.2013.02.034; PMID: 23540653. 54. Alharbi M, Straiton N, Gallagher R. Harnessing the potential of wearable activity trackers for heart failure self-care. Curr Heart Fail Rep 2017;14:23–9. https://doi.org/10.1007/s11897017-0318-z; PMID: 28181075. 55. Thorup C, Hansen J, Grønkjær M, et al. Cardiac patients’ walking activity determined by a step counter in cardiac

Digital Health: Implications For HF Management telerehabilitation: data from the intervention arm of a randomized controlled trial. J Med Internet Res 2016;18:e69. https://doi.org/10.2196/jmir.5191; PMID: 27044310. 56. Fraser AG, Byrne RA, Kautzner J, et al. Implementing the new European Regulations on medical devices – clinical responsibilities for evidence-based practice: a report from the Regulatory Affairs Committee of the European Society of Cardiology. Eur Heart J 2020;41:2589–96. https://doi. org/10.1093/eurheartj/ehaa382; PMID: 32484542. 57. Jensen MT, Treskes RW, Caiani EG, et al. ESC working group on e-cardiology position paper: use of commercially available wearable technology for heart rate and activity tracking in primary and secondary cardiovascular prevention. Eur Heart J Digital Health 2021. https://doi. org/10.1093/ehjdh/ztab011; epub ahead of press. 58. Stehlik J, Schmalfuss C, Bozkurt B, et al. Continuous wearable monitoring analytics predict heart failure hospitalization: the LINK-HF Multicenter Study. Circ Heart Fail 2020;13:e006513. https://doi.org/10.1161/ CIRCHEARTFAILURE.119.006513; PMID: 32093506. 59. Attia ZI, Noseworthy PA, Lopez-Jimenez F, et al. An artificial intelligence-enabled ECG algorithm for the identification of

patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction. Lancet 2019;394:861–7. https://doi.org/10.1016/S0140-6736(19)317210; PMID: 31378392. 60. Adedinsewo D, Carter RE, Attia Z, et al. Artificial intelligenceenabled ECG algorithm to identify patients with left ventricular systolic dysfunction presenting to the emergency department with dyspnea. Circ Arrhythm Electrophysiol 2020;13:e008437. https://doi.org/10.1161/CIRCEP.120.008437; PMID: 32986471. 61. Dey D, Slomka PJ, Leeson P, et al. Artificial intelligence in cardiovascular imaging: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:1317–35. https://doi.org/10.1016/j. jacc.2018.12.054; PMID: 30898208. 62. Tucker KL, Sheppard JP, Stevens R, et al. Self-monitoring of blood pressure in hypertension: a systematic review and individual patient data meta-analysis. PLoS Med 2017;14:e1002389. https://doi.org/10.1371/journal. pmed.1002389; PMID: 28926573. 63. Cowie MR, Bax J, Bruining N, et al. e-Health: a position statement of the European Society of Cardiology. Eur Heart J 2016;37:63–6. https://doi.org/10.1093/eurheartj/ehv416;

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PMID: 26303835. 64. WHO. mHealth: new horizons for health through mobile technologies. Geneva: WHO, 2011. https://www.who.int/goe/ publications/goe_mhealth_web.pdf (accessed 19 January 2021). 65. WHO. Telehealth. 2016. https://www.who.int/gho/goe/ telehealth/en/ (accessed 19 January 2021). 66. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:1169–86. https://doi.org/10.1002/ejhf.1531; PMID: 31129923. 67. American Heart Association. Using remote patient monitoring technologies for better cardiovascular disease outcomes: guidance. AHA, 2019. https://www.heart.org/-/media/files/ about-us/policy-research/policy-positions/clinical-care/ remote-patient-monitoring-guidance-2019.pdf (accessed 19 January 2021).

Clinical Syndromes

Fatal Enterovirus-related Myocarditis in a Patient with Devic’s Syndrome Treated with Rituximab Ava Diarra ,1 Guillaume Gantois ,2 Mouna Lazrek ,3 Basile Verdier,4 Vincent Elsermans ,5 Hélène Zephir ,6 Benjamin Longère ,7 Xristos Gkizas,7 Céline Goeminne ,4 Gilles Lemesle ,4 Francis Juthier ,4 Johana Bene,8 David Launay ,1,9,10 Romain Dubois,11 Sandrine Morell-Dubois ,1 Fanny Vuotto 12 and Anne-Laure Piton1 1. Department of Internal Medicine and Clinical immunology, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), CHU Lille, Lille, France; 2. Centre for Anaesthesia and Resuscitation, CHU Lille, Lille, France; 3. Laboratory of Virology, CHU Lille, Lille University, EA3610, Lille, France; 4. Department of Cardiology, CHU Lille, Lille, France; 5. Institute of Immunology, CHU Lille, Lille, France; 6. CRC-SEP, CHU Lille, Lille, France; 7. Department of Cardiovascular Radiology, CHU Lille, Lille, France; 8. Regional Centre of Pharmacovigilance, CHU Lille, Lille, France; 9. Institute for Translational Research in Inflammation (INFINITE – U1286), Lille, France; 10. Inserm, Lille, France; 11. Department of Anatomy and Pathology, CHU Lille, Lille, France; 12. Department of Infectious Diseases, CHU Lille, Lille, France

Abstract

Enteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses – in particular, the Coxsackie B viruses – are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies.

Keywords

Devic’s syndrome, enterovirus, myocarditis, rituximab Disclosure: The authors have no conflicts of interest to declare. Received: 23 December 2020 Accepted: 15 January 2021 Citation: Cardiac Failure Review 2021;7:e09. DOI: https://doi.org/10.15420/cfr.2020.33 Correspondence: Ava Diarra, CHU Lille, Département de médecine interne et immunologie clinique, Centre de référence des maladies autoimmunes systémiques rares du Nord et Nord-Ouest de France (CeRAINO), F-59000 Lille, France. E: ava.diarra@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Devic’s syndrome (or neuromyelitis optica spectrum disorder; NMOSD) is a rare autoimmune disorder involving the central nervous system. The disease spectrum includes longitudinally extensive transverse myelitis and optic neuritis. Treatment relies on high-dose steroids and maintenance immunosuppressant therapy, such as rituximab.1 Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. It causes depletion of CD20+ B cells and decreased immunoglobulin production.

The differential diagnosis included autoimmune or giant-cell myocarditis. This case highlights the importance of the complete diagnosis workup in difficult cases of myocarditis, including endomyocardial biopsies.

Many reports in the literature suggest a higher risk of infection – including viral infection – following repeated rituximab therapy.2 Human enteroviruses are a group of viruses related to the picornavirus family. They are a known cause of myocarditis – in particular Coxsackie B viruses.3 Reports of enterovirus-related myocarditis due to rituximab are scarce.4,5 Cases of acute fatal viral myocarditis are mostly described among neonatal and young patients, in contrast to chronic forms of heart failure and dilated cardiomyopathy, which are more common in the adult population.6

Case Report

Here, we describe the case of a patient with NMOSD who developed a severe and fatal enterovirus-related myocarditis after rituximab therapy.

In accordance with French legislation, written information was provided and consent was obtained from the patient. French legislation does not require that written consent is obtained for this type of study. We report a 29-year-old patient with NMOSD associated with antiaquaporin-4-antibodies. She experienced multiple retrobulbar optic neuritis despite corticosteroid therapy. Since 2012, she received prednisone pulses and plasma exchange for the management of these optical attacks. Since the introduction of rituximab in 2012, prednisone and plasma exchange were not repeated. A 1 g dose of rituximab was administered on day 1, repeated on day 15, then followed by rituximab maintenance therapy of 1 g every 6 months for 7 years. The eleventh and final rituximab infusion was performed in September 2019, thus a total dose of 11 g had been administered with three missed administrations over the years of treatment due to pregnancies.

Enterovirus-related Myocarditis in a Rituximab-treated Patient Prior to rituximab initiation, the patient’s immunoglobulin level was normal (gammaglobulin 9.6 g/l; normal range 8.0–13.5 g/l) along with CD4 cell count (755/mm3; normal range 400–1,300/mm3). After rituximab treatment, CD19 depletion was complete. Immunoglobulin G (IgG) level in the remission phase of the disease was low, reaching 6.2 g/l. In November 2019, 2 months after the last rituximab infusion, the patient suddenly developed cyanotic acute respiratory failure and loss of consciousness while resting. When the rescue team found the patient, she was in cardiac arrest. Transthoracic echocardiogram revealed a left ventricle ejection fraction of 35% (compared with a normal value of 65%during a previous assessment in 2012). Cardiac MRI revealed global hypokinesia with concentric left ventricle hypertrophy and significant increase of T2 mapping values, suggesting a diffuse myocardial oedema. CT coronary angiography revealed no significant stenosis. A subcutaneous defibrillator was implanted on day 22 post cardiac arrest. The patient was eventually discharged without a clear final diagnosis. On day 47, 10 days after discharge, she was re-admitted to the intensive cardiac care unit with recurrent ventricular tachycardia, despite treatment with amiodarone and lidocaine, resulting in severe cardiogenic shock. With the working hypothesis of giant cell myocarditis, she received prednisone pulses before further results. Myocardial biopsy was performed on day 51. It revealed acute inflammatory myocardial lymphocytic infiltrate with no signs of giant cells or eosinophilic infiltration. We completed the diagnostic workup, including exhaustive serology and molecular testing. This revealed a positive enterovirus reverse-transcriptase polymerase chain reaction (RT-PCR) on blood, identified as Coxsackie type B4. The first positive enterovirus RTPCR on blood was reported on day 47. Retrospectively, the analysis of blood sample and pectoral biopsies dating from days 12 and 22 were also positive for enterovirus. Enterovirus RT-PCR was also strongly positive on myocardial tissue. Stool and throat samples were negative, suggesting a long-term enteroviral infection. Based on these results, the final diagnosis was acute enterovirus-related myocarditis in an immunocompromised patient receiving rituximab. In the absence of specific antiviral treatment, she received IV immunoglobulin 0.4 g/kg/day over 5 days from day 53 to day 57 along with blood PCR monitoring. Enterovirus viral load dramatically decreased from the initiation of IV immunoglobulin therapy. Heart transplantation would have been the best therapeutic option in this situation. However, our patient had high panel reactive alloantibodies and no desensitisation strategies allowing access to heart transplantation in safe conditions. She was finally implanted with a biventricular extracorporeal total artificial heart (Berlin Heart) as a bridge to transplant. Nonetheless, after 6 weeks of intensive resuscitation the patient deteriorated despite maximum therapy and ultimately died on day 91.

Discussion

We describe the case of a patient with NMOSD who developed a severe and fatal enterovirus-related myocarditis after rituximab therapy. Because of the multiple possible causes of myocarditis in this context, we considered the following hypotheses. First, we explored the possibility of a cardiac manifestation of the underlying autoimmune condition. To our knowledge, no cardiac symptoms have been described so far with NMOSD. Second, in light of the severe presentation and

rhythmic disorders, we considered giant cell myocarditis. This particular myocarditis affects younger patients with an autoimmune disorder in 20% of cases, causing rapidly progressive and heart failure that is frequently fatal.7 Because of the patient’s severe presentation, we decided to start immediate corticosteroids and consider rapid immunosuppression. However, we were concerned by the immunocompromised status of the patient. Moreover, although guidelines are scarce, official guidelines of the European Society of Cardiology advocates the role of endomyocardial biopsies in the management of patients with viral PCR both on blood and myocardium.8 Thus, before starting immunosuppression, we performed a thorough diagnostic workup including myocardial biopsies. In our patient, RT-PCR for enterovirus was positive both in blood and in myocardium, establishing the diagnosis of enterovirus-related myocarditis. Interestingly, the PCR was positive for samples taken during herfirst admission, allowing us to consider retrospectively that the patient had this diagnosis since the first event. Severe enterovirus infections, including meningoencephalitis and myocarditis, are usually described among neonates. Among adults, patients with primary humoral immune deficiencies such as Bruton’s X-linked agammaglobulinaemia are more likely to develop chronic enterovirus meningoencephalitis. Low immunoglobulin count increases sensitivity toward enteroviral infections. Our patient was clearly immunocompromised as a result of the rituximab treatment, having low levels of IgG, immunoglobulin (IgM) and CD19. Rituximab induces B-cell depletion via different mechanisms, including complement- and antibody-dependent cellular cytotoxicity along with induced apoptosis. CD20-expressing cells remain undetectable for approximately 6 months post first administration.9 Repeated cycles of rituximab are associated with low IgM and, to a lesser degree, low IgG, especially in patients with an underlying B-cell maturation defect. However, data concerning the risk of infection associated with rituximab are contradictory, varying according to the population studied and the accompanying treatments. Some studies do not find significant increase in the risk of infection under rituximab therapy, despite decreased immunoglobulin levels, whereas multiple reports have identified a link between rituximab regimen therapy and the occurrence of severe infection.9 Moreover, in a recent study, our team showed that the 1- and 2-year incidences of serious infections were 17.3 (12.0–22.5) and 11.3 (8.1–14.5) per 100 person-years, respectively. Identified risk factors of severe infections were age, history of diabetes, history of cancer, concomitant steroid treatment and low CD4 lymphocyte count at rituximab initiation. Immunoglobulin replacement therapy was started in 22 rituximab courses (8%).10 Acute and chronic enterovirus meningoencephalitis have been described among patients under rituximab therapy for B-cell malignancies or autoimmune disorders. Chronic enteroviral myocarditis is more frequent among adults, resulting in dilated cardiomyopathy.11–13 However, rituximabrelated enterovirus myocarditis observations are very scarce. Only one report of a child receiving rituximab treatment for nephrotic syndrome and one report of an adult treated for lymphoma were found in the literature. 4,5 In terms of treatment, by the time the diagnosis of enterovirus had been made, the patient’s clinical status was already severely compromised.

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Enterovirus-related Myocarditis in a Rituximab-treated Patient Therapeutic options are scarce. Pleconaril, pirodavir, and vapendavir are capsid-binding agents that are theoretically active on enteroviruses with modest antiviral activity, unapproved in the therapeutic arsenal of enterovirus infections. Interferon beta has been tested in phase 2 trials for cases of persistent left ventricle dysfunction linked to chronic enteroviral infection, but without success. In the absence of availability of specific treatments, we started IV immunoglobulin therapy, based on protocols used in paediatric and immunocompromised populations. Of note, following IV immunoglobulin therapy, the enteroviral RNA load rapidly dropped to zero, yet without any obvious effect on clinical status and myocardium recovery. 1. Patterson SL, Goglin SE. Neuromyelitis optica. Rheum Dis Clin N Am 2017;43:579–91. https://doi.org/10.1177/ 1352458513495939; PMID: 23846353. 2. Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456–73. https://doi.org/10.1016/j. ctrv.2005.05.007; PMID: 16054760. 3. Fairley CK, Ryan M, Wall PG, et al. The organisms reported to cause myocarditis and pericarditis in England and Wales. J Infect 1996;32:223–5. https://doi.org/10.1016/s01634453(96)80023-5; PMID: 8793712. 4. Sellier-Leclerc A-L, Belli E, Guérin V, et al. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr Nephrol 2013;28:1875–9. https://doi. org/10.1007/s00467-013-2485-9; PMID: 23700173. 5. Alonso JJ, Cánovas A, Rubio G. Lethal enterovirus myocarditis associated with rituximab and chemotherapy for follicular lymphoma. Med Clínica (Barc) 2013;141:459–60 [in Spanish]. https://doi.org/10.1016/j.medcli.2013.03.001; PMID: 23622890.

Our case is a red flag for physicians about the possible association between rituximab and life-threatening enteroviral myocarditis in other immunocompromised patients. It also highlights the importance of a correct diagnostic workup including endomyocardial biopsies and viral PCR. Without them, we could have wrongly concluded on autoimmune myocarditis or giant cell myocarditis. In our case, despite a fatal course of evolution, the administration of IV immunoglobulin was highly effective on enterovirus RNA viral load, yet without leading to clinical improvement in an already severe patient. Earlier administration – when the patient was first admitted – may have changed the course and the patient’s outcome.

6. Kim -S, Hufnagel G, Chapman NM and Tracy S. The group B coxsackieviruses and myocarditis. Rev Med Virol 2001;11:355–68. https://doi.org/10.1002/rmv.326; PMID: 11746998. 7. Kasouridis I, Majo J, MacGowan G and Clark AL. Giant cell myocarditis presenting with acute heart failure. BMJ Case Rep 2017;bcr-2017-219574. http://doi.org/10.1136/bcr-2017219574; PMID: 28536222. 8. Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636–48. https://doi.org/10.1093/eurheartj/eht210; PMID: 23824828. 9. Cooper N, Arnold DM. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol 2010;149:3–13. https://doi.org/10.1111/j.1365-2141.2010.08076.x;

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PMID: 20151975. 10. Stabler S, Giovannelli J, Launay D, et al. Serious infectious events and immunoglobulin replacement therapy in patients with autoimmune diseases receiving rituximab: a retrospective cohort study. Clin Infect Dis 2021;72:727–37. https://doi.org/10.1093/cid/ciaa127; PMID: 32067031. 11. Kim K-S, Hufnagel G, Chapman NM, Tracy S. The group B coxsackieviruses and myocarditis. Rev Med Virol 2001;11:355–68. https://doi.org/10.1002/rmv.326; PMID: 11746998. 12. Rose NR. Viral myocarditis. Curr Opin Rheumatol 2016;28(4):383–9. https://doi.org/10.1097/ BOR.0000000000000303; PMID: 27166925. 13. Liu Z, Yuan J, Yanagawa B, Qiu D, McManus BM, Yang D. Coxsackievirus-induced myocarditis: new trends in treatment. Expert Rev Anti Infect Ther 2005;3(4):641–50. https://doi.org/10.1586/14787210.3.4.641; PMID: 16107202.

Comorbidities

Hyperkalaemia in Heart Failure Umar Ismail , Kiran Sidhu and Shelley Zieroth Section of Cardiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

Abstract

Hyperkalaemia has become an increasingly prevalent finding in patients with heart failure (HF), especially with renin–angiotensin–aldosterone system (RAAS) inhibitors and angiotensin–neprilysin inhibitors being the cornerstone of medical therapy. Patients living with HF often have other comorbidities, such as diabetes and chronic kidney disease, which predispose to hyperkalaemia. Until now, we have not had any reliable or tolerable therapies for the treatment of hyperkalaemia to facilitate implementation or achievement of target doses of RAAS inhibition. Patiromer sorbitex calcium and sodium zirconium cyclosilicate are two novel potassium-binding resins that have shown promise in the management of patients predisposed to developing recurrent hyperkalaemia, and their use may allow for further optimisation of guideline directed medical therapy.

Keywords

Chronic kidney disease, heart failure, hyperkalaemia, patiromer, sodium zirconium cyclosilicate Disclosure: SZ has received consulting and speaking fees from Astra Zeneca and Vifor. All other authors have no conflicts of interest to declare. Received: 7 December 2020 Accepted: 24 January 2021 Citation: Cardiac Failure Review 2021;7:e10. DOI: https://doi.org/10.15420/cfr.2020.29 Correspondence: Shelley Zieroth, Room Y3014, St Boniface Hospital, 409 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada. E: szieroth@sbgh.mb.ca Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is defined as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood”.1 Hyperkalaemia is commonly encountered in HF patients. Registry data estimate the prevalence to be between 16% and 25%.2,3 The definition of hyperkalaemia varies, but has generally been defined as a potassium level >5 mEq/l.4 It can be further subclassified into mild (5–5.5 mEq/l), moderate (5.5–6 mEq/l) and severe (>6 mEq/l).1 Hyperkalaemia poses a major obstacle in the management of HF patients. It can result in electrical issues from conduction system abnormalities to life-threatening rhythm disorders and interference with defibrillator function.5 It can also lead to the downtitration and discontinuation of renin–angiotensin–aldosterone system inhibitors (RAASi) and angiotensin–neprilysin inhibitors, which are the cornerstones of HF therapy.6,7 Furthermore, hyperkalaemia is a marker associated with an increase in hospital length of stay and mortality.8

Pathophysiology of Hyperkalaemia

Hyperkalaemia occurs due to decreased excretion or increased intake of potassium (Table 1). Potassium levels are tightly regulated in the body; under normal circumstances, 98% of potassium is intracellular, with 2% being extracellular in the plasma.9 Approximately 90% of the potassium filtered through the glomerulus will be reabsorbed in the proximal tubule and the loop of Henle, and 10% will reach the distal tubules.9 During times of renal hypoperfusion, such as in HF, renin is secreted by the juxtaglomerular cells in the kidneys; this allows angiotensinogen to be cleaved to angiotensin I, which is then converted to angiotensin II in the endothelial cells of the lungs under the influence of angiotensinconverting enzyme (ACE).10 Angiotensin II acts on the cells of the zona glomerulosa to secrete aldosterone, which in turn promotes sodium and

water retention.10 Aldosterone activates the Na+/K+ pumps in the basolateral membrane of the distal tubule and collecting ducts, creating a concentration gradient that results in the reabsorption of sodium and secretion of potassium ions. It also upregulates the epithelial sodium channels and potassium efflux at the luminal surface leading to further reabsorption of sodium and excretion of potassium.10 Patients with HF often have other comorbidities, including diabetes, chronic kidney disease (CKD) and hypertension.1 Therefore, the aetiology of hyperkalaemia in patients with HF can be multifactorial, as seen in acute decompensated HF, cardiogenic shock and chronic HF.11,12 Kidney injury, which may be in the setting of cardiorenal syndrome (type I and type II), results in hyperkalaemia due to reduced renal potassium excretion.11 Some diabetic patients can develop a type IV renal tubular acidosis that can directly result in hyperkalaemia.10 In clinical practice, medications are the most common cause of hyperkalaemia in HF patients. ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) decrease the production of aldosterone in the adrenal gland, while mineralocorticoid receptor antagonists (MRA) block the receptor.13,14

Incidence and Significance of Hyperkalaemia in the Heart Failure Population

Clinical trials involving RAASi have demonstrated varying rates of hyperkalaemia due to variability in the definition of hyperkalaemia used. In SOLVD, there was a 7.8% occurrence of hyperkalaemia (defined as a potassium level >5.5 mEq/l) in the enalapril arm compared with placebo.15 In CHARM, the incidence of hyperkalaemia was 5.2%.16 In PARADIGM-HF, the incidence of hyperkalaemia (potassium level >5.5 mEq/l) was similar

Hyperkalaemia in Heart Failure Table 1: Common Aetiologies for Hyperkalaemia in Heart Failure Patients

non-fatal cardiac events, as well as overall mortality.27 For MRAs in particular, registry analyses show that many other factors are associated with their underutilisation, including CKD, higher ejection fraction, male sex, older age and lower income.28

• Increased potassium supplementation from diet • Metabolic shifts • Hyperglycaemia • Metabolic acidosis • Iatrogenic • Renin–angiotensin–aldosterone system inhibitors • Angiotensin–neprilysin inhibitors • Digoxin • β-blockers • Chronic kidney disease • Type IV renal tubular acidosis between the sacubitril/valsartan and the enalapril arms, but the incidence of severe hyperkalaemia was lower in the sacubitril/valsartan arm (4.3% versus 5.6%).17 Interestingly, a follow-up analysis of PARADIGM-HF showed that sacubitril/valsartan had no effect on potassium levels overall, and in fact, those on therapy had a slight reduction in potassium levels compared with enalapril, especially when the latter was combined with an MRA.18 In EMPHASIS-HF, hyperkalaemia (defined as a potassium level >5.5 mEq/l) occurred in 11.8% of patients receiving eplerenone, whereas serious hyperkalaemia (potassium level >6 mEq/l) occurred in 2.5% of patients in the eplerenone group.19 In RALES, where an ACEi was combined with spironolactone, the incidence of hyperkalaemia (potassium level >5.5 mEq/l) was 13%, whereas serious hyperkalaemia (potassium level >6 mEq/l) was seen in only 2% of patients.20 Following the publication of RALES, data from Ontario, Canada showed a higher incidence of serious hyperkalaemia and higher rates of hospitalisation and in-hospital mortality. Those findings were later attributed to the widespread inappropriate prescription of MRAs.21,22 More recently, in January 2020, Rossignol et al. used the EPHESUS data to develop a risk prediction score that was then validated in the EMPHASIS cohort.23 The risk model incorporated multiple variables, including MRA use and time-dependent potassium levels. They found this model to be better than the MAGGIC score to describe the risk of cardiovascular events.23 A strong relationship between potassium levels and mortality in patients with chronic HF has been demonstrated in multiple trials.3,24,25 This may lead the clinician to consider withdrawal of therapies with proven mortality benefit, which may also lead to higher mortality.3 Beusekamp et al. analysed patients in the PROTECT trial to look for associations between hyperkalaemia and mortality in patients admitted for HF exacerbations.26 Potassium levels were followed daily until discharge or day 7 of admission. RAASi use was common, with 76% of patients on an ACEi and 46% on an MRA. Incident hyperkalaemia (defined as any potassium level >5 mEq/l) was seen in 35% of patients. Although incident hyperkalaemia was not associated with increased mortality at 180 days, it was associated with downtitration or even discontinuation of RAASi, especially MRAs, a variable that was independently associated with increased mortality.26 These findings are further supported by real-world data published from a large observational cohort of more than 114,000 patients (most had CKD and 13,113 had HF), where potassium levels >5 mEq/l led to downtitration of RAASi. This change was independently associated with major fatal and

A Swedish nationwide registry found that the association between potassium levels and mortality in HF patients was U-shaped, and suggested that the optimal potassium level in HF patients is 4.2 mEq/l, with higher and lower levels associated with higher mortality.29 Interestingly, another analysis of the Swedish registry noted that the incidence of hyperkalaemia was higher in patients with HF with preserved ejection fraction, including severe hyperkalaemia.30 The 2016 European Society of Cardiology Guidelines recommend short-term cessation of RAASi and MRAs to manage acute hyperkalaemia, followed by careful reintroduction of the discontinued drug(s).4 These guidelines were published prior to the trials discussed above.

Acute Management of Hyperkalaemia

The most dreaded consequence of hyperkalaemia is the development of electrical abnormalities.31 As such, it is of paramount importance to stabilise the myocardial membrane with intravenous calcium, either in the form of calcium gluconate or calcium chloride, both of which act within 5 minutes.31 Potential side-effects include vasodilation-related hypotension and bradycardia. Calcium itself does not lower potassium levels in the bloodstream.31 Calcium chloride contains three times more elemental calcium than calcium gluconate. Therefore, in acute situations, calcium chloride is preferred. However, in less critical cases, the preferred agent is the gluconate salt, because it is less likely to cause tissue necrosis if it extravasates.32 To acutely lower the potassium levels in the blood, agents that shift potassium from the extracellular to the intracellular space are utilised (Figure 1A). The most commonly used agents are short-acting insulins in combination with 25–50g of dextrose (unless hyperglycaemic). Insulin shifts potassium into the intracellular compartment via the action of the Na+/K+ ATPase pump. It works rapidly within 15 minutes. β2 agonists work similarly. Salbutamol is usually given at a dose of 10 mg and acts within 15–30 minutes. Side-effects include tachycardia, anxiety and headaches. Sodium bicarbonate can also be considered if the acutely hyperkalaemic patient is acidotic.33 After stabilisation, the next step is elimination. This is typically accomplished with loop diuretics, commonly furosemide. Furosemide works by inhibiting the Na+/K+/2Cl– cotransporter in the loop of Henle, and thus blocking sodium and potassium reabsorption. Increased sodium delivery to the distal nephron stimulates potassium excretion. Loop diuretics can precipitate hypokalaemia and are typically reserved for hyperkalaemic patients who are volume overloaded. Dialysis is recommended in cases of hyperkalaemia refractory to medical management (Figures 1B and 1C).34 The final step of hyperkalaemia management is maintenance. This is usually achieved on a long-term basis by eliminating the precipitants, minimising intake in the diet and reducing supplementation. Finally, binding resins can also be used if recurrent hyperkalaemia becomes an issue.5,35

Chronic Management of Hyperkalaemia in HF Sodium Polystyrene Sulfate

Sodium polystyrene sulfate (SPS) is the oldest binding resin available. It is a non-specific binder that works to bind potassium ions in the gut in

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Hyperkalaemia in Heart Failure Figure 1: Mechanism of Action of Drugs for Hyperkalaemia A

ECF

2. HCO3−/K+ cotransporter

1. Na+/K+ ATPase

2K+

2HCO3−

Na+

ATPase

3Na+

Insulin β2 agonist

3Na+ ICF

D Interstitium Na+ K+

TAL

Sodium zirconium cyclosilicate

Na+/K+/2Cl− cotransporter 2Cl−

Loop diuretics

Intraluminal space

Sodium polystyrene sulfate

Patiromer

1: Shift K+ into cells. A: β2 agonists and insulin stimulate the Na+/K+ ATPase allowing exchange of extracellular K+ for intracellular sodium. B: Sodium bicarbonate stimulates the HCO3–/K+ cotransporter promoting HCO3– and K+ cotransport in exchange for intracellular sodium. 2: Promote K+ removal. C: Through the urine. Loop diuretics work on the thick ascending limb of the loop of Henle inhibiting the Na+/K+/2Cl– cotransporter and resulting in decreased Na+ and K+ reabsorption. D: Via the gastrointestinal tract (GI). Sodium zirconium cyclosilicate, patiromer, and sodium polystyrene sulfate work by binding K+ in exchange for H+, Ca2+, and Na+, respectively, in the GI lumen, allowing more K+ excretion. ECF = extracellular fluid; ICF = intracellular fluid; S = sorbitol; TAL = thick ascending limb. Source: Sidhu et al. 2020.62 Adapted with permission from Wolters Kluwer Health.

exchange for sodium (Figure 1D). As it is non-specific, it can also bind to calcium and magnesium. The potassium-bound SPS is eventually eliminated from the body in the faeces.36 The initial evidence for the use of SPS, culminating in its approval in hyperkalaemia, comes from two small trials published in the early 1960s.37,38 SPS is combined with sorbitol to relieve its constipating effects. It can be administered either as an oral (15 g 1–4 times/day) or rectal formulation (30–50 g every 6 hours). SPS use for hyperkalaemia is hampered by the fact that it has not been studied in large randomised controlled trials.39 One small trial of 33 outpatients with CKD evaluated the effect of SPS on mild hyperkalaemia (5–5.9 mmol/l) at a dose of 30 g for 7 days. The average reduction in potassium was 1.25 mEq/l. Normokalaemia was achieved in 73% of the patients on SPS.40 The main side-effects of SPS are gastrointestinal (GI), and include nausea, vomiting, constipation and diarrhoea. Serious side-effects have been reported with SPS, including colonic perforation and necrosis.41,42 This has been mainly attributed to the sorbitol added to SPS, which led to a black box warning in 2009 by the Food and Drug Administration. More relevant

to a HF population, SPS can lead to worsening HF symptoms, as it exchanges potassium ions for sodium ions.43

Sodium Zirconium Cyclosilicate

Sodium zirconium cyclosilicate (SZC) is a novel binding resin. It is a nonabsorbable, inorganic polymer of zirconium silicate, with the ion channels formed by its atomic structure mimicking those of endogenous potassium channels.44 It preferentially captures potassium ions, in exchange for hydrogen and sodium ions, through a selectivity filter (Figure 1D). SZC works in the entirety of the GI tract; is not systemically absorbed and is excreted in the faeces. In vitro studies have shown that SZC can achieve a potassium equilibrium in as early as 20 minutes.45 As such, it can be used for acute (10 mg orally three-times a day for up to 48 hours) and chronic hyperkalaemia (5–15 mg orally daily). SZC demonstrated significant efficacy in reducing K+ levels when used for hyperkalaemia in an emergency department setting compared with placebo, regardless of aetiology.46 When used as maintenance for chronic hyperkalaemia, SZC can be continued as long as it is clinically indicated.44

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Hyperkalaemia in Heart Failure Table 2: Studies that Evaluated Sodium Zirconium Cyclosilicate in Hyperkalaemia Trial

Population

Intervention

ZS-003: Double-blind phase III RCT44

753 patients with K+ 5–6.5 mmol/l • 60% CKD • 60% diabetes • 40% HF • 67% RAASi

SZC at doses of 1.25–10 g three K+ values at 48 hours, times daily for 48 hours, then once 2 weeks daily for 2 weeks Placebo for 48 hours, then for 2 weeks

Endpoints

Results At 48 hours: reduction of K+ by 0.46, 0.54, and 0.73 mmol/l in the 2.5, 5 and 10 g groups, respectively, and 0.25 mmol/l with placebo At 2 weeks: for those who received 5 g and 10 g SZC, K+ levels were 4.76 mmol/l and 4.58 mmol/l, respectively, compared with 5.10 mmol/l in the placebo group

HARMONIZE (ZS-004): Doubleblind phase III RCT48

258 patients with K+ >5 mmol/l • 66% CKD • 66% diabetes • 36% HF • 70% RAASi

Phase 1 (open label): all patients received 10 g of SZC three times daily for 48 hours Phase 2 (randomised): normokalaemic patients randomised to: • 5–15 g of SZC for 4 weeks • Placebo for 4 weeks

K+ values at 48 hours, 4 weeks

At 48 hours: K+ levels decreased from 5.6 to 4.5 mmol/l At 4 weeks: K+ levels declined with all SZC doses versus placebo (4.8 mmol/l, 4.5 mmol/l and 4.4 mmol/l for 5, 10 and 15 g, respectively); 5.1 mmol/l for placebo

NCT02163499: open-label, single-arm, phase III trial51

751 patients with K+ >5.1 mmol/l • 65% CKD • 64% diabetes • 15% HF • 65% RAASi

Phase 1 (correction phase): all patients received 10 g of SZC three times daily for 24–72 hours Phase 2 (maintenance phase): eligible patients received SZC 5 g once daily titrated to maintain normokalaemia

Restoration of normal K+ (3.5–5 mmol/l) during the correction phase, and maintenance of K+ <5.1 mmol/l during the maintenance phase

99% achieved normokalaemia during the correction phase (mean K+ 4.8 mmol/l), and 88% maintained normokalaemia (mean K+ 4.7 mmol/l) at 12 months in the maintenance phase

CKD = chronic kidney disease; HF = heart failure; RAASi = renin–angiotensin–aldosterone system inhibitors; RCT = randomised controlled trial; SZC = sodium zirconium cyclosilicate.

As it is not systemically absorbed following oral administration, SZC is thought to be safe in pregnant and lactating women.47 ZS-003 was a phase III trial that randomised 753 hyperkalaemic patients to receive SZC or placebo three times daily for 48 hours (see Table 2).44 Patients who achieved normokalaemia were then reassigned to receive placebo or SZC once daily for 2 weeks. Serum potassium was significantly lower in patients receiving the 5 and 10 g doses of SZC compared with placebo. The most common side-effects were GI related and occurred in 12.9% of patients on SZC. HARMONIZE enrolled 258 ambulatory patients with hyperkalaemia. In the first 48 hours, they received 10 g SZC three-times a day (see Table 2). Nearly all were normokalaemic at 48 hours.48 This was followed by a maintenance phase, in which patients who achieved normokalaemia were randomised to receive SZC or placebo daily for 28 days. Normokalaemia was higher in all treatment groups versus placebo. Oedema was more common in SZC (2– 6%). GI side-effects occurred in 2–9% of the patients on SZC, and these were dose dependent. HARMONIZE-Global was a follow-up trial that enrolled patients with a more diverse geographical distribution. Results were congruent with HARMONIZE, with 77.3% of the SZC group achieving normokalaemia compared with only 24% in the placebo group.49 In the subgroup of HF patients (n=94) from HARMONIZE, all three doses of SZC were effective in lowering and maintaining normokalaemia, including in those taking RAASi (n=60) .50 More recently, Spinowitz et al. assessed SZC in a single-arm study. SZC was able to acutely achieve normokalaemia during the first 72 hours of administration in nearly all patients (see Table 2).51 Following a 12-month maintenance period, 88% were normokalaemic and this enabled the initiation and/or uptitration of RAASi.51

Patiromer Sorbitex Calcium

Patiromer sorbitex calcium (patiromer) is a 100 µm bead organic polymer that preferentially uses calcium ions to exchange potassium ions

(Figure 1D), although it can bind to magnesium and sodium. Patiromer is not systemically absorbed and is excreted in the faeces.52 It can be given as a starting dose of 8.4 g, and is increased in 4.2 g increments up to a dose of 25.2 g. It has a slow onset of action of approximately 7 hours, and therefore is only approved for chronic hyperkalaemia. Patiromer can be continued as long as it is clinically indicated.53 As it is not systemically absorbed following oral administration, SZC is thought to be safe in pregnant and lactating women.54 OPAL-HK was a study of 237 CKD patients with hyperkalaemia who were on RAASi (see Table 3).55 The study was divided into two phases: an initial 4-week phase where everyone received patiromer twice daily, followed by an 8-week withdrawal phase, in which patients were randomly assigned to continue the initial dose or placebo. By the end of the first phase, 76% of the study population were normokalaemic. During the withdrawal phase, there was a 15% incidence of hyperkalaemia in the treatment group compared with 60% in the placebo group. In the placebo group, 50% of patients were taken off RAASi in the withdrawal phase, whereas this occurred in only 6% of the patients in the patiromer group. The reported side-effects in this trial were constipation (11%), diarrhoea (8%), hypomagnesemia (8%), and hypokalaemia (3%). A subgroup analysis of the OPAL-HK trial considered the effects of patiromer in HF (ejection fraction <35%) patients. Of the 102 patients with HF (42% of the study population), 76% were normokalaemic after the first 4 weeks. In the withdrawal phase, hyperkalaemia occurred in 52% of patients taking placebo and 8% of those on patiromer.55 PEARL-HF studied patiromer in patients with chronic HF (see Table 3). Patients included in the study either had stage III CKD or a history of hyperkalaemia necessitating the discontinuation of RAASi.56 A total of 105 patients were initiated on 25 mg/day of spironolactone, and were randomised to treatment with patiromer or placebo for 4 weeks. At 4 weeks, 92.7% of the patients in the patiromer group achieved normokalaemia compared with 75.5% in the placebo group. The patiromer

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Hyperkalaemia in Heart Failure Table 3. Studies that Evaluated Patiromer in Hyperkalaemia Trial

Population

Intervention

Endpoints

Results

OPAL-HK: phase III, single-blind RCT55

237 CKD patients on RAASi and K+ of 5.1–6.5 mmol/l • 57% diabetes • 42% HF

Phase 1 (open label): 4-week treatment with 4.2 or 8.4 g of patiromer twice daily Phase 2 (randomised withdrawal phase): normokalaemic patients randomised to: • 4.2 or 8.2 g of patiromer for 8 weeks • Placebo for 8 weeks

Change in mean K+ levels in first 4 weeks of phase 1 and change in median K+ levels in the first 4 weeks of phase 2

Phase 1: mean change in K+ levels from baseline was –1.01 mmol/l Phase 2: median change in the K+ from the start of the randomised withdrawal phase to week 4 of the phase was 0.72 mmol/l in the placebo group and 0 mmol/l in the patiromer group At week 8, 60% of patients in the placebo group had recurrence of hyperkalaemia (K+ >5.5 mmol/l) versus 15% in the treatment group

PEARL-HF: phase III, 105 HF patients on standard double-blind RCT56 therapy and either CKD or prior hyperkalaemia requiring cessation of RAASi • Mean EF 40% • NYHA II–III

Two randomised groups: Mean change in K+ levels at 4 weeks • 15 g of patiromer twice daily for 4 weeks • Placebo for 4 weeks Both groups on spironolactone 25–50 mg/day

At 4 weeks, patiromer lowered K+ by 0.45 mmol/l compared with placebo

AMBER: phase II, double-blind RCT57

Two randomised groups that Between-group difference at week 12 received open-label spironolactone in patients on spironolactone in addition to 8.2 g of patiromer or placebo

At 12 weeks, 66% of patients in the placebo group and 86% of patients in the patiromer group remained on spironolactone (between-group difference of 19.5%)

295 patients with CKD (eGFR 25–45 ml/min) and uncontrolled resistant hypertension • 50% diabetes • 45% HF

CKD = chronic kidney disease; EF = ejection fraction; eGFR = estimated glomerular filtration rate; HF = heart failure; NYHA = New York Health Association; RAASi = renin–angiotensin–aldosterone system inhibitors; RCT = randomised controlled trial.

group was more likely to have had spironolactone increased to 50 mg/ day (91% versus 74%). Patiromer resulted in a 6% incidence of hypokalaemia in the trial, whereas hypomagnesemia occurred in 24% of the patients. AMBER evaluated the effect of patiromer versus placebo on the rates of discontinuation of spironolactone in 295 patients with stage IIIb CKD and resistant hypertension over a 12-week period (see Table 3). All patients initially had a potassium level of <5.1 mmol/l, and were on either ACEi or ARB at baseline and were initiated on spironolactone. At the end of the 12 weeks, 86% of the patients in the patiromer arm remained on spironolactone compared with 66% of the placebo group. In the subgroup analysis of the patients with HF in the study (45% of the population), 84.1% of HF patients in the patiromer group remained on spironolactone compared with 68.1% in the placebo group. Hyperkalaemia was the most common cause of discontinuation, occurring in 23% of the placebo group versus 7% in the spironolactone group.57

Economic Impact

Hyperkalaemia poses a significant financial burden on the healthcare system. Mu et al. analysed a 5% random sample of Medicare beneficiaries in the US between 2010 and 2014 and randomised them based on the presence of hyperkalaemia (potassium level >5 mEq/l).58 Those with hyperkalaemia had more inpatient admissions, outpatient and emergency 1. Roger VL. Epidemiology of heart failure. Circ Res 2013;113:646–59. https://doi.org/10.1161/ CIRCRESAHA.113.300268; PMID: 23989710. 2. Jain N, Kotla S, Little BB, et al. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol 2012;109:1510–3. https://doi.org/10.1016/j. amjcard.2012.01.367; PMID: 22342847. 3. Rossignol P, Lainscak M, Crespo-Leiro MG, et al. Unravelling the interplay between hyperkalaemia, renin-angiotensinaldosterone inhibitor use and clinical outcomes. Data from 9222 chronic heart failure patients of the ESC-HFA-EORP Heart Failure Long-Term Registry. Eur J Heart Fail

department visits and skilled nursing care facility admissions. Patients with hyperkalaemia and concomitant HF and/or CKD had even higher rates of hospital visits and longer inpatient stays. The subgroup of patients with HF and hyperkalaemia incurred a significant cost to the healthcare system at an average of US$11,750 over 30 days and US$49,244 over 1 year per patient compared with US$2,600 and US$23,936 in their normokalaemic counterparts. Newer agents for hyperkalaemia remain expensive, but may overall save costs to the healthcare system. SZC 10 mg is US$749 for a 30-day supply, whereas patiromer 8.4 g is US$947 per month.59,60 In the British National Formulary, these prices are £427.20 and £172.50, respectively.61

Conclusion

Hyperkalaemia is a frequent issue encountered in patients with HF and is associated with increased mortality. RAASi interfere with potassium homeostasis, resulting in hyperkalaemia and lead to dose reduction or discontinuation of these agents, which have proven mortality benefits. The novel potassium binding resins, SZC and patiromer, have shown positive short- and long-term results in counteracting hyperkalaemia and maintaining normokalaemia in various populations, including HF patients, and thus may aid in the optimisation of RAASi therapy and long-term maintenance.

2020;22:1378–89. https://doi.org/10.1002/ejhf.1793; PMID: 32243669. 4. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975. https://doi.org/10.1002/ ejhf.592; PMID: 27207191. 5. Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney Int

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

2016;89:546–54. https://doi.org/10.1016/j.kint.2015.11.018; PMID: 26880451. 6. Komajda M, Anker SD, Cowie MR, et al. Physicians’ adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail 2016;18:514–22. https://doi.org/10.1002/ejhf.510; PMID: 27095461. 7. Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and betablockers in patients with heart failure: a prospective European study. Eur Heart J 2017;38:1883–90. https://doi. org/10.1093/eurheartj/ehx026; PMID: 28329163.

Hyperkalaemia in Heart Failure 8. Núñez J, Bayés-Genís A, Zannad F, et al. Long-term potassium monitoring and dynamics in heart failure and risk of mortality. Circulation 2018;137:1320–30. https://doi. org/10.1161/CIRCULATIONAHA.117.030576; PMID: 29025765. 9. López Vilella R, Morillas Climent H, Plaza-López D, et al. Hyperkalemia in heart failure patients: current challenges and future prospects. Research Reports in Clinical Cardiology 2015;7:1–8. https://doi.org/10.2147/RRCC.S75680. 10. Sarwar CM, Papadimitriou L, Pitt B, et al. Hyperkalemia in heart failure. J Am Coll Cardiol 2016;68:1575–89. https://doi. org/10.1016/j.jacc.2016.06.060; PMID: 27687200. 11. Ferreira JP, Butler J, Rossignol P, et al. Abnormalities of potassium in heart failure: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:2836–50. https://doi.org/10.1016/j. jacc.2020.04.021; PMID: 32498812. 12. Dunn JD, Benton WW, Orozco-Torrentera E, et al. The burden of hyperkalemia in patients with cardiovascular and renal disease. Am J Manag Care 2015;21(15 Suppl):307–15. PMID: 26788745. 13. Lehnhardt A, Kemper MJ. Pathogenesis, diagnosis and management of hyperkalemia. Pediatr Nephrol 2011;26:377– 84. https://doi.org/10.1007/s00467-010-1699-3; PMID: 21181208. 14. Weir MR, Rolfe M. Potassium homeostasis and reninangiotensin-aldosterone system inhibitors. Clin J Am Soc Nephrol 2010;5:531–48. https://doi.org/10.2215/ CJN.07821109; PMID: 20150448. 15. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302. https://doi.org/10.1056/NEJM199108013250501; PMID: 2057034. 16. Desai AS, Swedberg K, McMurray JJ, et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J Am Coll Cardiol 2007;50:1959–66. https://doi.org/10.1016/j.jacc.2007.07.067; PMID: 17996561. 17. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/ NEJMoa1409077; PMID: 25176015. 18. Ferreira JP, Mogensen UM, Jhund PS, et al. Serum potassium in the PARADIGM-HF trial. Eur J Heart Fail 2020;22:2056–64. https://doi.org/10.1002/ejhf.1987; PMID: 32809261. 19. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. https://doi.org/10.1056/ NEJMoa1009492; PMID: 21073363. 20. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–17. https:// doi.org/10.1056/NEJM199909023411001; PMID: 10471456. 21. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543–51. https://doi.org/10.1056/nejmoa040135; PMID: 15295047. 22. Dev S, Lacy ME, Masoudi FA, et al. Temporal trends and hospital variation in mineralocorticoid receptor antagonist use in veterans discharged with heart failure. J Am Heart Assoc 2015;4:e002268. https://doi.org/10.1161/ JAHA.115.002268; PMID: 26702082. 23. Rossignol P, Duarte K, Girerd N, et al. Cardiovascular risk associated with serum potassium in the context of mineralocorticoid receptor antagonist use in patients with heart failure and left ventricular dysfunction. Eur J Heart Fail 2020;22:1402–11. https://doi.org/10.1002/ejhf.1724; PMID: 31919958. 24. Collins AJ, Pitt B, Reaven N, et al. Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes. Am J Nephrol 2017;46:213–21. https://doi. org/10.1159/000479802; PMID: 28866674. 25. Aldahl M, Jensen AC, Davidsen L, et al. Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J 2017;38:2890–6. https://doi. org/10.1093/eurheartj/ehx460; PMID: 29019614. 26. Beusekamp JC, Tromp J, Cleland JGF, et al. Hyperkalemia and treatment with RAAS inhibitors during acute heart failure hospitalizations and their association with mortality. JACC Heart Fail 2019;7:970–9. https://doi.org/10.1016/j.

jchf.2019.07.010; PMID: 31606364. 27. Linde C, Bakhai A, Furuland H, et al. Real-world associations of renin-angiotensin-aldosterone system inhibitor dose, hyperkalemia, and adverse clinical outcomes in a cohort of patients with new-onset chronic kidney disease or heart failure in the United Kingdom. J Am Heart Assoc 2019;8:e012655. https://doi.org/10.1161/JAHA.119.012655; PMID: 31711387. 28. Savarese G, Carrero JJ, Pitt B, et al. Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry. Eur J Heart Fail 2018;20:1326–34. https://doi.org/10.1002/ejhf.1182; PMID: 29578280. 29. Cooper LB, Benson L, Mentz RJ, et al. Association between potassium level and outcomes in heart failure with reduced ejection fraction: a cohort study from the Swedish Heart Failure Registry. Eur J Heart Fail 2020;22:1390–8. https://doi. org/10.1002/ejhf.1757; PubMed PMID: 32078214. 30. Savarese G, Xu H, Trevisan M, et al. Incidence, predictors, and outcome associations of dyskalemia in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2019;7:65–76. https://doi.org/10.1016/j. jchf.2018.10.003; PMID: 30553905. 31. Dépret F, Peacock WF, Liu K,D et al. Management of hyperkalemia in the acutely ill patient. Ann Intensive Care 2019;9:32. https://doi.org/10.1186/s13613-019-0509-8; PMID: 30820692. 32. Semple P, Booth C. Calcium chloride; a reminder. Anaesthesia 1996;51:93. https://doi.org/10.1111/j.1365-2044. 1996.tb07673.x; PMID: 8669584. 33. Liu M, Rafique Z. Acute management of hyperkalemia. Curr Heart Fail Rep 2019;16:67–74. https://doi.org/10.1007/s11897019-00425-2; PMID: 30972536. 34. Fordjour K, Walton, T, Doran JJ. Management of hyperkalemia in hospitalized patients. Am J Med Sci 2014;347:93–100. https://doi.org/10.1097/MAJ. 0b013e318279b105; PMID: 23255245. 35. Sterns RH, Rojas M, Bernstein P, et al. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010;21:733–5. https://doi. org/10.1681/ASN.2010010079; PMID: 20167700. 36. Beccari MV, Meaney CJ. Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review. Core Evid 2017;12:11–24. https://doi.org/10.2147/CE. S129555; PMID: 28356904. 37. Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med 1961;264:111–5. https://doi. org/10.1056/NEJM196101192640302; PMID: 13700297. 38. Scherr L, Ogden DA, Mead AW, et al. Management of hyperkalemia with a cation-exchange resin. N Engl J Med 1961;264:115–9. https://doi.org/10.1056/ NEJM196101192640303; PMID: 13747532. 39. Kessler C, Ng J, Valdez K, et al. The use of sodium polystyrene sulfonate in the inpatient management of hyperkalemia. J Hosp Med 2011;6:136–40. https://doi. org/10.1002/jhm.834; PMID: 21387549. 40. Lepage L, Dufour AC, Doiron J, et al. Randomized clinical trial of sodium polystyrene sulfonate for the treatment of mild hyperkalemia in CKD. Clin J Am Soc Nephrol 2015;10:2136–42. https://doi.org/10.2215/CJN.03640415; PMID: 26576619. 41. Scott TR, Graham SM, Schweitzer EJ, et al. Colonic necrosis following sodium polystyrene sulfonate (Kayexalate)-sorbitol enema in a renal transplant patient. Report of a case and review of the literature. Dis Colon Rectum 1993;36:607–9. https://doi.org/10.1007/BF02049870; PMID: 8500380. 42. Yuan CM, Nee R, Little DJ, Abbott KC. Incidence of sodium polystyrene sulfonate-associated colonic necrosis. Am J Med 2013;126:e13. https://doi.org/10.1016/j.amjmed.2013.02.034; PMID: 23968906. 43. Chaitman M, Dixit D, Bridgeman MB. Potassium-binding agents for the clinical management of hyperkalemia. P T 2016;41:43–50. PMID: 26765867. 44. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015;372:222–31. https://doi.org/10.1056/NEJMoa1411487; PMID: 25415807. 45. Stavros F, Yang A, Leon A, et al. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS

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One 2014;9:e114686. https://doi.org/10.1371/journal. pone.0114686; PMID: 25531770. 46. Peacock WF, Rafique Z, Vishnevskiy K, et al. Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase ii, randomized, doubleblind, placebo-controlled study (ENERGIZE). Acad Emerg Med 2020;27:475–86. https://doi.org/10.1111/acem.13954; PMID: 32149451. 47. FDA. Lokelmatm (sodium zirconium cyclosilicate) for oral suspension. Prescribing Information. FDA. May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2018/207078s000lbl.pdf (accessed 31 December 2020). 48. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA 2014;312:2223–33. https:// doi.org/10.1001/jama.2014.15688; PMID: 25402495. 49. Zannad F, Hsu BG, Maeda Y, et al. Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study. ESC Heart Fail 2020;7:54–64. https://doi.org/10.1002/ ehf2.12561; PMID: 31944628. 50. Anker SD, Kosiborod M, Zannad F, et al. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail 2015;17:1050–6. https://doi.org/10.1002/ejhf.300; PMID: 26011677. 51. Spinowitz BS, Fishbane S, Pergola PE, et al. Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study. Clin J Am Soc Nephrol 2019;14:798–809. https://doi.org/10.2215/ CJN.12651018; PMID: 31110051. 52. Li L, Harrison SD, Cope MJ, et al. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross-linked polymer that lowers serum potassium concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther 2016;21:456–65. https://doi.org/10.1177/1074248416629549; PMID: 26856345. 53. Bakris GL, Pitt B, Weir MR, et al. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial. JAMA 2015;314:151–61. https://doi.org/10.1001/ jama.2015.7446; PMID: 26172895. 54. FDA. Veltassa (patiromer) for oral suspension. FDA. October 2015. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2015/205739s000lbl.pdf (accessed 31 December 2020). 55. Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail 2015;17:1057–65. https://doi.org/10.1002/ejhf.402; PMID: 26459796. 56. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011;32:820–8. https://doi.org/10.1093/eurheartj/ ehq502; PMID: 21208974. 57. Agarwal R, Rossignol P, Romero A, et al. Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2019;394:1540–50. https://doi.org/10.1016/s01406736(19)32135-x; PMID: 31533906. 58. Mu F, Betts KA, Woolley JM, et al. Prevalence and economic burden of hyperkalemia in the United States Medicare population. Curr Med Res Opin 2020;36:1333–41. https://doi. org/10.1080/03007995.2020.1775072; PMID: 32459116. 59. Drugs.com. Lokelma Prices, Coupons and Patient Assistance Programs. https://www.drugs.com/price-guide/lokelma (accessed 11 March 2021). 60. Drugs.com. Veltassa Prices, Coupons and Patient Assistance Programs. https://www.drugs.com/price-guide/veltassa (accessed 11 March 2021). 61. British National Formulary. London: Royal Pharmaceutical Society; 2021. 62. Sidhu K, Sanjanwala R, Zieroth S. Hyperkalemia in heart failure. Curr Opin Cardiol 2020;35:150–5. https://doi.org/ 10.1097/HCO.0000000000000709; PMID: 31833959.

Treatment

The Future of Telemedicine in the Management of Heart Failure Patients José Silva-Cardoso ,1,2,3 José Ramón González Juanatey ,4 Josep Comin-Colet ,5,6,7 José Maria Sousa ,2,3 Ana Cavalheiro 3,8 and Emília Moreira 1,3 1. Faculty of Medicine, University of Porto, Porto, Portugal; 2. São João University Hospital Centre, Porto, Portugal; 3. CINTESIS, Centre for Health Technology and Services Research, Faculty of Medicine, University of Porto, Porto, Portugal; 4. Santiago de Compostela University Hospital, Santiago de Compostela, Spain; 5. Bio-Heart Cardiovascular Diseases Research Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; 6. Community Heart Failure Program, Cardiology Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 7. Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain; 8. Department of Physical Rehabilitation, Centro Hospitalar do Porto, Porto, Portugal

Abstract

Telemedicine (TM) is potentially a way of escalating heart failure (HF) multidisciplinary integrated care. Despite the initial efforts to implement TM in HF management, we are still at an early stage of its implementation. The coronavirus disease 2019 pandemic led to an increased utilisation of TM. This tendency will probably remain after the resolution of this threat. Face-to-face medical interventions are gradually transitioning to the virtual setting by using TM. TM can improve healthcare accessibility and overcome geographic inequalities. It promotes healthcare system efficiency gains, and improves patient self-management and empowerment. In cooperation with human intervention, artificial intelligence can enhance TM by helping to deal with the complexities of multicomorbidity management in HF, and will play a relevant role towards a personalised HF patient approach. Artificial intelligence-powered/telemedical/heart team/multidisciplinary integrated care may be the next step of HF management. In this review, the authors analyse TM trends in the management of HF patients and foresee its future challenges within the scope of HF multidisciplinary integrated care.

Keywords

Heart failure, telemedicine, multidisciplinary integrated care, telemonitoring, artificial intelligence Funding: This article was supported by national funds through Fundação para a Ciência e a Tecnologia, within CINTESIS, R&D Unit (UIDB/4255/2020) and Project ‘AdHeart – Engage with your heart: Improving therapeutic adherence with a telemonitoring system for chronic heart failure patients,’ NORTE-01-0145-FEDER-032069, financed by European Regional Development Fund (ERDF) through NORTE 2020 (Programa Operacional Regional do Norte) and by Portuguese funds through Fundação para a Ciência e Tecnologia. Disclosure: The authors have no conflicts of interest to declare. Received: 17 December 2020 Accepted: 22 February 2021 Citation: Cardiac Failure Review 2021;7:e11. DOI: https://doi.org/10.15420/cfr.2020.32 Correspondence: José Silva-Cardoso, Centre for Health Technology and Services Research, Faculty of Medicine, University of Porto, CardioCare Group, Centro de Investigação Médica, Rua Plácido da Costa, 4200-450, Porto, Portugal. E: silvacardoso30@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a frequent, incapacitating, unstable, progressive and bad prognosis syndrome that causes a high logistical burden and expenditure.1 HF management goals include the improvement of symptoms, functional capacity, quality of life and patient empowerment, as well as the reduction of hospitalisations and mortality, and the decrease of logistical burden and costs.1 To reach all these goals, an improvement in present care delivery systems is required. The vital journey for HF patients unfolds in the ambulatory setting, and is punctuated by frequent hospital visits during decompensations and back to ambulatory when stabilised.1 This is the rationale for HF multidisciplinary integrated care, which involves close collaboration between hospital-based HF specialists and general practitioners, among many other HF specialists, including nurses, pharmacists and others.1–4 Multidisciplinary and integrated care programs are the current gold standard of HF patient management.1 Their scope can be expanded using telemedicine (TM), allowing patient management at a distance.2–7

Although the initial experience with TM in this context was published in the mid-1990s, we are still in the early stages of widespread implementation in everyday clinical practice.8–13 In this review, we sought to analyse TM evolution in HF, and tried to foresee its future and challenges within the scope of HF multidisciplinary integrated care. The expansion of TM will most probably be part of the reshaping of the present care delivery systems to improve their efficacy and extend their scope.2

Telemedicine in Heart Failure: Remote Patient Management

TM, digital health and e-health refer to the exchange of health information and/or care instructions using a digital support, to allow and optimise the process of care.2,6,7 TM encompasses teleconsultation, telemonitoring, telerehabilitation (TR), shared electronic patient records and medical teleconferencing (Figure 1).

The Future of Telemedicine in Heart Failure Management Figure 1: The Future of Telemedicine in the Management of Heart Failure Patients HF characteristics

HF management needs

HF current standard of care

Drivers for TM implementation in HF

• Frequent • Incapacitating • Unstable • Progressive • Bad prognosis • High expenditure

To improve: • Symptoms • Functional capacity • QoL • Patient empowerment

Multidisciplinary integrated care teams

• Haemodynamic instability of HF • High HF prevalence • Organisational burden of HF • High costs of HF • Need for patient empowerment

To reduce: • Hospitalisations • Mortality • Costs • Logistical burden

Current TM solutions in HF • Teleconsultation • Telemonitoring • Telerehabilitation • Shared electronic patient records • Teleconferencing

Future organisation of HF care

Barriers to TM implementation in HF

AI-powered/ telemedical/ heart team/ multidisciplinary integrated care team

• Reimbursement policy • Regulatory constraints • Technological barriers • Adherence by patients and caregivers

AI = artificial intelligence; HF = heart failure; MIC = multidisciplinary integrated care teams; TM = telemedicine; QoL = quality of life.

TM allows more agile and frequent patient status monitoring, and enables HF patients to be cared for while staying safely at home. TM facilitates non-pharmacological and pharmacological therapy, as well as TR, and this was proven to translate into morbidity and mortality gains.9,10,14–17 TM reinforces the patient’s role in HF self-management and promotes patient empowerment.2,4 It is a powerful tool for patients’ continuous education, self-care promotion and therapy adherence.4 Patients frequently describe an increased sensation of being in control of the disease process and an enhanced proximity to the medical team, which convey heightened feelings of safety.2,18,19 TM has also been shown to improve depressive symptoms and quality of life in HF patients with moderate depression.20 TM increases accessibility to healthcare, helping to overcome geographic inequalities.2–5 In addition, it decreases overload on health systems and results in efficiency gains.2,6,7 TM reduces healthcare professionals’ burden and patients’ risks, and contributes to reducing costs.2–7,9-15,21–25

Teleconsultation

Teleconsultation allows for the assessment of symptoms, physical signs (weight, blood pressure, heart rate) and ambulatory blood tests results, promoting more agile patient management.2 It may be useful in the rapid initiation and titration of HF prognosis-modifying therapy, in the close follow-up of haemodynamically unstable patients, in the reduction of the in-presence stable patients’ medical appointments and in the closer contact with patients under palliative care.1,2

Telemonitoring

The main goal of HF remote monitoring is to detect HF haemodynamic decompensation early, allowing an early intervention and thus averting HF hospitalisations.2,6–8 Usually, it uses a multiparametric approach, including, among others, HF symptoms, heart rate, blood pressure and an evaluation of congestion status, by a number of different methodologies (e.g. weight, bioimpedance, etc).2,6–8,12 HF telemonitoring may assume the form of invasive monitoring with dedicated sensors, invasive monitoring associated with medical devices (ICDs or CRTs devices equipped with an optivol algorithm) and noninvasive monitoring.2,8,12,14,26–34 The latter involves patient participation in a daily auto-evaluation routine, which is transmitted to a care facility, triggering a therapeutic response in case haemodynamic

decompensation signals are detected. Patients’ long-term adherence to this daily routine may be challenging.2,14–19 To circumvent this, telemonitoring progressively relies more on wearables (e.g. smartwatches, sensors embedded in T-shirts, socks and other clothing), automatic data collection and analysis, as well as on algorithms for detecting haemodynamic decompensation and initiating therapeutic responses in a strategy of non-intrusive monitoring.2,3,12,14,32,33 Future developments will include the internet of things for continuous and imperceptible health status monitoring.12,35,36 TM may also involve arrhythmia detection using ICD- or CRT-based algorithms or dedicated long-term implanted devices.12,27,28,30,31 A recent meta-analysis including 29 randomised clinical trials and 10,981 patients focused on the effectiveness of telemonitoring versus usual care. It showed that TM systems with medical support were associated with fewer all-cause and cardiac hospitalisations, shorter length of stay, as well as lower all-cause and cardiac mortality.15 In a Cochrane review involving patients with HF, both non-invasive remote monitoring and structured telephone support were associated with meaningful clinical status benefits and reduced all-cause mortality.14

Telerehabilitation

TR uses digital technology (smartphone applications, smart-watches, etc.) and teleconsultations to deliver cardiac rehabilitation from a distance.16,17,37,38 Patients perform rehabilitation exercises at home, while being monitored by the medical team at the hospital. TR may become an important alternative to standard centre-based cardiac rehabilitation, allowing to circumvent the very limited availability of the latter.16,17,37 Previous evidence on TR showed its effectiveness on improving functional capacity and quality of life.16,17 Preliminary evidence indicates the potential for TR to be cost-effective and safe.16,17,37,38

Shared Electronic Patient Records and Teleconferencing

Agile communication is key for multidisciplinary integrated teams’ efficient performance.1–7 The use of shared electronic patient records was revealed to be relevant to this strategy, allowing real-time clinical information sharing.6,7 The communication between hospital and primary care professionals may be further facilitated by means of additional forms of communication, such as teleconferences, dedicated mobile phone contacts and others.2,12,9–11,15

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The Future of Telemedicine in Heart Failure Management Electronic patient records may also allow continuous HF registries, based on automated patients’ medical records data collection.2,9–11 This will enable up-to-date knowledge of the global health status of HF populations, which in turn, can be a tool to improve quality of care, through benchmarking among national medical centres and different national health systems.9–11 This may, however, be limited by national regulatory restraints, particular to each different country.

Telemedicine Future Developments: Artificial Intelligence

Artificial intelligence (AI) will certainly play a progressively more important role in managing the immense data generated by TM.39 In the case of telemonitoring, patient data will be automatically screened, and a hierarchical automated efferent loop organised, producing automatic communication with the patient, in the case of minor physiological deviations; or alternatively, a communication with either the nurse or the physician, according to increasingly severe detected abnormalities.39,40 AI may also assist patients in improving technological and health literacy towards increased patient active participation in HF self-management.12,39

In summary, AI may contribute to reducing clinicians’ margin of error, and improving therapeutic decision-making, while reducing workload and improving the patient–doctor relationship.39,40 AI can increase patient empowerment, through shared decision-making and enhanced self- disease management efficacy.39,42 AI can improve HF healthcare organisation by reducing patient waiting times and per capita costs, while increasing accessibility, productivity and overall patient experience.39-42

The Digital Patient Twin Care

Another future development will be the digital patient twin.43,44 This is an AI construct based on the patient clinical information integrated with registries-derived big data to produce a digital representation of a patient. The resultant digital patient twin can be used to virtually test the effect of different therapeutic options and predict the potential results, to optimise treatment choices and avoid side-effects.43,44 These models can be enhanced with the huge amount of clinical data derived from the HF telemonitoring databases, with the purpose of a more accurate prediction of therapeutic interventions.43,44

Technological barriers to TM must be surpassed to fulfil the aforementioned objectives. Faster and more stable internet pathways, such as 5G-technology, will certainly be required in the near future, to deal with the exponentially growing annual data generation.2,12

The Digital Transformation of Heart Failure Care

Towards an AI-powered/Telemedical/Heart Team/Multidisciplinary Integrated Care

• The intrinsic haemodynamic instability of HF: HF typically evolves by

Typically, HF patients present many comorbidities, which increase the complexity of patient management. Conventionally, these comorbidities were addressed by separate medical specialities, particularly when severe. However, patients are holistic beings, and many difficult decisions are nowadays addressed within the so-called heart team.1 The huge volume of data derived from comorbidities assessment is amplified by the outpouring data generated by telemedical solutions used in the follow up of HF patients.40,41 These big data can be managed by AI to unravel patterns of disease progression and facilitate a more personalised patient approach.41,42 AI is transforming cardiovascular diagnosis through interpreting and finding meaning in vast sets of data, in a faster and more effective way. AI is able to deal with complex combinations of biological markers and monitoring data, to predict and help prevent the deterioration of complex syndromes, such as HF.40,41 By the development of learning algorithms, machine learning techniques allow the identification of patterns in new data, which enable the creation of a specific logic to continuously improve disease prognostication and treatment decisions.40,41 Additionally, AI can also enable the aggregation of data from multiple sources, and the creation of a common and shared patient electronic record, facilitating a multidisciplinary team approach towards precision medicine.40,42 In the future, patient cardiological data will be interpreted in conjunction with that derived from other organs and systems, to build a more holistic patient approach.39-42 AI models of disease progression will be built based on patient telemedical-generated data.41 Contrary to being viewed as an alternative to human intelligence, AI may help to deal with the complexities of multicomorbidity management in HF, thereby amplifying human reasoning.39–41 Thus, AI-powered/ telemedical/ heart team/ multidisciplinary integrated care may be the next step of HF management. Somewhat counterintuitively, this may lead to a more personalised medicine.2,39-42

With two and a half decades of existence in HF, TM is still in its infancy in this field.13 Many factors will boost its widespread use in HF in the near future, among which are (Table 1):

• • • •

bouts of haemodynamic deterioration, triggered by a vast number of factors, and leading to frequent and high-mortality hospitalisations.1 In fact, HF is the leading cause of hospitalisations among individuals aged above 65 years in the EU and the US. HF telemonitoring, by detecting haemodynamic decompensation early and promoting its timely correction, was shown to be able to increase the survival time and time out of hospital, and the rate of HF-related hospitalisations at 6 months.9,26,45,46 The high prevalence of HF – estimated to be 15 million in the EU and 64 million worldwide – imposing a high burden on institutions and caregivers, which can be alleviated with telemedical solutions.2,3,45,46 The high costs associated with HF – mainly derived from HF hospitalisations – which can be mitigated by TM.2,3,14,15,21–25 The heavy logistics and organisational burden of HF, which can be eased by TM.2–4 The need for HF patient empowerment and proximity care, which can be addressed by TM, and will become a relevant tool in promoting a personalised medicine.2–4,9,19,20,40

The coronavirus disease 2019 (COVID-19) pandemic exposed more clearly the unmet need for the widespread use of TM solutions in HF patients.5,47–52 However, the need for TM use in HF patients is independent of the COVID-19 pandemic, and digital medicine will certainly continue to expand in this field long after the COVID-19 pandemic is controlled.2,52 Multiple options of care will probably emerge, combining conventional and telemedical care, according to patients’ needs and preferences, as well as health services resources.2,3 The goal of healthcare systems is to organise a cost-effective and universal, yet personalised, methodology of delivering care.1–4 Face-toface medical assessment is gradually transitioning to the virtual setting in certain circumstances with the use TM, including not only teleconsultation, but also remote patient monitoring and TR.2

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The Future of Telemedicine in Heart Failure Management Table 1: Telemedicine Implementation in Heart Failure: Drivers, Current Solutions and Barriers Drivers for TM Implementation

Current TM Solutions

Barriers to TM Implementation

• Haemodynamic instability • High prevalence • Organisational burden • High HF-associated costs • Need for patient empowerment

• Teleconsultation • Telemonitoring • Telerehabilitation • Shared electronic patient records • Teleconferencing

• Reimbursement • Policy • Regulatory constraints • Technological barriers • Patients and caregivers adherence

HF = heart failure; TM = telemedicine.

Costs and Barriers to Telemedicine Implementation

The main drivers of HF TM costs are the dedicated human resources, the provision of appropriated technology and the medical team–patient interactions.2,21–25 This expenditure needs to be compared with HF economic burden itself, to evaluate TM cost-effectiveness.2,25 Nevertheless, appropriate HF TM economic evaluation studies are lacking.25 An analysis of HF economic burden worldwide in 2021 estimated the cost of HF to be US$108 billion per annum, with US$65 billon attributed to direct costs and US$43 billon to indirect costs.53,54 HF expenditure accounts for 1–2% of total health costs in the US and in Europe.54 Hospitalisations, mainly due to haemodynamic congestion, are responsible for more than 80% of HF-related costs.55 Telemedical solutions, such as telemonitoring, can reduce approximately 30% of HF hospitalisations through early congestion detection and correction.14 This would represent approximately US$15.6 billion of savings per year.14,53–55 Other recent studies associated TM interventions with an overall HF care costs reduction.21–24,47,48 A slight increase in ambulatory care costs in the telemedical intervention arm was observed, compared with the usual care arm.23,24 This was probably due to the higher frequency of virtual visits compared with face-to-face appointments.25 Reimbursement by national regulatory agencies is one of the major challenges for TM implementation, scale-up and widespread adoption in 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/ eurheartj/ehw128; PMID: 27206819. 2. Di Lenarda A, Casolo G, Gulizia MM, et al. The future of telemedicine for the management of heart failure patients: a consensus document of the Italian Association of Hospital Cardiologists (A.N.M.C.O), the Italian Society of Cardiology (S.I.C.) and the Italian Society for Telemedicine and eHealth (Digital S.I.T.). Eur Heart J Suppl 2017;19(Suppl D):D113–29. https://doi.org/10.1093/eurheartj/sux024; PMID: 28751839. 3. Cowie MR. Building the new digital world: launch of the European Heart Journal – Digital Health. Eur Heart J Digital Health 2020;1:3. https://doi.org/10.1093/ehjdh/ztaa002. 4. Jaarsma T, Hill L, Bayes-Genis A, et al. Self-care of heart failure patients: practical management recommendations from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021;23:157–74. https://doi. org/10.1002/ejhf.2008; PMID: 32945600. 5. Neubeck L, Hansen T, Jaarsma T, et al. Delivering healthcare remotely to cardiovascular patients during COVID-19: a rapid review of the evidence. Eur J Cardiovasc Nurs 2020;19:486–94. https://doi.org/10.1177/ 1474515120924530; PMID: 32380858. 6. Iellamo F, Sposato B, Volterrani M. Telemonitoring for the

7. 8.

10.

11.

12.

HF.2,25 Different reimbursement policies result in TM access disparities among countries.25 Standardisation of procedures will help promote pricing and reimbursement of TM services, thus facilitating a more widespread TM adoption.2,25 National regulatory constraints, namely regarding data protection, security and privacy, represent other important barriers to TM implementation, but its relevance varies among countries. Finally, widespread TM accessibility may be hindered by poor internet services and other technological deficiencies in a number of countries, as well as by low technological adherence from both patients and caregivers.2,3 The latter may be improved with patient education, as well as with patients and medical team technological training, resulting in a heightened perception of benefit.2,19,20

Conclusion

By enhancing patient monitoring, management and therapeutic optimisation, TM will emerge as an improvement in HF patients’ care strategy. Its implementation was accelerated during the COVID-19 pandemic and will most likely be reinforced afterwards, as part of a hybrid HF healthcare delivery system. AI promises to become an important component of future telemedical solutions, nevertheless, presently, its clinical relevance still requires further validation. When managing HF patients, a humane and personalised approach is at the core. TM will certainly become an important tool for achieving this goal.

management of patients with heart failure. Card Fail Rev 2020;6:e07. https://doi.org/10.15420/cfr.2019.20; PMID: 32377386. Planinc I, Milicic D, Cikes M. Telemonitoring in heart failure management. Card Fail Rev 2020;6:e06. https://doi.org/ 10.15420/cfr.2019.12; PMID: 32377385. Adamson PB. Pathophysiology of the transition from chronic compensated and acute decompensated heart failure: new insights from continuous monitoring devices. Curr Heart Fail Rep 2009;6:287–92. https://doi.org/10.1007/s11897-0090039-z; PMID: 19948098. Koehler F, Koehler K, Deckwart O, et al. Telemedical Interventional Management in Heart Failure II (TIM-HF2), a randomised, controlled trial investigating the impact of telemedicine on unplanned cardiovascular hospitalisations and mortality in heart failure patients: study design and description of the intervention. Eur J Heart Fail 2018;20:1485–93. https://doi.org/10.1002/ejhf.1300; PMID: 30230666. Comín-Colet J, Verdú-Rotellar JM, Vela E, et al. Efficacy of an integrated hospital-primary care program for heart failure: a population-based analysis of 56,742 patients. Rev Esp Cardiol (Engl Ed) 2014;67:283–93. https://doi.org/10.1016/j. rec.2013.12.005; PMID: 24774591. González-Juanatey JR, Virgós Lamela A, García-Acuña JM, Pais Iglesias B. Clinical management in cardiology. Measurement as a means to improvement. Rev Esp Cardiol 2021;74:8–14 [in Spanish]. https://doi.org/10.1016/j. recesp.2020.05.032; PMID: 32836662. Bekfani T, Fudim M, Cleland JGF, et al. A current and future

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The Future of Telemedicine in Heart Failure Management smartphone-based heart failure telemonitoring solution. IFMBE Proceedings 2019. https://doi.org/10.1007/978-3-03031635-8_167. 20. Koehler J, Stengel A, Hofmann T, et al. Telemonitoring in patients with chronic heart failure and moderate depressed symptoms: results of the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) study. Eur J Heart Fail 2021;23:186–94. https://doi.org/10.1002/ejhf.2025; PMID: 33063412. 21. Vestergaard AS, Hansen L, Sørensen SS, et al. Is telehealthcare for heart failure patients cost-effective? An economic evaluation alongside the Danish TeleCare North heart failure trial. BMJ Open 2020;10:e031670. https://doi. org/10.1136/bmjopen-2019-031670; PMID: 31992604. 22. Jiménez-Marrero S, Yun S, Cainzos-Achirica M, et al. Impact of telemedicine on the clinical outcomes and healthcare costs of patients with chronic heart failure and mid-range or preserved ejection fraction managed in a multidisciplinary chronic heart failure programme: a sub-analysis of the iCOR randomized trial. J Telemed Telecare 2020;26:64–72. https:// doi.org/10.1177/1357633X18796439; PMID: 30193564. 23. Herold R, Hoffmann W, van den Berg N. Telemedical monitoring of patients with chronic heart failure has a positive effect on total health costs. BMC Health Serv Res 2018;18:271. https://doi.org/10.1186/s12913-018-3070-5; PMID: 29636040. 24. Comín-Colet J, Enjuanes C, Verdú-Rotellar JM, et al. Impact on clinical events and healthcare costs of adding telemedicine to multidisciplinary disease management programmes for heart failure: results of a randomized controlled trial. J Telemed Telecare 2016;22:282–95. https:// doi.org/10.1177/1357633X15600583; PMID: 26350543. 25. Gensini GF, Alderighi C, Rasoini R, et al. Value of telemonitoring and telemedicine in heart failure management. Card Fail Rev 2017;3:116–21. https://doi. org/10.15420/cfr.2017:6:2; PMID: 29387464. 26. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S01406736(11)60101-3; PMID: 21315441. 27. Lindenfeld J, Abraham WT, Maisel A, et al. HemodynamicGUIDEd management of Heart Failure (GUIDE-HF). Am Heart J 2019;214:18–27. https://doi.org/10.1016/j.ahj.2019.04.014; PMID: 31150790. 28. Abraham J, McCann PJ, Guglin ME et al. Management of the patient with heart failure and an implantable pulmonary artery hemodynamic sensor. Curr Cardiovasc Risk Rep 2020;14:12. https://doi.org/10.1007/s12170-020-00646-4. 29. Angermann CE, Assmus B, Anker SD, et al. Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). Eur J Heart Fail 2020;22:1891–901. https://doi.org/10.1002/ejhf.1943; PMID: 32592227. 30. Halawa A, Enezate T, Flaker G. Device monitoring in heart

failure management: outcomes based on a systematic review and meta-analysis. Cardiovasc Diagn Ther 2019;9:386–93. https://doi.org/10.21037/cdt.2019.01.02; PMID: 31555544. 31. Alotaibi S, Hernandez-Montfort J, Ali OE, et al. Remote monitoring of implantable cardiac devices in heart failure patients: a systematic review and meta-analysis of randomized controlled trials. Heart Fail Rev 2020;25:469–79. https://doi.org/10.1007/s10741-020-09923-1; PMID: 32002732. 32. Mortara A, Vaira L, Palmieri V, et al. Would you prescribe mobile health apps for heart failure self-care? An integrated review of commercially available mobile technology for heart failure patients. Card Fail Rev 2020;6:e13. https://doi. org/10.15420/cfr.2019.11; PMID: 32537246. 33. Ahmed N, Ahmed S, Grapsa J. Apps and online platforms for patients with heart failure. Card Fail Rev 2020;6:e14. https:// doi.org/10.15420/cfr.2019.15; PMID: 32537247. 34. Veenis JF, Brugts JJ. Remote monitoring of chronic heart failure patients: invasive versus non-invasive tools for optimising patient management. Neth Heart J 2020;28:3–13. https://doi.org/10.1007/s12471-019-01342-8; PMID: 31745814. 35. Conn NJ, Schwarz KQ, Borkholder DA. In-home cardiovascular monitoring system for heart failure: comparative study. JMIR Mhealth Uhealth 2019;7:e12419. https://doi.org/10.2196/12419; PMID: 30664492. 36. Spanakis EG, Psaraki M, Sakkalis V. Congestive heart failure risk assessment monitoring through internet of things and mobile personal health systems. Annu Int Conf IEEE Eng Med Biol Soc 2018;2018:2925–8. https://doi.org/10.1109/ EMBC.2018.8513024; PMID: 30441013. 37. Snoek JA, Prescott EI, van der Velde AE, et al. Effectiveness of home-based mobile guided cardiac rehabilitation as alternative strategy for nonparticipation in clinic-based cardiac rehabilitation among elderly patients in Europe: a randomized clinical trial. JAMA Cardiol 2020;28:e205218. https://doi.org/10.1001/jamacardio.2020.5218; PMID: 33112363. 38. Scherrenberg M, Falter M, Dendale P. Cost-effectiveness of cardiac telerehabilitation in coronary artery disease and heart failure patients: systematic review of randomized controlled trials. Eur Heart J Digital Health 2020;1:20–9. https://doi.org/10.1093/ehjdh/ztaa005. 39. Ski CF, Thompson DR, Brunner-La Rocca HP. Putting AI at the centre of heart failure care. ESC Heart Fail 2020;7:3257– 8. https://doi.org/10.1002/ehf2.12813; PMID: 32558251. 40. D’Amario D, Canonico F, Rodolico D, et al. Telemedicine, artificial intelligence and humanisation of clinical pathways in heart failure management: back to the future and beyond. Card Fail Rev 2020;6:e16. https://doi.org/10.15420/ cfr.2019.17; PMID: 32612852. 41. Ganguli I, Gordon WJ, Lupo C, et al. Machine learning and the pursuit of high-value health care. NEJM Catalyst 2020. https://doi.org/10.1056/CAT.20.0094. 42. Barrett M, Boyne J, Brandts J, et al. Artificial intelligence supported patient self-care in chronic heart failure: a

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paradigm shift from reactive to predictive, preventive and personalised care. EPMA J 2019;10:445–64. https://doi. org/10.1007/s13167-019-00188-9; PMID: 31832118. 43. Corral-Acero J, Margara F, Marciniak M, et al. The ‘Digital Twin’ to enable the vision of precision cardiology. Eur Heart J 2020;41:4556–64. https://doi.org/10.1093/eurheartj/ehaa159; PMID: 32128588. 44. Hirschvogel M, Jagschies L, Maier A, et al. An in silico twin for epicardial augmentation of the failing heart. Int J Numer Method Biomed Eng 2019;35:e3233. https://doi.org/10.1002/ cnm.3233; PMID: 31267697. 45. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789–858. https://doi.org/10.1016/ S0140-6736(18)32279-7. PMID: 30496104. 46. Coats AJS. Ageing, demographics, and heart failure. Eur Heart J Suppl 2019; 21 (Suppl L):L4–7. https://doi.org/10.1093/ eurheartj/suz235; PMID: 31885504. 47. Halamka J, Cerrato P. The digital reconstruction of health care. NEJM Catalyst 2020. https://doi.org/10.1056/ CAT.20.0082. 48. Keesara S, Jonas A, Schulman K. Covid-19 and health care’s digital revolution. N Engl J Med 2020;382:e82. https://doi. org/10.1056/NEJMp2005835; PMID: 32240581. 49. Amorim P, Brito D, Castelo-Branco M, et al. Telehealth opportunities in the COVID-19 pandemic early days: what happened, did not happen, should have happened, and must happen in the near future? Telemed J E Health 2020. https://doi.org/10.1089/tmj.2020.0386; PMID: 33264071; epub ahead of press. 50. Schuuring MJ, Kauw D, Bouma BJ. COVID-19 pandemic: practical considerations on rapid initiation of remote care in chronic cardiac patients Eur Heart J Digital Health 2020;1:8–9. https://doi.org/10.1093/ehjdh/ztaa007. 51. Thornton J. Clinicians are leading service reconfiguration to cope with covid-19. BMJ 2020;369:m1444. https://doi. org/10.1136/bmj.m1444; PMID: 32273263. 52. Shachar C, Engel J, Elwyn G. Implications for telehealth in a postpandemic future: Regulatory and privacy issues. JAMA 2020;323:2375–6. https://doi.org/10.1001/jama.2020.7943; PMID: 32421170. 53. Urbich M, Globe G, Pantiri K. et al. A systematic review of medical costs associated with heart failure in the USA (2014–2020). Pharmacoeconomics 2020;38:1219–36. https:// doi.org/10.1007/s40273-020-00952-0; PMID: 32812149. 54. Cook C, Cole G, Asaria P, et al. The annual global economic burden of heart failure. Int J Cardiol 2014;171:368–76. https://doi.org/10.1016/j.ijcard.2013.12.028; PMID: 24398230. 55. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602.

Clinical Practice

Evaluation and Management of Heart Block After Transcatheter Aortic Valve Replacement Anthony J Mazzella ,1 Sameer Arora,1 Michael J Hendrickson ,2 Mason Sanders,3 John P Vavalle 1 and Anil K Gehi1 1. Division of Cardiology, Department of Medicine, University of North Carolina Hospitals, Chapel Hill, NC, US; 2. University of North Carolina School of Medicine, Chapel Hill, NC, US; 3. Department of Medicine, University of North Carolina Hospitals, Chapel Hill, NC, US

Abstract

Transcatheter aortic valve replacement (TAVR) has developed substantially since its inception. Improvements in valve design, valve deployment technologies, preprocedural imaging and increased operator experience have led to a gradual decline in length of hospitalisation after TAVR. Despite these advances, the need for permanent pacemaker implantation for post-TAVR high-degree atrioventricular block (HAVB) has persisted and has well-established risk factors which can be used to identify patients who are at high risk and advise them accordingly. While most HAVB occurs within 48 hours of the procedure, there is a growing number of patients developing HAVB after initial hospitalisation for TAVR due to the trend for early discharge from hospital. Several observation and management strategies have been proposed. This article reviews major known risk factors for HAVB after TAVR, discusses trends in the timing of HAVB after TAVR and reviews some management strategies for observing transient HAVB after TAVR.

Keywords

Transcatheter aortic valve replacement, pacemaker, heart block, atrial fibrillation, ambulatory monitoring, temporary pacing Disclosure: AKG receives research funding from the Bristol Myers Squibb Foundation, a consulting fee from Biosense Webster and speaker’s honoraria from Abbott, Zoll Medical and Biotronik. All other authors have no conflicts of interest to declare. Received: 5 April 2021 Accepted: 28 May 2021 Citation: Cardiac Failure Review 2021;7:e12. DOI: https://doi.org/10.15420/cfr.2021.05 Correspondence: Anil K Gehi, Division of Cardiology, Department of Medicine, University of North Carolina Hospitals, CB 7075, 6025 Burnett-Womack Bldg, 160 Dental Circle, Chapel Hill, NC 27599–7075, US. E: anil_gehi@med.unc.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) is now the preferred strategy for aortic valve replacement in most patients with severe symptomatic aortic stenosis.1,2 Occasionally, injury to the conduction system during TAVR results in high-degree atrioventricular block (HAVB) necessitating permanent pacemaker (PPM) implantation. Analysis from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry demonstrates stable rates of PPM implantation after TAVR from 2012 to 2015 of between 9 and 2%.3 Despite exponential growth in TAVR and improved operator experience, HAVB continues to be a complication which may necessitate PPM implantation.4,5 Recent expert consensus guidelines have suggested management strategies post-TAVR but comprehensive and prospective data on optimal risk stratification methods and management are lacking.6,7 Risk stratification tools to predict HAVB post-TAVR have been developed, but these are mostly based on data from single-centre studies and focus on the immediate post-TAVR setting.8–12 Little is known specifically about patients who develop HAVB after the initial hospitalisation for TAVR.13 With a trend towards a reduced length of hospital stay after TAVR and stable rates of post-TAVR PPM implantation, the presentation of HAVB has shifted towards the time after discharge from the index hospitalisation.14–16 Understanding patterns in timing of HAVB post-TAVR may help identify which patients may be at risk for this complication and help to mitigate adverse events. The goals of this review are to look at known risk factors for developing HAVB after TAVR, discuss

trends in timing of presentation with HAVB after TAVR and explore the role of ambulatory monitoring in the management of HAVB after TAVR.

Risk Factors for Heart Block after Transcatheter Aortic Valve Replacement

The relationship between AV block and deployment of TAVR prosthesis is driven by several anatomical considerations. The AV node and bundle of His lie in proximity to the aortic annulus. As the TAVR valve is inflated, there can be direct mechanical insult to the AV conduction apparatus from the AV node down to the left bundle branch itself. The penetrating bundle of His traverses the membranous intraventricular septum in the region of the commissure of the non- and right-coronary cusps (Figure 1). Variations in anteroposterior positioning of the AV node and the length of the penetrating bundle of His may influence a patient’s baseline susceptibility to post-TAVR HAVB after valve deployment.17 Additionally, pre-existing conduction abnormalities and procedural factors may influence the magnitude of injury to the conduction system. Various risk factors for postTAVR HAVB have recently been reviewed, and while not a comprehensive list, this review highlights some of the more recognised risk factors, which can be divided into preprocedural and intraprocedural considerations.18

Preprocedural Factors

The most important risk factors for HAVB necessitating PPM implantation after TAVR are assessed in a preprocedural ECG. Specifically, pre-existing

Heart Block Post-TAVR Figure 1: Schematic Showing the Proximity of the Atrioventricular Node, Bundle of His and Aortic Valve Cusps

stratification based purely on conduction system anatomy needs further exploration.21 However, a simple 12-lead ECG to identify baseline conduction disease, in addition to patient-specific demographic and comorbidity characteristics provides valuable information to recognise patients who are at high risk of post-TAVR HAVB.

Procedural Factors

Transcatheter aortic valve protheses are deployed into the aortic valve annulus and secured into place using radial force applied to the native, often calcified, aortic valve. TAVR valves are deployed either by inflation and subsequent removal of an inner balloon over a wire or by an unsheathing technique which allows a controlled self-expansion into the annulus. Several procedural factors can influence the development of post-TAVR HAVB.18 The use of self-expanding valves over balloonexpandable valves, the degree of valve oversizing (greater than 15–20%) and lower implantation depth within the annulus have each been shown to increase the risk of HAVB after TAVR valve deployment.5,19,22–24 When a patient has been identified as having a high risk of HAVB, it may be warranted to use TAVR valves that convey lower risk for conduction defects.25

Timing of Heart Block Immediate Onset

The His bundle (highlighted in light blue) travels from the atrioventricular (AV) node through the membranous interventricular septum before bifurcating into the left and right bundle branches as the membranous septum transitions to the muscular septum. Variations in AV node position and the length of the penetrating His bundle may influence baseline susceptibility to AV conduction block after transcatheter aortic valve replacement deployment. Adapted from: Human Anatomy Atlas (Version 2021), from www.visiblebody.com (accessed 21 January 2021). Used with permission from Visible Body.

conduction defects, such as right bundle branch block (RBBB), left bundle branch block (LBBB), first-degree AVB, second-degree AVB and bifascicular block with or without first-degree AVB, have all been associated with an increased risk of HAVB after TAVR. Pre-existing RBBB represents one of the most significant risk factors.18 Deployment of the TAVR valve may injure the left bundle due to its proximity to the aortic annulus. Demographic and clinical characteristics that have been associated with post-TAVR PPM implantation include male gender and a history of AF.12,19,20 Our group previously analysed 62,083 TAVR patients from 2012 to 2017 from the Nationwide Readmissions Database in the US which further demonstrated that a history of diabetes, acute kidney injury, chronic kidney disease, dementia and hypertension were independently associated with PPM implantation within 30 days of TAVR (Figure 2).16 Pacemaker implantations post-TAVR were also stratified by whether they occurred early (prior to discharge from TAVR hospitalisation) or late (after discharge). Late PPM implantation after TAVR (versus no pacemaker implantation after TAVR) was also independently associated with a history of AF, diabetes and chronic kidney disease in addition to specific conduction abnormalities outlined later in this review. Acute kidney injury was less likely to be associated with late PPM than no PPM. While specific conduction tissue anatomy can be defined with more detail as imaging techniques continue to develop, routine imaging and risk

Transient HAVB is not uncommon with TAVR valve deployment and it is standard practice to have a temporary pacemaker wire in place both to rapidly pace the left ventricle to facilitate safe valve inflation with some implantation systems and as a safeguard in the event of HAVB developing. Most of this transient pacing requirement resolves on its own but it has also been shown to be associated with higher risk of the need for long-term pacing.12,26 Patients suspected to be in need of temporary pacing after the TAVR procedure should be considered for an internal jugular approach for the temporary pacing wire. This can improve patient comfort as observation periods with temporary pacing wires in place can go extend to 48 hours.7,12

Early Onset

Several studies have reported that 60–96% of post-TAVR cases of HAVB occur within 24 hours of TAVR, while 2–7% occur more than 48 hours after TAVR.4,5 Length of stay after TAVR has decreased substantially over the past several years to a median of 2 days.14–16 This increases the possibility of HAVB occurring after a patient has already been discharged from hospital. Rates of PPM implantation within 30 days of having TAVR have remained stable at an average of 11% since 2012. Most of those pacemakers (90%) are implanted during the index hospitalisation, while the remaining 10% are implanted after the patient has been discharged. Early PPM implants (during index hospitalisation) occur at a median of 2 days post-TAVR – interquartile range (IQR): 0.5–3.5 days – while late PPM (during a subsequent hospitalisation) implants occur at a median of 7 days post TAVR (IQR: 5.3–8.7 days). Of the late PPMs, 79.6% were implanted within 14 days of TAVR. From 2014–2017, both the absolute and relative number of late pacemakers implanted after discharge from TAVR hospitalisation increased (Figure 3). This is likely to be related to a shortening of the length of hospital stay for TAVR combined with stable rates of PPM required during this time (Figure 4).16

Late Onset

Studies have described risk factors associated with the need for pacemaker implantation after TAVR. However, few have focused specifically on late-onset HAVB. The need for PPM usually occurs within 14 days post-TAVR and has been associated with an increased 3-year mortality.16,27 Mangieri et al. identified 54 out of 611 patients who underwent

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

Heart Block Post-TAVR Figure 2: Multivariable Models for Odds of Permanent Pacemaker Implantation OR [95% CI] 1.02 [1.01–1.02]*** 1.02 [1.02–1.02]*** 1 [0.99–1.01]

Age

0.98 [0.93–1.04] 0.99 [0.94–1.05] 0.91 [0.78–1.06] 1.19 [1.12–1.25]*** 1.17 [1.11–1.24]*** 1.25 [1.05–1.47]** 1.14 [1.08–1.2]*** 1.13 [1.07–1.2]*** 1.23 [1.05–1.44]** 1.45 [1.34–1.56]*** 1.55 [1.43–1.67]*** 0.69 [0.52–0.89]** 1.12 [1.04–1.2]** 1.05 [0.98–1.11] 1.2 [1.02–1.41]*

Female AF Diabetes Acute kidney injury Chronic kidney disease

1.2 [1.05–1.37]** 1.21 [1.05–1.38]**

Dementia Hypertension

1.09 [1.02–1.17]* 1.19 [1.07–1.32]** 1.19 [1.06–1.32]** 1.9 [0.87–1.59] 7.36 [6.39–8.46]*** 7.92 [6.86–9.12]*** 2.82 [1.68–4.45]*** 1.86 [1.73–2]*** 1.89 [1.76–2.04]*** 1.61 [1.3–1.97]*** 4.57 [4.17–5.02]*** 4.65 [4.23–5.12]*** 3.54 [2.71–4.56]*** 6.16 [5.41–7.02]*** 6.58 [5.76–7.51]*** 2.47 [1.53–3.76]***

First-degree AV block Second-degree AV block LBBB RBBB Bifascicular block

10.37 [7.37–14.64]*** 11.66 [8.27–16.48]***

Bifascicular block and first-degree AV block 1

OR [95% CI] Pacemaker versus no pacemaker

Early pacemaker versus no pacemaker

Late pacemaker versus no pacemaker

Three models were generated from 62,083 transcatheter aortic valve replacement (TAVR) patients between 2012 to 2017 from the Nationwide Readmissions Database, comparing no pacemaker versus pacemaker at any time after TAVR implantation (shown in green, n=6,817), no pacemaker versus pacemaker after TAVR, but during the same hospitalisation (early permanent pacemaker, shown in blue, n=6,137), and no pacemaker versus pacemaker after discharge but within 30 days of TAVR hospitalisation (late permanent pacemaker, shown in yellow, n=680). ORs are shown with 95% CI. If no data exists for a particular covariate, then it was not included in that respective model. *p<0.05, **p<0.01 and ***p<0.001. AV = atrioventricular; LBBB = left bundle branch block, RBBB = right bundle branch block.

pacemaker implantation more than 48 hours after TAVR and found that baseline RBBB and an increase in PR interval after TAVR was associated with an increased risk of needing PPM, although it was unclear which patients were treated during the index hospitalisation or a subsequent stay after TAVR.28 Ream et al. demonstrated that RBBB was associated with delayed-onset HAVB at a median of 6 days after TAVR in 12 out of 113 patients monitored with a 30-day ambulatory monitor.29 Auffret et al. had similar findings in a multicentre sample of TAVR patients.30 Using ambulatory monitoring on discharge after TAVR, Tian et al. identified 11 out of 127 patients with delayed-onset symptomatic bradycardia and another nine patients with HAVB requiring PPM.31 Patients who develop late HAVB after discharge from TAVR hospitalisation represent a unique and growing group of patients at high risk for adverse complications of HAVB (Figure 4). These patients can present with syncope or sudden cardiac arrest which is particularly worrying in a frail and often elderly population who have undergone recent TAVR. In addition, there are significant healthcare costs associated with rehospitalisations in the

postprocedural period. Increasing awareness of the potential risk for HAVB after discharge is important to prompt development of risk stratification and monitoring protocols. Several groups have implemented risk stratification scores to predict PPM implementation, although these scores do not discriminate early from late-onset HAVB.10,11 One area of growing research is the role of monitored outpatient cardiac telemetry to detect HAVB in real time so interventions can be enacted quickly.29,32 The relationship between AF and TAVR remains is not yet fully understood, although ambulatory monitoring has also been shown to detect novel AF after TAVR, allowing clinicians to consider starting therapeutic anticoagulation when appropriate.33 Some studies have also suggested ambulatory monitoring for conduction defects and arrhythmias prior to TAVR to increase the sensitivity in detecting risk factors for HAVB which may develop after TAVR.34,35 Late-onset HAVB that occurs more than 30 days after TAVR is a rare very high-risk phenotype. It becomes more difficult to directly link a TAVR

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Heart Block Post-TAVR Figure 3: Time from Transcatheter Aortic Valve Replacement to Permanent Pacemaker Implantation 2014

600

2015

Management of Heart Block After Transcatheter Aortic Valve Replacement

400

200 Number of patients

procedure as a cause of PPM implantation as time passes. Patel et al. demonstrated a case of complete heart block 5 months after TAVR which was successfully treated with His bundle pacing.36 One theory about this degree of delay in presentation was subtle shifting in the valve over time, although the exact mechanism remains unknown.

0 2016

600

2017

400

200

0 0

Time to pacemaker implantation (days) Early pacemaker

Late pacemaker

Time from transcatheter aortic valve replacement to permanent pacemaker (PPM) implantation stratified by timing of PPM and year. PPM implanted during index hospitalisation (early PPM, purple) and during subsequent hospitalisation (late PPM, green). Data includes years 2014–2017 only due to limitations with timing variables available in the Nationwide Readmissions Database.

The 2013 European guidelines suggest a monitoring period of up to 7 days for resolution of HAVB after TAVR, while the 2012 American guidelines do not specifically address conduction defects after TAVR.37,38 Prospective randomised trials investigating surveillance for and management of HAVB after TAVR are lacking and current guidelines are based mostly on expert opinion.6,7 Our group has previously published our approach to conduction defects after TAVR, which primarily uses the presence of pre-existing RBBB and the need for immediate pacing requirement to provide risk stratification for patients and provides recommendations on duration of observation with temporary pacemaker wires in place (Figure 5).12 Some groups have also used intraprocedural rapid atrial pacing at the time of TAVR to uncover those with concealed intranodal conduction disease, as well as longer observation periods after TAVR using more durable screwin temporary pacing systems.39,40 Recent expert consensus documents emphasise that electrophysiology studies (EPS) do not have a clear role in the risk stratification and management of heart block after TAVR.7 This is mostly due to the fact that trials investigating the use of EPS post-TAVR are either retrospective or lack a control group. Some studies have established some electrophysiological parameters, such as prolongation

Figure 4: Pacemaker Frequency After Transcatheter Aortic Valve Replacement, 2012–2017 20%

15%

6 4 2

10%

0 2012

2013

2014

2015

2016

2017

5% Increasing PPM rates after discharge

0% 2012 2013 2014 2015 2016 2017

% TAVR patients undergoing pacemaker

95%

20% 15%

90%

10% 5%

85%

0% 2012

2013

2014

2015

2016

2017

80%

Stable overall PPM rates post-TAVR

Percentage of pacemakers implanted early

100%

Decreasing PPM rates before discharge

Percentage of pacemakers implanted late

Length of stay (days)

Decreasing TAVR LOS 10

2012 2013 2014 2015 2016 2017

From 2012 to 2017, LOS with index TAVR hospitalisation has decreased to a median of 2 days (p<0.001 for trend) and rates of PPM implantation after TAVR have ranged from 8% to 12.5% without a clear overall direction (p=0.632 for trend, shown in green). However, when pacemaker implantations are stratified into early (same hospitalisation as TAVR, shown in purple) and late (after discharge from TAVR, shown in blue), an increasing proportion of late PPM implantation is appreciated (p<0.0001 for trend). LOS = length of stay; PPM = permanent pacemaker; TAVR = transcatheter aortic valve replacement. Source: Mazzella et al. 2021.16 Used with permission from Elsevier.

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Heart Block Post-TAVR Figure 5: Pacemaker Risk Stratification and Management Strategy Low risk

Intermediate risk

High risk

No RBBB and no need for pacing or HAVB after TAVR

RBBB and no need for pacing or HAVB after TAVR

RBBB and need for pacing or HAVB at any time post-TAVR

Recommendations:

• Remove temporary wire at case conclusion • Discharge with live monitor if two minor risk factors are present*

• Keep temporary wire via IJ approach for 24 hours and remove if no pacing at 24 hours • Live monitor if no PPM implanted

If pacing is needed or HAVB is noted at any point, upgrade to high risk

If pacing is needed or HAVB is noted at any point upgrade to high risk

Major risk factors RBBB (if present, temporary pacemaker should be placed in the internal jugular position at the beginning of TAVR procedure) Need for any pacing or complete heart block after TAVR procedure Minor risk factors 1. History of AF or flutter. 2. Valve oversized >15%

Recommendation • Implant PPM as soon as feasible No RBBB and need for pacing or HAVB at any time post-TAVR Recommendations: • Reassess need for pacing at 24 hours • Implant at 24 hours if one or more minor risk factors still require pacing† • Implant at 48 hours still requiring pacing and no minor risk factors • Discharge with live monitor if not implanted

Previously published work has proposed outpatient and inpatient surveillance strategies for HAVB.12 *In the low-risk scenario, area under receiver operator curve (AUROC) = 0.67 and optimal discrimination occurs at 2 minor risk factors with an associated LR+ of 4.77 and LR− of 0.74 for PPM. †In the high-risk scenario, AUROC = 0.81 and optimal discrimination occurs at one minor risk factor with an associated LR+ of 2.57 and LR− of 0.21 for PPM. HAVB = high-degree atrioventricular block; IJ = internal jugular; LR = likelihood ratio; PPM = permanent pacemaker; RBBB = right bundle branch block; TAVR = transcatheter aortic valve replacement. Source: Mazzella et al. 2020.12 Used with permission from John Wiley and Sons.

of the HV interval of ≥13 ms after TAVR, or induction of second-degree AVB when pacing the atrium at a rate of <150 BPM.41,42 Furthermore, existing bradycardia guidelines regarding indications for permanent pacing continue to apply.43 Approximately half of patients implanted with PPM after TAVR have greater than 40% pacing burden at a median of 4 years of follow-up.44 As a significant portion of patients regain intrinsic conduction after implantation, follow up and pacemaker programming should promote spontaneous atrioventricular conduction when possible.45 Irrespective of pacing burden after TAVR, it has been recognised that patients who require post-TAVR PPM implantation may be at higher risk of short- and long-term morbidity and mortality.44,46,47 These higher rates of adverse events may be a signal of frailty in an otherwise vulnerable population, an increased risk of complications from pacemaker implantation itself or other unknown causes. There are no consensus documents regarding device selection for pacing after TAVR. Percutaneous leadless pacemakers are of growing interest for people who have TAVR, particularly with the advent of devices which promote atrioventricular synchrony.48,49 Future 1. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi. org/10.1056/NEJMoa1816885; PMID: 30883053. 2. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058. 3. Grover FL, Vemulapalli S, Carroll JD, et al. 2016 annual report of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. J Am Coll Cardiol 2017;69:1215–30. https://doi.org/10.1016/j. jacc.2016.11.033; PMID: 27956264. 4. Fadahunsi OO, Olowoyeye A, Ukaigwe A, et al. Incidence, predictors, and outcomes of permanent pacemaker implantation following transcatheter aortic valve replacement: analysis from the US Society of Thoracic Surgeons/American College of Cardiology TVT Registry. J Am Coll Cardiol Interv 2016;9:2189–99. https://doi.org/10.1016/j. jcin.2016.07.026; PMID: 27832844. 5. Auffret V, Puri R, Urena M, et al. Conduction disturbances after transcatheter aortic valve replacement: current status and future perspectives. Circulation 2017;136:1049–69. https://doi.org/10.1161/CIRCULATIONAHA.117.028352; PMID: 28893961. 6. Rodes-Cabau J, Ellenbogen KA, Krahn AD, et al. Management of conduction disturbances associated with

10.

11.

studies are needed to assess the long-term outcomes of leadless pacemaker implantation for post-TAVR conduction defects. With the increased risk of mortality in the setting of PPM implantation and the additional risk of a secondary procedure, minimally invasive approaches may be particularly advantageous for the TAVR population.

Conclusion

Post-TAVR HAVB requiring PPM placement remains a relatively common complication. However, well-established preprocedural and procedural risk factors can be used to identify and advise high-risk patients and guide management. While most HAVB occurs within 48 hours of TAVR, there is a growing number of patients developing HAVB after initial TAVR hospitalisation due to the trend for early discharge post-TAVR. Several observation and management strategies have been proposed. As the population of patients at increased risk for late presentation of HAVB grows, development of algorithms for extended in-hospital observation or for mobile outpatient cardiac telemetry monitoring post-TAVR, particularly in the first 2 weeks after discharge, may be needed to reduce the risk of adverse events.

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implantation after transcatheter aortic valve replacement. JACC Clin Electrophysiol 2020;6:295–303. https://doi. org/10.1016/j.jacep.2019.10.020; PMID: 32192680. Mazzella AJ, Sanders M, Yang H, et al. Predicting need for pacemaker implantation early and late after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2020;97:e588–96. https://doi.org/10.1002/ccd.29239; PMID: 32857905. Sandhu A, Tzou W, Ream K, et al. Heart block after discharge in patients undergoing TAVR with latestgeneration valves. J Am Coll Cardiol 2018;71:577–8. https://doi.org/10.1016/j.jacc.2017.11.057; PMID: 29406864. Arora S, Strassle PD, Kolte D, et al. Length of stay and discharge disposition after transcatheter versus surgical aortic valve replacement in the United States. Circ Cardiovasc Interv 2018;11:e006929. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.006929; PMID: 30354596. Al-Ogaili A, Fugar S, Okoh A, et al. Trends in complete heart block after transcatheter aortic valve replacement: a population based analysis. Catheter Cardiovasc Interv 2019;94:773–80. https://doi.org/10.1002/ccd.28156; PMID: 30790437. Mazzella AJ, Hendrickson MJ, Arora S, et al. Shifting trends in timing of pacemaker implantation after transcatheter aortic valve replacement. J Am Coll Cardiol Interv 2021;14:232–4. https://doi.org/10.1016/j.jcin.2020.09.034; PMID: 33183993.

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advanced conduction disturbances requiring a late (≥48 H) permanent pacemaker following transcatheter aortic valve replacement. J Am Coll Cardiol Interv 2018;11:1519–26. https:// doi.org/10.1016/j.jcin.2018.06.014; PMID: 30093056. 29. Ream K, Sandhu A, Valle J, et al. Ambulatory rhythm monitoring to detect late high-grade atrioventricular block following transcatheter aortic valve replacement. J Am Coll Cardiol 2019;73:2538–47. https://doi.org/10.1016/j. jacc.2019.02.068; PMID: 31118148. 30. Auffret V, Webb JG, Eltchaninoff H, et al. Clinical impact of baseline right bundle branch block in patients undergoing transcatheter aortic valve replacement. J Am Coll Cardiol Interv 2017;10:1564–74. https://doi.org/10.1016/j. jcin.2017.05.030; PMID: 28734885. 31. Tian Y, Padmanabhan D, McLeod CJ, et al. Utility of 30-day continuous ambulatory monitoring to identify patients with delayed occurrence of atrioventricular block after transcatheter aortic valve replacement. Circ Cardiovasc Interv 2019;12:e007635. https://doi.org/10.1161/ CIRCINTERVENTIONS.118.007635; PMID: 31833417. 32. Muntane-Carol G, Philippon F, Nault I, et al. Ambulatory electrocardiogram monitoring in patients undergoing transcatheter aortic valve replacement: JACC State-of-theArt Review. J Am Coll Cardiol 2021;77:1344–56. https://doi. org/10.1016/j.jacc.2020.12.062; PMID: 33706878. 33. Jorgensen TH, Thyregod HG, Tarp JB, et al. Temporal changes of new-onset atrial fibrillation in patients randomized to surgical or transcatheter aortic valve replacement. Int J Cardiol 2017;234:16–21. https://doi. org/10.1016/j.ijcard.2017.02.098; PMID: 28258844. 34. Winter JL, Healey JS, Sheth TN, et al. Remote ambulatory cardiac monitoring before and after transcatheter aortic valve replacement. CJC Open 2020;2:416–9. https://doi. org/10.1016/j.cjco.2020.04.006; PMID: 32995727. 35. Asmarats L, Nault I, Ferreira-Neto AN, et al. Prolonged continuous electrocardiographic monitoring prior to transcatheter aortic valve replacement: the PARE study. J Am Coll Cardiol Interv 2020;13:1763–73. https://doi.org/10.1016/j. jcin.2020.03.031; PMID: 32682674. 36. Patel S, Jamoor K, Khan A, Maskoun W. Late onset complete heart block after transcatheter aortic valve replacement treated with permanent His-bundle pacing. Pacing Clin Electrophysiol 2021;44:194–8. https://doi.org/10.1111/ pace.14074; PMID: 32940376. 37. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013;15:1070–118. https://doi.org/10.1093/europace/eut206; PMID: 23801827. 38. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/ AHA/HRS focused update incorporated into the ACCF/AHA/ HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6–75. https://doi.org/10.1016/j.

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Therapy

How to Implant His Bundle and Left Bundle Pacing Leads: Tips and Pearls Shunmuga Sundaram Ponnusamy

and Pugazhendhi Vijayaraman

1. Velammal Medical College, Madurai, India; 2. Geisinger Heart Institute, Geisinger Commonwealth School of Medicine, Wilkes Barre, PA, US

Abstract

Cardiac pacing is the treatment of choice for the management of patients with bradycardia. Although right ventricular apical pacing is the standard therapy, it is associated with an increased risk of pacing-induced cardiomyopathy and heart failure. Physiological pacing using His bundle pacing and left bundle branch pacing has recently evolved as the preferred alternative pacing option. Both His bundle pacing and left bundle branch pacing have also demonstrated significant efficacy in correcting left bundle branch block and achieving cardiac resynchronisation therapy. In this article, the authors review the implantation tools and techniques to perform conduction system pacing.

Keywords

His bundle pacing, left bundle branch pacing, cardiac resynchronisation therapy, atrioventricular block, left bundle branch block, heart failure; pacemaker Disclosure: SSP has worked as a consultant for Medtronic. PV has received speaker fees and fellowship support from Medtronic, has acted as a consultant for Medtronic and has conducted research for Medtronic, has acted as a consultant for Abbott, Biotronik, and Boston Scientific, and has a patent (US 10,737,097 B2) for a His bundle pacing delivery tool. Received: 30 March 2021 Accepted: 4 May 2021 Citation: Cardiac Failure Review 2021;7:e13. DOI: https://doi.org/10.15420/cfr.2021.04 Correspondence: Pugazhendhi Vijayaraman, Director, Cardiac Electrophysiology, Geisinger Heart Institute, MC 36–10, 1000 E Mountain Blvd, Wilkes-Barre, PA 18711, US. E: pvijayaraman1@geisinger.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiac pacing is the treatment of choice for the management of patients with symptomatic bradyarrhythmia. For nearly six decades, right ventricular (RV) apical (A) pacing has been the standard approach because it is a safe procedure with proven long-term efficacy. However, RVA pacing is fraught with limitations due to associated electrical and mechanical dyssynchrony.1 Pre-excitation of the septum coupled with delayed activation of the left ventricular (LV) free wall produces dyssynchronous activation and less effective contraction.2 Clinically, this can translate into pacing-induced cardiomyopathy in up to 20% of patients and increased risk for heart failure hospitalisation during long-term follow-up.3 The quest for alternative pacing sites has met with limited success because using the RV septum or RV outflow tract failed to demonstrate clinical pacing.4 Adopting biventricular pacing for all patients requiring ventricular pacing is not a cost-effective strategy. An ideal pacing site should provide synchronised ventricular activation by engaging the conduction system of the heart. The concept of conduction system pacing is not new, because temporary capture of the His bundle (HB) was demonstrated more than five decades ago by Scherlag et al.5 The feasibility of permanent HB pacing (HBP) was demonstrated only 30 years later by Deshmukh et al.6 This review provides insights into the procedural technique and clinical implications of HBP and left bundle branch pacing (LBBP).

Anatomy of the Cardiac Conduction System

The electrical impulse of the heart arises from the sinus node at the superior vena cava–right atrial junction and reaches the atrioventricular (AV) node via three internodal pathways. The AV node at the apex of Koch’s triangle

continues as the HB overlying the membranous septum.7 The membranous septum is divided by the septal tricuspid leaflet into an atrioventricular component and a ventriculoventricular component. The penetrating portion of the HB arises from the anterior end of the AV node with loosely arranged fibres in an interweaving pattern. It reaches the ventricle by penetrating the central fibrous body of the heart, where the fibres of left bundle branch (LBB) are given off after it emerges from the fibrous body at the level of the non-coronary aortic cusp. The branching portion of the HB starts from the point where the posterior-most fibres of the LBB arise (posterior fascicles), to the point where the HB continues as the right bundle branch (RBB) after giving rise to the anterior fascicles of the LBB (Figure 1). The LBB, after its origin, runs inferiorly and anteriorly for 10–15 mm, reaching its maximum width before dividing into anterior and posterior fascicles that head towards the corresponding papillary muscles of the LV.8 Anatomical studies have shown three common variations of HB relative to the ventricular aspect of the membranous septum.9 In the Type I variation (47%), the HB courses along the inferior border of the membranous septum with a thin layer of myocardial fibres spanning from the muscular septum. In the Type II variation (32%), the HB is separate to below the membranous septum and courses within the interventricular muscle. In the Type III variation (21%), the HB is exposed superficially, lying immediately below the endocardium (naked HB). Both atrial and ventricular components of the HB can be accessed for permanent HBP.

His Bundle Pacing: Implantation Technique

Deshmukh et al. first demonstrated the clinical feasibility of HBP in patients with AF and LV dysfunction using standard pacing leads by

How to Implant HBP and LBBP Leads

BH B

PH B

Figure 1: Anatomy of the Conduction System

LPF fibres

Gu et al. showed that visualisation of the tricuspid valve annulus by performing contrast angiography before lead implantation resulted in a shorter fluoroscopic time (7.1 versus 10.1 minutes) with similar capture thresholds.11 There was no significant difference in procedural success rates. Zanon et al. demonstrated that HBP can be performed primarily using an electrogram with zero or minimal fluoroscopy with high success rates.12 In that study, the sheath, along with the lead, was advanced gently with counterclockwise and clockwise rotation into the right atrium through a standard 7 Fr introducer. The pacing lead was then connected to the alligator cable in a unipolar fashion. After confirming the position of the sheath in the atrium by a sharp atrial signal in the recording system, the system was advanced gently to get both atrial and ventricular signals. Further anticlockwise rotation helped reach the HB area.12 Gentle manipulation of the system helped record a clear near-field His potential from the pacing lead. Unipolar threshold measurement was performed at a pulse width of 1 ms before fixing the lead in the membranous septum. Transient fluoroscopy was used in all patients to confirm lead stability before removing the C315 sheath. Both selective and non-selective HB capture was accepted as procedural success. HBP could be performed safely in 95% of patients (39/41) in that study using electrograms with minimal or zero fluoroscopy.12

LAF fibres

The His bundle (HB) has two components: the PHB portion and the BHB portion. The LBB branches out of the HB before the true bifurcation point and the RBB is considered as a direct continuation of the HB. Note the longitudinal dissociation as fibres are predestined inside the HB to reach the RBB or LBB. BHB = branching His bundle; LAF = left anterior fascicle; LBB = left bundle branch; LPF = left posterior fascicle; PHB = penetrating His bundle; RBB = right bundle branch.

reshaping the stylet.6 The lead placement was done by targeting the site with largest His deflection recorded from the electrophysiology mapping catheter. This technique was fraught with high pacing thresholds and frequent lead dislodgements. The development of specialised sheaths (C304, C315His and C304His, Selectsite; Medtronic) and a pacing lead (3830 Selectsecure; Medtronic) has made HBP technically feasible with high implant success rates.10 HBP is performed using continuous recording of intracardiac electrograms and 12-lead ECG in an electrophysiology (EP) recording system.10 His signals are recorded directly from the pacing lead tip in a unipolar connection, and are simultaneously recorded in the EP system and in the pacing system analyser (PSA). After obtaining venous access, the C315 sheath is introduced over the guidewire and placed across the tricuspid valve. The sheath has a proximal curve to point towards the tricuspid annulus and a septal curve to direct the lead towards the His region. A 3830 Selectsecure lead is then advanced just exposing the helix outside the sheath, and the His signals mapped in unipolar fashion. Both the atrial and ventricular parts of the membranous septum can be targeted for HBP. If a predominant atrial signal is recorded, the sheath is moved gently forward with clockwise rotation aiming for a larger His signal with a small or no atrial component.

Alternatively, HBP can be performed using 3D electroanatomical mapping (EAM), especially in patients with complex heart disease.13 Sharma et al. created EAM of the RA before lead placement using a conventional 3D mapping system.13 His bundle potentials were tagged. The approach to mapping was axillary or cephalic unless the patient was undergoing an AV junction ablation, in which case a femoral approach was used. Pacing was done at the sites with His potentials to note the response to pacing. The 3830 lead was implanted using a C315 or C304 sheath with continuous tracking of the lead course using the 3D system. Transient fluoroscopy was used to confirm full helix deployment and lead slack. Sharma et al. concluded that EAM-guided HBP could significantly reduce fluoroscopy duration and exposure.13 Once a sharp near-field His signal is identified, unipolar pacing is done to confirm the capture of the HB. Intracardiac electrograms and 12-lead ECG will help assess conduction system capture. In patients with underlying bundle branch block or His–ventricle (HV) block, mapping of the distal HB must be done to achieve complete correction of bundle branch block or to overcome HV block. If an optimal site is identified, the fluoroscopic image may be saved as a reference in orthogonal oblique views (left anterior oblique [LAO] 30° and right anterior oblique [RAO] 30°). The sheath is held firmly with a gentle counterclockwise torque to oppose it towards the septum and five to six clockwise rotations are given to the pacing lead without releasing it between rotations. Lead rotations can be best visualised in the LAO 30° fluoroscopic view. Rebound of the lead after the rotation will confirm its penetration into the membranous septum. If lead rebound is not observed, the sheath position is optimised to provide adequate support before giving further rotations. Care must be taken to avoid pinning the tricuspid leaflet into the septum when the ventricular component is targeted by using contrast angiography or echocardiography if there is difficulty in deploying the lead. Alternatively, the sheath can be moved into the RV apex and pulled back gradually to the target site. After confirming lead fixation, the sheath is gently withdrawn into the high right atrium, providing adequate slack for the lead. The lead parameters are checked in both the unipolar and bipolar configuration. Optimal parameters include a unipolar pacing threshold of <1.5 V at a pulse width of 1 ms and a sensed R-wave of >1.5–2 mV without atrial oversensing. An

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How to Implant HBP and LBBP Leads HB current of injury (COI) recorded from the pacing lead electrogram indicates lead fixation in the HB and predicts excellent pacing thresholds.

Figure 2: Non-selective to Selective His Bundle Pacing 200 ms

Defining Selective and Non-selective Capture of the His Bundle

II III aVR

Based on the paced QRS morphology, two forms of HB capture can be observed: selective (S) and non-selective (NS) HBP.14 During selective capture, pacing will result in direct activation of the HB alone and the ventricular activation occurs completely through the His–Purkinje system (HPS). Because the impulse takes 35–55 ms to reach the ventricular myocardium, there will be an isoelectric interval before the onset of QRS, and the interval from the pacing spike to the onset of QRS (S-QRS) will be equal to the native HV interval. However, in patients with significant HPS disease, the S-QRS would be less than the native HV interval. The lead electrogram will show the ventricular electrogram discrete from the pacing artefact, and the paced QRS morphology is same as the native QRS. During NS-HBP, there will be simultaneous activation of both the HB and the surrounding myocardium (Figure 2). Because ventricular activation starts simultaneously with the pacing artefact due to local myocardial capture, NS-HB capture is characterised by an absent isoelectric interval and slurred QRS upstroke (pseudo-delta wave) and the absence of a discrete local electrogram. The paced QRS duration will be longer than the native QRS duration. There will be two distinct capture thresholds: RV and His capture. In patients with HPS disease, three distinct thresholds may be observed: RV, His capture with correction of bundle branch block and His capture without correction. Various characteristics of S- and NS-HBP in normal and diseased HPS are presented in Table 1. Although S-HBP results in ideal QRS morphology, studies using myocardial perfusion imaging have shown preserved LV electromechanical synchrony even in patients with NS-HBP.15,16 In patients with HV block, NS-HBP provides the advantage of myocardial safety pacing. A recent observational study showed no significant difference in clinical outcomes between S- and NS-HBP.17

Clinical Implications of His Bundle Pacing

HBP is considered as an effective alternative to RVA pacing because it avoids many of the limitations of RVA. HBP can be considered in any patient with symptomatic bradycardia requiring ventricular pacing. Vijayaraman et al. reported an 84% success rate in 100 consecutive patients with AV block.18 The procedural success was higher in patients with AV nodal block (93%) than in patients with infranodal block (76%).18 The three proposed mechanisms for the correction of infranodal block are pacing the HB distal to the site of block, a virtual electrode polarisation effect and a differential source–sink relationship. The role of the HBP as an alternative to biventricular pacing for cardiac resynchronisation therapy (CRT) has been explored with good success. In a retrospective study, Sharma et al. reported 90% procedural success for HBP in 106 CRT-eligible patients.19 On-treatment comparison analysis of the His-Sync Pilot trial showed that patients receiving His CRT had superior electrical resynchronisation and a non-significantly higher echocardiographic response than those receiving biventricular CRT.20 In patients with dilated cardiomyopathy and left bundle branch block (LBBB), Huang et al. achieved a 76% success rate for permanent HBP to achieve CRT and demonstrated very high rates (>85%) of echocardiographic super-response (Figure 3).21 Vijayaraman et al. reported a 95% success rate for HBP in patients with AF and uncontrolled ventricular rates undergoing AV node ablation.22 LV ejection fraction improved from 43% to 50%, with a significant

aVL aVF V1 V2 V3 V4 V5 V6

HIS d

HB Po 1.25 V

1.25 V

1.0 V

As the pacing output is reduced, note the change in QRS morphology and the local ventricular electrogram during non-selective to selective His bundle capture transition. HB Po = His potential.

Figure 3: Left Bundle Branch Block Correction by His Bundle Pacing I II III aVR aVL aVF V1 V2 V3 V4 V5 V6

HIS d HB Po

1.75 V

1.5 V

1.25 V

Complete correction of left bundle branch block could be achieved at a pacing output of 1.5 V at a pulse width of 1 ms (bundle branch block correction threshold). HB Po = His potential.

improvement in functional class.22 In another study of 94 patients undergoing AV node ablation, HBP was successful in 86% of patients with an improvement in LV ejection fraction (from 44.9 ± 14.9% [mean ± standard deviation] at baseline to 57.6 ± 12.5% after a median follow-up of 3.0 years).23 The efficacy of HBP may be uncertain in patients with intraventricular conduction delay, significant LV scar and in 10–30% of LBBB patients in whom the site of block may be distal to the HB.

Limitations of His Bundle Pacing

Although considered an acceptable alternative to RV pacing, HBP has some inherent limitations. Because the fibres are electrically insulated from the surrounding myocardium in the membranous septum, the capture threshold for HBP can be higher than that of RV pacing in 10– 20% of patients. In our experience, HBP can be successfully achieved in >95% of patients with normal His–Purkinje conduction. In patients with a deeply seated HB, the helix may not be long enough to provide an acceptable pacing threshold. A capture threshold of >2 V at a pulse width of 1 ms may be seen in approximately 10% of patients and, before the advent of left bundle pacing, these values were accepted if NS-HB capture could be demonstrated with a significantly lower RV capture threshold. Approximately 12% of patients were noted to have an increase in pacing threshold of >1 V in our cohort of patients followed up for 5 years.24 Lead revisions may be required during follow-up for an unacceptable increase in threshold in 5–7% of patients.10 During the early phase of the learning curve, RV back-up pacing with an additional

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How to Implant HBP and LBBP Leads Table 1: Criteria for His Bundle Pacing Baseline Normal QRS S-HBP

NS-HBP

S-QRS = H-QRS with isoelectric interval

His–Purkinje Conduction Disease With Correction

Without Correction

S-QRS ≤ H-QRS with isoelectric interval

S-QRS ≤ or > H-QRS with isoelectric interval

Discrete local ventricular electrogram in HBP lead with Discrete local ventricular electrogram in HBP lead S-V = H-V

Discrete local ventricular electrogram in HBP lead

Paced QRS = native QRS

Paced QRS < native QRS

Paced QRS = native QRS

Single capture threshold (His bundle)

Two distinct capture thresholds (HBP with BBB correction, HBP without BBB correction)

Single capture threshold (HBP with BBB)

S-QRS < H-QRS (S-QRS usually 0, S-QRSend = H-QRSend) S-QRS < H-QRS (S-QRS usually 0, S-QRSend < H-QRSend) S-QRS < H-QRS (S-QRS usually 0) with or without with or without isoelectric interval (pseudo-delta with or without isoelectric interval (pseudo-delta wave isoelectric interval (pseudo-delta wave +/–) wave +/–) +/–) Direct capture of local ventricular electrogram in HBP Direct capture of local ventricular electrogram in HBP Direct capture of local ventricular electrogram in HBP lead by stimulus artefact (local myocardial capture) lead by stimulus artefact lead by stimulus artefact Paced QRS > native QRS with normalisation of precordial and limb lead axes with respect to rapid dV/dt components of the QRS

Paced QRS ≤ native QRS

Paced QRS > native QRS

Two distinct capture thresholds (His bundle capture, RV capture)

Three distinct capture thresholds possible (HBP with BBB correction, HBP without BBB correction, RV capture)

Two distinct capture thresholds (HBP with BBB, RV capture)

BBB = bundle branch block; dV/dt = rate of change in voltage; HBP = His bundle pacing; H-V = His–ventricular; H-QRS = His–QRS; NS-HBP = His bundle pacing; RV = right ventricle; S-HBP = selective His bundle pacing; S-QRS = stimulus–QRS; S-V = stimulus–ventricular. Source: Vijayaraman et al.14 Adapted with permission from Elsevier.

lead can be considered. However, if the unipolar pacing threshold is <1.5 V at a pulse width of 1 ms with COI at the time of implantation, backup pacing may not be required. Other limitations include atrial oversensing, ventricular undersensing, premature battery depletion due to high output pacing and an inability to correct distal conduction system disease.

Left Bundle Branch Pacing

In an attempt to overcome the limitations of HBP, distal conduction system capture was first demonstrated by Huang et al. by deep septal placement of the lead.25 LBBP is defined as the capture of either the proximal left bundle or one of its fascicles along with the septal myocardium at a low threshold.26,27 Anatomically, the left bundle branch is a wide target, with fibres fanning on the left subendocardial aspect of the proximal interventricular septum, compared with the narrow band of the HB. Criteria for confirming LBB capture have been proposed but not validated in large trials. LBB capture is confirmed by paced QRS morphology of RBB delay pattern (qR or rSR in lead V1) along with any one of the following criteria:26,27 • Demonstration of non-selective to selective capture or non-selective to septal capture transition during threshold testing. • Abrupt shortening of R-wave peak times (RWPT), as measured in leads V5 or V6 during lead implantation at the mid-septum and subsequent short and constant RWPT at the final site. • Demonstration of LBB potential. • Programmed deep septal stimulation from the pacing lead to demonstrate conduction system capture, especially selective capture.27 • Meeting physiology-based electrocardiographic criteria, namely paced RWPT in V6 (measured from QRS onset) equals the native RWPT and paced RWPT (measured from the stimulus) equals the LBBP potential to V6.29

Left Bundle Branch Pacing Implantation Techniques

The LBBP implantation tools are the same as those for HBP. Preimplantation echocardiography should be performed to assess the

thickness of the interventricular septum in multiple views, the presence of septal scar, dilatation of cardiac chambers and valvular regurgitation. Careful assessment of the proximal septum is important because it determines procedural success. Intracardiac electrograms and 12-lead ECG are continuously recorded using an EP recording system. Placing a quadripolar mapping catheter across the HB is optional to delineate the distal extent of His electrograms. Alternatively, the pacing lead can be used to map the HB to mark its distal extent. After obtaining venous access, the C315 sheath, along with the 3830 lead (Figure 4), is placed in the proximal interventricular septum 1–1.5 cm below the distal HB along an imaginary line connecting the distal HB to the RVA in the RAO 30° fluoroscopic view. Pace mapping of the septum is done by gentle counterclockwise rotation of the sheath to obtain a paced QRS morphology of a ‘W’ pattern in lead V1 with the notch on the nadir of QRS, tall R in lead II, RS in lead III and discordant QRS complexes in leads aVR and aVL. Although classically described, the W pattern is not mandatory, and, in our experience, this is not seen in 20% of patients. The sheath should be held firmly with counterclockwise torque, with the hub of the sheath pointing towards the right hand of the implanter (3 o’clock to 4 o’clock position) to orient it perpendicular to the septum. Once the optimal site is identified on the right side of the septum, lead deployment can be done by one of two techniques: • conventional (gradual deployment with monitoring of paced QRS morphology and unipolar pacing impedance); or • premature ventricular complex (PVC) guided (rapid deployment with monitoring of PVC morphology). In the conventional technique, the lead is deployed gradually with a few rapid rotations at a time and monitoring of three important parameters: paced QRS morphology (the notch on the nadir of lead V1 will gradually ascend to form an R wave), unipolar pacing impedance (increases gradually before it drops by 100–200 Ω as the lead reaches the LV subendocardium) and myocardial COI on the lead electrogram.26 A drop in pacing impedance of >200 Ω, unipolar impedance <400 Ω and a reduction

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How to Implant HBP and LBBP Leads Figure 4: Left Bundle Branch Pacing Implantation Technique A

His

RAO 30°

RBB

LBB

RBB Lead

(Fitt. 1) RVA B

RBB

RV subendocardium

RBB

Mid-septum

Left bundle area

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6 HB

His Po LB Po

LBP Imp 400 Ω

660 Ω

750 Ω

940 Ω

800 Ω

LB Po

A: RAO fluoroscopic view showing the course of the HB and LBB. The ideal target site is 1–1.5 cm below the HB along an imaginary line connecting the distal HB to the RVA. B: Rapid rotation of the lead must be performed with the hub of the sheath pointing towards the 3- to 4-o’clock position, with preferably dry gloves closer to the sheath. C: Pacing the target site at the right side of the septum will show the ‘W’ pattern in lead V1, tall R in lead II and discordant QRS complexes in aVR and aVL. As the lead reaches the LBB area, paced QRS will show a qR pattern in lead V1 along with LB Po preceding the local ventricular electrogram. HB = His bundle; LBB = left bundle branch; LB Po = left bundle potential; RAO = Right anterior oblique; RBB = right bundle branch; RV = right ventricle; RVA = right ventricle apex.

in sensed R wave amplitude with loss of COI in the unipolar electrogram may suggest lead perforation into the LV cavity. In the PVC-guided lead deployment technique, rapid turns are given to deploy the lead.30 Lead movement during rapid deployment can be appreciated in the LAO 30° view. PVCs are commonly noted during rapid penetration of the lead into the septum (Figure 5). The morphology of PVCs changes from wide QRS with QS morphology in lead V1 to narrow QRS with an RBB delay pattern (qR/rSR) as the lead traverses from the right to left side of the septum. Template or fixation beat is defined as a PVC with an RBB delay pattern and a duration of <130 ms.29–31 Rotations should be stopped immediately on observing a template beat. LBB capture can be confirmed at this site by the aforementioned criteria. Template beat-guided LBBP is associated with less fluoroscopic time and minimal myocardial injury, and avoids septal perforation during lead deployment.29,31 In patients with narrow QRS or RBBB morphology at baseline, a sharp high-frequency LBB potential should be seen preceding the local ventricular electrogram by 20–35 ms. In patients with LBBB, antegrade activation of LBB will not occur due to complete block of conduction in the distal HB/proximal LBB. LBB potential may be demonstrated by Hiscorrective pacing in patients with LBBB. In some patients the LBB potential may be masked due to significant COI. Concealed LBB potential must be considered before repositioning the lead if other parameters confirm LBB capture.32 Non-selective left bundle (NS-LB) to selective left bundle (S-LB) branch capture transition can be demonstrated during threshold testing at near-threshold output (Figure 6). S-LB capture is characterised by a distinct local ventricular electrogram on the pacing lead separate from the pacing artefact, along with a change in paced QRS morphology. NS-LB is characterised

Figure 5: Template or Fixation Beats During Lead Deployment I II III aVR aVL

PVCs

aVF V1

Template beat

V2 V3 V4 V5 V6

PVCs are generated during lead deployment with morphology changing from QS to qR (template beat) in lead V1 as it reaches the left bundle branch area. PVC = premature ventricular complex.

by a pacing artefact immediately followed by a local ventricular electrogram with a pseudo-delta wave on the surface ECG. However, in many patients, demonstration of the isoelectric interval or discrete local electrogram may be difficult due to short stimulus to QRS intervals. RWPT is measured in leads V5 or V6 from the onset of the pacing spike to the peak of the R wave. Differential pacing at 10 and 2 V must produce short and constant RWPT (preferably <80 ms) to confirm the capture of the LBB. If peak LV activation time is prolonged at 2 V compared with

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How to Implant HBP and LBBP Leads Figure 6: Non-selective to Selective Left Bundle Branch Capture

Figure 7: Physiology-based ECG Criteria for Left Bundle Branch Capture A

I I II Non-selective to selective capture II

III aVR

III

aVL aVR

aVF V1

aVL

V2 aVF V3 V1

V4 V5

V6 V3 His-D V4

LBP 0.4 V

0.4 V

0.3 V

As the output is reduced from 0.4 to 0.3 V at a pulse width of 0.5 ms, non-selective to selective left bundle branch (LBB) capture is seen. Note the discrete local ventricular electrogram from the pacing artefact during selective capture of the LBB along with subtle changes in QRS morphology. LBP = left bundle pacing lead.

pacing at 10 V, additional turns are given to get the shortest RWPT. In patients with cardiomyopathy, LV hypertrophy and distal conduction system disease, RWPT is generally <90 ms, but occasionally may be longer.33 The novel physiology-based ECG criteria for LBB capture proposed by Jastrzebski et al., namely paced RWPT in V6 (measured from QRS onset) equal to native V6 RWPT and paced RWPT (measured from stimulus) equal to the LBB potential to V6 RWPT (Figure 7), had sensitivity and specificity of 98–88% and 85–95% respectively.29 When measured from stimulus, the optimal and 100% specific V6 RWPT values for differentiating LBB capture from LV septal capture in patients with narrow QRS/RBBB were 83 and 74 ms, respectively. In patients with LBBB/ventricular escape rhythm, the optimal and 100% specific values were 101 and 80 ms, respectively.29 After confirming LBB capture, the sheath is gently pulled back into the right atrium with adequate lead slack. There is a tendency for the formation of an alpha loop in the lead while removing the sheath. The alpha loop can be undone in the RAO view by gently retracting the lead back with a counterclockwise rotation. Pacing parameters must be checked again in both the unipolar and bipolar configurations. Because part of the anode is often inside the septum, the anodal capture threshold must be checked by gradually reducing the pacing output in the bipolar configuration. Lead V1 will show changes in QRS morphology from the QS pattern (as the anode captures the right side of the septum) to the qR/rSR pattern once the anode loses it capture. Electroanatomical mapping with creation of 3D geometry of the atrium and ventricle, along with delineation of His signals to facilitate lead deployment, can minimise radiation exposure.34

V5 90 ms

90 ms V6

H His-D LB

LBP

R-Wave peak time in lead V6 during native rhythm (A), as measured from the onset of LBP, will be equal to the R-wave peak time during left bundle branch pacing (B), as measured from the onset of pacing artefact. Also note the LB current of injury immediately after the LBP (black arrow). H = His; LB = left bundle; LBP = left bundle branch potential.

Troubleshooting Difficult Cases

The reported success rate for LBBP is between 80.5% and 97%.35–37 The reasons for failure include inability of the lead to penetrate deep into the septum, inadequate sheath support and improper sheath–septal orientation. Both the gloves and the lead must be dry while performing rapid rotations. If the basal septum is scarred, the left posterior fascicle can be targeted by placing the lead in mid-septum posteriorly.38 Entanglement of the septal tricuspid leaflet may prevent deep septal penetration of the lead. To overcome this issue, the sheath is advanced towards the RV apex before bringing it back to the target site. RBB conduction delay created by pacing the LBB can be corrected by optimising the AV delay to allow native fusion, by programming pacing output to allow the anodal capture or by placing additional lead in the RV septum. In patients with cardiomyopathy and a diseased distal conduction system, LBBP may not result in ideal electrical resynchronisation. In these patients, LBBP may be combined with a coronary venous lead to achieve maximum electrical resynchronisation.

Clinical Implications

LBBP has the potential to overcome the limitations of HBP because it provides a low and stable threshold, excellent lead stability and the

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How to Implant HBP and LBBP Leads Figure 8: Atrioventricular Junction Ablation and Left Bundle Branch Pacing A

B I

aVR

aVL

C RAO 25°

aVF

aVR

aVL

III

aVF

V5 HB

III

Abl

LBBP

A: Baseline ECG showing AF with a fast ventricular rate. B: Note the distance between the Abl and the LBBP. C: Final paced QRS duration of 90 min with a qR pattern in V1. Abl = ablation catheter; HB = His bundle; LBBP = left bundle branch pacing lead; RAO = right anterior oblique.

ability to correct conduction disease in the distal HB/proximal LB. In patients with AV block after transcatheter aortic valve replacement, Vijayaraman et al. reported success rates of 63% and 93% for HBP and LBBP, respectively.39 Huang et al. reported a 97% success rate in patients with non-ischaemic cardiomyopathy and LBBB, with significant improvement in LV function.40 A retrospective multicentre study by Vijayaraman et al. reported an 85% acute procedural success rate for LBBP in 325 CRT-eligible patients.33 LBBP resulted in a reduction in QRS duration from 152 to 137 ms, along with an improvement in LV ejection fraction from 33% to 44%.33 In patients undergoing AV junction ablation, LBBP provides additional safety because the lead is away from the site of ablation compared with HBP (Figure 8).

Limitations of Left Bundle Branch Pacing

Although LBBP provides a low capture threshold, excellent lead stability and a shorter learning curve, long-term safety data are lacking. In a recent report of 632 patients, Su et al. reported a 97.8% success rate for LBBP.41 1. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol 2009;54:764–76. https://doi.org/10.1016/j.jacc.2009.06.006; PMID: 19695453. 2. Poole JE, Singh JP, Birgersdotter-Green U. QRS duration or QRS morphology: what really matters in cardiac resynchronization therapy? J Am Coll Cardiol 2016;67:1104–17. https://doi.org/10.1016/j.jacc.2015.12.039; PMID: 26940932. 3. Kurshid S, Epstein AE, Verdino RJ, et al. Incidence and predictors of right ventricular pacing-induced cardiomyopathy. Heart Rhythm 2014;11:1619–25. https://doi. org/10.1016/j.hrthm.2014.05.040; PMID: 24893122. 4. Kaye GC, Linker NJ, Marwick TH, et al. Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: results of the Protect-Pace study. Eur Heart J 2015;36:856–62. https://doi. org/10.1093/eurheartj/ehu304; PMID: 25189602. 5. Scherlag BJ, Lau SH, Helfant RH, et al. Catheter technique for recording His bundle activity in man. Circulation 1969;39:13–8. https://doi.org/10.1161/01.CIR.39.1.13; PMID: 5782803 6. Deshmukh P, Casavant DA, Romanyshyn M, et al. Permanent, direct His-bundle pacing: a novel approach to cardiac pacing in patients with normal His–Purkinje activation. Circulation 2000;101:869–77. https://doi. org/10.1161/01.CIR.101.8.869; PMID: 10694526. 7. Tawara S. Das Reizleitungssystem des Saügetierherzens. Jena: GustavFischer, 1906;135–8. 8. Hudson REB. Surgical pathology of the conducting system of the heart. Br Heart J 1967;29:646–70. https://doi. org/10.1136/hrt.29.5.646; PMID: 6039160. 9. Kawashima T, Sasaki H. A macroscopic anatomical investigation of atrioventricular bundle locational variation relative to the membranous part of the ventricular septum in elderly human hearts. Surg Radiol Anat 2005;27:206–13.

The mean follow-up time in that study was 18.6 months and the LBBP capture threshold remained stable at the 2-year follow-up. RBB injury was noted in 8.9% of patients and 1% of patients had either loss of capture or an increase in the threshold to >3 V with successful LBBP.41 Lead perforation into the LV cavity, RBB injury, myocardial trauma with troponin release, septal arterial injury and coronary cameral fistula are potential complications to be monitored.42–44 The implications of extraction of an LBBP lead implanted deep in the septum are unknown. Large-scale randomised multicentre studies are required to establish the long-term safety and efficacy of LBBP before it can be adopted as the main pacing strategy.

Conclusion

Conduction system pacing has gained significant interest over the past decade with the development of specially designed tools. HBP and LBBP are acceptable alternatives to RV pacing. The limitations of HBP are well addressed by LBBP, which provides a remarkably low and stable threshold. Early data suggest that HBP and LBBP may also be reasonable alternatives to biventricular pacing to achieve CRT.

https://doi.org/10.1007/s00276-004-0302-7; PMID: 15723154. 10. Vijayaraman P, Chung MK, Dandamudi G, et al. His bundle pacing. J Am Coll Cardiol 2018;72:927–47. https://doi. org/10.1016/j.jacc.2018.06.017; PMID: 30115232. 11. Gu M, Niu H, Hu Y, et al. Permanent His bundle pacing implantation facility by visualization of the tricuspid valve annulus. Circ Arrhythm Electrophysiol. 2020;13:e008370. https://doi.org/10.1161/CIRCEP.120.008370; PMID: 32911981. 12. Zanon F, Marcantoni L, Zuin M, et al. Electrogram-only guided approach to His bundle pacing with minimal fluoroscopy: a single-center experience. J Cardiovasc Electrophysiol 2020;31:805–12. https://doi.org/10.1111/ jce.14366; PMID: 31976602. 13. Sharma PS, Huang HD, Trohman RG, et al. Low fluoroscopy permanent His bundle pacing using electroanatomic mapping: a feasibility study. Circ Arrhythm Electrophysiol. 2019;12:e006967. https://doi.org/10.1161/CIRCEP.118.006967; PMID: 30704289. 14. Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing (HBP): recommendations from International HBP Collaborative Group for standardization of definitions, implant measurements and follow-up. Heart Rhythm 2018;15:460–8. https://doi.org/10.1016/j.hrthm.2017.10.039; PMID: 29107697. 15. Zhang J, Guo J, Hou X, et al. Comparison of the effects of selective and non-selective His bundle pacing on cardiac electrical and mechanical synchrony. Europace 2018;20:1010–7. https://doi.org/10.1093/europace/eux120; PMID: 28575215. 16. Upadhyay GA, Tung R. Selective versus nonselective His bundle pacing for cardiac resynchronization therapy. J Electrocardiol 2017;50:191–4. https://doi.org/10.1016/j. jelectrocard.2016.10.003; PMID: 27890282. 17. Beer D, Sharma PS, Subzposh FA, et al. Clinical outcomes of selective versus nonselective His bundle pacing. JACC Clin

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Electrophysiol 2019;5:766–74. https://doi.org/10.1016/j. jacep.2019.04.008; PMID: 31320004. 18. Vijayaraman P, Naperkowski A, Ellenbogen KA, Dandamudi G. Electrophysiologic insights into site of atrioventricular block: lessons from permanent His bundle pacing. JACC Clin Electrophysiol 2015;1:571–81. https://doi.org/10.1016/j. jacep.2015.09.012; PMID: 29759411. 19. Sharma PS, Dandamudi G, Herweg B, et al. Permanent His bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: a multicenter experience. Heart Rhythm 2018;15:413–20. https://doi.org/10.1016/j. hrthm.2017.10.014; PMID: 29031929. 20. Upadhyay GA, Vijayaraman P, Nayak HM, et al. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: a secondary analysis of His-SYNC pilot trial. Heart Rhythm 2019;16:1797–807. https://doi.org/10.1016/j. hrthm.2019.05.009; PMID: 31096064. 21. Huang W, Su L, Wu S, et al. Long-term outcomes of His bundle pacing in patients with heart failure with left bundle branch block. Heart 2019;105:137–43. https://doi.org/10.1136/ heartjnl-2018-313415; PMID: 30093543. 22. Vijayaraman P, Subzposh FA, Naperkowski A. Atrioventricular node ablation and His bundle pacing. Europace 2017;19(Suppl 4):iv10–6. https://doi.org/10.1093/ europace/eux263; PMID: 29220422. 23. Su L, Cai M, Wu S, et al. Long-term performance and risk factors analysis after permanent His-bundle pacing and atrioventricular node ablation in patients with atrial fibrillation and heart failure. Europace 2020;22(Suppl 2):ii19– 26. https://doi.org/10.1093/europace/euaa306; PMID: 33370800. 24. Vijayaraman P, Naperkowski A, Subzposh FA, et al. Permanent His-bundle pacing: Long-term lead performance and clinical outcomes. Heart Rhythm 2018;15:696–702.

How to Implant HBP and LBBP Leads https://doi.org/10.1016/j.hrthm.2017.12.022; PMID: 29274474. 25. Huang W, Su L, Wu S, et al. A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block. Can J Cardiol 2017;33:1736.e1–3. https://doi.org/10.1016/j.cjca.2017.09.013; PMID: 29173611. 26. Huang W, Chen X, Su L, et al. A beginner’s guide to permanent left bundle branch pacing. Heart Rhythm 2019;16;1791–6. https://doi.org/10.1016/j.hrthm.2019.06.016; PMID: 31233818. 27. Ponnusamy SS, Arora V, Namboodiri N, et al. Left bundle branch pacing: a comprehensive review. J Cardiovasc Electrophysiol 2020;31:2462–73 https://doi.org/10.1111/ jce.14681; PMID: 32681681. 28. Jastrzebski M, Moskal P, Bednarek A, et al. Programmed deep septal stimulation – a novel maneuver for the diagnosis of left bundle branch capture during permanent pacing. J Cardiovasc Electrophysiol 2020;31:485–93. https://doi.org/10.1111/jce.14352; PMID: 31930753. 29. Jastrzebski M, Keilbasa G, Curila K, et al. Physiology-based electrocardiographic criteria for left bundle branch capture. Heart Rhythm 2021;18:935–43. https://doi. org/10.1016/j.hrthm.2021.02.021; PMID: 33677102. 30. Ponnusamy SS, Vijayaraman P. Left bundle branch pacing guided by premature ventricular complexes during implant. HeartRhythm Case Rep 2020;6:850–3 https://doi.org/10.1016/j. hrcr.2020.08.010; PMID: 33204621. 31. Ponnusamy SS, Ganesan V, Syed T, et al. Template beat: a novel marker for left bundle branch capture during physiological pacing. Circ Arrhythm Electrophysiol

2021;14:e009677. https://doi.org/10.1161/CIRCEP.120.009677; PMID: 33858179. 32. Ponnusamy SS, Vijayaraman P. Concealed left bundle branch potential during physiological pacing. J Interv Card Electrophysiol 2021;61:213–4. https://doi.org/10.1007/s10840020-00899-4; PMID: 33146852. 33. Vijayaraman P, Ponnusamy SS, Cano O, et al. Left bundle branch area pacing for cardiac resynchronization therapy: results from international LBBAP collaborative study group. JACC Clin Electrophysiol 2021;7:135–47. https://doi. org/10.1016/j.jacep.2020.08.015; PMID: 33602393. 34. Ponnusamy SS, Bopanna D, Kumar S. Electro-anatomical mapping guided low fluoroscopy left bundle branch pacing. JACC Clin Electrophysiol 2020;6:1045–7. https://doi. org/10.1016/j.jacep.2020.05.020; PMID: 32819522. 35. Vijayaraman P, Subzposh FA, Naperkowski A, et al. Prospective evaluation of feasibility, electrophysiologic and echocardiographic characteristics of left bundle branch area pacing. Heart Rhythm 2019;16:1774–82. https://doi. org/10.1016/j.hrthm.2019.05.011; PMID: 31136869. 36. Ponnusamy SS, Muthu G, Kumar M, et al. Mid-term feasibility, safety and outcomes of left bundle branch pacing – single center experience. J Interv Card Electrophysiol 2021;60:337–46. https://doi.org/10.1007/s10840-02000807-w; PMID: 32623624. 37. Li Y, Chen K, Dai Y, et al. Left bundle branch pacing for symptomatic bradycardia: implant success rate, safety, and pacing characteristics. Heart Rhythm 2019;16:1758–65. https://doi.org/10.1016/j.hrthm.2019.05.014; PMID: 31125667. 38. Ponnusamy SS, Syed T, Kumar S. Left posterior fascicular

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pacing. J Innov Card Rhythm Manag 2021;12:4493–6. https:// doi.org/10.19102/icrm.2021.120506; PMID: 34035980. 39. Vijayaraman P, Cano O, Koruth JS, et al. His–Purikinje conduction system pacing following transcatheter aortic valve replacement – feasibility and safety. JACC Clin Electrophysio. 2020;6:649–57. https://doi.org/10.1016/j. jacep.2020.02.010; PMID: 32553214. 40. Huang W, Wu S, Vijayaraman P, et al. Cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy utilizing left bundle branch pacing. JACC Clin Electrophysiol 2020;6:849–58 https://doi.org/10.1016/j. jacep.2020.04.011; PMID: 32703568. 41. Su L, Wang S, Wu S, et al. Long-term safety and feasibility of left bundle branch pacing in a large single-center study. Circ Arrhythm Electrophysiol 2021;14:e009261. https://doi. org/10.1161/CIRCEP.120.009261; PMID: 33426907. 42. Ravi V, Larsen T, Ooms S, et al. Late-onset interventricular septal perforation from left bundle branch pacing. HeartRhythm Case Rep 2020;6:627–31. https://doi. org/10.1016/j.hrcr.2020.06.008; PMID: 32983881. 43. Ponnusamy SS, Patel NR, Naperkowski A, et al. Cardiac troponin release following left bundle branch pacing. J Cardiovasc Electrophysiol 2021;32:851–5. https://doi. org/10.1111/jce.14905; PMID: 33484212. 44. Ponnusamy SS, Vijayaraman P. Aborted ST-elevation myocardial infarction – an unusual complication of left bundle branch pacing. HeartRhythm Case Rep 2020;6:520–2. https://doi.org/10.1016/j.hrcr.2020.05.010; PMID: 32817832.

Letter to the Editor

Unknown Risks of Transplantation in Adults with Congenital Heart Disease Aniket S Rali ,1 Angela Weingarten ,1 Emily Sandhaus,1 Richa Gupta ,1 Allman Rollins,1 David Bichell,2 Nhue Do,2 D Marshall Brinkley ,1 Kelly H Schlendorf,1 Daniel Freno,3 Keki Balsara 3 and Jonathan N Menachem1 1. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, US; 2. Division of Pediatric Cardiac Surgery, Monroe Carell Jr Children’s Hospital at Vanderbilt, Nashville, TN, US; 3. Division of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, TN, US

Disclosure: ASR is on the Cardiac Failure Review editorial board. All other authors have no conflicts of interest to declare. Acknowledgements: The authors thank the Brett Boyer Foundation and the Pete Huttlinger Fund for Adult Congenital Cardiac Research for their continued support and dedication to improving outcomes for those with congenital heart disease. Received: 10 May 2021 Accepted: 5 June 2021 Citation: Cardiac Failure Review 2021;7:e14. DOI: https://doi.org/10.15420/cfr.2021.09 Correspondence: Jonathan N Menachem, 1215 21st Avenue South, MCE South Tower, Suite 5209, Nashville, TN 37232-8802, US. E: jonathan.n.menachem@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

According to the International Society for Heart and Lung Transplantation 2015 registry update, only 3.3% of adult heart transplants between 2009 and 2014 were for congenital heart disease (CHD).1 This may be due in part to a higher early 30-day mortality in CHD patients compared with non-CHD patients.2 The higher mortality in adults with CHD undergoing orthotopic heart transplantation (OHT) is the result of numerous factors, including surgical complexity and endorgan dysfunction, frailty and arrhythmias that present late in the disease process. We report the case of a patient with complex CHD who underwent OHT at our centre and who had an extremely rare haemorrhagic complication. Permission was obtained from the patient’s family for the publication of this article.

Initial Medical History

The patient was a 43-year-old woman with complex CHD and end-stage heart failure. With regard to the anatomy, the patient had a double-inlet left ventricle, with the aorta arising from the hypoplastic right ventricle. The patient was initially palliated with a pulmonary artery (PA) band, and later the superior vena cava (SVC) was anastomosed to the right PA (classic Glenn) with antegrade filling of the left PA from the single functional ventricle (Figure 1). Details and an explanation of why the patient had never proceeded to total cavopulmonary connection (palliated as a Fontan) were not known. The patient had chronically elevated SVC pressures (20–24 mmHg), leading to decompression of the SVC to the inferior vena cava and pulmonary vasculature by the collateral veins, flow reversal in the azygous system, and pulmonary arteriovenous malformations. These venous collaterals, including a collateral vein traversing immediately posterior to the sternum, put the patient at prohibitive risk of bleeding during OHT, and she was ultimately deemed a non-candidate at other centres due to the surgical complexity despite the preserved end-organ function and favourable human leukocyte antigen antibody status (21% Class I panel reactive antibodies [PRA] and 0% Class II PRA; non-complement fixing). The patient was brought to our centre for full OHT evaluation.

Due to chronic hypoxia (baseline saturations 75–80%) the patient was polycythaemic (haemoglobin 24 g/dl). In addition, her saturations worsened with recurrent paroxysmal, but haemodynamically unstable, symptomatic atrial arrhythmias. Supraventricular tachycardia remained refractory to multiple cardioversions and treatment with amiodarone. The best course of action to stabilise the patient was deemed to be radiofrequency ablation (RFA). The procedure involved left atrial (LA) pulmonary vein isolation, posterior LA isolation, cavotricuspid isthmus ablation and ablation along the septal atriotomy for atrial arrhythmias (Figure 2). Despite the RFA, the patient continued to have frequent arrhythmias, severe shortness of breath and hypoxaemia. It was the decision of a multidisciplinary team from multiple institutions that the best course of action would be to move forward with urgent OHT at our institution.

Pre-transplant Hospital Course

Six days after the RFA, the patient was admitted to our centre and underwent successful coiling of the large vessel immediately posterior to the sternum (Figure 3) in the paediatrics cardiac catheterisation lab to reduce her risk of bleeding on surgical entry for OHT. Cardiac catheterisation demonstrated elevated SVC pressure (22 mmHg), a mean right PA pressure of 22 mmHg and a mean left PA pressure of 26 mmHg, with a calculated cardiac output (Qs) of 3.51 l/min (cardiac index, 2.31 l/min/m2; Figure 1). Chest CT angiography showed severe stenosis just distal to the pulmonic valve with post-stenotic dilatation, a dilated inferior vena cava draining into the right atrium and a venous collateral immediately posterior to the sternum. The patient was subsequently listed for OHT.

Post-transplant Hospital Course

Twenty-eight days after ablation and 7 days after the listing for transplantation, the patient underwent OHT with a sex-matched donor allograft with bicaval anastomosis, with the recipient’s LA cuff including pulmonary veins anastomosed to the donor’s LA. No abnormalities

Unknown Transplantation Risks in Adults with CHD Figure 1: Schematic Diagram of the Palliated Heart

RPCW 16/18 58% 15

91/57 73

62% 22

83%

34/20 26 pO2 236 on 100% FiO2

92%

81%

35/18 26

After transplantation, the oxygenation saturations improved to above 90% and the patient was extubated on postoperative day (POD) 1. The patient was transferred out of the intensive care unit in a stable condition on POD 5. Pending discharge, the patient underwent a screening nasopharyngeal swab for COVID-19 on POD 10. After the swab, the patient experienced mild epistaxis that self-resolved. The following morning the patient had large-volume haematemesis, leading to cardiopulmonary arrest with pulseless electrical activity. The initial aetiology of the massive haematemesis was believed to be swabrelated trauma to chronically dilated (due to the single-ventricle physiology) venous structures in the posterior nasopharynx; however, the actual aetiology was confirmed later. The patient underwent emergency cannulation at the bedside for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and was taken to the operating theatre for LA venting along with exploration of persistent haematemesis. Interestingly, the bleeding resolved almost immediately once the LA was vented.

94% pO2 236 on 100% FiO2

were noted of the LA posterior wall at the time of transplantation. The ischaemic time was 252 minutes. The patient did not require any packed red blood cell transfusions, and post-transplant trans-oesophageal echocardiography (TOE) confirmed normal biventricular function.

23/22 17

62% 21/22 16 72% 143/15

74% 99/57 74 Initial pulmonary artery (PA) banding was followed by superior vena cava anastomoses to the right PA (classic Glenn) with antegrade filling of the left PA from the single functional ventricle. FiO2 = fraction of inspired oxygen; RPCW = right pulmonary capillary wedge.

The otolaryngology team performed an emergency nasopharyngoscopy to rule out bleeding from the nasopharynx. The gastroenterology team performed an emergency oesophagogastroduodenoscopy (OGD) in the operating theatre. Immediately following oesophageal insufflation, air was noted in the arterial cannula of the VA-ECMO circuit with a drop in flow. This finding prompted an evaluation for a fistula capable of explaining air in the ECMO circuit due to insufflation. A large LA–oesophageal fistula was identified (Figure 4), which was repaired by oversewing the LA and then placing a 23 × 125 Wallflex oesophageal stent. Despite initial cardiac

Figure 2: Radiofrequency Ablation and Pulmonary Vein Isolation

Posterior view of the left atrium demonstrating the circumferential pulmonary vein isolation, as well as the roof and floor lines, isolating the posterior left atrium.

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Unknown Transplantation Risks in Adults with CHD Figure 3: Venogram of the Coiling of the Venous Collateral

Figure 4: Oesophagogastroduodenoscopy Showing an Atrio-oesophageal Fistula

The oesophagogastroduodenoscopy shows an atrio-oesophageal fistula (yellow arrow).

post-RFA atrio-oesophageal fistula is well-described, this case is unique because the patient had RFA performed on her native heart and the complication occurred after OHT, with a seemingly ‘new’ heart. However, it should be highlighted that in the present case the patient’s native atrial cuff was anastomosed to the donor heart during the most common bicaval anastomosis surgical technique of OHT. Hence, the cuff had undergone an ablation. As such, we hypothesise that the patient had experienced atrial and oesophageal tissue damage during the RFA procedure, which progressed to a fistula over the following 3 weeks. It is also possible that the already friable atrial cuff tissue of the native heart was further exacerbated during the transplant surgery, increasing the odds of such a fistula formation.

The venogram shows the substernal venous collateral (thick blue arrow) at the time of its coiling and previous coils (thin red arrows).

For patients in whom atrio-oesophageal fistula is suspected, any oesophageal manipulation should be avoided (TOE, nasogastric tube placement etc.), and in particular insufflation, given that it will lead to LA air and resultant stroke or coronary embolisation. Unfortunately, in the present case none of the workup prior to the OGD was suggestive of atrio-oesophageal fistula.

pulsatility, in the hours following, this worsened as it became evident that the patient had had an MI as a probable result of air in the coronaries. The patient was also noted to have had ischaemia on head CT. Ultimately, the patient’s condition was deemed unrecoverable. After discussion with her family, the patient’s care was withdrawn.

End-stage single-ventricle patients frequently require extensive atrial ablations for symptomatic and haemodynamically significant arrhythmias. The present patient’s unfortunate outcome raises the question of whether, prior to OHT, routine surveillance imaging such as chest CT or direct visualisation with OGD should be obtained in patients who have undergone RFA in the past month to rule out oesophageal trauma.

Discussion

We report a case of post-RFA atrio-oesophageal fistula, a rare but often fatal complication. The reported incidence of atrio-oesophageal fistula after RFA in the general population ranges from <0.01% to 0.25%, and it usually occurs at a median of 19.3 days after the procedure.3,4 Although 1. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-second Official Adult Heart Transplantation Report – 2015; focus theme: early graft failure. J Heart Lung Transplant 2015;34:1244–54. https://doi. org/10.1016/j.healun.2015.08.003; PMID: 26454738. 2. Doumouras BS, Alba AC, Foroutan F, et al. Outcomes in adult congenital heart disease patients undergoing heart

Furthermore, despite a well-planned and thorough ablation, the present patient still continued to have atrial arrhythmias, highlighting the challenge in the treatment of patients such as this. As such, it is of the utmost importance to recognise rhythm disturbances as a warning sign of the potential need of evaluation for advanced therapies.

transplantation: a systematic review and meta-analysis. J Heart Lung Transplant 2016;35:1337–47. https://doi. org/10.1016/j.healun.2016.06.003; PMID: 27431751. 3. Barbhaiya CR, Kumar S, Guo Y, et al. Global survey of esophageal and gastric injury in atrial fibrillation ablation: incidence, time to presentation, and outcomes. J Am Coll Cardiol 2015;65:1377–8. https://doi.org/10.1016/j. jacep.2015.10.013; PMID: 25835452.

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4. Calkins H, Kuck KH, Cappato R, et al. HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. J Interv Card Electrophysiol 2012;33:171–257. https://doi. org/10.1007/s10840-012-9672-7; PMID: 22382715.

Treatment

Effect of Statin Intensity on the Progression of Cardiac Allograft Vasculopathy Tracey M Ellimuttil ,1 Kimberly Harrison ,1,2 Allman T Rollins ,2,3 Irene D Feurer ,2,4,5 Scott A Rega ,2 Jennifer Gray 1,2 and Jonathan N Menachem 2,3 1. Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, US; 2. Vanderbilt Transplant Center, Nashville, TN, US; 3. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, US; 4. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, US; 5. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, US

Abstract

Background: In the non-transplant population, hyperlipidaemia has shifted from targeting LDL goals to statin intensity-based treatment. It is unknown whether this strategy is also beneficial in cardiac transplantation. Methods: This single-centre retrospective study evaluated the effect of statin use and intensity on time to cardiac allograft vasculopathy (CAV) after cardiac transplantation. Kaplan–Meier and Cox proportional hazards regression survival methods were used to assess the association of statin intensity and median post-transplant LDL on CAV-free survival. Results: The study involved 143 adults (71% men, average follow-up of 25 ± 14 months) who underwent transplant between 2013 and 2017. Mean CAV-free survival was 47.5 months (95% CI [43.1–51.8]), with 29 patients having CAV grade 1 or greater. Median LDL was not associated with time to CAV (p=0.790). CAV-free survival did not differ between intensity groups (p=0.435). Conclusion: Given the non-statistically significant difference in time to CAV with higher intensity statins, the data suggest that advancing moderate- or high-intensity statin after cardiac transplantation may not provide additional long-term clinical benefit. Trial registration: Not applicable.

Keywords

Coronary allograft vasculopathy, heart transplantation complication, 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor Disclosure: The authors have no conflicts of interest to declare. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical conduct of research: This study complies with the Declaration of Helsinki and was approved by the VUMC Institutional Review Board (IRB#181865). Funding: This project was supported by CTSA award No. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Received: 23 April 2021 Accepted: 3 September 2021 Citation: Cardiac Failure Review 2021;7:e15. DOI: https://doi.org/10.15420/cfr.2021.07 Correspondence: Kimberly Harrison, Suite 536 Oxford House, 1313 21st Avenue South, Nashville, TN 37232, US. E: kimberly.m.harrison@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiac allograft vasculopathy (CAV), a potential complication after cardiac transplantation, presents as a diffuse, progressive thickening of the myocardial arteries and remains a major cause of increased morbidity and mortality after transplant due to the development of ventricular dysfunction and life-threatening arrhythmias.1 The prevalence of CAV increases with increased duration of graft survival, with rates of 8%, 29% and 47% at 1, 5 and 10 years following cardiac transplantation.2 Invasive techniques, such as coronary angiography and IV ultrasound, are gold standards for diagnosis of CAV, although the use of non-invasive imaging such as stress echocardiogram and myocardial perfusion imaging is on the rise. Both immunological and non-immunological factors have been associated with an increased risk of CAV. Immunological risk factors include differences in donor and recipient human leukocyte antigen (HLA), presence of alloreactive antibodies and episodes of acute rejection.2 T-cell activation leads to expression of adhesion molecules on the surface of endothelial tissues.2 Non-immunological factors, such as hyperlipidaemia, hyperglycaemia and history of cytomegalovirus viraemia or infection, have all been determined to be independent risk factors for the development of

CAV.3 Various medication therapies are used in modern clinical practice to reduce CAV risk or delay its progression including aspirin, mammalian target of rapamycin (mTOR) inhibitors and 3-hydroxy-3methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins). A prospective, randomised open-label trial of 97 heart transplant recipients showed that the use of pravastatin 40 mg daily after cardiac transplant led to a reduction in cholesterol levels, a lower incidence of CAV, and increased patient survival.4 A 10-year follow-up to this study demonstrated similar effects, with increased 10-year graft survival and 10year freedom from CAV and death.5 The beneficial effects of statins were verified with a randomised controlled trial of simvastatin, up-titrated to a dose of 20 mg per day, compared with diet alone, which demonstrated a significant reduction in LDL, lower incidence of CAV and improved 4-year patient survival.6 A recent retrospective analysis demonstrated lower change in plaque index and decreased risk of CAV-associated events with early initiation of statins (defined as less than 2 years after transplant) compared with late initiation in the context of modern immunosuppression and diagnostic techniques.7 The cardiovascular benefit associated with statins has been hypothesised to be due to their effect on lowering total

Statin Intensity and Cardiac Allograft Vasculopathy cholesterol and LDL. A 2018 retrospective cohort analysis evaluated the relative risk of developing CAV with respect to LDL reduction and found that patients who achieved a median LDL of <2.6 mmol/l had a delay in time to CAV. This benefit was not seen with an LDL goal of <1.8 mmol/l.8 In the non-transplant population, the focus on prevention of atherosclerotic cardiovascular disease has shifted from targeting specific LDL goals to placing patients on higher intensity statins.9,10 In the transplant population, the use of specific statin medications and doses can be limited due to pharmacological interactions with calcineurin inhibitors (cyclosporine and tacrolimus) and other post-transplant medications. These drug interactions can increase statin exposure and place patients at risk for myopathy and rhabdomyolysis.11–14 Pharmacokinetic studies have evaluated the interaction of cyclosporine with high-intensity doses of atorvastatin and rosuvastatin, and noted a 6–15-fold and 7.1-fold increase in the atorvastatin and rosuvastatin areas under the curve, respectively.15,16 Unlike cyclosporine, tacrolimus is only a substrate and not an inhibitor of cytochrome P450 3A4, and is therefore theoretically safer in combination with higher intensity statins. A retrospective study of 24 heart transplant recipients receiving tacrolimus therapy showed that high-intensity statins were well tolerated, with only one patient experiencing myalgias and none experiencing rhabdomyolysis or hepatotoxicity.17 A retrospective study of 346 patients found that greater statin intensity significantly prolonged time to a composite primary endpoint of heart failure hospitalisation, revascularisation, MI or death.18 Another report of 131 heart transplant patients found no association between high-intensity statins and the incidence of CAV at 1 or 3 years.19 Although statin intensity has been associated with reduction in atherosclerotic cardiovascular disease in non-transplant patients, the effect of statin intensity on CAV reduction in the cardiac transplant population is still unknown. The primary aim of this study is to evaluate the effect of statin intensity on the time to the development of CAV after cardiac transplantation.

Methods Design and Clinical Protocol

This single-centre retrospective cohort analysis was approved by the Vanderbilt University Medical Center Institutional Review Board. Analyses were conducted in late 2018 and early 2019. Adults (age ≥18 years) were included if they: received an orthotopic heart transplant at our institution between February 2013 and April 2017, thus allowing for at least 12 months of potential follow-up; were managed after transplant at our institution; began statin therapy within 1 year after transplantation; and had at least one cardiac angiogram and one lipid panel after transplantation. Multiorgan transplant recipients, those with a history of previous heart transplant, and recipients of hepatitis C-positive organs were excluded. Based on our institutional protocol, all heart transplant recipients are placed on tacrolimus with a tacrolimus trough goal of 8–12 ng/ml, mycophenolate mofetil 1,000 mg every 12 hours, and prednisone taper with therapeutic alterations based on the patient’s individual posttransplant course. Unless contraindicated, patients are also started on statin therapy prior to discharge from their transplant hospital admission. The choice of statin agent is based on the patient’s statin therapy prior to transplant and on their baseline lipid panel. Per protocol, patients who had non-ischemic cardiomyopathy as the indication for transplant had a post-transplant LDL goal of < 2.6 mmol/l, and patients with a history of ischaemic cardiomyopathy prior to transplant had an LDL goal of <1.8 mmol/l. Doses are increased until patients achieve their LDL goal, or they are intolerant to therapy. Lipid panels are evaluated every 3 months

for those who remain above their LDL goal or who have any change in statin therapy. Coronary angiography is obtained at 1, 3 and 5 years after transplantation unless contraindicated by severe renal impairment, defined as an estimated glomerular filtration rate <30 ml/min/1.73m2. Coronary angiography may be obtained earlier, and more frequently, if there is a clinical suspicion of CAV.

Data Encoding

Statin therapies were classified as low, moderate and high intensity, based on American College of Cardiology and American Heart Association classifications.20 They were stratified, for the purpose of these analyses, as low and moderate/high due to the small proportion of patients receiving high-intensity statins. The presence or absence of CAV was defined according to the 2010 International Society of Heart and Lung Transplant standardised nomenclature using coronary angiography only, which was reviewed by both interventional and transplant cardiologists.21 The CAV follow-up period was defined as the time (in months) from the transplant to the determinative CAV follow-up date, which was either the date of the first or only CAV-positive coronary angiography (CAV-1, CAV-2, or CAV-3), or the date of the last angiography that was CAV negative (CAV-0). Demographic and clinical data collected included age, history of diabetes, history of hypertension, history of chronic kidney disease, indication for transplant, donor and recipient cytomegalovirus serology, and smoking history. Lipid panels and HbA1c data were collected at baseline, which was defined as 2 weeks prior to/after transplantation, and longitudinally after transplant. Dyslipidaemia therapy was assessed immediately prior to transplantation, at discharge, and annually. Statin intensity was determined based on the medication and dose that was closest to and ≤6 months before or after the CAV follow-up date. Immunosuppression was documented at discharge and annually after transplantation. NonCAV outcomes, such as post-transplant lipids, were monitored throughout the CAV follow-up period, with a tolerance of 14 days following the CAV follow-up date. The number of biopsy-proven rejection episodes with a grade greater than or equal to 2R in the CAV follow-up period was tallied and coded as a binary variable, the presence or absence of rejection. Within-subject median post-transplant values for lipids and HbA1c were calculated for those patients having at least two data points in their CAV follow-up period.

Statistical Analysis

Differences in demographic and clinical characteristics based on statin use and intensity groups (none, low, moderate/high), and in posttransplant measures between statin intensity groups (low, moderate/high) were evaluated using analysis of variance or χ-squared tests, with z-tests of column proportions. Kaplan–Meier survival methods with the log rank test were used to evaluate CAV-free survival in the entire cohort, between those who were and were not receiving statin therapy, and the effect of statin intensity (low versus moderate/high) in patients receiving statin therapy. Cox proportional hazards regression was used to test the association between within-subject median post-transplant LDL and CAVfree survival. Analysis of co-variance was used to test the differences between median post-transplant total cholesterol, LDL, HDL, triglycerides and HbA1c between those with and without CAV, and between the three statin groups (none, low, moderate/high) after adjusting for CAV follow-up time. Multivariable logistic regression was used to test the effect of rejection on the likelihood of CAV after adjusting for CAV follow-up time. Some study data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at Vanderbilt University Medical

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Statin Intensity and Cardiac Allograft Vasculopathy Table 1: Patient Characteristics by Statin Intensity No Statin (n=7)

Low-intensity Statin (n=62

Moderate-/High-intensity Statin (n=74)

Age at transplant

53 ± 13 years

51 ± 13 years

54 ± 10 years

Male sex

6 (85.7%)

39 (62.9%)

57 (77.0%)

4 (57.1%)

49 (79.0%)

56 (75.7%)

3 (42.9%)

13 (21.0%)

14 (18.9%)

0 (0%)

1 (1.4%)

0 (0%)

3 (4.1%)

3 (42.9%)

16 (25.8%)

17 (23.0%)

6 (85.7%)

47 (75.8%)

65 (87.80%)

5 (71.4%)

33 (53.2%)

42 (56.8%)

5.4 ± 1.0%

5.6 ± 0.8%

4 (57.1%)

41 (66.1%)

36 (48.6%)

3 (42.9%)

21 (33.9%)

38 (51.4%)

2.57 ± 5.97%

7.52 ± 18.88%

9.36 ± 22.09%

3.43 ± 9.07%

4.42 ± 18.12%

3.55 ± 11.39%

• High (D+/R−) • Moderate (D+/R+ or D−/R+) • Low (D−/R−)

0 (0%)

18 (29.0%)

15 (20.3%)

6 (85.7%)

37 (59.7%)

48 (64.9%)

1 (14.3%)

7 (11.3%)

11 (14.9%)

Smoking history

1 (14.3%)a,b

26 (44.1%)a

45 (63.4%)b

• Tacrolimus • Cyclosporine† • Mycophenolate • Azathioprine† • Prednisone ≥20 mg • Prednisone 10–19 mg† • Prednisone <10 mg

7 (100%)

60 (96.8%)

72 (97.3%)

0 (0)%

1 (1.6%)

2 (2.7%)

7 (100%)

62 (100%)

71 (95.9%)

0 (0)

2 (2.7%)

6 (85.7)

56 (90.3)

67 (90.5%)

0 (0)

6 (9.7)

7 (9.5)

1 (14.3)

0 (0)

CAV follow-up time (months)

14.7 ± 4.4 monthsa,c

26.3 ± 14.6 monthsa

25.0 ± 14.4 monthsc

Ethnicity:

• White • Black • Asian • Other Comorbidities:

• Diabetes • Hypertension • Chronic kidney disease • Pre-transplant HbA1c* Indication for transplant:

• Non-ischaemic cardiomyopathy • Ischaemic cardiomyopathy Peak pre-transplant PRA:

• Class I • Class II Cytomegalovirus donor/recipient risk:

Immunosuppression on discharge:

*Data were not fully populated in the low- and moderate-/high-intensity groups, total n=114. †χ-squared test was not interpretable due to small cell sizes. All p-values are >0.10 unless noted as: ap<0.05, b p<0.05 and c0.05>p<0.10. CAV = cardiac allograft vasculopathy; D+ = donor positive; D− = donor negative; PRA = panel-reactive antibody; R+ = recipient positive; R− = recipient negative.

Center. REDCap is a secure, web-based application designed to support data capture for research studies.22 All analyses were conducted using IBM SPSS (version 25.0; IBM) and statistical significance was indicated if a non-directional p-value was less than 0.05.

Results

In total, 217 adults underwent transplantation between February 2013 and April 2017. Of those, 74 (34%) were excluded. Sixty-five people (30%) met a single exclusion criterion: multi-organ transplant (n=10, 5%), previous heart transplant (n=5, 2%), followed up at a different institution (n=33, 15%), and unavailable cardiac catheterisation data (n=17, 8%); and nine people (4%) were excluded for two or more reasons. Of the 143 people included in the primary analysis, seven were not on a statin, 62 were on a low-intensity statin and 74 patients were on a moderate- or high-intensity statin at the CAV follow-up date. Agents that were included in this cohort included atorvastatin, pravastatin, simvastatin, rosuvastatin and

pitavastatin. As shown in Table 1, with the exception that a higher proportion of patients in the low-intensity and moderate-/high-intensity groups had a smoking history prior to transplantation compared with the no statin group, there were no statistically significant differences in baseline characteristics between the three groups (all p>0.10). Recipients were predominantly white, male, and had an average age of 53 years. The mean panel of reactive antibody for both Class I and Class II was less than 10% in all groups. The majority of patients were discharged after transplantation on tacrolimus, mycophenolate and prednisone. On analyses of post-transplant outcomes, 29 (20%) were diagnosed with CAV-1 or greater and 114 remained CAV free over the total follow-up period, which averaged 25.1 ± 14.4 months (range, 6.1–62.6 months). Mean CAV-free survival was 47.5 months (95% CI [43.1–51.8]) (Figure 1). Although the sample was substantively smaller and the follow-up time substantively shorter in the group that did not receive statin therapy

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Statin Intensity and Cardiac Allograft Vasculopathy Figure 1: Kaplan–Meier Overall Cardiac Allograft Vasculopathy-free Survival

CAV (all p≥0.350). After adjusting for CAV follow-up time, patients who had at least one rejection episode were 2.9-fold more likely to have CAV than those who remained rejection free (HR 2.87; 95% CI [1.17–7.04; p=0.022). Average LDL in the no statin, low-intensity, and moderate-/highintensity statin groups, after adjusting for follow-up time, was also not statistically significantly different, at 2.54 ± 0.67 mmol/l, 2.20 ± 0.68 mmol/l and 2.36 ± 0.57 mmol/l, respectively (p=0.168; Table 3).

1.0

Cumulative CAV-free survival

0.9 0.8 0.7

Discussion

0.6 0.5 0.4 0.3 0.2

Survival function Censored

0.1 0.0

Follow-up time (months) The overall mean cardiac allograft vasculopathy-free survival for the entire cohort was 47.5 months after cardiac transplantation. CAV = cardiac allograft vasculopathy.

Figure 2: Kaplan–Meier CAV-free Survival by Statin Intensity 1.0

Cumulative CAV-free survival

0.9

Previous studies have demonstrated benefits of statins in prolonging survival and reduction in CAV progression; however, many evaluated them as a class effect, without evaluating the differences in dosing regimens.4–6 This study has demonstrated that, irrespective of the statin intensity, patients had similar CAV-free survival durations, given that there was no difference in time to CAV between the low-intensity and moderate-/ high-intensity statin groups. These data add to the limited literature regarding whether statin intensity has an impact on clinical outcomes after heart transplant. Given the drug–drug interactions that exist between calcineurin inhibitors, other post-transplant medications, and statins, patients may equally benefit from lower dose statins to mitigate the risk of drug-related adverse effects. Despite being on different intensity statins, patients in the low-intensity and moderate-/high-intensity groups had statistically similar median post-transplant LDL levels of 2.2 mmol/l and 2.35 mmol/l, respectively. This affects the applicability of placing all patients on low-intensity statins after heart transplantation, and would only be applied to the group of patients who achieve an LDL <2.6 mmol/l on a low-intensity statin.

0.8 0.7

p=0.435

0.6 0.5 0.4 0.3 Statin intensity level Low Moderate/high

0.2 0.1 0.0

24 36 48 Follow-up time (months)

There was no statistically significant difference in cardiac allograft vasculopathy (CAV)-free survival between the low-intensity and moderate-/high-intensity groups, with a mean CAV-free survival of 48.5 months and 46.1 months, respectively (p=0.435). CAV = cardiac allograft vasculopathy.

(Table 1), treatment with a statin after transplantation showed a trend towards improved CAV-free survival compared with those who did not receive statin therapy (p=0.055). There was no statistically significant difference in CAV-free survival between the two statin groups, with a mean CAV-free survival of 48.5 and 46.1 months in the low- and moderate-/ high-intensity statin groups, respectively (p=0.435) (Figure 2). In those for whom it could be calculated (n=136), median post-transplant LDL was not associated with time to CAV (p=0.790). This lack of association was also reflected when median post-transplant LDL was stratified as <1.8, 1.8 to 2.5, and ≥2.6 mmol/l (all log-rank p≥0.467). Related analyses showed that, after adjusting for follow-up time, median post-transplant LDL in those who developed CAV compared with those who were CAV free averaged 2.34 ± 0.6 mmol/l and 2.29 ± 0.63 mmol/l, respectively (p=0.747) (Table 2). Similarly, after adjusting for follow-up time, there were no statistically significant differences in median post-transplant total cholesterol, HDL, triglycerides or HbA1c between those with and without

There was no association between median post-transplant LDL and time to CAV, suggesting that the benefit of statins may be independent of LDL reduction. It has been previously hypothesised that the effects of statins on CAV progression may be impacted by mechanisms independent of their effect on atherosclerosis through reduction in cholesterol deposition.23–25 Non-lipid-related mechanisms have been proposed based on animal models that include attenuation of vascular smooth muscle proliferation, downregulation of growth factor genes in smooth muscle cells, and downregulation of endothelial nitric oxide production.23–26 This conclusion cannot be fully applied to our cohort given that patients in both statin intensity groups had a median LDL level <2.6 mmol/l, which has been previously shown to delay time to CAV.8 The two statin intensity groups were well balanced and the only statistically significant difference in the baseline characteristics was smoking history prior to transplant, which was higher in the statin groups. On univariate analysis to evaluate the risk factors for CAV there were no differences in post-transplant median total cholesterol, LDL, HDL, triglycerides or HbA1c. The only significant effect identified was that patients who had rejection grade 2R or greater were approximately threefold more likely to develop CAV, which aligns with previously published studies.26,27 The limitations of this study include those inherent to single-centre, retrospective designs. Post-transplant monitoring was not uniform for all of the patients; however, all available data between the transplant and the determinative CAV follow-up date were collected, and differences in follow-up time were addressed through survival and co-variance-adjusted statistical methods. The timing and duration of mTOR inhibitors were difficult to capture. However, at our institution, mTOR inhibitors are frequently started in patients who develop CAV and therefore they do not interfere with CAV-free survival in this cohort. Detection of CAV in this

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Statin Intensity and Cardiac Allograft Vasculopathy Table 2: Follow-up Time-adjusted Comparisons by Cardiac Allograft Vasculopathy Status No CAV

CAV

p-value

Analysis Sample (n)

Summary Data

Analysis Sample (n)

Summary Data

Total cholesterol*

110

4.41 ± 0.88 mmol/l

4.38 ± 0.87 mmol/l

0.889

LDL*

110

2.29 ± 0.63 mmol/l

2.34 ± 0.60 mmol/l

0.747

HDL*

110

1.15 ± 0.32 mmol/l

1.09 ± 0.24 mmol/l

0.350

Triglycerides*

110

1.98 ± 1.09 mmol/l

2.01 ± 1.22 mmol/l

0.901

HbA1c*

6.3 ± 1.1 %

6.1 ± 1.5 %

0.422

Any rejection†

114

55 (48.2%)

21 (72.4%)

0.022

*Medians were calculated if there were ≥2 data points in the CAV follow-up period. †Based on a logistic regression model adjusted for follow-up time. Data are given as the mean (SD) of median post-transplant values, or n (%). CAV = cardiac allograft vasculopathy.

Table 3: Follow-up Time-adjusted Comparisons by Statin Intensity Group No Statin

Low-intensity Statin

Moderate-/High-intensity Statin

Analysis Sample (n)

Summary Data

Analysis Sample (n)

Summary Data

Analysis Sample (n)

Summary Data

p-value

Total cholesterol

4.55 ± 0.85 mmol/l

4.30 ± 0.92 mmol/l

4.48 ± 0.83 mmol/l

0.449

LDL

2.54 ± 0.67 mmol/l

2.2 ± 0.68 mmol/l

2.36 ± 0.57 mmol/l

0.168

HDL

1.18 ± 0.36 mmol/l

1.15 ± 0.33 mmol/l

1.13 ± 0.28 mmol/l

0.911

Triglycerides

1.35 ± 0.48 mmol/l

2.02 ± 1.34 mmol/l

2.01 ± 0.92 mmol/l

0.291

HbA1c

6.1 ± 1.4%

6.2 ± 1.3%

6.3 ± 1.2%

0.872

Data are given as the mean (SD) of median post-transplant values. Medians were calculated if there were ≥2 data points in the cardiac allograft vasculopathy follow-up period.

cohort was mostly done using cardiac catheterisation and not intravascular ultrasound, therefore, the sensitivity of CAV detection may be reduced in this study. Finally, baseline and donor angiography were not analysed, meaning that the effects of pre-existing disease cannot be determined.

Conclusion

HMG-CoA reductase inhibitors, as a class, have been shown to be beneficial in treating dyslipidaemia and preventing CAV after heart transplantation. Guidelines for the prevention of atherosclerotic 1. Lars HL, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report 2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:996–1008. https://doi.org/10.1016/j. healun.2014.08.003; PMID: 25242124. 2. Moien-Afshari F, McManus BM, Laher I. Immunosuppression and transplant vascular disease: benefits and adverse effects. Pharmacol Ther 2003;100:141–56. https://doi. org/10.1016/j.pharmthera.2003.08.002; PMID: 14609717. 3. Escobar A, Ventura HO, Stapleton DD, et al. Cardiac allograft vasculopathy assessed by intravascular ultrasonography and nonimmunologic risk factors. Am J Cardiol 1994;74:1042– 6. https://doi.org/10.1016/0002-9149(94)90856-7; PMID: 7977044. 4. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621–7. https://doi.org/10.1056/ NEJM199509073331003; PMID: 7637722. 5. Kobashigawa JA, Moriguchi JD, Laks H, et al. Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 2005;24:1736–40. https://doi.org/10.1016/j.healun.2005.02.009; PMID: 16297773. 6. Wenke K, Meiser B, Thiery J, et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96:1398–402. https://doi.org/10.1161/01.cir.96.5.1398; PMID: 9315523. 7. Asleh R, Briasoulis A, Pereira NL, et al. Timing of 3-hydroxy3-methylglutaryl-coenzyme A reductase inhibitor initiation and allograft vasculopathy progression and outcomes in heart transplant recipients. ESC Heart Fail 2018;5:1118–29.

cardiovascular disease in non-transplant patients recommend the use of high-intensity statins. Whether high-intensity statins convey a similar benefit in heart transplant recipients is unknown. Our study showed no difference in time to CAV between heart transplant recipients treated with low intensity compared with moderate-/high-intensity statins. Our data suggest that patients may have prolonged CAV-free survival while being on a statin therapy that provides adequate LDL reduction irrespective of statin intensity. A larger, prospective study is needed to confirm these findings.

https://doi.org/10.1002/ehf2.12329; PMID: 30019530. 8. Harris J, Teuteberg J, Shullo M. Optimal low-density lipoprotein concentration for cardiac allograft vasculopathy prevention. Clin Transplant 2018;32:e13248. https://doi. org/10.1111/ctr.13248; PMID: 29603413. 9. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81. https://doi. org/10.1016/S0140-6736(10)61350-5; PMID: 21067804. 10. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168– 209. https://doi.org/10.1016/j.jacc.2018.11.002; PMID: 30423391. 11. Wiggins BS, Saseen JJ, Page RL, et al. Recommendations for management of clinically significant drug–drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2016;134:468–95. https://doi.org/10.1161/CIR.0000000000000456; PMID: 27754879. 12. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003;163:553–64. https://doi.org/10.1001/ archinte.163.5.553; PMID: 12622602. 13. Gullestad L, Nordal KP, Berg KJ, et al. Interaction between lovastatin and cyclosporine A after heart and kidney transplantation. Transplant Proc 1999;31:2163–5. https://doi.

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org/10.1016/s0041-1345(99)00295-x; PMID: 10456002. 14. Campana C, Iacona I, Regazzi MB, et al. Efficacy and pharmacokinetics of simvastatin in heart transplant recipients. Ann Pharmacother 1995;29:235–9. https://doi. org/10.1177/106002809502900301; PMID: 7606066. 15. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81. https://doi.org/10.1016/j. clpt.2006.09.003; PMID: 17178259. 16. Simonson SG, Raza A, Martin PD, et al. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther 2004;76:167–77. https://doi. org/10.1016/j.clpt.2004.03.010; PMID: 15289793. 17. Heeney SA, Tjugum SL, Corkish ME, et al. Safety and tolerability of high-intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus. Clin Transplant 2019;33(1):e13454. https://doi.org/10.1111/ctr.13454; PMID: 30485535. 18. Golbus JR, Adie S, Yosef M, et al. Statin intensity and risk for cardiovascular events after heart transplantation. ESC Heart Fail 2020;7:2074–81. https://doi.org/10.1002/ehf2.12784; PMID: 32578953. 19. Goehring K, Kuan W, Sieg A, et al. Effect of statin intensity in the prevention of cardiac allograft vasculopathy. J Heart Lung Transplant 2020;39:S212–13. https://doi.org/10.1016/j. healun.2020.01.839. 20. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll

Statin Intensity and Cardiac Allograft Vasculopathy Cardiol 2014;63:2889–934. https://doi.org/10.1016/j. jacc.2013.11.002; PMID: 24239923. 21. Mehra MR, Crespo-Leiro MG, Dipchand A, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010. J Heart Lung Transplant 2010;29:717–27. https://doi.org/10.1016/j.healun.2010.05.017; PMID: 20620917. 22. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap): a meta-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–81. https:// doi.org/10.1016/j.jbi.2008.08.010; PMID: 18929686.

23. Alfon J, Guasch JF, Berrozpe M, et al. Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors. Atherosclerosis 1999;145:325–31. https://doi. org/10.1016/s0021-9150(99)00084-2; PMID: 10488960. 24. Weis M, Pehlivanli S, Meiser BM, et al. Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol 2001;38:814–8. https://doi.org/10.1016/s0735-1097(01)01430-9; PMID: 11527639. 25. Farmer JA. Pleiotropic effects of statins. Curr Atheroscler Rep 2000;2:208–17. https://doi.org/10.1007/s11883-000-0022-3;

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PMID: 11122746. 26. Uretsky BF, Murali S, Reddy S, et al. Development of coronary artery disease in cardiac transplant recipients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation 1987;76:827–34. https://doi. org/10.1161/01.cir.76.4.827; PMID: 3308166. 27. Radovancevic B, Poindexter S, Birovljev S, et al. Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients. Eur J Cardiothorac Surg 1990;4:309–13. https://doi.org/10.1016/10107940(90)90207-g; PMID: 2361019.

Diagnosis

Left Ventricular Systolic Dysfunction Due to Atrial Fibrillation: Clinical and Echocardiographic Predictors Erez Marcusohn ,1 Ofer Kobo ,2 Maria Postnikov,1 Danny Epstein ,3 Yoram Agmon,1,4 Lior Gepstein,1,4 Yaron Hellman1 and Robert Zukermann 1 1. Department of Cardiology, Rambam Health Care Campus, Haifa, Israel; 2. Department of Cardiology, Hillel Yaffe Medical Center, Hadera, Israel; 3. Intensive Care Unit, Rambam Health Care Campus, Haifa, Israel; 4. Rappaport – Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel

Abstract

Background: Diagnosis of AF-induced cardiomyopathy can be challenging and relies on ruling out other causes of cardiomyopathy and, after restoration of sinus rhythm, recovery of left ventricular (LV) function. The aim of this study was to identify clinical and echocardiographic predictors for developing cardiomyopathy with systolic dysfunction in patients with atrial tachyarrhythmia. Methods: This retrospective study was conducted in a large tertiary care centre and compared patients who experienced deterioration of LV ejection fraction (EF) during paroxysmal AF, demonstrated by precardioversion transoesophageal echocardiography with patients with preserved LV function during AF. All patients had documented preserved LVEF at baseline (EF >50%) while in sinus rhythm. Results: Of 482 patients included in the final analysis, 80 (17%) had reduced and 402 (83%) had preserved LV function during the precardioversion transoesophageal echocardiography. Patients with reduced LVEF were more likely to be men and to have a more rapid ventricular response during AF or atrial flutter (AFL). A history of prosthetic valves was also identified as a risk factor for reduced LVEF. Patients with reduced LVEF also had higher incidence of tricuspid regurgitation and right ventricular dysfunction. Conclusion: In ‘real-world’ experience, male patients with rapid ventricular response during paroxysmal AF or AFL are more prone to LVEF reduction. Patients with prosthetic valves are also at risk for LVEF reduction during AF/AFL. Finally, tricuspid regurgitation and right ventricular dysfunction may indicate relatively long-standing AF with an associated reduction in LVEF.

Keywords

AF, tachycardia induced cardiomyopathy, heart failure with reduced ejection fraction Disclosure: The authors have no conflicts of interest to declare. Funding: This study did not receive any specific funding. Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Acknowledgements: YH and RZ contributed equally. Received: 1 August 2021 Accepted: 18 September 2021 Citation: Cardiac Failure Review 2021;7:e16. DOI: https://doi.org/10.15420/cfr.2021.17 Correspondence: Robert Zukermann, Department of Cardiology, Rambam Health Care Campus, Haifa 31096, Israel. E: robert.zukermann@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

AF is the most common sustained arrhythmia among adults; it is associated with substantial morbidity and mortality and affects 2–4% of the adult population.1 Subsequently, AF is also the major cause of arrhythmiainduced cardiomyopathy. The incidence and prevalence of AF-induced cardiomyopathy is currently unknown, but can reach up to 77% depending on the study population because this cardiomyopathy appears to be under-recognised.2 Patients with both AF and heart failure are expected to experience worse outcomes.3 Diagnosis arrhythmia-induced cardiomyopathy relies on ruling out other causes of dilated cardiomyopathy, such as coronary artery disease and severe valvular disease, and proving left ventricular (LV) function improvement after restoration of sinus rhythm (SR).4 LV systolic dysfunction associated with AF-induced cardiomyopathy is thought to be secondary to many different possible aetiologies, such as poor ventricular rate control and irregularity of the ventricular response. Loss of atrial systolic activity combined with a loss of atrioventricular (AV)

synchrony is associated with impaired diastolic filling and elevated diastolic atrial pressure.5,6 In animal models, rapid ventricular pacing results in severe biventricular systolic dysfunction with an increase in LV and right ventricular (RV) filling pressures, decreased cardiac output and increased systemic vascular resistance without changes in LV mass, but with evidence of LV dilatation and diminished contractile reserve.5,7–9 The irregularity of the RR interval, which is pathognomonic in AF, is another aspect that may itself predispose to cardiomyopathy and heart failure, apart from the effects of a rapid heart rate.10 A previous study evaluating different types of tachycardia-mediated cardiomyopathy with reduced LV ejection fraction (LVEF) showed that in focal atrial tachycardia, younger male patients with a slower ventricular rate and incessant tachycardias were more prone to develop ventricular dysfunction.11 The aim of the present study was to identify clinical and echocardiographic predictors for the development of new LV systolic dysfunction in patients with paroxysmal/persistent AF or atrial flutter (AFL).

Predictors for AF-related Cardiomyopathy Figure 1: Study Flow Chart 1,551 patients had AF or atrial flutter during TOE 200 patients were excluded: • 112 in the reduced LVEF group did not have documentation of preserved LVEF in the previous year • 88 patients had previously documented left ventricular dysfunction

682 patients underwent TOE with the intention of performing CV

482 patients were included in the analysis

402 had preserved LVEF during AF

80 had reduced LVEF during AF

CV = cardioversion; LVEF = left ventricular ejection fraction; TOE = transoesophageal echocardiography.

retrieved from the patients’ electronic medical records. Comorbidities data included smoking history, hypertension, diabetes, hyperlipidaemia, ischaemic heart disease based on previous coronary angiography, alcohol use, major valvular disease, a history of valvular surgery and a history of AF. Echocardiography data included data retrieved from TOE: LV and RV function, LV dimensions and thickness, left atrial size, valvular disease, spontaneous echocardiography contrast and the presence of a left atrial appendage thrombus. These parameters were described semiquantitatively; therefore, chamber function and size were graded categorically as normal, mild, moderate and severe. LVEF data for the group with reduced LVEF was retrieved from examinations performed up to 1 year before and up to 1 year after the index hospitalisation. LV function on TOE during AF/AFL was defined as normal if LVEF was >50%, and the grade of LV dysfunction as categorised as mild, moderate and severe if LVEF was 45–49%, 30–44% and <30%, respectively. LV and RV function were estimated visually as recommended in previous studies that demonstrated that this method is precise and less time consuming.12

Statistical Analysis

Methods Study Design and Data Sources

This was a retrospective study conducted in a large tertiary care centre. Patients known to have normal LV function in SR and who, during an episode of paroxysmal/persistent AF or AFL, had evidence of LV dysfunction were compared with patients who did not develop reductions in LVEF during atrial tachyarrhythmias. This study was approved by the Institutional Review Board at Rambam Health Care Campus. The need for written informed consent was waived because of the retrospective nature of the study. All patients had symptomatic AF with palpitations, shortness of breath and/or chest pain no longer than 1 month before admission, and all had successful cardioversion and a return to SR. The duration of AF is based on patients’ reports of symptom duration. For patients with reduced LVEF during AF/AFL, LV dysfunction was presumed to be AF related after excluding other causes of dilated cardiomyopathy during hospitalisation. This was presumed according to the documentation summary at discharge from the treating cardiologist, excluding coronary disease and other triggers for new LVEF reductions. In addition, in the group in which LVEF was reduced during AF, improvement in LV function was documented in follow-up echocardiography. Regarding the type of AF, based on documentation of SR in the previous year, we can assume that most, if not all, patients had paroxysmal/ persistent AF or a new diagnosis of AF. Our cohort of patients included all patients who underwent transoesophageal echocardiography (TOE) to rule out left atrial appendage thrombus before cardioversion (electrical or pharmacological) or AF ablation (pulmonary vein isolation). Patients with a previous history of LV systolic dysfunction or dilated cardiomyopathy during SR were excluded (n=88). In addition, 112 patients were excluded in the group with LVEF reduction because no information was available about LV function while in SR in the year before the cardioversion. Another patient from this group was excluded because follow-up LV function data after cardioversion were unavailable. Demographic (age, sex), comorbidities and echocardiography data were

Baseline characteristics were summarised using descriptive statistics. Categorical variables were compared using Pearson’s χ-squared test or the Fisher exact test, whereas continuous variables were compared using the t-test or the Mann–Whitney U test, as appropriate. Variables that were significant in univariate analysis (p<0.05) were entered into a multivariate backward stepwise logistic regression analysis. Variables not contributing to the model’s predictive ability were excluded from the final model. Twosided p<0.05 was considered to be statistically significant. Non-normally distributed quantitative variables are presented as the median with interquartile range (IQR). Data analyses were conducted using SPSS version 23.0.

Results

In all, 1,551 TOE examinations were performed between 1 April 2011 and 31 December 2019 in our medical centre (Rambam Health Care Campus) for patients experiencing paroxysmal/persistent AF or AFL. Among these, 682 patients underwent TOE in order to rule out left atrial appendage thrombus before cardioversion or ablation. Two hundred patients were excluded from the study: 112 patients in the reduced LVEF group who did not have documented preserved LVEF during the previous year while in SR and 88 patients who had previously documented reduced LVEF (<50%). Thus, 482 patients were included in the present study (Figure 1). From a total of 482 patients included in the final analysis, 80 (17%) had reduced LV function and 402 had preserved LV function during the precardioversion TOE. In patients with reduced LVEF during AF, the median LVEF during SR before AF occurrence and after return to SR following cardioversion was 65% (IQR 60–65%). Compared with patients with preserved LV function, patients with reduced LVEF were more likely to be male (53% versus 68%; p=0.015) and to have a history of valvular replacement surgery (5% versus 13%; p=0.011). Patients with reduced LVEF had a more rapid ventricular response during AF/AFL than patients with preserved LVEF (mean 103 BPM versus 120 BPM, respectively). There was no significant difference between groups regarding anti-arrhythmic medications, except for the prevalence of treatment with β-blockers, which was more frequent in the group with reduced LVEF (Table 1). Compared with patients with preserved LVEF, patients with reduced LVEF were more likely to present with RV systolic dysfunction (15% versus 0.5%; p<0.001) and tricuspid regurgitation (30% versus 17%; p=0.009). The

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Predictors for AF-related Cardiomyopathy Table 1: Demographics and Clinical Characteristics of Patients With and Without Left Ventricular Ejection Fraction Reduction During AF Preserved LVEF During AF (n=402)

Reduced LVEF During AF (n=80)

P-value

Male sex

212 (53)

54 (68)

0.015

Age (years)

72 [64–79]

73 [64–80]

0.796

Hypertension

288 (72)

59 (74)

0.701

Diabetes

119 (30)

24 (30)

0.943

Smoker

88 (22)

25 (31)

0.071

Dyslipidaemia

181 (45)

40 (50)

0.415

Ischaemic heart disease

117 (29)

23 (29)

0.949

S/P cerebrovascular event

26 (7)

4 (5)

0.620

History of AF

120 (30)

30 (37)

0.177

347 (86)

68 (85)

0.756

Prosthetic valve

20 (5)

10 (13)

0.011

Heart rate (BPM)

103 [85–124]

120 [106–136]

<0.001

Creatinine (mg/dl)

0.93 [0.8–1.15]

0.93 [0.83–1.18]

0.845

Haemoglobin (mg/dl)

13.1 [11.5–14.4]

13.3 [11.7–14.3]

0.966

ACEI/ARB

235 (58.5)

52 (65)

0.28

Spironolactone

30 (7.5)

5 (6.3)

0.71

Anti-arrhythmic medications

259

0.328

β-blockers

243 (60.4)

58 (72.5)

0.042

Verapamil/diltiazem

20 (5)

3 (3.8)

0.64

Amiodarone

20 (5)

8 (10)

0.079

Dronedarone

3 (0.7)

2 (2.5)

0.157

Flecainide

6 (1.4)

2 (2.5)

0.519

Propafenone

26 (6.5)

7 (8.8)

0.46

Sotalol

4 (1)

1 (1.3)

0.159

ACEI/ARB

246 (61.2)

58 (72.5)

0.056

Spironolactone

57 (14.2)

12 (15)

0.85

Anti-arrhythmic medications

381

0.296

Beta-blockers

347 (86.3)

71 (88.8)

0.56

Verapamil/diltiazem

22 (5.5)

6 (7.5)

0.48

Amiodarone

136 (33.8)

47 (58.8)

<0.001

Dronedarone

5 (1.2)

1 (1.3)

0.584

Flecainide

13 (3.3)

1 (1.3)

0.335

Propafenone

99 (24.6)

8 (10)

0.006

Sotalol

9 (2.2)

4 (5)

0.31

Medications from Home

Medications at Discharge

Unless indicated otherwise, data are given as the median [interquartile range] or n (%). ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVEF = left ventricular ejection fraction; S/P = status post.

prevalence of aortic regurgitation and stenosis, as well as mitral regurgitation and stenosis, was similar in the two groups (Table 2). As indicated in Table 3, the rates of hospitalisations and mortality at 1 year were similar in the two groups. Table 4 summarises independent predictors of developing LVEF reduction during AF/AFL after multivariate analysis. Male sex, tricuspid regurgitation, a more rapid ventricular response and a history of valvular replacement surgery were significantly associated with reduced LVEF.

Discussion

This study examined a cohort of patients hospitalised for AF/AFL with rapid ventricular response. Approximately one-fifth of patients with normal LVEF in SR at baseline (up to 1 year before the index hospitalisation) had reduced LV systolic function and 15% of patients had a concomitant reduction in RV function (Table 2), as demonstrated on precardioversion TOE. In addition, this study showed that compared with patients without LV dysfunction, patients with LV dysfunction during atrial tachyarrhythmias presented with more rapid ventricular rate, had more prevalent severe tricuspid regurgitation and had a history of valvular surgery replacement.

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Predictors for AF-related Cardiomyopathy Table 2: Precardioversion Transoesophageal Echocardiography Data of Patients with and without Left Ventricular Ejection Fraction Reduction During AF Preserved LVEF During AF (n=402)

Reduced LVEF During AF (n=80)

p-value

LA dilatation

144 (36)

30 (37)

0.775

Severe SEC/LA thrombus

29 (7)

7 (9)

0.833

Moderate to severe LV dilatation

1 (0.2)

2 (3)

0.019

LV wall thickening (>11 mm)

12 (3)

1 (1)

0.382

Moderate to severe RV failure

2 (0.5)

12 (15)

<0.001

Moderate to severe AR

13 (3)

2 (2)

0.73

Moderate to severe AS

10 (3)

0 (0)

0.154

Moderate to severe MR

64 (16)

17 (21)

0.244

Moderate to severe MS

6 (2)

2 (3)

0.519

Moderate to severe TR

70 (17)

24 (30)

0.009

Unless indicated otherwise, data are given as n (%). AR = aortic regurgitation; AS = aortic stenosis; LA = left atrium; LV = left ventricle; LVEF = left ventricular ejection fraction; MR = mitral regurgitation; MS = mitral stenosis; RV = right ventricle; SEC = spontaneous echo contrast; TR = tricuspid regurgitation.

Table 3: Clinical Outcomes of Patients with and without Left Ventricular Ejection Fraction Reduction During AF After 1 Year Preserved LVEF During AF (n=402)

Reduced LVEF During AF (n=80)

p-value

Completed follow-up

380 (94.5)

79 (98.8)

0.106

Readmission due to AF

92 (22.9)

20 (25)

0.683

Readmission due to ADHF

25 (6.2)

2 (2.5)

0.186

Readmission due to any cause

212 (52.7)

42 (52.5)

0.969

Mortality

20 (5)

5 (6.3)

0.639

Unless indicated otherwise, data are given as n (%). ADHF = acute decompensated heart failure; LVEF = left ventricular ejection fraction.

Table 4: Independent Factors Associated With Left Ventricular Ejection Fraction Reduction During AF: Multivariate Analysis OR (95% CI)

p-value

Female sex

0.41 (0.23–0.71)

0.002

Tricuspid regurgitation

2.42 (1.33–4.41)

0.004

Heart rate

1.02 (1.01–1.03)

<0.001

Prosthetic valve

2.73 (1.13–6.59)

0.026

We did not find any differences between the two groups regarding clinical endpoint, mortality or rehospitalisations for AF or acute decompensated heart failure. The relationship between AF and the myocardial structural abnormality that will lead to LV dysfunction can be the cause or effect of the tachyarrhythmia. AF has many effects on cardiac function and cavity size that have been well described in animal models, but with less data in humans, with these effects mitigated by neurohormonal, cell signalling and remodelling mechanisms.4,13,14 The deleterious effect of AF on myocardial function can be more pronounced with biventricular dysfunction. The pathophysiology of RV dysfunction is probably the same

as that of LV dysfunction but more prominent at higher ventricular rates because, in the present study, a higher median heart rate was significantly associated with reduced LVEF in both univariate and multivariate analyses (Tables 2 and 4). The effect of atrial tachyarrhythmias with rapid ventricular response presented in this study was first described by Whipple et al. in 1962 while pacing animal atria.15 As mentioned before, the effect of AF on LV function is compounded by its irregularity and its rate conducted through the AV node.16 The rate itself increases metabolic demand and impairs haemodynamics, as shown in animal models leading to heart failure.17–19 However, controlling rate is not enough to improve the incidence of heart failure.20,21 Tricuspid regurgitation was significantly more prevalent in the reduced LVEF group (Tables 2 and 4). Atrial arrhythmias are associated with atrial remodelling and subsequent tricuspid regurgitation due to annular dilatation.13 Because these changes take time to evolve, it may be that patients with reduced LVEF had AF/AFL for a longer period of time. In addition, tricuspid regurgitation may serve as a marker of left-sided heart disease and is related to volume overload with possible RV dysfunction, which was also demonstrated in the reduced LVEF group.2,22–24 This study also identified prosthetic valves as an independent risk factor for reduced LVEF (Table 4). Patients with prosthetic valves are more likely to have atrial and ventricular myocardial pathology due to the progression of valvular heart disease preceding replacement, as well as the postoperative effects of open heart surgery. Perhaps a more aggressive preventive rhythm control approach should be adopted in these patients (e.g. Maze procedure during surgery, postoperative AF/AFL surveillance).25 Regarding clinical endpoints, we did not find any differences in mortality or hospitalisations between the two groups (Table 3). However, this study is underpowered for these endpoints, which may change with larger cohorts and prolonged follow-up. Nonetheless, the findings may indicate that rhythm control is, indeed, the correct way to treat patients with AF and reduced LVEF and for proving AF was the cause of the reduction in LVEF.

Limitations

The present study was retrospective in nature and focused on a selected

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Predictors for AF-related Cardiomyopathy group of patients. The cohort did not include patients with AF who were treated with rate control medications and therefore did not undergo TOE. Furthermore, we relied on TOE assessment of LVEF, which is less accurate than transthoracic echocardiography. The major limitation of this study, similar to all other AF studies, is the relatively unknown exact timing of arrhythmia onset. It is reasonable to assume that some of the patients who did not develop LVEF reduction had AF for a shorter period of time. 1. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics 2019 update: a report from the American Heart Association. Circulation 2019;139:e56–528. https://doi. org/10.1161/CIR.0000000000000659; PMID: 30700139. 2. Stronati G, Guerra F, Urbinati A. Tachycardiomyopathy in patients without underlying structural heart disease. J Clin Med 2019;8:1411. https://doi.org/10.3390/jcm8091411; PMID: 31500364. 3. Ziff OJ, Carter PR, McGowan J, et al. The interplay between atrial fibrillation and heart failure on long-term mortality and length of stay: insights from the, United Kingdom ACALM registry. Int J Cardiol 2018;252:117–21. https://doi. org/10.1016/j.ijcard.2017.06.033; PMID: 29249421. 4. Simantirakis EN, Koutalas EP, Vardas PE. Arrhythmia-induced cardiomyopathies: the riddle of the chicken and the egg still unanswered? Europace 2012;14:466–73. https://doi. org/10.1093/europace/eur348; PMID: 22084300. 5. Gupta S, Figueredo VM. Tachycardia mediated cardiomyopathy: pathophysiology, mechanisms, clinical features, and management. Int J Cardiol 2014;172:40–6. https://doi.org/10.1016/j.ijcard.2013.12.180; PMID: 24447747. 6. Naito M, David D, Michelson EL. The hemodynamic consequences of cardiac arrhythmias: evaluation of the relative roles of abnormal atrioventricular sequencing, irregularity of ventricular rhythm, and atrial fibrillation in a canine model. Am Heart J 1983;106:284–91. https://doi. org/10.1016/0002-8703(83)90194-1; PMID: 6869209. 7. Spinale FG, Hendrick DA, Crawford FA, et al. Chronic supraventricular tachycardia causes ventricular dysfunction and subendocardial injury in swine. Am J Physiol 1990;259:H218–29. https://doi.org/10.1152/ ajpheart.1990.259.1.H218; PMID: 2375409. 8. Chow E, Woodard JC, Farrar DJ. Rapid ventricular pacing in pigs: an experimental model of congestive heart failure. Am J Physiol 1990;258:H1603–5. https://doi.org/10.1152/ ajpheart.1990.258.5.H1603; PMID: 2337189. 9. Shinbane JS, Wood MA, Jensen DN, et al. Tachycardiainduced cardiomyopathy: a review of animal models and

10.

11.

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13.

14. 15. 16.

17.

18. 19.

Finally, because this is a cross-sectional study, causation cannot be definitely inferred.

Conclusion

In ‘real-world’ experience, male patients with a rapid ventricular response during paroxysmal AF or AFL are more prone to LVEF reduction. Patients with prosthetic valves are also at risk of LVEF reduction during AF/AFL. Finally, tricuspid regurgitation and RV dysfunction may indicate relatively long-standing AF with an associated reduction in LVEF.

clinical studies. J Am Coll Cardiol 1997;29:709–15. https://doi. org/10.1016/S0735-1097(96)00592-X; PMID: 9091514. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamic effects of an irregular sequence of ventricular cycle lengths during atrial fibrillation. J Am Coll Cardiol 1997;30:1039–45. https://doi.org/10.1016/S0735-1097(97)00254-4; PMID: 9316536. Medi C, Kalman JM, Haqqani H. Tachycardia-mediated cardiomyopathy secondary to focal atrial tachycardia: longterm outcome after catheter ablation. J Am Coll Cardiol 2009;53:1791–7. https://doi.org/10.1016/j.jacc.2009.02.014; PMID: 19422986. Troianos CA, Porembka DT. Assessment of left ventricular function and hemodynamics with transesophageal echocardiography. Crit Care Clin 1996;12:253–72. https://doi. org/10.1016/S0749-0704(05)70248-7; PMID: 8860842. Gopinathannair R, Etheridge SP, Marchlinski FE. Arrhythmiainduced cardiomyopathies: mechanisms, recognition, and management. J Am Coll Cardiol 2015;66:1714–28. https://doi. org/10.1016/j.jacc.2015.08.038; PMID: 26449143. Langer GA. Heart: excitation–contraction coupling. Annu Rev Physiol 1973;35:55–86. https://doi.org/10.1146/annurev. ph.35.030173.000415; PMID: 4196573. Whipple GH, Sheffield LT, Woodman EG, et al. Reversible congestive heart failure due to chronic rapid stimulation of the normal heart. Proc N Engl Cardiovasc Soc 1962;20:39–40. Martin CA, Lambiase PD. Pathophysiology, diagnosis and treatment of tachycardiomyopathy. Heart 2017;103:1543–52. https://doi.org/10.1136/heartjnl-2016-310391; PMID: 28855272. Raymond-Paquin A, Nattel S, Wakili R, Tadros R. Mechanisms and clinical significance of arrhythmia-induced cardiomyopathy. Can J Cardiol 2018;34:1449–60. https://doi. org/10.1016/j.cjca.2018.07.475; PMID: 30404750. Aiba T, Tomaselli GF. Electrical remodeling in the failing heart. Curr Opin Cardiol 2010;25:29–36. https://doi. org/10.1097/HCO.0b013e328333d3d6; PMID: 19907317. Moe GW, Armstrong P. Pacing-induced heart failure: a model

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to study the mechanism of disease progression and novel therapy in heart failure. Cardiovasc Res 1999;42:591–9. https://doi.org/10.1016/S0008-6363(99)00032-2; PMID: 10533598. 20. Groenveld HF, Crijns HJ, Van den Berg MP, et al. The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study. J Am Coll Cardiol 2011;58:1795–803. https://doi.org/10.1016/j.jacc.2011.06.055; PMID: 21996393. 21. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73. https://doi.org/10.1056/ NEJMoa1001337; PMID: 20231232. 22. Mutlak D, Khalil J, Lessick J, et al. Risk factors for the development of functional tricuspid regurgitation and their population-attributable fractions. JACC Cardiovasc Imaging 2020;13:1643–51. https://doi.org/10.1016/j.jcmg.2020.01.015; PMID: 32305485. 23. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611–44. https://doi. org/10.1093/ehjci/jet105; PMID: 23733442. 24. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol 1998;32:197–204. https://doi.org/10.1016/S07351097(98)00221-6; PMID: 9669270. 25. Stulak JM, Suri RM, Dearani JA, et al. When should prophylactic maze procedure be considered in patients undergoing mitral valve surgery? Ann Thorac Surg 2010;89:1395–401. https://doi.org/10.1016/j. athoracsur.2010.02.018; PMID: 20417751.

Treatment

Cardiac Sarcoidosis: When and How to Treat Inflammation Gerard T Giblin ,1 Laura Murphy ,2 Garrick C Stewart ,1 Akshay S Desai ,1 Marcelo F Di Carli ,2 Ron Blankstein ,2 Michael M Givertz ,1 Usha B Tedrow ,3 William H Sauer ,3 Gary M Hunninghake ,4 Paul F Dellaripa ,4 Sanjay Divakaran 1 and Neal K Lakdawala 1 1. Center for Advanced Heart Disease, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US; 2. Cardiovascular Imaging Program and Departments of Medicine and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US; 3. Cardiac Arrhythmia Service, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US; 4. Interstitial Lung Disease Program, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, US

Abstract

Sarcoidosis is a complex, multisystem inflammatory disease with a heterogeneous clinical spectrum. Approximately 25% of patients with systemic sarcoidosis will have cardiac involvement that portends a poorer outcome. The diagnosis, particularly of isolated cardiac sarcoidosis, can be challenging. A paucity of randomised data exist on who, when and how to treat myocardial inflammation in cardiac sarcoidosis. Despite this, corticosteroids continue to be the mainstay of therapy for the inflammatory phase, with an evolving role for steroid-sparing and biological agents. This review explores the immunopathogenesis of inflammation in sarcoidosis, current evidence-based treatment indications and commonly used immunosuppression agents. It explores a multidisciplinary treatment and monitoring approach to myocardial inflammation and outlines current gaps in our understanding of this condition, emerging research and future directions in this field.

Keywords

Cardiac sarcoidosis, immunosuppression, inflammation, cardiac PET, corticosteroid Disclosures: MFDC has received research grant support from Spectrum Dynamics and consulting fees from Sanofi and General Electric. UBT has received honoraria and consulting fees from Biosense Webster, Boston Scientific, Abbott Medical and Thermedical. RB receives research support from Amgen and Novartis. All other authors have no conflicts of interest to declare. Funding: SD was supported by a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D Pepper Older Americans Independence Center (5P30AG031679-10). Acknowledgement: SD and NKL contributed equally. Received: 21 July 2021 Accepted: 18 September 2021 Citation: Cardiac Failure Review 2021;7:e17. DOI: https://doi.org/10.15420/cfr.2021.16 Correspondence: Neal K Lakdawala, Center for Advanced Heart Disease, Brigham and Women’s Hospital and Harvard Medical School, 15 Francis St, Boston, MA 02115, US. E: nlakdawala@bwh.harvard.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sarcoidosis is an idiopathic, heterogeneous systemic condition characterised by non-necrotising granulomatous inflammation, most commonly affecting the lungs and thoracic lymph nodes. Cardiac sarcoidosis (CS) may accompany multisystem manifestations or occur in isolation and it remains a diagnostic and therapeutic challenge, with a paucity of data to guide management. The natural history is not well known, and the presentation can vary from asymptomatic cardiac inflammation to high-grade atrioventricular (AV) block, ventricular arrhythmia, heart failure, and/or sudden cardiac death. Clinically manifest cardiac involvement is estimated to occur in approximately 25–50% of cases of systemic sarcoidosis depending on the means of ascertainment.1–3 Cardiac involvement conveys a worse prognosis and a recent large contemporary registry demonstrated a higher 10-year risk of heart failure, arrhythmic complications, and all-cause mortality in patients with sarcoidosis compared with matched control subjects.4 Despite a limited evidence base, corticosteroids remain the cornerstone of treatment for active CS. Limited data exist on who and when to treat,

and the optimal immunosuppression regimen and duration of therapy remains unknown. This review aims to describe the indications for immunosuppressive therapy in CS and the commonly used therapeutic agents and combinations, and will present a centre-specific, interdisciplinary approach to treatment planning and the monitoring of therapeutic response.

Immunopathogenesis of Cardiac Sarcoidosis

Non-necrotising granulomas are the histopathological hallmark of sarcoidosis. Granulomas are organised collections of macrophages and epithelioid cells surrounded by lymphocytes, fibroblasts, and collagen. The inciting precipitant for their formation in CS is not known. Multiple hypotheses about the trigger for granuloma formation abound. These range from infectious agents to environmental particles to an autoantigen with a dysregulated antigenic or T-cell response in individuals with a potential genetic predisposition and/or certain human leucocyte antigen (HLA) polymorphisms.5,6 Antigen-presenting cells, such as macrophages and dendritic cells, process this antigen and activate naïve CD4 T-cells,

Cardiac Sarcoidosis: When and How to Treat Inflammation Figure 1: Immunopathogenesis of Granuloma Formation and Therapeutic Targets in Cardiac Sarcoidosis

Unidentified antigen

Antigen presentation

Antimetabolites: methotrexate, azathioprine, mycophenolate

Genetic susceptibility S

CD4 T-cell +

APC

Cell cycle

G2 M

Corticosteroid Th1/17

TNFi biologics

Th2

TNF-α, IFN-γ, IL-2, IL-12

Macrophage

Fibroblast

Treg

In 2014, the Heart Rhythm Society (HRS) developed an expert consensus statement to provide standardised contemporary recommendations on the diagnosis and treatment of CS.11 These diagnostic criteria incorporate either a histological diagnosis from myocardial sampling or a clinical diagnosis based on appropriate clinical context and cardiac imaging, when there is biopsy-proven extracardiac sarcoid. Given the heterogeneous presentation and often elusive nature on imaging or histological sampling, the probability of a diagnosis of CS can be determined using the World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG) organ assessment instrument, which defines three categories of probability of organ involvement in sarcoidosis: highly probable (>90% likelihood), probable (50–90% likelihood) and possible (<50% likelihood of organ involvement).12 A probable diagnosis is considered adequate to establish a clinical diagnosis of CS according to the expert consensus recommendations.11 When immunosuppressive therapy is being considered in suspected CS, a complementary imaging approach involving cardiac MRI (CMR) and fluorodeoxyglucose-PET (FDGPET) is often used to determine the likelihood of the diagnosis and improve diagnostic accuracy.13 When FDG-PET information is added to CMR, up to 45% of patients are reclassified as having a higher or lower likelihood of CS.14 Both modalities have also been shown to provide independent prognostic information in suspected CS.15–18 A suggested diagnostic algorithm using multimodality cardiac imaging and incorporating the current HRS and WASOG consensus statements is shown in Figure 2.11,12,14

Isolated Cardiac Sarcoidosis Granuloma formation

Antigen clearance and resolution of granulomatous inflammation

Residual fibrosis and ventricular remodelling

APC = antigen-presenting cell; INF = interferon; IL = interleukin; Th = T-helper cell; TNFi = tumour necrosis factor inhibitor; Treg = regulatory T-cell. Created with BioRender.com

Isolated CS may account for up to 25% of cases of CS.19 Diagnostic certainty for this entity is often limited and the current diagnostic criteria for CS have limited sensitivity given the absence of extracardiac disease and the low sensitivity of right ventricular endomyocardial biopsy.11,14,15 A combined approach to diagnosis using CMR and FDG-PET is often required to more accurately determine probability. Isolated CS has been associated with worse prognosis compared with systemic sarcoidosis and cardiac involvement.20

resulting in the proliferation of exaggerated T-helper (Th)1 and Th17 T-cell populations. These cells promote cell-mediated immunity and secrete pro-inflammatory cytokines such as interleukin (IL)-2, IL-12, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ.7 These cytokines aggregate macrophages, giant cells, and lymphocytes into tightly packed granulomas surrounding the inciting antigen. In the chronic phase, there is a shift from Th1 to Th2 T-cells secreting various cytokines and chemokines including IL-4, IL-10, and tumour growth factor (TGF)-β. These cytokines promote fibroblast recruitment and extracellular matrix deposition and fibrosis.5,8 Compounding this aberrant pro-inflammatory response is the decreased efficacy of regulatory T-cells (Tregs). Tregs normally maintain immune homeostasis and prevent autoimmunity by suppressing granuloma formation.9,10 An overview of the proposed pathogenesis of granulomatous inflammation and associated treatment targets in CS are shown in Figure 1.

Mimics of Cardiac Sarcoidosis

Diagnosis of Cardiac Sarcoidosis

Indications for Immunosuppression

The clinical presentation of CS ranges widely, from an incidentally discovered condition to heart failure, bradyarrhythmias and tachyarrhythmias, or even sudden death. Diagnosing CS can be challenging given the lack of a single blood or imaging biomarker and the paucity of prospective studies centred on diagnostic criteria. As a result, CS may be under-recognised in clinical practice and an appropriate index of suspicion is required during diagnostic evaluation.

Potential mimics include lymphocytic myocarditis, hibernating myocardium due to underlying obstructive coronary artery disease, some genetic cardiomyopathies, and physiological FDG uptake in heart failure. A high index of suspicion is required for giant cell myocarditis (GCM), although compared with CS this idiopathic inflammatory condition is typically marked by a heavier burden of arrhythmia and haemodynamic compromise. CS and GCM may even present as a continuum of a single inflammatory process rather than as two distinct entities. Arrhythmogenic cardiomyopathy due to desmoplakin mutations can mimic active isolated CS and present with episodic acute left ventricular (LV) myocardial injury and associated myocardial inflammation on FDG-PET.21 As a result, threegeneration pedigree and genetic testing should be undertaken in selected cases when familial cardiomyopathy is suspected prior to embarking on immunosuppressive therapy. Much of how myocardial inflammation in CS is treated is based on limited retrospective evidence or extrapolation from studies of extracardiac disease. The HRS consensus statement makes recommendations for immunosuppression in the setting of myocardial inflammation by either myocardial histology, CMR or FDG-PET in the following scenarios: highgrade AV block; frequent ventricular ectopy or non-sustained ventricular tachycardia (VT) and evidence of myocardial inflammation; and sustained

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Cardiac Sarcoidosis: When and How to Treat Inflammation ventricular arrhythmias and evidence of myocardial inflammation.11 Although no formal recommendation was made on the use of immunosuppressive therapy in patients with LV systolic dysfunction and myocardial inflammation, this is a widely accepted indication for consideration of immunosuppressive therapy in CS.22 The goal of therapy is to reduce myocardial inflammation to limit the development of myocardial fibrosis and the associated re-entrant ventricular arrhythmias, heart block, and new or worsening of LV dysfunction and heart failure. Some also hypothesise that active inflammation itself may be a source of ventricular arrhythmias in CS. The presence of FDG uptake in addition to abnormal perfusion in patients with suspected CS is associated with a higher risk of death or sustained VT even when adjusted for LV ejection fraction (LVEF). However, it is not known if a reduction in the extent of inflammation translates to a reduction in adverse clinical events.15 Patients with right ventricular inflammation should also be considered for treatment, given an association with worse prognosis.15,23 Whether immunosuppressive therapy should be initiated in patients with asymptomatic metabolically active CS on FDG-PET and normal ventricular function is less clear and is largely extrapolated from studies of those with LV dysfunction. In these cases, individualised assessment is required, including balancing the amount of myocardial inflammation, the extent of systemic involvement, and the clinical likelihood of CS (if uncertain) with the potential risks of therapy. In such cases, the presence of both a resting myocardial perfusion defect and FDG uptake on FDG-PET may be useful in the decision-making process given their association with adverse cardiac outcomes.15,23

Conduction Disease

Sarcoidosis may affect any component of the cardiac conduction system but symptomatic high-grade second-degree or third-degree AV block is the most common presenting feature of CS, with an incidence of 42% from Finnish registry data.24,25 High-grade AV block in CS is thought to occur due to involvement of the basal interventricular septum by either granulomatous inflammation or residual fibrosis. Immunosuppressive therapy should be considered in the setting of advanced AV block. Although the evidence base for immunosuppressive therapy in CS is limited, much of it focuses on the effect of corticosteroids on the recovery of AV nodal conduction. In the absence of prospective randomised data in this area, a 2013 meta-analysis examined 10 studies of poor to fair quality in 299 patients with CS.26 This included 73 patients with AV conduction disease, 57 (78%) of whom were treated with corticosteroid. Of those treated, 47.4% had improved AV conduction while none of the 16 patients who did not receive corticosteroid therapy improved. Variable definitions were used for AV conduction disease and recovery in these studies. However, most focused on third-degree AV block that resolved with treatment. Imaging of myocardial inflammation in the region of the AV node with either FDG-PET or T2-weighted CMR has the potential to predict recovery of AV nodal function and guide immunosuppression. A retrospective study examined response to corticosteroids in 10 patients with newly diagnosed CS and third-degree AV block who had undergone both CMR with late gadolinium enhancement (LGE) and FDG-PET.27 All patients had pretreatment LGE in the basal interventricular septum. The six patients with functional AV nodal recovery had pre-treatment focal inflammation in the basal interventricular septum on FDG-PET, while those without recovery

Figure 2: Suggested Diagnostic Algorithm for Cardiac Sarcoidosis Incorporating Multimodality Imaging Clinical suspicion of cardiac sarcoidosis: 1 Unexplained advanced AV block in adults <60 years of age, heart failure or ventricular arrhythmia AND/OR 2 Radiological ± histological extracardiac sarcoidosis with CV symptoms, abnormal ECG or abnormal echocardiogram AND 3 Other causes including CAD/myocardial ischaemia excluded CMR

CMR

No LGE: CS unlikely (consider FDG-PET if clinical suspicion remains high)

If contraindication to CMR, consider proceeding directly to FDG-PET

Positive LGE in a pattern consistent with sarcoidosis or inconclusive Cardiac/whole-body FDG-PET and gated rest perfusion imaging

No FDG uptake

Positive FDG uptake ± perfusion deficit

No LGE on CMR, normal rest perfusion and no FDG uptake on FDG-PET: CS unlikely

Probable or highly probable CS with active inflammation

Positive LGE on CMR, abnormal rest perfusion and no FDG uptake on FDG-PET: CS possible (without active inflammation)

AV = atrioventricular; CAD = coronary artery disease; CMR = cardiac MRI; CS = cardiac sarcoidosis; CV = cardiovascular; FDG = fluorodeoxyglucose; LGE = late gadolinium enhancement.

had either no FDG uptake or FDG uptake with thinning of the interventricular septum. Although the number of subjects was small, this suggests that AV nodal recovery after steroid therapy may be more likely in those with basal septal inflammation on metabolic imaging but with preserved wall thickness, and that recovery may be possible even in the presence of LGE in the region of the AV node (Figure 3). Although AV conduction disease may resolve with corticosteroid treatment, isolated AV block due to CS is not a benign entity. A retrospective study from Japan that included 22 patients with high-grade AV block found that 41% had a fatal major adverse cardiac event over a median of 34 months, principally due to ventricular arrhythmia.28 Similar fatal event rates were seen in the subgroup who recovered normal AV nodal function after the initiation of corticosteroid therapy. This reinforces the consensus recommendation for ICD implantation whenever permanent pacing is required in CS, given that the potential for reversibility is unpredictable and even with reversibility, the risk of sudden cardiac death persists.11 It is important that appropriate cardiovascular implantable electronic device (CIED) therapy should not be delayed while awaiting response to immunosuppressive therapy.

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Cardiac Sarcoidosis: When and How to Treat Inflammation Figure 3: Serial Imaging in a Patient with Recovered AV Node Function After Immunosuppressive Therapy Pre-treatment CMR

Baseline PET

3-month PET

6-month PET

inflammation. In another retrospective study, 14 patients with CS presenting with VT and PET-FDG uptake had a good early response to a combination of prednisolone and methotrexate (13/14).35 Four patients had recurrence of VT during follow-up, three of whom had disease reactivation on PET, all of whom had no further VT with intensified immunosuppression. In cases of ventricular arrhythmia, the presence and extent of myocardial inflammation should ideally be defined with either FDG-PET (or T2weighted CMR) before commencing immunosuppressive treatment. However, in certain cases of ventricular arrhythmia in patients with known CS who may be too unstable to undergo advanced imaging, empirical treatment is recommended.11

Left Ventricular Dysfunction D

PET 1 Prednisone dose 3

FDG volume (cm )

PET 2

40 mg

PET 3

PET 4

30 mg 20 mg 15 mg 10 mg

Diagnosis 3 months 6 months

5 mg

0 12 months

A 52-year-old patient with newly diagnosed cardiac sarcoidosis was evaluated due to complete heart block. A: Late gadolinium enhancement cardiac MRI (LGE-CMR) showing delayed enhancement in the basal interventricular septum (white arrow; top = basal short-axis view, bottom = two-chamber left ventricular view). B: Serial 99mTc single-photon emission CT showing a perfusion defect in the basal septum (yellow arrow) that resolves with treatment. C: Fluorodeoxyglucose (FDG)-PET demonstrating FDG uptake in the basal anteroseptum (red arrow), which resolves with corticosteroid treatment. D: Immunosuppressive regimen in relation to serial FDG-PET showing the reducing volume of myocardial inflammation (above a standardised uptake value threshold of 2.7) with treatment. AV = atrioventricular.

Ventricular Arrhythmias

Ventricular arrhythmia is a feared complication of CS and a significant predictor of mortality.29 The predominant mechanisms of arrhythmogenesis are abnormal automaticity and triggered activity in the inflammatory phase and scar-mediated re-entrant circuits in areas of residual fibrosis.30,31 Multiple VT mechanisms can be present in the same patient depending on disease stage. An FDG-PET-based study in patients with CS found that myocardial inflammation intensity was greater and LVEF lower in those presenting with VT compared with those with AV block or controls with clinically silent CS.32 The evidence base for immunosuppression in patients with ventricular arrhythmias and myocardial inflammation is limited and no randomised data exist. However, the current expert consensus recommendation is that immunosuppression and anti-arrhythmic drug therapy should be administered if active inflammation is present and should occur in tandem with defibrillator implantation when appropriate.33 These measures may be considered over catheter ablation when active inflammation is present in the setting of VT.31 Conversely, in CS patients without active inflammation, immunosuppressive therapy as a component of VT management is generally not indicated. In a retrospective study of corticosteroid treatment for frequent premature ventricular contractions (PVCs) in 31 patients with CS, there was no difference in PVC burden or prevalence of non-sustained VT before and after steroid treatment.34 However, when stratified by LV systolic function, these events were significantly reduced in the cohort with LVEF ≥35%. Moreover, this subgroup contained all patients in the study with uptake on gallium scintigraphy, indicative of myocardial inflammation. Resolution of uptake occurred in 80% of these patients, suggesting greater benefit of immunosuppressive therapy in ventricular arrhythmia before the onset of a more scarred, remodelled ventricle and in the presence of active

Symptomatic heart failure as the initial manifestation of cardiac involvement in sarcoidosis is less common than either high-grade AV block or ventricular arrhythmias (18% in Finnish Registry).20 LV systolic dysfunction at presentation has been well described as an independent predictor of adverse outcomes and mortality irrespective of the degree of myocardial inflammation, with a 10-year transplantation-free survival of only 53%.20,26,29 Chiu et al. investigated the effect of corticosteroid therapy over a mean follow-up of 88 months in the prevention of LV remodelling.36 Forty-three patients treated with prednisolone were retrospectively stratified by LVEF. Those with an LVEF >55% had unchanged LV volumes and function after treatment while those with an LVEF 30–55% had a significant reduction in volume and improvement in LVEF. Patients with an LVEF <30% had no positive remodelling or improvement in LVEF (LVEF decreased from 22% to 19%; p=0.08). Pre-treatment decreased LVEF was associated with increased mortality. Nagai et al. found that a cohort of patients treated with steroids, the majority of whom had myocardial inflammation identified on either Gallium scintigraphy or FDG-PET, had a greater increase in LVEF and reduced heart failure hospitalisations but no difference in cardiac death or arrhythmias compared with those who did not receive steroids.37 These studies support the role of corticosteroids in preventing and reversing LV remodelling in the early and middle stages of the disease, and suggest that immunosuppression may not be as effective in later stages when fibrosis predominates and more advanced LV dysfunction is present.

Therapeutic Agents Corticosteroids

Oral corticosteroids are commonly used as first-line therapy for active CS and are the focus of the majority of available research in this area.11,26,38 Steroids non-selectively suppress production of the cytokines involved in granuloma formation including TNF-α and IFN-γ (Figure 1), inhibiting inflammatory cell migration and restoring CD4+ T-cell function as well as the balance between the subtypes of effector CD4+ T-cells seen in sarcoidosis.7,10 The optimal dose, duration, and tapering regimen for corticosteroid therapy have not been established. The Japanese Circulation Society recommended an initial prednisolone dose of 30 mg daily or 60 mg on alternate days for a 4-week period, followed by tapering of 5 mg monthly to reach a maintenance dose of 5–10 mg daily or 10–20 mg on alternate days by 6 months.38 However, the extent of myocardial inflammation and severity of clinical presentation may warrant a higher starting dose. Although oral steroids are most commonly used, small case series have described the use of IV methylprednisolone at doses of 500–1,000 mg for

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Cardiac Sarcoidosis: When and How to Treat Inflammation 1–3 days in the acute treatment of refractory ventricular arrhythmias in the setting of active myocardial inflammation.39,40

shown to be well tolerated in patients with systemic sarcoidosis at a mean dose of 10 mg weekly.51

A prolonged need for immunosuppressive therapy is often required and therefore early addition of a steroid-sparing agent is frequently used to minimise steroid toxicity while achieving early remission of inflammation. The median duration of steroid treatment in a larger retrospective cohort with CS was 22 months, although in that study the steroid treatment was not associated with improved outcomes.41 It is unknown what the risk of disease relapse is following steroid cessation when treatment is guided by FDG-PET. The baseline potential for corticosteroid toxicity should be factored into the decision-making process prior to initiation. Important toxicities that should be anticipated and which are recommended for monitoring are listed in Table 1.

Alternative Steroid-sparing Agents

Methotrexate

Patients with inflammatory disease refractory to tiered therapy with corticosteroid and a steroid-sparing agent such as methotrexate should be considered for third-line treatment with a biologic agent, such as a TNF-α inhibitor. In one large retrospective cohort with CS, biologic therapy was used in 8%.41 TNF is a cytokine central to the development and maintenance of granulomas, and TNF-α inhibitors including infliximab (chimeric monoclonal antibody) and adalimumab (humanised monoclonal antibody) have been used in CS. Infliximab has been used with good effect in refractory pulmonary sarcoidosis, albeit with substantial adverse event and discontinuation rates of up of 52% and 23%, respectively, in one study.52–54

Methotrexate is recommended as the second-line or add-on therapy for systemic sarcoidosis in the case of inadequate response to steroid therapy or to minimise cumulative steroid exposure.42 It may be used in the first line as a methotrexate–steroid combination or as monotherapy in cases when exposure to corticosteroid is best avoided. Methotrexate regulates the cellular function of multiple cells involved in inflammatory pathways including T-cells (Figure 1). Methotrexate inhibits the folatedependent de novo synthesis of purines and pyrimidines necessary for inflammatory cellular replication. It also increases the extracellular adenosine level, which may have anti-inflammatory effects.43 Methotrexate is the most widely used antimetabolite or steroid-sparing agent in pulmonary sarcoidosis and has been extrapolated to the treatment of CS.44 Baughman et al. completed a small randomised controlled trial of patients with acute pulmonary sarcoidosis who took 10 mg methotrexate weekly versus placebo and found that the methotrexate group required a significantly lower dose of corticosteroid at 12 months.45 A prospective study that compared 17 patients with CS treated with either a combination of methotrexate and low-dose steroid (5–15 mg/day) or steroid monotherapy found that at 3 years, LVEF and N-terminal pro-B-type natriuretic peptide were significantly more stable in the combination group.46 Methotrexate added to low-dose prednisone (<10 mg/day) after 4–8 weeks of high-dose steroid has also been shown to have a high rate of remission of inflammation on FDG-PET, supporting its use as a steroid sparing agent.47 Methotrexate should be dose adjusted in the case of renal impairment (50% dose reduction for estimated glomerular filtration rate [eGFR] 30– 49 ml/min/1.73 m2) and avoided in advanced renal impairment (eGFR <30 ml/min/1.73 m2) or non-sarcoidosis-related hepatic dysfunction.48 A starting dose of 5–15 mg weekly is recommended, followed by uptitration by 5 mg every 2–4 weeks to a target of 20 mg with serial monitoring for leukopenia, renal dysfunction, and hepatotoxicity (Table 1).42 Steady-state levels of methotrexate and maximum therapeutic effect can take up to 6 months to become apparent, which should be factored into the surveillance plan for FDG-PET if monotherapy is used.49 The most frequent adverse events are fatigue and gastrointestinal side-effects, while the incidence of clinically important cytopenia is estimated to be <1%.49 Concurrent folic acid should be given at a dose of 1 mg daily or 5 mg weekly to minimise fatigue, gastrointestinal side-effects and hepatotoxicity without compromising efficacy.50 Higher dose folic acid or a transition to leucovorin (folinic acid) can be used as rescue therapy to minimise these side-effects. Longer term use of methotrexate for up to 2 years has been

Azathioprine, mycophenolate, leflunomide, hydroxychloroquine, cyclophosphamide, and sirolimus are alternative steroid-sparing agents that have been used in extracardiac sarcoidosis in those unresponsive to or intolerant of methotrexate. However, their use in CS is limited to case reports. Fussner et al. reported on their longitudinal experiences of management of CS across two large North American centres and noted that mycophenolate mofetil was their most commonly used steroidsparing agent (37%), but limited data are available to support its use over other agents.41

Biologic Therapy

A retrospective study by Harper et al. of 36 patients with refractory CS treated with infliximab demonstrated a significant reduction in steroid dosing at 6 and 12 months without worsening of heart failure.55 Both infliximab and adalimumab have been shown to reduce the extent and intensity of inflammation on serial FDG-PET in a multicentre retrospective study with no significant change in LVEF, with 11% requiring hospitalisation for HF and a 5% discontinuation rate.56 The optimal duration for TNF-α inhibitor therapy and the risk of disease relapse in CS is not known, but expert consensus recommends continuing for at least 3–6 months, with response most frequently observed in the first month of treatment when these agents are used in rheumatic inflammatory conditions.57 Due to the potential for the development of neutralising antibodies to biologic therapy that can limit efficacy, concurrent treatment with methotrexate (typically 10 mg weekly) is often pursued to mitigate this risk.58 Alternative TNF-α inhibitors golimumab and etanercept have not been found to be effective in extracardiac sarcoidosis.8 Rituximab, an antiCD20 B-cell-depleting humanised monoclonal antibody, has shown limited results in a small prospective study of refractory pulmonary sarcoidosis, while its effectiveness in CS is limited to case reports.59,60 Importantly, infliximab at a dose of 10 mg/kg was associated with an increased risk of worsening heart failure or death in a randomised trial conducted in patients with reduced LVEF and New York Heart Association (NYHA) class III–IV heart failure. Although that study was not conducted in patients with CS per se, we generally avoid TNF-α inhibitors in patients with severe systolic dysfunction and associated heart failure for this reason.61,62 Biological therapy should not be initiated in the presence of serious active infection, and screening should be performed for tuberculosis before initiating treatment, as well as for viral hepatitis and HIV in those at risk.63

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Cardiac Sarcoidosis: When and How to Treat Inflammation Table 1: Common Immunosuppressive Agents in Cardiac Sarcoidosis, Dosing, Toxicities, Surveillance and Prophylaxis Recommendations Drug

Suggested dosing Important toxicities

Other considerations

Corticosteroid Prednisone

0.5–1 mg/kg daily (max dose 60 mg daily) with tapering guided by clinical and imaging response. See treatment algorithm (Figure 4)

• Neuropsychiatric: depression, insomnia, psychosis Pre-treatment: • Sodium and fluid retention; worsening heart failure • Assess cardiovascular risk (lipid, hypertension and glycaemic status) and optimise where possible • Impaired wound healing • Exclude latent TB and ensure vaccinations up to date • Hyperglycaemia 70 • Hypertension and increased risk of cardiovascular • Determine fracture risk using validated tool (e.g. FRAX) and bone

densitometry as required disease • • Musculoskeletal: myopathy, osteoporosis, avascular Screen for psychiatric comorbidities that may be exacerbated by steroid use • Baseline eye exam necrosis • Adrenal insufficiency Monitoring: • Gastrointestinal: gastritis and ulceration • Hypertension, hyperglycaemia and hyperlipidaemia screening • Close monitoring for fluid retention • Regular review of fracture risk and bone density screening as required • Eye screening for glaucoma and cataract formation Prophylaxis: • Gastric: H2 blocker or PPI • Pneumocystis prophylaxis for doses ≥20 mg daily • Pharmacologic therapy for osteoporosis if indicated by fracture risk

Antimetabolite Methotrexate Initiate at 5–15 mg weekly. Titrate in 5 mg increments every 4 weeks to a target dose of 20 mg weekly42

• Hepatotoxicity: avoid concurrent alcohol use Pre-treatment:48 • Myelosuppression: may be preceded by rising MCV • Exclude latent TB. Screen for hepatitis B and C and HIV if at risk • Gastrointestinal side-effects: consider increased • Baseline chest radiograph, CBC, LFTs, serum creatinine folic acid or leucovorin rescue therapy; consider • Ensure vaccinations up to date splitting daily doses or change to subcutaneous therapy • Mucositis: dose dependent • Pneumonitis: usually within first year of treatment. • Teratogenic: contraindicated in men and women 3 months before planned pregnancy, during pregnancy and breastfeeding

Monitoring: • CBC, LFTs and serum creatinine every 2–4 weeks for first 3 months of treatment, every 8–12 weeks for months 3–6 of therapy and every 12 weeks beyond 6 months of therapy71 Prophylaxis: • Folic acid 1 mg daily or 5 mg weekly. Consider leucovorin (folinic acid) rescue therapy in toxicity unresponsive to increased folic acid

TNFi biologic agent Infliximab

3–5 mg/kg at weeks 0, 2, 6 and every 4–8 weeks8

• Worsening of pre-existing heart failure • Hypersensitivity reactions • Worsening of multiple sclerosis and other demyelinating diseases: avoid63

• Risk of serious infections and malignancy

Pre-treatment: • Exclude latent TB. Screen for hepatitis B and C and HIV if at risk • Baseline chest radiograph, CBC, LFTs, serum creatinine and LVEF • Ensure vaccinations up to date Monitoring: • Regular specialist review every 1–3 months with CBC and LFTs • Active infection: temporarily hold. High index of suspicion for opportunistic infections and PML • Close monitoring in patients with LV dysfunction for decompensated heart failure • Local recommended population-based malignancy screening Prophylaxis: • Low-dose methotrexate ± corticosteroid should be considered to limit development of anti-TNF antibodies

Adalimumab 80–160 mg at week 0, 40 mg at week 1 and 40 mg weekly thereafter57

• Similar to infliximab

CBC = complete blood count; CS = cardiac sarcoidosis; FRAX = fracture risk assessment tool; LFT = liver function test; LV = left ventricular; LVEF = left ventricular ejection fraction; MCV = mean corpuscular volume; PML = progressive multifocal leukoencephalopathy; PPI = proton pump inhibitor; TB = tuberculosis; TNFi = tumour necrosis factor inhibitor.

These agents should not be commenced in patients with a known or suspected malignancy. Although there is no conclusive evidence for an increased risk of lymphoproliferative disease or solid organ malignancy

with TNF-α inhibitor treatment in patients with rheumatological conditions, vigilance is recommended, with standard screening and preventive measures.63

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Cardiac Sarcoidosis: When and How to Treat Inflammation Monitoring Response to Treatment

Clinical assessment, device interrogation, and echocardiography are used routinely in the longitudinal follow-up of patients receiving immunosuppressive therapy for CS. However, it is not possible to determine the presence of ongoing myocardial inflammation from these studies alone, or to differentiate between active inflammation and myocardial fibrosis as a cause of clinical events. To date, no cardiacspecific or inflammatory blood-based biomarkers have been found to correlate with the presence and extent of either cardiac or extracardiac granulomatous inflammation, nor have there been any studies on their use in guiding immunosuppressive therapy. FGD-PET-CT is commonly integrated with echocardiography, CMR, and tissue sampling for the diagnosis and monitoring of response to immunosuppression in CS (Figure 4). Although there is a growing evidence base supporting the role of FDG-PET in the diagnosis and prognostication of CS, data on the optimal interval between follow-up assessments and on the potential for PET-guided therapy are limited.15,16 Whether resolution of myocardial FDG uptake is the optimal endpoint for immunosuppressive treatment in CS remains unclear. At our institution, Osborne et al. retrospectively studied 23 patients with CS who were predominantly treated with corticosteroid and underwent serial FDG-PET with a median of four scans per patient.64 We demonstrated that a reduction in the intensity and extent of myocardial inflammation measured quantitatively (maximum standardised uptake value [SUVmax] and the volume of myocardial FDG uptake above a prespecified SUV threshold) was associated with an improvement in LVEF. These data are promising but it is not yet known whether this reduction or resolution of myocardial inflammation translates into a reduction in adverse clinical outcomes or residual myocardial fibrosis, and which treatment regimen, if any, serves best to achieve this inflammatory resolution. Persistence of perfusion defects on FDG-PET following steroid therapy has been associated with higher rates of adverse outcomes and so may be a potential treatment target on serial imaging.65 To facilitate accurate and reliable comparison between serial FDG-PET scans when monitoring therapy response, a consistent reproducible technique is required at an institutional level with particular attention paid to patient dietary preparation in order to achieve adequate suppression of physiological myocardial uptake, which can interfere with interpretation.66

Treatment Approach

The treatment of myocardial inflammation in CS is largely empirical and highly variable. A survey of 42 sarcoidosis experts in 2012 was unable to demonstrate a consensus on the optimal dose of prednisone, the use of steroid-sparing agents, or the duration of treatment, highlighting the uncertainty and divergence of opinion that exists in the field.67 The treatment approach should focus on treating granulomatous inflammation in the context of patient-specific comorbid conditions while anticipating and offsetting common toxicities. The treatment algorithm used in the Cardiac Sarcoidosis and Inflammatory Heart Disease Program at Brigham and Women’s Hospital, for those with clinically manifest CS and an accepted indication for immunosuppression (high-grade AV block, VT or heart failure) is shown in Figure 5. Our approach incorporates clinical status in combination with FDG uptake as the endpoint of therapy when possible. Immunosuppressive treatment in those with CS and isolated atrial

Figure 4: Serial FDG-PET-guided Immunosuppressive Therapy in a Patient with Active Sarcoidosis Presenting with Ventricular Tachycardia Baseline

3 months

12 months

24 months

FDG volume 316 cm3 10 cm3 SUVmax 18.2 6.1

89 cm3 14.0

0 cm3 <2.7

Prednisone Methotrexate Infliximab Baseline 3-month PET PET

12-month PET

24-month PET

A: Coronal whole-body fluorodeoxyglucose (FDG)-PET showing cardiac (red arrow) and extracardiac FDG uptake (blue arrow). B: Representative axial views of PET-CT fusion imaging showing biventricular FDG uptake. C: Timeline of tiered immunosuppressive therapy showing the response in volume of myocardial inflammation and the maximum standardised uptake value (SUVmax) on serial imaging (using an SUV threshold of 2.7). VT = ventricular tachycardia.

arrhythmias or asymptomatic LV dysfunction is not represented in the currently available literature or expert consensus guidelines, and requires a patient-specific approach. When anti-inflammatory therapy is indicated, a shared decision-making approach with the patient is used, taking into account several factors (Table 2). All patients commencing immunosuppressive therapy are screened for latent tuberculosis using a whole blood IFN-γ release assay (e.g. T-Spot). In the Cardiac Sarcoidosis and Inflammatory Heart Disease Program at Brigham and Women’s Hospital, we typically defer initiation of immunosuppressive therapy for 2–6 weeks after CIED implantation to allow for adequate wound healing and to minimise pocket infection risk. For immunosuppressive therapy, we initiate oral prednisone at a dose of 0.5–1 mg/kg daily with a maximum daily dose of 60 mg. Depending on clinical response, we taper by 10 mg monthly to a target of 20 mg daily by the time of first follow-up FDG-PET scan at approximately 3–4 months. All patients receive pneumocystis pneumonia prophylaxis with either sulfamethoxazole/trimethoprim or atovaquone while requiring prednisone doses ≥20 mg daily, in addition to gastric ulceration and osteoporosis prophylaxis when appropriate (Table 1). Given that overproduction of 1,25-dihydroxy vitamin D is common in sarcoidosis and can result in increased intestinal absorption of calcium, increased bone resorption and hypercalciuria with or without hypercalcemia, we avoid empirical initiation of calcium and vitamin D supplementation in patients with sarcoidosis.68 In general, we aim to wean the patients off corticosteroids over a 12–24-month period, as guided by clinical events and demonstration of resolution of myocardial inflammation on serial FDG-PET scans. This taper is often performed slowly at doses <20 mg daily so that any potential inflammatory reactivation can be detected early.

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

Cardiac Sarcoidosis: When and How to Treat Inflammation Figure 5: Suggested Treatment Algorithm for Myocardial Inflammation Used in Cardiac Sarcoidosis High-grade AV block and/or

Clinical suspicion of cardiac sarcoidosis (>50% probability of CS)

Heart failure and/or

Myocardial FDG uptake on FDG-PET

Ventricular arrhythmia Treatment decision based on shared decision-making with patient and consideration of factors in Table 2

1 Corticosteroid

2 Low-dose steroid and methotrexate combination

3 Methotrexate

Prednisone 0.5–1 mg/kg PO daily (max. 60 mg) and taper by 10 mg monthly to 20 mg by 3 months

Prednisone 0.25–0.5 mg/kg PO daily and taper to 10 mg by 3 months; MTx dosed as per treatment option 3

Initiate at 7.5–10 mg weekly and increase by 5 mg every 2 weeks to a maximum dose of 20 mg

Repeat FDG-PET after 3–6 months

Unchanged/increased FDG uptake

Improved/resolved FDG uptake Taper prednisone over 3–6 months

Continue current regimen without tapering

and/or Consider slow methotrexate wean over 12 months

Maximise or add methotrexate

and/or Add low-dose corticosteroid and/or Consider alternative antimetabolite (Aza/MMF) If ongoing indication for immunosuppressive therapy, repeat FDG-PET after a further 6 months of therapy

Improved/resolved FDG uptake

Unchanged/increased FDG uptake

Taper prednisone over 3–6 months and/or

Maximise or add methotrexate or

Consider slow methotrexate wean over 12 months

Consider alternative antimetabolite (Aza/MMF)

and/or

Low-dose maintenance steroid or steroid-sparing agent

Initiate or increase corticosteroid dose and/or Consider TNFi biologic agent

Repeat FDG-PET guided by treatment regimen and clinical events AV = atrioventricular; Aza = azathioprine; CS = cardiac sarcoidosis; FDG = fluorodeoxyglucose; MMF = mycophenolate mofetil; MTx = methotrexate; PO = per os; TNFi = tumour necrosis factor inhibitor.

In patients with a contraindication to higher doses of corticosteroids, we typically initiate either methotrexate monotherapy or methotrexate as an adjunct to lower dose corticosteroid therapy. Methotrexate is initiated at a dose of 7.5–10 mg weekly. In general, this is titrated in increments of 2.5–5 mg weekly every 2–4 weeks to a target dose of

20 mg weekly, along with monitoring for leukopenia and hepatotoxicity (Table 1). If chronic maintenance methotrexate is required, we aim to use the lowest possible dose to suppress myocardial inflammation while minimising toxicity. In general, we use serial FDG-PET to guide treatment escalations and weaning, and for serial LVEF assessments

CARDIAC FAILURE REVIEW Access at: www.CFRjournal.com

Cardiac Sarcoidosis: When and How to Treat Inflammation (Figure 5). However, we recognise that the availability and cost of cardiac PET remain significant limitations to more widespread use. In these cases, we recommend a surveillance approach using a combination of serial echocardiography, ECG, and clinical assessments to monitor response to treatment. We use ECG to assess for recovery or progression of conduction system disease, and device interrogation for arrhythmia burden and recovery of AV nodal function (via the percentage of ventricular pacing) in those patients with high-grade AV block and a pacer. In patients who have an unsatisfactory response to tiered therapy with corticosteroid and a steroid-sparing antimetabolite agent, thirdline treatment involves the addition of a biologic such as the TNF-α inhibitor infliximab in the absence of symptomatic heart failure with reduced LVEF.

Table 2: Factors Influencing Treatment Decisions in Cardiac Sarcoidosis

For centres aiming to establish a dedicated CS clinic or service, we suggest the adoption of a diagnostic and treatment algorithm (Figures 2 and 5, respectively). Timely integration of both high-quality CMR and FDGPET (incorporating rest perfusion imaging) into these algorithms is paramount for accurate diagnosis, immunosuppression surveillance, and prompt device therapy. Organised multisystem protocols should encompass, for example, pulmonary or ophthalmological screening as necessary and establish pathways for the expert review of histology and management of biological therapy as required.

randomised controlled trial in CS, it aims to demonstrate the non-inferiority of a low-dose combination corticosteroid and methotrexate regimen to the intermediate corticosteroid dosing traditionally used in CS. For inclusion, patients must have at least one out of the classical CS triad of high-grade AV block, ventricular dysfunction or ventricular arrhythmia, in addition to both myocardial and regional lymph node FDG uptake on a recent FDG-PET and either histological correlation or CT chest with typical sarcoidosis features. The primary endpoint will be the summed perfusion rest score on myocardial perfusion imaging as a measure of myocardial scar over a 6-month period. Patients will be randomised to either a combination therapy arm with prednisone 20 mg/day for month one, 10 mg/day for month two and 5 mg/day for month three, in addition to methotrexate 10–20 mg weekly for 6 months or a corticosteroid monotherapy arm with prednisone 0.5 mg/kg/day for 6 months, with a maximum dose of 30 mg daily. The trial has limitations, such as its relatively small, anticipated recruitment of 194 patients; the use of summed perfusion rest score as the primary endpoint to assess scar burden instead of myocardial FDG uptake as a measure of inflammation burden; and its open-label nature.

Uncertainties and Future Directions

The treatment of inflammation and its relationship to clinical outcomes in CS remain poorly defined. As a community, our challenge is to discern whom we should treat, when we should treat them, and how we should do it. Some of the key uncertainties that remain relate to the effect of corticosteroid therapy on clinical outcomes; the identification of biomarkers or imaging parameters that allow us to best predict and monitor response to therapy; which subgroups of patients are suitable for initiation of first-line steroid-sparing agents to minimise the metabolic disarray; the relative efficacy of different anti-inflammatory agents (steroid versus steroid-sparing; low-dose versus high-dose steroid); the place of watch and wait approaches to treatment in those patients with myocardial inflammation but normal cardiac function or clinically silent CS; and if and when biological therapy should be considered. The relatively small patient numbers, delayed recognition, and the elusive nature of CS with regard to histological diagnosis have limited randomised trials and the observational study of treatment in this arena. The CHASM CS-RCT (NCT03593759) is an ongoing multicentre, open-label, randomised controlled trial to evaluate initial treatment strategies in immunosuppression-naïve patients with clinically active CS.69 As the first 1. Patel MR, Cawley PJ, Heitner JF, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009;120:1969–77. https://doi.org/10.1161/ CIRCULATIONAHA.109.851352; PMID: 19884472. 2. Hu X, Carmona EM, Yi ES, et al. Causes of death in patients with chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2016;33:275–80. PMID: 27758994. 3. Iwai K, Takemura T, Kitaichi M, et al. Pathological studies on sarcoidosis autopsy. II. Early change, mode of progression and death pattern. Acta Pathol Jpn 1993;43:377–85. https:// doi.org/10.1111/j.1440-1827.1993.tb01149.x; PMID: 8372683. 4. Yafasova A, Fosbol EL, Schou M, et al. Long-term adverse cardiac outcomes in patients with sarcoidosis. J Am Coll Cardiol 2020;76:767–77. https://doi.org/10.1016/j. jacc.2020.06.038; PMID: 32792073. 5. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–65. https://doi.org/10.1056/ NEJMra071714; PMID: 18032765. 6. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med

9. 10.

11.

Factors Degree of LV dysfunction and established fibrosis at diagnosis Extent of inflammation on cardiac PET Ventricular arrhythmia burden Presence of systemic sarcoidosis also warranting immunosuppressive therapy Metabolic complication risk Opportunistic infection risk Malignancy risk with chronic immunosuppression LV = left ventricular.

The MAGiC-ART trial (NCT 04017936) is currently evaluating the role of anakinra, an IL-1 blocker, in the treatment of active CS in a cohort of 28 patients using changes in C-reactive protein over a 28-day period as a primary endpoint and changes in FDG uptake on PET, changes in LGE on CMR and clinical events over the same time point as secondary endpoints. While many unanswered questions abound in the treatment of patients with CS, the care of these complex patients often requires a collaborative effort by subspecialists across the spectrum of cardiovascular medicine and other multidisciplinary specialists at referral centres similar to the Cardiac Sarcoidosis Program at the Brigham and Women’s Hospital.

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Treatment

and Gregg C Fonarow

1,2

1. Division of Cardiology, University of California Los Angeles (UCLA), Los Angeles, CA, US; 2. Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan-UCLA Medical Center, Los Angeles, CA, US

Abstract

There are gaps in the use of therapies that save lives and improve quality of life for patients with heart failure with reduced ejection fraction, both in the US and abroad. The evidence is clear that initiation and titration of guideline-directed medical therapy (GDMT) and comprehensive disease-modifying medical therapy (CDMMT) to maximally tolerated doses improves patient-focused outcomes, yet observational data suggest this does not happen. The purpose of this review is to describe the gap in the use of optimal treatment worldwide and discuss the benefits of newer heart failure therapies including angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors. It will also cover the efficacy and safety of such treatments and provide potential pathways for the initiation and rapid titration of GDMT/CDMMT.

Keywords

Heart failure, guideline-directed medical therapy, comprehensive disease-modifying medical therapy, rates of use, cost benefits, early treatment initiation Disclosure: GCF reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck and Novartis. All other authors have no conflicts of interest to declare. Received: 17 August 2021 Accepted: 6 October 2021 Citation: Cardiac Failure Review 2021;7:e18. DOI: https://doi.org/10.15420/cfr.2021.18 Correspondence: Gregg C Fonarow, Ronald Reagan UCLA Medical Center, 757 Westwood Plaza, Los Angeles, CA 90095, US. E: GFonarow@mednet.ucla.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 suggests an estimated 6.2 million people in the US over 20 years old have heart failure (HF), an increase from 5.7 million in 2009– 2012.1 With an annual incidence of about 1 million, the number of people affected in the US is expected to grow to more than 8 million by 2030.1,2 The financial burden is monumental; in a given year, 809,000 hospital discharges, 2 million primary care visits and 414,000 emergency department (ED) visits are due to a primary diagnosis of HF.1 This leads to an annual cost of US$30.7 billion as of 2012, with a projected cost of US$69.8 billion by 2030.2 Furthermore, patients with HF suffer from high rates of adverse clinical outcomes. HF carries a 50% 5-year mortality rate and median survival is 5–6 times less for people with HF compared with the general US population.3,4 Given the financial, medical and public health burden, HF is understandably a target for numerous established and novel interventions. With multiple pharmaceuticals shown to benefit cardiovascular outcomes in HF with reduced ejection fraction (HFrEF), support for the initiation of comprehensive disease-modifying medical therapy (CDMMT) – including an angiotensin receptor-neprilysin inhibitor (ARNI), evidence-based β-blocker, mineralocorticoid receptor antagonist (MRA) and a sodiumglucose cotransporter 2 inhibitor (SGLT2i) – has come to the forefront of HFrEF care.5 These four pillars of HFrEF therapy are known to reduce allcause mortality and morbidity in a cost-effective manner; however, they are underused worldwide.

The purpose of this review is to discuss the current gap in the use of CDMMT, before discussing the benefits of the newest inclusions to guideline-directed medical therapy (GDMT), including SGLT2is and ARNIs. It will cover the efficacy, value, tolerability and safety of these new therapies and will end with suggestions for the initiation and uptitration of CDMMT with potential pathways to guide treatment.

Use of Guideline-directed Medical Therapy: The Gap to Fill

Despite the abundance of data supporting the benefits of GDMT and CDMMT, its use in the US is inadequate. The CHAMP-HF registry includes 5,000 outpatients with HFrEF on at least one GDMT medication. It encompasses data from more than 150 cardiology practices across the country. Data was collected for 2 years or until patient withdrawal or death. Analysis from 2018 showed that one-third of eligible patients with HFrEF were not prescribed an angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or ARNI; one-third were not prescribed a β-blocker; and two-thirds were not prescribed an MRA. ARNIs have been shown to be clinically superior to ACEIs yet are still being underused and 86% of patients without a contraindication to ARNI initiation were not being treated.6,7 Similar data is available from the US PINNACLE registry, the largest outpatient cardiovascular practice registry to date, including over 6 million patients cared for by 8,800 providers. As of 2017, more than 700,000

60% 30.5% 70.8% 76.6% 60% 99.1% 98.2% 60% 67% 69.3% 33.1% MRA

*% of patients on medication. †% of all study patients. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; CDMMT = comprehensive disease modifying medical therapy; GDMT = guideline-directed medical therapy; MRA = mineralocorticoid receptor antagonist.

10%

12% 12%

20%

14.8% 30% 40% 54.3%

67% 23.5%

74.6%

86.7%

27.8%

66.8% ARB

β-blocker

21.5%

70.7% 65.7% 54.8% ACEI

92.7%

90%

45%

76%

53% 39.8%

43.5% 8.5%

92.2%

85%

73%

40.4% 78.0%

17.5%

24.1% 6.9%

27.5% 19% 39.5%

51.8%

27.9% 28% 63.3%

29.3%

27%

15%

30% 22% 17.5%

14.0%

59.9% ACEI/ARB

53% 12.8% ARNI

16.8% 72.1% ACEI/ARB/ARNI

CHAMP-HF QUALIFY ESC-HF BIOSTATSavarese 20176* 201620* 201321* CHF 201722† et al. 202123† CHAMP- PINNACLE QUALIFY ESC-HF BIOSTATSavarese CHAMP-HF BIOSTATQUALIFY Savarese HF 20187 20208 201620 201321 CHF 201722 et al. 20176* CHF 201722† 201620* et al. 202123 202123† GDMT/ CDMMT

Percentage at target Percentage at ≥50% target Percentage of Patients on Treatment

Table 1: Current Usage Rates of Guideline-Directed Medical Therapy and Comprehensive Disease Modifying Medical Therapy

CDMMT for HFrEF HFrEF patients were included in the registry. Rates of use from PINNACLE were slightly better than CHAMP-HF, suggesting 74.6% of HFrEF patients were at least receiving a β-blocker; 78% were at least receiving an ACEI/ ARB/ARNI; and 72.8% were receiving both a β-blocker and an ACEI/ARB/ ARNI. However, the use of ARNIs is lacking, with only 8.5% on treatment.8 SGLT2is have been known to reduce major adverse cardiovascular events in people with diabetes; however, in 2020, the FDA approved the SGLT2i dapagliflozin for the treatment of all-comers with HFrEF given its reduction in worsening HF or cardiovascular death.9–11 This was followed by the formal recommendation of SGLT2is in both the 2021 European Society of Cardiology (ESC) Guidelines for Heart Failure as well as the 2021 updates to the 2017 American College of Cardiology (ACC) Expert Consensus Decision Pathway on HFrEF treatment.12,13 Although shifts in prescription patterns are expected, the most recent data suggest current uptake is low; among people with diabetes in CHAMP-HF, only 2% were being treated with SGLT2i; in contrast, people with diabetes had similar baseline rates of ACEI/ARB/ARNI, β-blocker, and MRA use, compared to people without diabetes.14 Again, the CHAMP-HF database ran from 2015 to 2017; more contemporary studies will clarify whether its use has changed now that SGLT2is have been formally recommended as a treatment for HFrEF. Taken together, data from CHAMP-HF and PINNACLE suggest a massive therapeutic gap in the US, with up to one-third of patients not on individual components of GDMT. Worse still, the use of more novel therapies like ARNIs is lacking, and suggests a need to move away from the prior mainstays of ACEIs and ARBs. Available data for the use of SGLT2i are similarly poor, but monitoring is worthwhile given the medication was only recently recommended for the treatment of HFrEF.

Target Dosing and Titration of GDMT/CDMMT Over Time

It is well known that medications like ACEI/ARBs and β-blockers not only improve cardiovascular outcomes in HFrEF patients, but that higher doses lead to superior clinical results.15–17 In the US, the use of optimal target dosing for HFrEF therapy is poor. Using 2015–2017 data derived from CHAMP-HF, among those on ACEIs or ARBs, only 18% of patients were at target; similarly, 14% of ARNI users and 28% of β-blocker users were at target. Out of all patients included in the study (n=3,158), only 37 (1%) were prescribed the target dose for all ACEI/ARB/ARNI, β-blocker and MRA.7 Clearly titration to target dosing is an issue. The IMPROVE-HF study evaluated the effectiveness of a quality improvement intervention for the use of GDMT. It included 167 outpatient cardiology practices with more than 34,000 patients and was completed in 2009. Rates of target dosing only increased modestly over the 2-year follow up period, with ACEI/ARB increasing from 36.1% to 37.9%, β-blocker increasing from 20.5% to 30.3%, and MRA increasing from 74.4% to 78.4%.18 More recent data on 2,500 outpatients from the CHAMP-HF registry suggests use and target dosing has not improved since. In CHAMP-HF, patients were followed for medication titration over time. At 12 months follow-up, the proportion of patients who had GDMT initiated or increased at 12 months was 7% for ACEI/ARB, 10% for ARNI, 10% for β-blocker, and 6% for MRA. In contrast, those who had discontinued GDMT or had decreased dosing were 11%, 3%, 7%, and 4%, respectively. Less than 1% of all patients were treated with target doses of ACEI/ARB/ARNI, β-blocker and MRA.19 Findings thus suggest target dosing is extremely low despite sufficient time for uptitration and it is clear that optimising CDMMT and GDMT to therapeutic doses needs to be addressed at a national level.

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CDMMT for HFrEF International Use and Dosing of GDMT

Internationally, the data appears to be slightly better than the US. Performed between 2013 and 2014 in more than 36 countries around the world, the QUALIFY registry is an observational, longitudinal, prospective survey of over 7,000 HF patients who were recruited after hospitalisation for acute decompensated HF. GDMT usage was higher than CHAMP-HF and PINNACLE, with 65.7% of patients on ACEIs, 86.7% on β-blockers and 69.3% on MRAs.20 Similar numbers are noted in the ESC-HF Long-Term Registry, which ran from 2011 to 2013 and included 12,440 patients from 21 European countries. The registry incorporated data from inpatients with acute decompensated HF and outpatients with chronic HF. At time of discharge, those who were hospitalised had 77% ACEI/ARB usage, 71.8% β-blocker usage and 55.3% MRA usage; the rate of GDMT usage significantly increased compared to their pre-hospitalisation values, suggesting initiation of GDMT during an inpatient stay. Outpatients with HFrEF had even higher usage rates, with 92.2% ACEI/ARB usage; 92.7% β-blocker usage; and 67% MRA usage.21 Overall, data from both QUALIFY and the ESC-HF Registry seems to suggest that the use of GDMT is somewhat higher outside the US (Table 1). However, the proportion of patients at target dose was comparably low. In the ESC-HF Long-Term Registry, target dosage rates were 29.3% for ACEI users, 24.1% for ARB users, 17.5% for β-blocker users and 30.5% for MRA users.21 In the QUALIFY registry, among individuals on medication, those at ≥50% target dose and 100% target dose was 63.3% and 27.9% for ACEIs; 39.5% and 6.9% for ARBs; 51.8% and 14.8% for β-blockers; and 99.1% and 70.8% for MRAs, respectively.20 Similar findings have been noted in BIOSTAT-CHF, a registry that included 11 European countries with 2,100 HF patients. When it was published in 2017, among all study participants, those at ≥50% target dose and 100% target dose was 53% and 22% for ACEI/ARBs, and 40% and 12% for β-blockers, respectively.22 Overall, the use of certain therapies appears better than in the US, but optimal utilisation is equivocally lacking. The data presented in the aforementioned studies are derived from registries; real-world data are similarly dismal. A recent multinational study analysing healthcare databases from the US, UK and Sweden cements the findings of suboptimal titration, as well as high rates of premature discontinuation.23 In patients who have been hospitalised with a recent diagnosis of HF and subsequently initiated on GDMT, after a follow-up of 12 months, target dosage rates were 15% for ACEIs, 10% for ARBs, 12% for β-blockers and 30% for ARNIs. MRAs, in contrast, reached target dose at a rate of 60%. Discontinuation rates were far higher than CHAMP-HF, reaching 55% for ACEIs, 33% for ARBs, 24% for β-blockers, 27% for ARNIs and 40% for MRAs.19,23

Should We Fill the Gap? The Additive Benefit and Impact of Optimal Treatment

The effects of such a lapse in treatment are profound. Numerous studies have shown an incremental benefit of each component of GDMT when added to background HF therapy. As an example, the addition of β-blocker to ACEI/ARB is associated with higher 2-year survival rates for HFrEF patients.24 Furthermore, analysis of the QUALIFY registry noted that at 18 months, adherence to GDMT recommendations was associated with a reduction in death due to HF as well as the composite of cardiovascular death or hospitalisation for HF.25 Failing to treat, unsurprisingly, is associated with the opposite; in BIOSTAT-CHF, reaching <50% of target dose was associated with worse survival.22 Similar concerns regarding morbidity of HF were noted in a subsequent study from the PINNACLE registry, which looked at 11,000 patients with stable HFrEF. As may be

expected, the majority of those with an acute decompensation were undertreated, with 42.4% on one medication and 43.4% on two medications. Worse still, 40–50% of patients were on suboptimal dosing, defined as less than 50% of the target dose. Given that the mean time to event was 1.5 years after the initial diagnosis of HFrEF, there was ample time for uptitration of therapy, yet it did not occur.26 Transitioning from the old mainstays of GDMT to the novel regimen of CDMMT is similarly important for patient outcomes. A cross-trial analysis of EMPHASIS-HF, PARADIGM-HF and DAPA-HF sought to evaluate the benefit of CDMMT (ARNI, β-blocker, MRA, and SGLT2i) compared to conventional therapy (ACEI/ARB and β-blocker). When compared to conventional therapy, CDMMT would be expected to lower the risk of cardiovascular death or hospital admission for HF by over 60% (HR 0.38; 95% CI [0.30–0.47]). Similarly, CDMMT would be expected to reduce the risk of all-cause mortality by just under 50% (HR 0.53; 95% CI [0.40–0.70]). Treatment with ARNI, β-blocker, MRA and SGLT2i could add between 2.7 and 8.3 additional years free from cardiovascular death or HF hospital admission and between 1.4 and 6.3 additional years of survival.27 While there is a clear benefit to shifting from GDMT to CDMMT, the lack of use comes at a cost. Older studies have suggested that in the US, optimal implementation of ACEI/ARBs could save over 6,000 lives annually; β-blockers over 12,000 annually; and MRAs over 20,000 annually. When accounting for all GDMT therapies, almost 68,000 lives could be saved.28 Optimal use of more novel therapeutics, namely ARNIs, could potentially prevent another 28,000 deaths annually.29 One recent study used a decision analytical model to approximate the magnitude of the benefit of optimal implementation of SGLT2is for the HFrEF population in the US. Extrapolating from DAPA-HF, SGLT2is could prevent more than 34,000 deaths each year.30 In sum, every 10% improvement in guideline directed care is associated with 13% lower odds of 2-year mortality risk.31 The impact goes beyond the projected mortality rates of optimal treatment; all medications in GDMT and CDMMT are considered cost effective and have high/intermediate value, with some even considered cost-saving. The newer treatments are more expensive than the old GDMT mainstays, yet the incremental cost-effectiveness ratio (ICER) of dapagliflozin, based on DAPA-HF outcomes, is US$8,000–11,000 per quality-adjusted life year (QALY).32 In addition, the ICER of an ARNI (compared to an ACEI) is US$23,000–45,000 per QALY.33–35 Both of these novel therapies fall under the high value category (ICER <US$50,000) as stated in the 2014 ACC/AHA Statement on Cost/Value.36 Even better, β-blocker and MRA are considered cost dominant, meaning they are both clinically superior and cost-saving.37 Incremental cost-effectiveness analysis for GDMT, namely ACEI/ARB, β-blocker and MRA, have noted cost-effectiveness, as well as cost-savings for each medication added to a patient’s regimen. Specifically, the ICER for ACEI + β-blocker compared to ACEI alone, as well as the ICER for ACEI + β-blocker + MRA compared to ACEI + β-blocker was <US$1,500 per QALY.38 Thus, the traditional treatment of HFrEF with GDMT, as well as the more novel approach with CDMMT, have dramatic cost/benefit ratios and could potentially save thousands of lives (and dollars) annually. Despite this, barriers to treatment exist, including gaps in knowledge and awareness of CDMMT, therapeutic inertia, concerns about drug safety and sideeffects and uncertainty surrounding the effectiveness of treatment.39 Use in the US is uniquely hindered by large variability in pharmaceutical pricing, as well as high out-of-pocket costs and the need for prior authorisations for the more novel ARNI and SGLT2i.12,40–42 A call for reform

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CDMMT for HFrEF Table 2: Relative Risk Reduction in Mortality and Heart Failure Hospitalisation CDMMT

Relative Risk Reduction in Mortality

Absolute 2-year Mortality Rate

Relative Risk Reduction in HF Hospitalisations

Absolute 2-year HF Hospitalisation Rate

None

35%

39%

ACEI or ARB

17%

29%

31%

27%

ARNI*

16%

24%

21%

β-blocker

35%

16%

41%

13%

MRA

30%

11%

35%

SGLT2i

17%

30%

Cumulative

74% RRR

26% ARR

85% RRR

33% ARR

*Replacing ACEI/ARB. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARR = absolute risk reduction; ARNI = angiotensin receptor-neprilysin inhibitor; CDMMT = comprehensive disease-modifying medical therapy; HF = heart failure; MRA = mineralocorticoid receptor antagonist; RRR = relative risk reduction; SGLT2 = sodium glucose cotransporter 2 inhibitor. Source: Fonarow et al. 2021.37,39

of the utilisation management requirements and prior authorisation process signed by 17 medical organisations, including the ACC and the AMA, hopes to curb the negative impact felt by patients.43 Whether this will improve timely and affordable access to optimal care remains to be seen.

The Push for Early Initiation – Rationale and Safety

CDMMT is presumed to reduce the risk of death by 74% over a 2-year period, leading to a number needed to treat of just four (Table 2); thus timely initiation is paramount to the treatment of HFrEF.37 Such a benefit is quick to occur. With regard to the mainstays of GDMT, initiation of carvedilol against a background of ACEI/ARB in the COPERNICUS trial suggested benefit for both all-cause mortality and for the combined endpoints of death, hospitalisation or withdrawal as early as 14–21 days after initiation of treatment.44 Findings for metoprolol succinate in the MERIT-HF trial were concurrent, with the reduction in all-cause mortality/ all-cause hospitalisation occurring by week 8.45 Finally, EMPHASIS-HF noted a benefit with MRA in reducing the endpoint of cardiovascular mortality and HF hospitalisation as early as 30 days.46 Similar findings are noted for CDMMT. ARNIs were first studied in the stable HF population in the PARADIGM-HF trial; treatment protocol indicated that sacubitril-valsartan should be started and uptitrated within 4–6 weeks and the benefit of reducing the risk of death and hospitalisation for HF was noted soon after.47 Subjective improvement with ARNIs occurred quickly as well; in a subsequent analysis of the same trial, there was a greater mean improvement in self-reported health status based on the 12-item Kansas City Cardiomyopathy Questionnaire, which occurred at a median timepoint of 57 days.48 For SGLT2is, the EMPEROR-Reduced trial showed that empagliflozin reduced the combined risk of death, hospitalisation for HF, or emergent/urgent HF visit requiring IV treatment as early as 12 days after initiation.49,50 In subsequent analysis of DAPA-HF, dapagliflozin was shown to reduce the composite endpoint of cardiovascular death or worsening HF as early as 28 days after randomisation, with a sustained significant benefit throughout the study.11,51 Given this quick onset of medical benefits to the patient, initiation of all GDMT/CDMMT medications should be prompt; of top concern, however, is whether such a multi-drug regimen is safe. Safety of additional therapy is well demonstrated when analysing the randomised control trials that established GDMT. In the original β-blocker trials, over 95% of subjects were already on ACEI/ARBs, and for MRAs, over 90% of EMPHASIS-HF

enrollees were already on ACEI/ARBs and over 85% were on β-blockers.46,52–55 For newer therapies, in PARADIGM-HF, 93% of patients were on β-blockers and 56% were on MRAs; fewer patients in the ARNI group stopped their medication for an adverse event, compared to those in the control group (enalapril).47 In DAPA-HF, 95.1% of patients were on an ACEI/ARB/ARNI, 96% were on a β-blocker, and 71.5% were on an MRA, yet frequency of adverse events did not differ between the dapagliflozin group and the control group (placebo).11 Similar baseline therapy rates were comparable in EMPEROR-Reduced, which compared empagliflozin to placebo and found with the exception of genital tract infections, there was no significant difference in adverse events.50 Taken together, the components of GDMT and CDMMT should be consider safe to use with one another. With these safety profiles and the quick onset of benefit, the question then becomes whether such medications are safe and/or more effective when started quickly, namely in the inpatient setting or whether titration needs to be prolonged to prevent side-effects. Available studies support the former. Medications that were first shown to be safe for initiation prior to hospital discharge included GDMT, namely β-blockers (specifically carvedilol), ACEI/ARBs and MRAs.56–59 The benefit of early initiation is certainly present for β-blockers and ACEI/ARBs; in observational studies, β-blocker initiation prior to hospital discharge was associated with lower mortality and lower readmission rates.60,61 Similar findings have been noted for ACEI/ARBs started prior to hospital discharge.57,62 MRAs, in contrast, have been associated with improved overall survival in some studies and lower risk of HF rehospitalisation in others, but the findings are not as consistent.63–65 Nonetheless, the available data suggests GDMT medications should be started while individuals are in hospital prior to discharge. Fortunately, national trends suggest this is the case; in the GWTG-HF registry, 90% of treatment-naïve HF patients were initiated on β-blocker and 87% were initiated on ACEI/ARB during hospitalisation or at discharge. However, only 25% were initiated on MRA.66 As opposed to the observational studies for GDMT inpatient initiation, the more novel CDMMT are the subject of more proactive trials. PIONEER-HF evaluated ARNI initiation specifically in those with acute decompensated HF. ARNIs were not only safe in the context of acute HF, but they were also associated with a greater reduction in NT-proBNP; further, in exploratory analyses, ARNIs were associated with reduction in the composite of cardiovascular death or rehospitalisation from HF as soon as 30 days after initiation.67,68 Similar findings were noted in the safety-driven TRANSITION trial, wherein patients treated for acute decompensated HF were randomised to ARNI initiation either prior to

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CDMMT for HFrEF Table 3: Potential Starting Doses and Titration of Comprehensive Disease-modifying Medical Therapy CDMMT

Starting Dose

Typical Titration Dose(s)

Final Dose

Monitoring Parameters

Captopril

6.25 mg three-times daily

12.5 mg three-times daily; 25 mg three-times daily

50 mg three-times daily

Enalapril

2.5 mg twice daily

5 mg twice daily; 10 mg twice daily

10–20 mg twice daily

Lisinopril

2.5–5 mg daily

10 mg daily; 20 mg daily

20–40 mg daily

Monitor blood pressure, electrolytes and renal function Can titrate every 1–2 weeks in outpatients and every 1–2 days in hospitalised patients

Ramipril

1.25 mg daily

2.5 mg daily; 5 mg daily

10 mg daily

Candesartan

4-8 mg daily

16 mg daily

32 mg daily

Losartan

25–50 mg daily

100 mg daily

150 mg daily

Valsartan

40 mg twice daily

80 mg twice daily

160 mg twice daily

24/26 mg twice daily

49/51 mg twice daily

97/103 mg twice daily

Monitoring same as ACEI or ARB Starting dose based on daily equivalent of ACEI

Bisoprolol

1.25 mg daily

2.5 mg daily; 5 mg daily

10 mg daily

Carvedilol

3.125 mg twice daily

6.25 mg twice daily; 12.5 mg twice daily

25 mg twice daily*

Metoprolol succinate

12.5–25 mg daily

50 mg daily; 100 mg daily

200 mg daily

Initiate only in stable patients Monitor blood pressure, heart rate and for signs of congestion Can titrate every 2 weeks

Eplerenone

25 mg daily

50 mg daily

Spironolactone

12.5–25 mg daily

25–50 mg daily

Dapagliflozin

10 mg daily

Dapagliflozin: Only if eGFR ≥30 ml/min/1.73 m2

Empagliflozin

10 mg daily

Empagliflozin: Only if eGFR ≥20 ml/min/1.73 m2

ACEI or ARB

ARNI Sacubitril/valsartan

β-blocker

MRA Monitor electrolytes and renal function. Avoid in eGFR ≥30 ml/min/1.73 m2 or K+ >5 mEq/l

SGLT2i

*Maximum dose of carvedilol is 50 mg twice daily for weight ≥85 kg. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI: angiotensin receptor-neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; eGFR = estimated glomerular filtration rate; K+ = potassium; SGLT2i = sodium glucose cotransporter 2 inhibitor. Source: Fonarow et al. 202137,39

hospital discharge or within 14 days of discharge; safety endpoints were similar for both strategies, indicating no significant disadvantage to early initiation of ARNIs.69 With the remarkable findings of rapid benefit in EMPEROR-Reduced and DAPA-HF, the SOLOIST-WHF trial was specifically designed to show that an SGLT2i could safely be started before or shortly after hospital discharge for acute decompensated HF; sotagliflozin was initiated prior to discharge in 48.8% of patients or at a median of 2 days after discharge in 51.2%. Compared to placebo, sotagliflozin reduced the primary endpoint of cardiovascular death and hospitalisations/urgent visits for HF and with the exception of diarrhoea and severe hypoglycaemia, safety endpoints were similar between the two treatment arms.70 Two ongoing trials, EMPULSE and DAPA ACT HF-TIMI 68 (NCT04363697), are further evaluating the clinical benefit of SGLT2i in patients hospitalised with HF.71 Both GDMT mainstays and the more novel therapies of CDMMT can be used together safely. Furthermore, they can be safely initiated and uptitrated quickly, without concern for higher rates of adverse events. Given their dramatic benefit for cardiovascular outcomes, such early initiation and rapid titration of GDMT and/or CDMMT needs to occur as soon as a diagnosis of HFrEF is made.

Simultaneous/Rapid Sequence Initiation and Optimal Titration: A Conceptual Framework and a Call for Action

A conceptual framework for the rapid initiation of CDMMT for HF is readily available, but bears repeating.5,12,13,37,72 The aforementioned

observational studies in the US and around the world suggest that ARNIs are beneficial compared to ACEI/ARBs, yet they are extremely underprescribed; a reasonable step is thus to convert all HFrEF patients on ACEI/ARB to ARNI, barring any contraindication. It should be noted that there is a difference in US guidelines compared to other countries. According to the ACC, ARNI is preferred, but if ARNI administration is not feasible, then an ACEI/ARB can be offered instead; per the ESC, either ARNI or ACEI/ARB can be offered as a first-line option.12,13 β-blockers are cost-dominant and are being used at a decent rate, but target dosing could be improved. MRAs are also cost-dominant, yet despite their low cost, they are underused and frequently not titrated to target dose. Finally, SGLT2is have been shown to be a cost-effective and beneficial addition to the mainstays of HF therapy but as they were only approved for HFrEF within the past year, data on usage have not yet been described. These four medications should be started and uptitrated in a timely manner to derive the highest benefit for the HFrEF patient. The rationale goes beyond the reduction in cardiovascular outcomes. Treatment with an ARNI, compared to an ACEI, has less risk of severe hyperkalaemia, which could reduce discontinuation of an MRA.5,73 Treatment with an SGLT2i reduces the worsening of renal function and delays progression to end-stage renal disease, which may allow for longer usage of ARNIs and MRAs.5,10 While some may feel uncomfortable with a rapid initiation of multiple medications for HFrEF, there is no evidence to date that suggests such a strategy would produce adverse events; in fact, a delay in treatment would lead to unnecessary clinical worsening and cardiovascular death.22,27,31,37

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CDMMT for HFrEF

ARNI*

β-blocker

MRA

SGLT2i

Day 1

Initiate†

Initiate

Initiate†

Initiate

Day 7–14

Continue

Uptitrate‡

Continue

Day 14–28

Uptitrate‡

Continue

Day 21–42

Uptitrate‡

Continue

Day 43 to long term

Continue

*ARNI preferred to ACEI/ARB per ACC guidelines, but ESC guidelines consider ARNI equivalent to ACEI as first-line therapy.12,13 †Low guideline-recommended starting dose. ‡As well tolerated. Starting doses for medications: ARNI (sacubitril/valsartan 24/26 mg twice daily. β-blocker bisoprolol 1.25 mg daily; carvedilol 3.125 mg twice daily; metroprolol succinate 12.5–25 mg daily. MRA (eplerenone 25 mg daily; spironolactone 12.5–25 mg daily). SGLT2i (dapagliflozin 10 mg daily; empagliflozin 10 mg daily). ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist; SGLT2i: sodium–glucose cotransporter 2 inhibitor. Source: Fonarow et al.37,39

Suggestions on initiation and titration of CDMMT are shown in Table 3 and Figure 1. All four medications can be started upon diagnosis of HFrEF, including in the inpatient setting prior to discharge. Medications should be started at a low dose. At 7–14 days, β-blocker can be uptitrated; at 14–28 days, the ARNI, β-blocker and MRA can all be uptitrated; and at 21–42 days, the ARNI and β-blocker can be increased to their maximum dose. By 2 months, the patient can safely be taking the maximum dosing of CDMMT. Throughout initiation and titration of CDMMT, the patient should have their volume status monitored with the goal of euvolaemia. If congestion is present, the patient should be initiated on a loop diuretic, which can be titrated to the relief of congestion. Though they lack the benefits to mortality of CDMMT, diuretics alleviate HF symptoms and reduce HF hospitalisations. Providers should be aware that diuretic dosing can change in the setting of increased CDMMT dosing and may even be reduced or stopped altogether. Only once maximal dosing of CDMMT is established should additional HFrEF therapies be considered. Such medications include hydralazine/isosorbide dinitrate for persistent symptoms in black patients, ivabradine for patients 1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics — 2020 update: a report from the American Heart Association. Circulation 2020;141:e139–596. https://doi. org/10.1161/CIR.0000000000000757; PMID: 31992061. 2. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. https://doi.org/10.1161/ HHF.0b013e318291329a; PMID: 23616602. 3. Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 2017;70:2476–86. https://doi. org/10.1016/j.jacc.2017.08.074; PMID: 29141781. 4. Taylor CJ, Ordóñez-Mena JM, Roalfe AK, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000–2017: population based cohort study. BMJ 2019:364:l223. https://doi.org/10.1136/bmj.l223; PMID: 30760447. 5. Greene SJ, Butler J, Fonarow GC. Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure – optimizing therapy with the need for speed. JAMA Cardiol 2021;6:743–4. https://doi.org/10.1001/ jamacardio.2021.0496; PMID: 33787823. 6. DeVore AD, Thomas L, Albert NM, et al. Change the

10.

11.

Knowledge and awareness gaps

Simultaneous CDMMT initiation

Therapeutic inertia

Medication initiation in hospital

Applicability of clinical trials to real-world patients Drug safety, tolerability and side-effects Uncertainty about treatment effectiveness Bias Concerns about access and cost

Improving Use of CDMMT

Medication

Figure 2: Reasons for Underuse of Comprehensive Disease-modifying Medical Therapy and Potential Interventions for Improvement

Reasons for Underuse of CDMMT

Figure 1: Simultaneous/Rapid Sequence Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy

CDMMT-specific clinics Multidisciplinary HF management programmes Electronically administered patient awareness tools Telehealth EMR interventions for providers

CDMMT = comprehensive disease-modifying medical therapy; EMR = electronic patient record. Source: Fonarow et al.39

with a resting heart rate above 70 BPM, and vericiguat for all patients with persistent symptoms.12,13 Evidence-based mechanisms to facilitate ongoing CDMMT usage and titration are numerous and should be used to ensure maximum benefit. Such strategies include enhancing patient awareness through electronically-administered activation tools, improving provider awareness through the electronic medical record and employing both inperson and telehealth GDMT clinics designed for initiation and titration of medications (Figure 2).39,74–79

Conclusion

Despite an abundance of evidence for the benefit of HFrEF medical therapy, data from the US and around the world suggests that the use of GDMT and CDMMT has substantial treatment and dosing gaps. Both the use of medications, as well as increasing medications to optimal dosing, needs substantial improvement to derive the maximum benefit of HFrEF treatment. The mainstays of therapy, the four pillars of CDMMT, are proven to be safe, effective and well tolerated. These therapies can be started at the time of HFrEF diagnosis, including in-hospital, at a low dose and then optimally titrated over time. By following a simple and effective algorithm for the initiation of CDMMT, the quality of HF care can be improved with the potential for tens of thousands of lives being saved.

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Diagnosis

Carbohydrate Antigen 125: A Biomarker at the Crossroads of Congestion and Inflammation in Heart Failure Marko Kumric ,1 Tina Ticinovic Kurir,1,2 Josko Bozic,1 Duska Glavas,3 Tina Saric,4 Bjørnar Marcelius ,1 Domenico D’Amario5,6 and Josip A Borovac 1,3,7 1. Department of Pathophysiology, University of Split School of Medicine, Split, Croatia; 2. Department of Endocrinology and Diabetology, University Hospital of Split, Split, Croatia; 3. Clinic for Heart and Vascular Diseases, University Hospital of Split, Split, Croatia; 4. Institute of Emergency Medicine of Split-Dalmatia County, Split, Croatia; 5. Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico A Gemelli IRCCS, Rome, Italy; 6. Catholic University of the Sacred Heart, Rome, Italy; 7. Department of Health Studies, University of Split, Split, Croatia

Abstract

Because heart failure (HF) is more lethal than some of the common malignancies in the general population, such as prostate cancer in men and breast cancer in women, there is a need for a cost-effective prognostic biomarker in HF beyond natriuretic peptides, especially concerning congestion, the most common reason for the hospitalisation of patients with worsening of HF. Furthermore, despite diuretics being the mainstay of treatment for volume overload in HF patients, no randomised trials have shown the mortality benefits of diuretics in HF patients, and appropriate diuretic titration strategies in this population are unclear. Recently, carbohydrate antigen (CA) 125, a well-established marker of ovarian cancer, emerged as both a prognostic indicator and a guide in tailoring decongestion therapy for patients with HF. Hence, in this review the authors present the molecular background regarding the role of CA125 in HF and address valuable clinical aspects regarding the relationship of CA125 with both prognosis and therapeutic management in HF.

Keywords

CA125, carbohydrate antigen, congestion, decompensation, heart failure, inflammation, tailored therapy Disclosure: JAB is on the Cardiac Failure Review editorial board; this did not influence peer review. All other authors have no conflicts of interest to declare. Received: 31 August 2021 Accepted: 20 October 2021 Citation: Cardiac Failure Review 2021;7:e19. DOI: https://doi.org/10.15420/cfr.2021.22 Correspondence: Josip A Borovac, Clinic for Heart and Vascular Diseases, University Hospital of Split, Spinciceva 1, 21000 Split, Croatia. E: jborovac@mefst.hr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a major global non-communicable health problem that is estimated to affect at least 64.3 million people worldwide, with the prevalence of known (clinically diagnosed) HF in the general adult population being 1–2%.1,2 In fact, following normal childbirth, HF is the most common reason for hospitalisation.3 Moreover, approximately 2% of the total annual healthcare budgets in Europe and the US is spent on HFrelated care.4 HF is also deadlier than some of the common malignancies in the general population, such as prostate and bladder cancer in men and breast cancer in women.5 Although the incidence of HF remains fairly constant, large population studies have reported an increase in the prevalence of HF over time.6 This is important because the observed increase will inevitably lead to further increases in hospitalisation rates, with a concomitant increase in health care expenditures. Hence, there is a need for a cost-effective prognostic biomarker in HF beyond natriuretic peptides. In light of available evidence, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) consensus meeting recommended a multimarker approach, including cardiac troponins, natriuretic peptides and soluble suppression of tumorigenicity-2 (sST2).7 In this review, we focus on the role of carbohydrate antigen (CA) 125, a high molecular weight transmembrane glycoprotein most commonly associated with ovarian cancer.8 CA125 is normally expressed on the cell

surface in various tissues, including the pleura, pericardium, peritoneum, endometrium, endocervix, salpinges, lung, conjunctiva and prostate.9 The physiological role of CA125 is to hydrate and lubricate epithelial luminal surfaces, which protects them against mechanical stress and stretch imposed on the cells.8 Furthermore, the interaction between transmembrane mucins and adjacent proteins supports the role of CA125 in processes involving fluid and cell transport, inflammation, tissue repair and tumour dissemination.10,11 Finally, CA125 has been shown to modulate both innate and adaptive immune processes, such as suppression of natural killer (NK) cell activity and regulation of galectin activity.12,13 Increased plasma CA125 concentrations are not exclusive indicators of neoplastic states, because CA125 levels are normally elevated during menstruation and in the early stages of pregnancy.14 Furthermore, CA125 is upregulated in multiple pathological states, such as liver cirrhosis, pelvic inflammatory disease, peritoneal trauma, ascites and lung malignancies.15 However, the clinical use of this biomarker has been predominantly associated with the work-up of patients with suspected or diagnosed ovarian cancer.16 In fact, CA125 has served as the main biomarker for ovarian cancer for almost four decades, playing an important role in the treatment and follow-up phases of ovarian cancer management.16,17

CA125 as a Biomarker in Heart Failure Figure 1: Pathophysiological Role of CA125 at the Crossroads of Volume Overload and Inflammation in Heart Failure CA125 available for peripheral blood detection

N-Terminal domain NH2 Tandem repeats domain

Congestive heart

Volume overload

Mechanical stress CA125 shedding ***

Inflammation

Cleavage site

SEA molecules

JNK pathway

IL-1, TNF-α, IL-6

CA125 synthesis

Cytoplasmic tail COOH

*Inflammatory stimuli lead to fluid overload by affecting neurohumoral and endocrine activity. **Venous congestion changes the expression patterns in endothelium and perivascular tissue towards the activated state (pro-oxidant, proinflammatory environment). ***Synthesis of hyaluronan and cytoplasmic fibres leads to changes in cytomorphology and cell stability. IL = interleukin; JNK = c-Jun N-terminal kinase; SEA = sea urchin sperm protein, enterokinase, and agrin module; TM = transmembrane domain; TNF-α = tumour necrosis factor-α.

Apart from being elevated in many physiological and pathological conditions, accumulating evidence implicates CA125 in pathophysiological processes underlying HF.18,19 Thus, in this review, we present the molecular background regarding the role of CA125 in HF and address valuable clinical aspects concerning the relationship between CA125 and both prognosis and the therapeutic management of HF.

Challenges Assessing Congestion in Heart Failure: Urgent Need for Improvement

The development of congestion leading to HF decompensation is a strong predictor of poor patient outcomes.20 Thus, the timely detection of congestion, and subsequent monitoring, is vital before it leads to cardiac decompensation. However, accurate quantification of congestion in daily clinical practice is challenging. Quantification is very challenging when the extrapulmonary signs of congestion are mild, such as in the setting of acute pulmonary congestion due to hypertension or in patients near discharge after HF hospitalisation. Although increased intracardiac filling pressures can frequently precede the appearance of overt congestive symptoms by days or weeks, the increase is often subtle and difficult to detect, and may be masked by other comorbidities.21 Clinical scoring systems combining several clinical variables have been shown to assess the level of congestion more accurately than any individual indicator used in isolation. Among the many scoring systems developed, evidence is strongest for the EVEREST score, derived from the EVEREST trial, and it appears to be the best candidate for routine use in AHF management.20,22 Another valuable tool to assess congestion is lung ultrasound (LUS), which enables precise assessment of extravascular lung water.23 Aside from the CHAMPION trial, there is scarce evidence that HF management guided by standardised congestion assessment strategies results in a better prognosis.21 Thus, invasive strategies, such as pulmonary artery pressure-guided HF management should only be considered in a select group of patients in whom mechanism of clinical deterioration is

unclear. Importantly, natriuretic peptide-guided therapy in high-risk patients with HF yielded disappointing results with regard to clinical outcomes.24

Interaction Between CA125 and Congestion and Inflammation in Heart Failure

The exact mechanisms that could explain elevated plasma CA125 concentrations in the setting of HF are yet to be fully elucidated. However, accumulating data suggest that the observed increase in circulating CA125 concentrations in HF is due to at least two pathophysiological mechanisms that partially overlap.25 It has so far been well established in a various malignant and non-malignant pathologies that CA125 correlates with physical and objective signs indicative of fluid congestion and effusions. For example, serum CA125 concentrations are positively correlated with pleural effusion volume in patients with chronic obstructive pulmonary disease, as well as with serosal fluid accumulation and ascites in patients with ovarian cancer and other non-ovarian benign and malignant diseases.26,27 Accordingly, Núñez et al. reported that the presence of clinical signs associated with volume overload was most robustly related to increased serum CA125 concentrations in acute HF.28 Even in the setting of ovarian cancer, CA125 concentrations were shown to be more significantly associated with ascites volume and peritoneal carcinomatosis than with the ovarian mass volumes and carcinoma per se.29 The mediator between volume overload and elevated CA125 concentrations is the mechanical stress produced by excessive fluid accumulation. Subsequently, increased mechanical stress or inflammatory stimuli (as discussed below) trigger c-Jun N-terminal kinase (JNK) pathways, resulting in two cellular changes that lead to an increase in CA125.30 First, activation of JNK stimulates the synthesis of CA125. Second, because CA125 is linked to the actin cytoskeleton, the change in the morphology the stability of the cell membrane, along with the

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CA125 as a Biomarker in Heart Failure mechanical stress, activates the O-glycosylated extracellular domain of CA125, shedding it from mesothelial cells and thus increasing its concentration in the periphery.31 Nevertheless, CA125 seems to be associated with increased 6-month mortality independent of evidence of fluid overload, indicating the involvement of CA125 in other pathogenic processes underlying HF.25 Inflammation has arisen as a viable culprit, because correlation between CA125 and proinflammatory cytokines, such as tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10, has been identified.32 In addition, Zeillemaker et al. demonstrated that CA125 secretion could be enhanced by the inflammatory cytokines IL-1β, TNF-α and lipopolysaccharide of Escherichia coli.33 As noted above, the proposed mechanism by which systemic inflammation affects CA125 concentrations also involves JNK molecular pathways. Notably, it has been established that venous congestion changes expression patterns in the endothelium and perivascular congested tissue towards the activated state, leading to upregulation of pro-oxidant, proinflammatory and vasoconstricting factors.34 Accumulating data suggests that CA125 may even play a role in the cardiac remodelling process by regulating galectin activity or modifying the mass and stiffness of the intercellular matrix. For example, in patients admitted to hospital with acute decompensated HF, positive correlations between galectin-3 and proxies of inflammation were observed only in patients with CA125 concentrations above the median value.12 Furthermore, in oedematous patients, such as those with HF decompensation, bacterial endotoxin translocation occurs from the gut into the circulation, stimulating the activation of the immune response.35 Conversely, inflammatory stimuli worsen fluid overload by affecting neurohumoral and endocrine activity.36 Overall, volume overload and inflammation in HF mutually interact, augmenting each other’s activity in a bidirectional manner, thus creating a positive feedback loop that leads to elevated CA125 concentrations (Figure 1).

CA125 as an Indicator of Congestion in Heart Failure and its Relationship With Haemodynamic and Echocardiographic Parameters

Although congestion plays an important role in the pathogenesis of acute HF, its severity and organ distribution are largely heterogeneous.37,38 Of note, fluid retention and congestion are the most common reasons for the hospitalisation of patients with worsening of HF and present important therapeutic targets in routine clinical practice.39 However, complete and efficacious decongestion in patients with HF is challenging, because residual congestion, such as that present in tissues, may be underappreciated in a sizeable number of HF patients at discharge, thus exposing them to an increased risk of early rehospitalisation and death.40 Moreover, methods for identifying and quantifying systemic congestion in clinical practice are fairly limited because two types of congestion, both implicated in the outcomes of HF patients, must be evaluated: intravascular and tissue congestion. Residual congestion at discharge strongly portends worse outcomes, whereas diuretic resistance and poor diuretic response complicate the accomplishment of euvolaemia.41 Although current expert recommendations suggest an integrative multiparameter-based evaluation of congestion, there is growing interest in the establishment of a cost-effective and reliable biomarker of fluid overload in HF.37,38,42 CA125 emerged as a potential candidate providing additional information beyond intravascular volume status, because plasma CA125 concentrations seem to be positively associated with the

signs and symptoms of congestion, including peripheral oedema and serosal effusion, in patients with HF.43,44 Similarly, in patients with STelevation MI (STEMI) complicated with HF (Killip Class ≥II), circulating CA125 concentrations were correlated with pulmonary congestion and had similar prognostic power for mortality as high-sensitivity C-reactive protein and N-terminal pro B-type natriuretic peptide (NT-proBNP) in the STEMI population.45,46 In line with this, CA125 was shown to be associated with well-established laboratory proxies of clinical congestion, such as bio-adrenomedullin and NT-proBNP.47 In fact, one study showed that in clinical scenarios marked by systemic congestion and right ventricular dysfunction, CA125 may even outperform NT-proBNP in predicting mortality.48 The main differences between the two biomarkers are seen in their metabolism and in their relationship to age, as well as kidney and cardiac function. Specifically, CA125 has a significantly longer half-life than NTproBNP (days versus minutes), and, in contrast to NT-proBNP, CA125 concentrations are not substantially modified by age and renal dysfunction or ejection fraction.49 Overall, because NT-proBNP is primarily a proxy of left ventricular myocardial stretch and because CA125 is better correlated with indices of right-sided HF, Núñez et al. suggested the complementary use of both markers to assess the degree of participation of each heart side.50 In practical terms, by accounting for the notable differences between the two biomarkers, CA125 may be more valuable in older patients with impaired renal function and predominant involvement of the right side of the heart, whereas NT-proBNP may be more valuable in euvolemic or mildly congested patients with predominant involvement of the left side of the heart. Moreover, a recent meta-analysis by Li et al. showed that, among patients with acute HF, CA125 concentrations were significantly higher in those with than without pleural effusions.51 Nevertheless, in patients with refractory congestive HF treated with continuous peritoneal dialysis, CA125 concentrations decreased with decongestion, despite the presence of an osmotic solution in the peritoneum and concomitant peritoneal irritation induced by it.52 From these findings, doubts were raised as to whether the observed association between an increase in CA125 and serosal effusion merely represents parallel processes caused by a common pathophysiological culprit or a causal relationship between the two. In summary, future studies should explore the relationship between CA125 and other established laboratory and imaging markers of congestion, as well as investigate the role of CA125 in the identification of intravascular versus extravascular congestion. Apart from clinical parameters of congestion, the authors of a pivotal study reported that CA125 concentrations are correlated with haemodynamic parameters, right atrial pressure and pulmonary capillary wedge pressure, further supporting the association between congestion and CA125.53 Importantly, the same study demonstrated that, during follow-up, CA125 concentrations decreased in patients after heart transplantation or clinical stabilisation of HF, but increased in patients in whom further deterioration of HF was recorded. Several authors have reported a correlation between CA125 and echocardiographic parameters in HF. In an early report, Kouris et al. reported that serum CA125 concentrations were weakly correlated with approximated right ventricular systolic pressure and renal function, but no significant correlations were found between CA125 and any of the following echocardiographic parameters: E wave deceleration time on Doppler echocardiography, left ventricular ejection fraction (LVEF) or left

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CA125 as a Biomarker in Heart Failure Table 1: Summary of Clinical Studies That Have Investigated the Prognostic Role of CA125 in Heart Failure Study

No. Patients

Follow-up

Study Population Study Population Main Outcomes by HF by LVEF

Núñez et al.50

2356

21 months

AHF

HFrEF

Death at 1 year and the composite Increased risk of mortality and the of death/HF readmission composite of death/HF readmission

Li et al.51*

8401

13 months

AHF

HFrEF

Mortality and HF readmission

Increase in mortality and HF readmission

Nägele et al.53

2 years

CHF (patients undergoing cardiac transplantation)

HFrEF

Neurohormones and filling pressures

Correlation with neurohormones and filling pressures; decrease after transplantation or stabilisation and an increase during worsening of HF

D’Aloia et al.55

286

6 months

CHF

Mortality or readmission

Increase in mortality and readmission

Yilmaz et al.

150

8 months

AHF/CHF

HFrEF and HFpEF

Mortality or readmission

Increase in mortality and readmission

Núñez et al.59

946

2.6 years

AHF

HFrEF

Mortality

Increase in mortality

Núñez et al.

1111

N/A

AHF

HFrEF and HFpEF

Mortality

Increase in mortality

Núñez et al.61

380

1 year

AHF

HFrEF and HFpEF

Mortality or readmission

Increase in readmission

Yoon et al.

413

20 months

AHF

HFrEF

All-cause mortality

Increase in all-cause mortality; combination with NT-proBNP improved the prediction of mortality

Hung et al.63

158

27 months

CHF

HFpEF

Readmission

Increase in readmission

Mansour et al.64

172

40 months

AHF

HFrEF

Mortality or readmission

Increase in mortality and readmission

Monteiro et al.

13 months

CHF

HFrEF

Mortality or transplantation

Increase in mortality and transplantation

Becerra-Munoz et al.66

N/A

CHF (patients undergoing cardiac transplantation)

HFrEF

Post-transplantation mortality

Increase in mortality

Núñez et al.67

3231

6 months

AHF

HFrEF

Death at 1 month or composite of For CA125 <23 U/ml: NPVs of 99.3% death and HF readmission and 94.1% for death and the composite endpoint, respectively

Results and Comments

*Meta-analysis. AHF = acute heart failure; CHF = chronic heart failure; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; NPV = negative predictive value; NT-proBNP = N-terminal pro B-type natriuretic peptide

ventricular end-diastolic diameter.54 Nevertheless, the authors of that study demonstrated that serum CA125 concentrations are associated with the clinical severity of chronic HF and are consistent with the symptoms and signs of fluid congestion.54 Conversely, D’Aloia et al. showed that serum CA125 concentrations were related to echocardiographic parameters reflecting increased left and right heart filling pressures and diastolic abnormalities.55 In line with this, Yilmaz et al. observed that CA125 concentrations were negatively correlated with LVEF and positively correlated with systolic pulmonary artery pressure in a retrospective study that included 150 patients with chronic and acute HF.56 In addition, the authors of that study showed that the presence of systolic dysfunction, right ventricular dilation and pericardial effusion were independent predictors of elevated CA125 concentrations.56 Finally, Vizzardi et al. showed that CA125 was positively correlated with parameters of diastolic and systolic function of the left ventricle, such as the E wave of Doppler mitral flow, the E/A ratio, isovolumic relaxation time, deceleration time and the myocardial performance index, in a cohort of 200 chronic HF patients with idiopathic or ischemic cardiomyopathy.57 Very recently, Núñez-Marín et al. demonstrated that CA125, but not NTproBNP, was significantly associated with congestive intrarenal venous flow patterns measured by Doppler ultrasound in patients with acute HF, thus indicating renal congestion.58 Unfortunately, to date, there are still no studies relating the findings of lung ultrasonography and bioimpedance to serum CA125 concentrations, and this is the avenue that should be explored in the future.

CA125 as a Prognostic Factor of Mortality and Readmissions Due to Heart Failure

Many study groups investigated the prognostic role of CA125 in patients with acute and chronic HF in terms of death and HF readmission in various clinical settings.44,47,51,53,55,56,59–67 Apart from a randomised clinical trial by Núñez et al. (CHANCE-HF), most of the studies were designed as observational studies, and they largely included patients with acute HF.61 In addition, only one study reported on the prognostic role of CA125 in patients with HF with preserved ejection fraction (HFpEF) exclusively.63 The authors of that study highlighted that, in women with HFpEF, CA125 may aid in the prediction of HF hospitalisations, especially if used in addition to standard NT-proBNP measurement.63 It is important to highlight that all the studies in question showed a positive correlation between CA125 concentrations and adverse events such as death or hospitalisation due to HF. Furthermore, it has been shown in many studies that CA125 remains a significant prognostic predictor of poor prognosis, even after adjustment for the relevant baseline covariates (sex, age, previous hospitalisations, systolic blood pressure, heart rate, renal function, pleural effusion, atrial fibrillation, LVEF, sodium plasma concentrations, in-hospital treatment and natriuretic peptide levels), thus bringing further evidence to the reallife clinical utility of this ‘cancer biomarker’ in the setting of HF. Finally, a recent subanalysis of the BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) study and the validation cohorts

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CA125 as a Biomarker in Heart Failure indicated that CA125 is strongly associated with a higher risk of 1-year allcause mortality and the combined endpoint of all-cause death and hospitalisation for HF.47 Apart from including the largest number of patients, this study stands out because it confirmed the prognostic value of CA125 independent of traditional confounders and, more importantly, highlighted the value of CA125 as a biomarker for risk stratification in HF independent of traditional symptoms and signs of congestion. Of note, the association between CA125 and adverse events remained significant in patients with mild, moderate and severe congestion, paving the way for the incorporation of CA125 into multiparametric congestion scores. Importantly, a clinical pearl that needs to be addressed is the fact that increased CA125 in the setting of HF may preclude its use as a biomarker of ovarian cancer. Accordingly, the newly established role of CA125 in HF should also be underscored in the gynaecological literature. The most recent study investigated what is the best laboratory cut-off point for the identification of patients who are least likely to experience 1-month death or the composite of death and HF readmission after being discharged for the index acute HF event.67 That study showed that among patients admitted with acute HF, CA125 concentrations <23 U/ml identified a subgroup of patients at low risk for adverse events who may not require intense post-discharge monitoring, with a negative predictive value of 98.6% for death and 96.6% for the composite endpoint during the 30 days after discharge.67 It is important to note that these results were derived from a large cohort of 3231 patients with acute HF, and were then externally validated in a cohort of patients hospitalised in the BIOSTATCHF study (n=1583). The studies that have investigated the prognostic role of CA125 in HF are summarised in Table 1.

CA125 as a Therapeutic Guide in Heart Failure

Decongestion therapy represents the cornerstone of HF management.68 Despite diuretics being the mainstay of treatment for volume overload in HF patients, no randomised trials have shown the mortality benefits of diuretics in HF patients, and the most effective diuretic titration strategies in this population are a question of debate.69 One of the most interesting properties of CA125 is its potential for monitoring and guiding decongestion treatment in the setting of acute HF.43,44,47,59 Specifically, according to several studies, plasma CA125 concentrations change in parallel to changes in the clinical status of HF patients.52,53,55 Moreover, Núñez et al. consecutively measured CA125 concentration trajectories in patients with acute HF and demonstrated that within the first month after hospital discharge, CA125 concentrations decreased towards normal in the subset of patients with lower risk.59 However, in patients in whom the CA125 concentrations remained high, there was an increased risk of allcause mortality after the decompensation episode.59 Based on these results, it could be argued that CA125 is a biomarker that reflects the degree of congestion resolution in patients with acute HF, thus implicating its potential role in tailoring decongestion treatment. Recently, the interest in the use of biomarkers to guide the course of decongestive treatment increased significantly. The main premise is to optimally escalate treatment in patients with volume overload (especially with residual congestion and/or diuretic resistance), but, more importantly, to reduce diuretic dosage in patients who would not benefit from this treatment modality, thus alleviating potential adverse effects. Nevertheless, studies that tried to use NT-proBNP for this purpose yielded heterogeneous and rather disappointing results, because the efficacy of guiding treatment by measuring NT-proBNP concentrations showed neutral results in terms of hospitalisations and cardiovascular mortality compared with the conventional strategy of decongestion treatment.70–73

Conversely, CA125 has shown promising properties for guiding treatment following an episode of acute HF. In a pivotal multicentre trial that included 380 patients with acute HF (CHANCE-HF), the authors sought to compare CA125-guided therapy, characterised by titrating the diuretic and statin dose, as well as modifying monitoring frequency, with standard of care (SOC) in terms of the composite outcome of 1-year death and acute HF readmissions.61 In that study, compared with SOC, CA125-guided therapy resulted in a significant reduction in the time to the first event and recurrent events at 1 year of follow-up.61 However, although the effect was attributed to better individualisation of patients’ decongestion treatment, it was mostly driven by the significant reduction in rehospitalisations (51%) without an effect on mortality. In addition, in patients assigned to the CA125-guided strategy, titration and clinical monitoring visits were much more frequent, and prescriptions of statins were notably increased (30%), raising doubts concerning the cost-effectiveness of such a strategy.61 Furthermore, in a recent review, the same authors proposed a modus operandi for using CA125 in tailoring decongestion treatment, which they put into practice in the aforementioned CHANCE-HF study.49 According to their suggestions, CA125 concentrations should be measured in each episode of HF decompensation and during outpatient visits following HF hospitalisation. Given that the half-life of CA125 ranges from approximately 5–7 to several days, the authors argue that, in most cases, it is sufficient to determine an initial value during the index hospitalisation, whereas in patients hospitalised for a longer time, serial measurements of CA125 could provide incremental clinical value.74,75 Conversely, there is currently no evidence to support the routine determination of CA125 in successive outpatient visits of stable patients without evidence of recent HF decompensation. Núñez et al. proposed a value of 35 U/ml CA123, defined by the commercial reagent, as a diagnostic threshold because it has been shown that this cut-off value provides robust discrimination between patients with better and worse prognoses.61 For patients in whom CA125 concentrations fall below the threshold of 35 U/ml at the first outpatient visit after hospitalisation for HF decompensation, less intensive diuretic management is advised, especially among patients who may receive an equivalent dose of furosemide ≥120 mg/day. Patients at intermediate risk, namely those who exhibit a 25% reduction in CA125 concentrations but without its ‘normalisation’ (i.e. CA125 >35 U/ml), should be followed more closely because there is a high probability that these patients will require intensification of diuretic treatment. Similarly, the addition of an aldosterone antagonist is advised or an increase in the total daily diuretic dose if furosemide equivalent <80 mg/ day is prescribed to these patients. Finally, among patients with persistently high or rising CA125 concentrations following a decompensation event, clinical escalation of diuretic treatment is advised, with an increase in the dose of loop diuretics and/or the addition of hydrochlorothiazide, chlortalidone or aldosterone antagonists, or the administration of intravenous furosemide. Similarly, a shorter outpatient follow-up period for these patients is advised and should be scheduled for 1–4 weeks. Of important note, using the proposed algorithm, Núñez et al. recently conducted an open-label randomised study in which the utility of the CA125-guided diuretic strategy was evaluated in patients with acute HF and renal dysfunction.76 That trial provided promising data, because the CA125-guided strategy significantly improved the estimated glomerular filtration rate and other parameters of renal function at 72 h. Furthermore,

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CA125 as a Biomarker in Heart Failure patients in the active arm with CA125 concentrations >35 U/ml received the highest furosemide equivalent dose and had higher diuresis compared with the usual-care group.76

Implementation of the Use of CA125 in Clinical Practice

Based on current findings, we can suggest that CA125 should be measured at the time of admission of patients with HF decompensation. Of note, because CA125 is not a cardiac-specific biomarker, its circulating concentrations should not be exclusively interpreted as a proxy of congestion. Measurement of CA125 concentrations should be complemented with clinical information obtained from physical examination, natriuretic peptide measurement and echocardiographic findings (e.g. the diameter of inferior vena cava, LUS, ultrasound examination of third-space fluids and extravasations, among others). Such findings, especially if concordant with CA125 concentrations, would help determine the cause and degree of congestion. Therefore, initially high CA125 concentrations may inform clinicians that the patient is at an increased risk of short-term adverse events compared with their counterparts who have normal CA125 concentrations. As highlighted previously, this may be particularly applicable for older patients with impaired renal function and predominant involvement of the right side of the heart, as well as for patients with subclinical congestion. Moreover, high CA125 concentrations may guide the clinician to use intensive decongestion strategies with more stringent monitoring, because this subgroup of patients may benefit from a more aggressive diuretic approach. Apart from prognostic assessment and choice of volume management strategy, some clinical value may be gained from serial measurements of CA125, because normalisation of CA125 and its lowering below the 35 U/ml threshold is the pattern that occurs most frequently and is associated with clinical improvement and a lower risk of adverse clinical events, regardless of the initially measured value. In this regard, it is critical to address the dynamics of the biological half-life of CA125. Namely, owing to the long half-life of CA125, serial measurements during the first days following a hospitalisation would be practically useless for capturing information about acute response to therapy. Because HF-related hospitalisations often last longer than 7 days, it would probably be a reasonable approach to measure CA125 concentrations at the time of admission for HF and at least 7 days after the initial measurement or near hospital discharge. With that said, a pattern of weekly kinetics of CA125 following decompensation could be a promising tool for monitoring decongestion efficacy among patients with HF, and would also be useful for risk stratification. 1. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev 2017;3:7–11. https://doi.org/10.15420/ cfr.2016:25:2; PMID: 28785469. 2. Groenewegen A, Rutten FH, Mosterd A, Hoes AW. Epidemiology of heart failure. Eur J Heart Fail 2020;22:1342– 56. https://doi.org/10.1002/ejhf.1858; PMID: 32483830. 3. Writing Group Members, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics – 2016 update: a report from the American Heart Association. Circulation 2016;133:e38–360. https://doi.org/10.1161/ CIR.0000000000000350; PMID: 26673558. 4. Lesyuk W, Kriza C, Kolominsky-Rabas P. Cost-of-illness studies in heart failure: a systematic review 2004–16. BMC Cardiovasc Disord 2018;18:74. https://doi.org/10.1186/s12872018-0815-3; PMID: 29716540. 5. Mamas MA, Sperrin M, Watson MC, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail 2017;19:1095–104. https://doi.org/10.1002/ ejhf.822; PMID: 28470962. 6. Ohlmeier C, Mikolajczyk R, Frick J, et al. Incidence,

7. 8.

10.

11.

Moreover, demonstrated by Yoon et al., patients with high CA125 but low NT-proBNP concentrations during hospital admission for acute decompensated HF have worse mid-term prognosis than patients with low CA125 and low NT-proBNP concentrations.77 Similarly, those with high NT-proBNP and high CA125 concentrations had the worst prognosis, and CA125 was found to be an independent factor associated with all-cause mortality in this population.77 Thus, the body of accumulating evidence suggests that the combined use of CA125 and NT-proBNP may be superior for risk estimation in this population than the conventional use of NTproBNP alone. In the years to come, further exploration will hopefully unravel the pathobiological role of CA125 in HF and answer whether CA125-guided decongestion strategies would have an effect on hard clinical endpoints, such as mortality.

Conclusion

Emerging data suggest that CA125 has the potential to be integrated into the daily clinical work-up of patients with HF, not only as a prognostic indicator, but also as a marker reflecting congestion (severity) status and as a guide in tailoring decongestion treatment. Several important points justify the role of CA125 for this application. First, at this point, there are no biomarkers in routine clinical practice that reflect the congestive status of patients with HF. Second, there is a substantial pathophysiological background supporting the role of CA125 in this setting. Third, emerging data show that CA125 provides additional prognostic information beyond classical biomarkers in HF, specifically NT-proBNP, and CA125 has proven to be a valuable guide in tailoring diuretic treatment. Fourth, unlike NTproBNP, CA125 does not appear to be significantly modified by anthropometric factors, such as age, weight or renal dysfunction, and given, its long half-life, plasma CA125 concentrations remain stable, improving its prognostic utility. Finally, the well-established and widely adopted use of CA125 as a biomarker in ovarian cancer for several decades has led to the wide availability and low cost of CA125 measurement, because this biomarker can be readily measured in most clinical centres and hospitals worldwide. Gaps in our full understanding of the molecular background, the speculative nature regarding the role of CA125 in HF progression, the lack of an optimal cut-off value and the lack of definitive data from large multicentre studies represent the main limitations that currently preclude the use of CA125 in HF. Hence, future well-designed, large-scale studies are needed to fully establish and validate the purpose, exact timing of measurement and effect of CA125-guided management in HF on relevant clinical endpoints, such as cardiovascular and all-cause death and HFrelated hospitalisations.

prevalence and 1-year all-cause mortality of heart failure in Germany: a study based on electronic healthcare data of more than six million persons. Clin Res Cardiol 2015;104:688– 96. https://doi.org/10.1007/s00392-015-0841-4; PMID: 25777937. Spoletini I, Coats AJS, Senni M, Rosano GMC. Monitoring of biomarkers in heart failure. Eur Heart J Suppl 2019;21:M5–8. https://doi.org/10.1093/eurheartj/suz215; PMID: 31908607. Felder M, Kapur A, Gonzalez-Bosquet J, et al. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol Cancer 2014;13:129. https://doi. org/10.1186/1476-4598-13-129; PMID: 24886523. Yin BW, Lloyd KO. Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. J Biol Chem 2001;276:27371–5. https://doi.org/10.1074/jbc. M103554200; PMID: 11369781. Lloyd KO, Yin BW. Synthesis and secretion of the ovarian cancer antigen CA125 by the human cancer cell line NIH:OVCAR-3. Tumour Biol 2001;22:77–82. https://doi. org/10.1159/000050600; PMID: 11125279. Zhang M, Zhang Y, Fu J, Zhang L. Serum CA125 levels are

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13.

14.

15.

decreased in rectal cancer but increased in fibrosisassociated diseases and in most types of cancers. Prog Mol Biol Transl Sci 2019;162:241–52. https://doi.org/10.1016/bs. pmbts.2018.12.012. Núñez J, Rabinovich GA, Sandino J, et al. Prognostic value of the interaction between galectin-3 and antigen carbohydrate 125 in acute heart failure. PLoS One 2015;10:e0122360. https://doi.org/10.1371/journal. pone.0122360; PMID: 25875367. Bottoni P, Scatena R. The role of CA125 as tumor marker: biochemical and clinical aspects. Adv Exp Med Biol 2015;867:229–44. https://doi.org/10.1007/978-94-017-72150_14; PMID: 26530369. Amampai R, Suprasert P. Cancer antigen 125 during pregnancy in women without ovarian tumor is not often rising. Obstet Gynecol Int 2018;2018:8141583. https://doi. org/10.1155/2018/8141583; PMID: 29805450. Miralles C, Orea M, España P, et al. Cancer antigen 125 associated with multiple benign and malignant pathologies. Ann Surg Oncol 2003;10:150–4. https://doi.org/10.1245/ ASO.2003.05.015; PMID: 12620910.

CA125 as a Biomarker in Heart Failure 16. Charkhchi P, Cybulski C, Gronwald J, et al. CA125 and ovarian cancer: a comprehensive review. Cancers (Basel) 2020;12:3730. https://doi.org/10.3390/cancers12123730; PMID: 33322519. 17. Muinao T, Deka Boruah HP, Pal M. Diagnostic and prognostic biomarkers in ovarian cancer and the potential roles of cancer stem cells – an updated review. Exp Cell Res 2018;362:1–10. https://doi.org/10.1016/j.yexcr.2017.10.018; PMID: 29079264. 18. Vizzardi E, D’Aloia A, Curnis A, et al. Carbohydrate antigen 125: a new biomarker in heart failure. Cardiol Rev 2013;21:23–6. https://doi.org/10.1097/ CRD.0b013e318265f58f; PMID: 22735832. 19. Hung CL, Hung TC, Lai YH, et al. Beyond malignancy: the role of carbohydrate antigen 125 in heart failure. Biomark Res 2013;1:25. https://doi.org/10.1186/2050-7771-1-25; PMID: 24252645. 20. de la Espriella-Juan R, Núñez E, Sanchis J, et al. Carbohydrate antigen-125 in heart failure: an overlooked biomarker of congestion. JACC Heart Fail 2018;6:441–2. https://doi.org/10.1016/j.jchf.2018.01.006; PMID: 29724371. 21. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011;377:658–66. https://doi.org/10.1016/S01406736(11)60101-3; PMID: 21315441. 22. Ambrosy AP, Pang PS, Khan S, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial. Eur Heart J 2013;34:835–43. https://doi. org/10.1093/eurheartj/ehs444; PMID: 23293303. 23. Gargani L. Lung ultrasound: a new tool for the cardiologist. Cardiovasc Ultrasound 2011;9:6. https://doi.org/10.1186/14767120-9-6; PMID: 21352576. 24. Felker GM, Anstrom KJ, Adams KF, et al. Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 2017;318:713–20. https://doi.org/10.1001/jama.2017.10565; PMID: 28829876. 25. Miñana G, Núñez J, Sanchis J, et al. CA125 and immunoinflammatory activity in acute heart failure. Int J Cardiol 2010;145:547–8. https://doi.org/10.1016/j. ijcard.2010.04.081; PMID: 20483181. 26. Li S, Ma H, Gan L, et al. Cancer antigen-125 levels correlate with pleural effusions and COPD-related complications in people living at high altitude. Medicine (Baltimore) 2018;97:e12993. https://doi.org/10.1097/ MD.0000000000012993; PMID: 30431573. 27. Topalak O, Saygili U, Soyturk M, et al. Serum, pleural effusion, and ascites CA-125 levels in ovarian cancer and nonovarian benign and malignant diseases: a comparative study. Gynecol Oncol 2002;85:108–13. https://doi.org/10.1006/ gyno.2001.6575; PMID: 11925128. 28. Núñez J, Núñez E, Consuegra L, et al. Carbohydrate antigen 125: an emerging prognostic risk factor in acute heart failure? Heart 2007;93:716–21. https://doi.org/10.1136/ hrt.2006.096016; PMID: 17164487. 29. Saygili U, Guclu S, Uslu T, et al. The effects of ascites, mass volume, and peritoneal carcinomatosis on serum CA125 levels in patients with ovarian carcinoma. Int J Gynecol Cancer 2002;12:438–42. https://doi.org/10.1136/ijgc00009577-200209000-00005; PMID: 12366659. 30. Leard LE, Broaddus VC. Mesothelial cell proliferation and apoptosis. Respirology 2004;9:292–9. https://doi. org/10.1111/j.1440-1843.2004.00602.x; PMID: 15362999. 31. Huang F, Chen J, Liu Y, et al. New mechanism of elevated CA125 in heart failure: the mechanical stress and inflammatory stimuli initiate CA125 synthesis. Med Hypotheses 2012;79:381–3. https://doi.org/10.1016/j. mehy.2012.05.042; PMID: 22743023. 32. Kosar F, Aksoy Y, Ozguntekin G, et al. Relationship between cytokines and tumour markers in patients with chronic heart failure. Eur J Heart Fail 2006;8: 270–4. https://doi. org/10.1016/j.ejheart.2005.09.002; PMID: 16309955. 33. Zeillemaker AM, Verbrugh HA, Hoynck van Papendrecht AA, et al. CA125 secretion by peritoneal mesothelial cells. J Clin Pathol 1994;47:263–5. https://doi.org/10.1136/jcp.47.3.263; PMID: 8163699. 34. Ganda A, Onat D, Demmer RT, et al. Venous congestion and endothelial cell activation in acute decompensated heart failure. Curr Heart Fail Rep 2010;7:66-74. https://doi. org/10.1007/s11897-010-0009-5; PMID: 20424989 35. Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999;353:1838–42. https://doi.org/10.1016/ S0140-6736(98)09286-1; PMID: 10359409. 36. Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol

2017;14:30–8. https://doi.org/10.1038/nrcardio.2016.163; PMID: 27708278. 37. Girerd N, Seronde MF, Coiro S, et al. Integrative assessment of congestion in heart failure throughout the patient journey. JACC Heart Fail 2018;6:273–85. https://doi. org/10.1016/j.jchf.2017.09.023; PMID: 29226815. 38. Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion – a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019;21:137–55. https://doi. org/10.1002/ejhf.1369; PMID: 30600580. 39. Shoaib A, Waleed M, Khan S, et al. Breathlessness at rest is not the dominant presentation of patients admitted with heart failure. Eur J Heart Fail 2014;16:1283–91. https://doi. org/10.1002/ejhf.153; PMID: 25452165. 40. Boorsma EM, Ter Maaten JM, Damman K, et al. Congestion in heart failure: a contemporary look at physiology, diagnosis and treatment. Nat Rev Cardiol 2020;17:641–55. https://doi.org/10.1038/s41569-020-0379-7; PMID: 32415147. 41. Kristjánsdóttir I, Thorvaldsen T, Lund LH. Congestion and diuretic resistance in acute or worsening heart failure. Card Fail Rev 2020;6:e25. https://doi.org/10.15420/cfr.2019.18; PMID: 33042585. 42. Ter Maaten JM, Kremer D, Demissei BG, et al. Bioadrenomedullin as a marker of congestion in patients with new-onset and worsening heart failure. Eur J Heart Fail 2019;21:732–43. https://doi.org/10.1002/ejhf.1437; PMID: 30843353. 43. Núñez J, Miñana G, Núñez E, et al. Clinical utility of antigen carbohydrate 125 in heart failure. Heart Fail Rev 2014;19:575– 84. https://doi.org/10.1007/s10741-013-9402-y; PMID: 23925386. 44. Llàcer P, Bayés-Genís A, Núñez J. Carbohydrate antigen 125 in heart failure. New era in the monitoring and control of treatment. Med Clin (Barc) 2019;152:266–73 [in Spanish]. https://doi.org/10.1016/j.medcli.2018.08.020; PMID: 30442374. 45. Falcão FJA, Oliveira FRA, Cantarelli F, et al. Carbohydrate antigen 125 predicts pulmonary congestion in patients with ST-segment elevation myocardial infarction. Braz J Med Biol Res 2019;52:e9124. https://doi.org/10.1590/1414431x20199124; PMID: 31826182. 46. Falcão F, Oliveira F, Cantarelli F, et al. Carbohydrate antigen 125 for mortality risk prediction following acute myocardial infarction. Sci Rep 2020;10:11016. https://doi.org/10.1038/ s41598-020-67548-8; PMID: 32620821. 47. Soler M, Miñana G, Santas E, et al. CA125 outperforms NT-proBNP in acute heart failure with severe tricuspid regurgitation. Int J Cardiol 2020;308:54–9. https://doi. org/10.1016/j.ijcard.2020.03.027; PMID: 32209267. 48. Miñana G, de la Espriella R, Mollar A, et al. Factors associated with plasma antigen carbohydrate 125 and amino-terminal pro-B-type natriuretic peptide concentrations in acute heart failure. Eur Heart J Acute Cardiovasc Care 2020;9:437–44. https://doi. org/10.1177/2048872620908033; PMID: 32129669. 49. Núñez J, de la Espriella R, Miñana G, et al. Antigen carbohydrate 125 as a biomarker in heart failure: a narrative review. Eur J Heart Fail 2021;23:1445–57.https://doi. org/10.1002/ejhf.2295; PMID: 34241936. 50. Núñez J, Bayés-Genís A, Revuelta-López E, et al. Clinical role of CA125 in worsening heart failure: a BIOSTAT-CHF study subanalysis. JACC Heart Fail 2020;8:386–97. https:// doi.org/10.1016/j.jchf.2019.12.005; PMID: 32171764. 51. Li KHC, Gong M, Li G, et al. Cancer antigen-125 and outcomes in acute heart failure: a systematic review and meta-analysis. Heart Asia 2018;10:e011044. https://doi. org/10.1136/heartasia-2018-011044; PMID: 30402141. 52. Núñez J, Miñana G, González M, et al. Antigen carbohydrate 125 in heart failure: not just a surrogate for serosal effusions? Int J Cardiol 2011;146:473–4. https://doi. org/10.1016/j.ijcard.2010.12.027; PMID: 21193243. 53. Nägele H, Bahlo M, Klapdor R, et al. CA 125 and its relation to cardiac function. Am Heart J 1999;137:1044–9. https://doi. org/10.1016/S0002-8703(99)70360-1. 54. Kouris NT, Zacharos ID, Kontogianni DD, et al. The significance of CA125 levels in patients with chronic congestive heart failure. Correlation with clinical and echocardiographic parameters. Eur J Heart Fail 2005;7:199– 203. https://doi.org/10.1016/j.ejheart.2004.07.015; PMID: 15701467. 55. D’Aloia A, Faggiano P, Aurigemma G, et al. Serum levels of carbohydrate antigen 125 in patients with chronic heart failure: relation to clinical severity, hemodynamic and Doppler echocardiographic abnormalities, and short-term prognosis. J Am Coll Cardiol 2003;41:1805–11. https://doi. org/10.1016/S0735-1097(03)00311-5; PMID: 12767668. 56. Yilmaz MB, Zorlu A, Tandogan I. Plasma CA-125 level is related to both sides of the heart: a retrospective analysis. Int J Cardiol 2011;149:80–2. https://doi.org/10.1016/j.

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ijcard.2009.12.003; PMID: 20022645. 57. Vizzardi E, Nodari S, D’Aloia A, et al. CA125 tumoral marker plasma levels relate to systolic and diastolic ventricular function and to the clinical status of patients with chronic heart failure. Echocardiography 2008;25:955–60. https://doi. org/10.1111/j.1540-8175.2008.00714.x; PMID: 18771557. 58. Núñez-Marín G, de la Espriella R, Santas E, et al. CA125 but not NT-proBNP predicts the presence of a congestive intrarenal venous flow in patients with acute heart failure. Eur Heart J Acute Cardiovasc Care 2021;10:475–83. https://doi. org/10.1093/ehjacc/zuab022; PMID: 33829233. 59. Núñez J, Núñez E, Bayés-Genís A, et al. Long-term serial kinetics of N-terminal pro B-type natriuretic peptide and carbohydrate antigen 125 for mortality risk prediction following acute heart failure. Eur Heart J Acute Cardiovasc Care 2017;6:685–96. https://doi. org/10.1177/2048872616649757; PMID: 27199489. 60. Núñez J, Sanchis J, Bodí V, et al. Improvement in risk stratification with the combination of the tumour marker antigen carbohydrate 125 and brain natriuretic peptide in patients with acute heart failure. Eur Heart J 2010;31:1752– 63. https://doi.org/10.1093/eurheartj/ehq142; PMID: 20501480. 61. Núñez J, Llàcer P, Bertomeu-González V; CHANCE-HF Investigators. Carbohydrate antigen-125-guided therapy in acute heart failure: CHANCE-HF: a randomized study. JACC Heart Fail 2016;4:833–43. https://doi.org/10.1016/j. jchf.2016.06.007; PMID: 27522630. 62. Jang SY, Yang DH, Kim CY, et al. Poster P1054. Prognostic value of CA-125 in combination with N-terminal pro-brain natriuretic peptide in patients with acute decompensated heart failure. Eur J Heart Fail 2016;18(Suppl 1):247. https://doi. org/10.1002/ejhf.539. 63. Hung CL, Hung TC, Liu CC, et al. Relation of carbohydrate antigen-125 to left atrial remodeling and its prognostic usefulness in patients with heart failure and preserved left ventricular ejection fraction in women. Am J Cardiol 2012;110:993–1000. https://doi.org/10.1016/j. amjcard.2012.05.030; PMID: 22728006. 64. Mansour IN, Napan S, Tarek Alahdab M, et al. Carbohydrate antigen 125 predicts long-term mortality in African American patients with acute decompensated heart failure. Congest Heart Fail 2010;16:15–20. https://doi.org/10.1111/j.1751-7133. 2009.00110.x; PMID: 20078623. 65. Monteiro S, Franco F, Costa S, et al. Prognostic value of CA125 in advanced heart failure patients. Int J Cardiol 2010;140:115–8. https://doi.org/10.1016/j.ijcard.2008.11.023; PMID: 19285353. 66. Becerra-Munoz VM, Sobrino-Márquez JM, Rangel-Sousa D, et al. Long-term prognostic role of CA-125 in noncongestive patients undergoing a cardiac transplantation. Biomark Med 2017;11:239–43. https://doi.org/10.2217/bmm-2016-0247; PMID: 28156128. 67. Núñez J, Bayés-Genís A, Revuelta-López E, et al. Optimal carbohydrate antigen 125 cutpoint for identifying low-risk patients after admission for acute heart failure. Rev Esp Cardiol (Engl Ed) 2021. https://doi.org/10.1016/j. rec.2021.02.002; PMID: 33745912; epub ahead of press. 68. Felker GM, Ellison DH, Mullens W, et al. Diuretic therapy for patients with heart failure: JACC state-of-the-art review. J Am Coll Cardiol 2020;75:1178–95. https://doi.org/10.1016/j. jacc.2019.12.059; PMID: 32164892. 69. Pellicori P, Kaur K, Clark AL. Fluid Management in patients with chronic heart failure. Card Fail Rev 2015;1:90–5. https:// doi.org/10.15420/cfr.2015.1.2.90; PMID: 28785439. 70. O’Donoghue M, Braunwald E. Natriuretic peptides in heart failure: should therapy be guided by BNP levels? Nat Rev Cardiol 2010;7:13–20. https://doi.org/10.1038/ nrcardio.2009.197; PMID: 19935742. 71. De Vecchis R, Esposito C, Di Biase G, et al. B-Type natriuretic peptide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis. J Cardiovasc Med (Hagerstown) 2014;15:122–34. https://doi.org/10.2459/ JCM.0b013e328364bde1; PMID: 24522083. 72. Stienen S, Salah K, Moons AH, et al. NT-proBNP (N-terminal pro-B-type natriuretic peptide)-guided therapy in acute decompensated heart failure: PRIMA II randomized controlled trial (can NT-ProBNP-guided therapy during hospital admission for acute decompensated heart failure reduce mortality and readmissions?). Circulation 2018;137:1671–83. https://doi.org/10.1161/ circulationaha.117.029882; PMID: 29242350. 73. Sanders-van Wijk S, Maeder MT, Nietlispach F, et al. Longterm results of intensified, N-terminal-pro-B-type natriuretic peptide-guided versus symptom-guided treatment in elderly patients with heart failure: five-year follow-up from TIMECHF. Circ Heart Fail 2014;7:131–9. https://doi.org/10.1161/ CIRCHEARTFAILURE.113.000527; PMID: 24352403. 74. Colaković S, Lukic V, Mitrovic L, et al. Prognostic value of

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Clinical Syndromes

Adjunctive Techniques for Repair of Ischaemic Mitral Regurgitation Sigrid L Johannesen ,1 Colin M Barker2 and Melissa M Levack3 1. Department of Cardiothoracic Surgery, Vanderbilt University Medical Centre, Nashville, TN, US; 2. Section of Interventional Cardiology, Vanderbilt University Medical Centre, Nashville, TN, US; 3. Department of Cardiac Surgery, Vanderbilt University Medical Centre, Nashville, TN, US

Abstract

Ischaemic mitral regurgitation is a complex process with debate in the literature as to the optimal treatment pathway. Multiple therapies are available to alleviate mitral regurgitation including medical management, transcatheter edge-to-edge repair, mitral valve repair and mitral valve replacement. Medical management with goal-directed therapy should be utilised in patients with heart failure and mild-to-moderate regurgitation. Transcatheter approaches are typically used in patients with prohibitive operative risk, although their use is expanding, especially in those with functional mitral regurgitation who are not responding to goal-directed medical therapy. It is generally accepted that patients with mild-to-moderate disease can avoid valve intervention if successful revascularisation is performed. A higher consideration should be given to valve replacement over repair in patients with severe mitral regurgitation in the setting of myocardial ischaemia. Operative course must be personalised to each patient, and continues to develop with improving technologies and ongoing research into optimal treatment.

Keywords

Ischaemic mitral regurgitation, mitral regurgitation, valvular heart disease, mitral valve repair, mitral valve replacement, MitraClip Disclosure: CMB receives research support from Abbott and Edwards. MML is a consultant for Boston Scientific. SLJ has no conflicts of interest to declare. Received: 16 April 2021 Accepted: 16 September 2021 Citation: Cardiac Failure Review 2021;7:e20. DOI: https://doi.org/10.15420/cfr.2021.06 Correspondence: Sigrid L Johannesen, Vanderbilt University Medical Centre, Department of Cardiothoracic Surgery, 1215 21st Ave South, 5th Floor, Nashville, TN 37232, US. E: sigrid.johannesen@vumc.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Mitral regurgitation (MR) is the primary cause of moderate-to-severe valvular disease in patients older than 55 years in the US.1 MR occurs when valve distortion leads to a retrograde blood flow from the left ventricle to the left atrium during systole. Proper functioning of the mitral valve requires an appropriate anatomical and physiological relationship between the mitral annulus, anterior and posterior leaflets, chordae tendineae, left atrium, and left ventricle. MR can be classified as organic (primary) or functional (secondary). Organic MR can occur due to multiple causes, including degenerative valve disease, myxomatous disease, chordal rupture and infective endocarditis. MI and ischaemic heart disease is a common cause of secondary MR, and is associated with a higher rate of cardiac-related morbidity and mortality than in patients with primary mitral valve disease.2 Ischaemic MR can occur in both an acute and chronic fashion. When MR occurs in the acute setting, it can be associated with papillary muscle rupture secondary to MI. These patients can present with cardiogenic shock and congestive heart failure, as the body does not have time to compensate for the changes in haemodynamics. Treatment is aimed at the management of shock, and these patients often require emergent surgical intervention. Acute MR can also manifest with more subtle changes, such as annular dilatation and subvalvular apparatus dysfunction. Revascularisation, whether surgical or percutaneous, should be accomplished to limit the extent of infarction. Consideration should also

be given to performing a concomitant mitral valve repair or replacement for moderate-to-severe and severe MR in the acute setting. While transcatheter edge-to-edge repair (TEER) has been described in limited case reports of acute ischaemic MR, the role for this is not well established. In contrast, chronic MR is often the result of a long-standing process in which left ventricular remodelling has occurred, leading to papillary muscle displacement. The result is annular dilatation with chordal restriction of leaflet motion, leading to incomplete mitral valve coaptation. Clinically, these patients can have a compensated process with preserved cardiac output or a decompensated process with reduced cardiac output. This article focuses on functional MR as it relates to chronic ischaemic cardiomyopathy and the treatment options available.

Diagnosis

Diagnosis should begin with a patient medical history, complete physical examination and laboratory studies. The classic clinical finding on physical examination is a holosystolic murmur radiating to the left axilla. Given that the severity of the regurgitant jet can vary under different loading conditions, an increase in the murmur can be elucidated utilising manoeuvres that increase left ventricular afterload. Similarly, a decrease in afterload may decrease the regurgitant volume. Symptoms and clinical signs of heart failure can be present if the patient is not well compensated. Additionally, the heart rhythm, rate and presence of a previous MI can affect the degree of MR. ECG changes usually indicate the presence of an old infarct, and AF is common. Chest X-ray can show an enlarged heart if there is severe left ventricular enlargement.

Ischaemic Mitral Regurgitation Review Figure 1: Echocardiographic Images of Ischaemic Mitral Regurgitations A

should be addressed with optimal medical management and lifestyle changes to prevent ischaemia and resultant myocardial remodelling. AF can increase left atrial preload, leading to atrial dilatation and subsequent increased severity of MR. Anti-arrhythmic medications and cardiac resynchronisation should be pursued, as restoring normal sinus rhythm decreases the severity of MR.6 In the event that maximal medical therapy is achieved with ongoing symptoms and residual MR, additional surgical and/or transcatheter interventions can be considered.

Operative Intervention C

The recommendation for surgical intervention for the treatment of MR varies based on patient characteristics, as well as the underlying pathophysiology and presentation of valvular disease (Table 1). Surgical intervention for severe primary MR is often recommended regardless of EF.7 Intervention for secondary MR, however, is reserved for patients with persistent symptoms despite GDMT who have moderate-to-severe or severe MR. A 3-month trial of GDMT should be pursued prior to consideration of operative intervention.7

A: Failure of leaflet coaptation; B: Central regurgitation jet; C: Annular dilatation; D: Tethered posterior leaflet with tethering angle (white arrow).

Transthoracic echocardiogram is the gold standard often initially used to characterise the directionality, eccentricity and severity of the regurgitant flow. Additionally, it can provide structural information regarding leaflet coaptation and tethering, and define the mechanism of MR (Figure 1). It allows for the assessment of left ventricular function and the determination of regional wall motion abnormalities. Cardiac MRI can be adjunctive in the work-up of mitral valve disease, including the quantification of MR. Severe MR is defined by a regurgitant volume >60 ml, regurgitant fraction >50%, effective regurgitant orifice >0.4 cm2, jet area >40% of the left atrial area or vena contracta width >0.7 cm.3,4 Ejection fraction (EF) is often a misrepresentation of cardiac functioning in these patients due to increased preload in the left atrium. Transoesophageal echocardiogram (TEE) is a third modality useful in the diagnosis of ischaemic MR and can help further identify the role of certain therapeutic options. The use of general anaesthesia in the operating room may decrease afterload, and this should be taken into consideration if a variation is noted from the preoperative transthoracic echocardiogram and intraoperative TEE. Finally, coronary angiography is also an important diagnostic tool to assess for ongoing coronary disease that may be amenable to intervention.

Medical Management

Once the diagnosis is made, the severity of MR needs to be established. Patients who are well compensated without heart failure and with mild and moderate MR do not require invasive therapy. However, the management of patients who present with heart failure and moderate-tosevere MR has evolved over time. The first-line approach to treatment in patients with heart failure and ischaemic MR is guideline-directed medical therapy (GDMT). Treatment, managed by a heart failure team, with β-blockers, angiotensin-converting enzyme inhibitors, diuretics, sodium-glucose cotransporter 2 inhibitors and angiotensin receptor blockers (with or without a neprilysin inhibitor) has been shown to improve survival.4,5 Underlying coronary artery disease

The pathology of ischaemic MR is largely due to increases in annular dimensions with resultant lack of leaflet coaptation. As a result, the central MR jet will often confirm a failure of leaflet coaptation based on annular size, rather than organic valvular dysfunction. In patients with minor left ventricular and subvalvular apparatus remodelling, and those in which gross inspection of the leaflets are normal, consideration for mitral valve repair should be given. This is accomplished with a downsized annuloplasty ring to reduce the annular dilatation and improve leaflet coaptation. In contrast, mitral valve repair is less favourable in patients with posterolateral wall dysfunction due to prior infarction, and advanced leaflet tethering and papillary muscle displacement where adequate coaptation is less likely to be durable with an annuloplasty ring alone. Chordal-sparing mitral valve replacement is preferred over mitral valve repair in these patients, given the high reoperation rates seen with mitral valve repair failures. In these cases, strong consideration should be made for replacement of the valve upfront, even when the leaflets appear normal, given the degree of leaflet tethering and ventricular remodelling. The American Heart Association/American College of Cardiology guidelines published in 2020 recommend operative intervention for patients with chronic severe symptomatic secondary MR with atrial annular dilatation and preserved EF.7,8 Consideration of concomitant procedures, such as ligation of the left atrial appendage, radiofrequency ablation or maze procedure, should be undertaken when performing a mitral valve operation on patients with associated arrhythmias. There have been numerous studies examination the benefit of repair versus replacement in ischaemic MR. One study comparing mitral valve repair with mitral valve replacement in patients with severe ischaemic MR showed decreased rates of moderate-to-severe MR after surgery, fewer adverse events and less frequent postoperative readmissions for patients who underwent mitral valve replacement.9 Conversely, a meta-analysis from 2014 reported that patients with ischaemic MR undergoing mitral valve repair showed similar outcomes between the two groups. Patients undergoing operative mitral valve repair had lower operative mortality, but higher long-term recurrence rates of mitral regurgitation. When repairs performed before 1998 were excluded, the operative mortality was found to be the same for the two techniques. No differences in postoperative change in EF, ventricular dimensions, New York Heart

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Ischaemic Mitral Regurgitation Review Table 1: Recent Literature for Treatment of Ischaemic Mitral Regurgitation Author

Year

Patients

Study Design

Degree of MR

Findings

Goldstein et al.9

2016

251

Randomised controlled trial

Moderate-to-severe

No difference in LVESV or survival for MV repair versus replacement MR more likely to recur for mitral valve repair

Dayan et al.10

2014

N/A

Meta-analysis

Moderate-to-severe

No difference in EF, LVESV or reoperation for mitral valve repair versus replacement Operative mortality lower after mitral valve repair MR more likely to recur for mitral valve repair

Michler et al.11

2016

301

Randomised controlled trial

Moderate

Patients undergoing CABG with moderate MR did not have improved LVESV if mitral valve was also repaired CABG + mitral valve repair did not improve survival over CABG alone

Chan et al.12

2012

Randomised controlled trial

Moderate

Mitral valve repair improves LV remodelling, functional capacity, MR severity and BNP in patients undergoing CABG

Stone et al.14

2018

614

Randomised controlled trial

Moderate-to-severe

Transcatheter mitral valve repair results in lower mortality and fewer hospitalisations in patients with heart failure on GDMT

Obadia et al.15

2018

152

Randomised controlled trial

Severe

No significant difference in hospitalisations and mortality between transcatheter mitral valve repair and GDMT in patients with heart failure

Acker et al.16

2014

251

Randomised controlled trial

Severe

No significant difference in LV remodelling or mortality between mitral valve repair and replacement Mitral valve replacement provided more durable correction

Khallaf et al.17

2020

Randomised controlled trial

Moderate

No significant difference in survival between patients undergoing CABG + mitral valve repair versus MV repair alone Trend towards improved degree of MR and NYHA class with combined CABG + MV repair

BNP = brain naturetic peptide; CABG = coronary artery bypass graft; EF = ejection fraction; GDMT = goal directed medical therapy; LV = left ventricular; LVESV = left ventricular end systolic volume; MR = mitral regurgitation; MV = mitral valve; N/A= not available; NYHA = New York Heart Association.

Association class or reoperation rates were found between the two groups.10 Patients with MR and coronary artery disease with viable myocardium and suitable targets are often additionally treated with coronary artery bypass grafting. As patients with severe secondary MR and coronary artery disease are recommended to have a valvular operation in conjunction with bypass surgery, it is essential to ensure evaluation with left heart catheterisation in the preoperative assessment.7 In patients with moderate ischaemic MR, some studies have shown that addressing the myocardial ischaemia with isolated coronary artery bypass grafting and deferring mitral valve intervention has no negative effect on survival.11 This technique is used in this particular patient population with the anticipation of improvement of the MR once myocardial ischaemia is reversed and cardiac remodelling can occur, which will often lead to improvement of the mitral regurgitation. Controversy surrounding this technique exists due to conflicting findings in the literature related to this patient population. One study included 73 patients with moderate ischaemic MR and EF >30% who were randomised to receive either a revascularisation procedure alone or coronary artery bypass grafting with concomitant mitral valve repair. Patients who underwent coronary artery bypass grafting and MV repair were shown to have greater peak oxygen consumption, and greater improvements in the left ventricular end systolic volume index, regurgitant volume and B-type natriuretic peptide levels after 1 year. Notably, survival was similar in the two groups.12 As such, patients with asymptomatic, moderate MR undergoing cardiotomy for alternative indications, such as coronary artery bypass grafting or aortic valve replacement, may be considered for intervention on the mitral valve at the time of operation based on the risk associated with the patient.

Catheter-based Treatment

Endovascular techniques for the management of MR have advanced over the last decade, and previously were pursued in patients with symptomatic severe MR who had a prohibitive operative risk secondary to medical comorbidities.7,8 During these procedures, venous access followed by a transseptal puncture is achieved, and a transcatheter edge-to-edge repair is performed using a device that reapproximates the central portion of the anterior and posterior mitral valve leaflets. The resultant anatomical configuration is similar to that of an operative Alfieri stitch.13 A 2018 study evaluated outcomes in 614 patients with heart failure and ischaemic MR randomly assigned to intervention with TEER in addition to GDMT versus GDMT alone. The results of this study, the COAPT Trial, showed improved survival at 2 years in the group who underwent TEER as opposed to GDMT alone.14 Prior to intervention, patients must be carefully assessed for candidacy. TEE should be performed to assess anatomical variables, including leaflet length, orifice area, presence of calcium burden and left ventricular cavity size, as these may be prohibitive to TEER.8 In addition, a coronary angiography should be considered to rule out underlying ischaemia that may be treatable and contributing to MR. Similar to trends in other transcatheter-based valvular procedures, such as transcatheter aortic valve replacement, TEER has increased in utilisation over the past several years to include some patients outside those originally considered medically prohibitive to operative intervention. Some conflicting data have emerged, as published in the MITRA-FR trial, which should be mentioned.15 In this large-volume randomised control trial, there was no improvement in hospital admissions or death after 1 year among patients with severe secondary MR treated with percutaneous mitral valve repair plus GDMT versus medical therapy alone.

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Ischaemic Mitral Regurgitation Review Despite these data, the candidacy for TEER has been expanded. In accordance with the most recent American Heart Association/American College of Cardiology guidelines in 2020, patients with chronic secondary MR and persistent symptoms despite GDMT with left ventricular EF of 20–50%, left ventricular end-systolic diameter <70 mm or pulmonary artery systolic pressure <70 mmHg can be treated with TEER.7 In addition, patients must be evaluated at a centre with a multidisciplinary team with expertise in heart failure and mitral valve disease. Given the success of TEER in the treatment of patients with severe functional MR, numerous new devices are being investigated for improved device delivery and reduced damage to the native leaflets. As more advanced devices become available, the indication for these therapies is likely to increase even further. In those patients who prove to be high or extreme risk for surgery and otherwise not candidates for TEER due to inadequate leaflet length, calcium burden or other prohibitive reasons, transcatheter mitral valve replacement is being studied as an alternative therapy. The results of this are yet to be determined and require further investigation. 1. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. https://doi.org/10.1016/S01406736(06)69208-8; PMID: 16980116. 2. Amigoni M, Meris A, Thune JJ, et al. Mitral regurgitation in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: prognostic significance and relation to ventricular size and function. Eur Heart J 2007;28:326–33. https://doi.org/10.1093/eurheartj/ehl464; PMID: 17251259. 3. Nishimura RA, Otto CM, Bonow RO, et. al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:2440–92. https:// doi.org/10.1161/CIR.0000000000000029; PMID: 24589852. 4. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;135:e1159–95. https://doi.org/10.1161/ CIR.0000000000000503; PMID: 28298458. 5. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–61. https://doi.

Conclusion

Proper functioning of the mitral valve requires a complex interplay between all involved structures. Multiple therapies are available to alleviate MR, including medical management, TEER, mitral valve repair and mitral valve replacement. Treatment should be undertaken after a thorough understanding of the underlying disease process leading to MR is obtained. Medical management with goal-directed therapy should be utilised in patients with heart failure and mild-to-moderate regurgitation. Transcatheter approaches are typically used in patients with prohibitive operative risk, although their use is expanding, especially in those with functional MR who are not responding to GDMT. Ischaemic MR is a complex process with debate in the surgical literature as to the optimal treatment pathway. It is generally accepted that patients with mild-tomoderate disease can avoid valve intervention if successful revascularisation is performed. A higher consideration should be given to valve replacement over repair in patients with severe MR in the setting of myocardial ischaemia. Operative course must be personalised to each patient, and continues to develop with improving technologies and ongoing research on optimal treatment.

org/10.1161/cir.0000000000000509; PMID: 28455343. 6. Gertz ZM, Raina A, Saghy L, et al. Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control. J Am Coll Cardiol 2011;58:1474–81. https://doi.org/10.1016/j.jacc.2011.06.032; PMID: 21939832. 7. Otto CM, Nashimura RA, Bonow RO, et al. 2020 ACC/AHA guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol 2021;77:450–500. https://doi. org/10.1016/j.jacc.2020.11.035; PMID: 33342587. 8. Bonow RO, O’Gara PT, Adams DH, et al. 2020 Focused Update of the 2017 ACC expert consensus decision pathway on the management of mitral regurgitation: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;75:2236–70. https://doi. org/10.1016/j.jacc.2020.02.005; PMID: 32068084. 9. Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med 2016;374:344–53. https://doi. org/10.1056/NEJMoa1512913; PMID: 26550689. 10. Dayan V, Gerardo S, Cura L, Mestres C. Similar survival after mitral valve replacement or repair for ischemic mitral regurgitation: a meta-analysis. Ann Thorac Surg 2014;97:758– 66. https://doi.org/10.1016/j.athoracsur.2013.10.044; PMID: 24370200. 11. Michler RE, Smith PL, Parides MK, et al. Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med 2016; 374:1932–41. https://doi. org/10.1056/NEJMoa1602003; PMID: 27040451.

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12. Chan KM, Punjabi PP, Pepper JR, et al. Coronary artery bypass surgery with or without mitral valve annuloplasty in moderate functional ischemic mitral regurgitation, final results of the Randomized Ischemic Mitral Evaluation (RIME) trial. Circulation 2012;126:2502–10. https://doi.org/10.1161/ CIRCULATIONAHA.112.143818; PMID: 23136163. 13. Fucci C, Sandrelli L, Alfieri O, et al. Improved results with mitral valve repair using new surgical techniques. Eur J Cardiothorac Surg 1995;9:621–7. https://doi.org/10.1016/S10107940(05)80107-1; PMID: 8751250. 14. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. 15. Obadia JF, Messika-Zeitoun D, Laurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med 2018;379:2297–306. https://doi.org/10.1056/NEJMoa1805374; PMID: 30145927. 16. Acker MA, Paridea, Perrault LP et al. Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 2014;370:23–32. https://doi.org/10.1056/ NEJMoa1312808; PMID: 24245543. 17. Khallaf A, Elzayadi M, Alkady H, Naggar A. Results of coronary artery bypass grafting alone versus combined surgical revascularization and mitral repair in patients with moderate ischemic mitral regurgitation. Heart Surg Forum 2020;23:e270–5. https://doi.org/10.1532/hsf.2773; PMID: 32524985.

Diagnosis

Isolated Left Ventricular Apical Hypoplasia Abhishek Dattani

and Rachana Prasad2

1. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; 2. Kettering General Hospital, Kettering, UK

Disclosure: The authors have no conflicts of interest to declare. Consent and ethics: Informed consent was obtained from the patient regarding the use of her case and images for this case report. This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Received: 7 September 2021 Accepted: 16 October 2021 Citation: Cardiac Failure Review 2021;7:e21. DOI: https://doi.org/10.15420/cfr.2021.24 Correspondence: Abhishek Dattani, Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, UK. E: a.dattani07@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

With this letter, the authors have the pleasure to present their views to the Editor-in-Chief. Based on our experience, we would like to discuss isolated left ventricular (LV) apical hypoplasia. In 2006, a 64-year-old Caucasian woman presented to the Emergency Department with breathlessness. She was an ex-smoker with a medical history of hypertension, hypercholesterolaemia and asthma. There was no family history of cardiac disease. Initial investigations, including chest radiograph, showed pulmonary oedema, which was treated with IV diuretics and continuous positive airway pressure non-invasive ventilation. ECG performed on admission showed left bundle branch block (LBBB). An echocardiogram showed severe LV systolic dysfunction with global hypokinesis (Supplementary Material Video 1). A coronary angiogram showed normal coronary arteries and a ventriculogram suggested severe LV impairment, apical akinesis, aneurysmal dilatation of the inferior wall and a possible mural thrombus. Her condition improved with medical therapy and the patient was discharged on furosemide, perindopril, bisoprolol and anticoagulation for the suspected mural thrombus. At outpatient clinic follow up, she was stable with New York Heart Association (NYHA) class II symptoms and discharged from routine follow-up. She remained stable in the community for 11 years until June 2017, when she re-presented to cardiology with worsening breathlessness and NYHA class III symptoms. ECG showed AF with an LBBB, QRS duration of 140 ms and a ventricular rate of 76 BPM. An echocardiogram showed a severely dilated LV with severe LV impairment (Supplementary Material Video 2). Her heart failure medication was optimised with the addition of eplerenone 25 mg daily. In contrast to 2006, the cardiology service in 2017 had access to cardiac MRI (CMR) to investigate the aetiology of the LV dysfunction; this showed absence of the LV apex with a spherical, truncated LV and bulging of the interventricular septum towards the right ventricle (RV). There was replacement of the LV apex with fat contiguous to the epicardial fat and the LV appeared moderately impaired with a reported ejection fraction of 45%. The RV was elongated at the apex and wrapped around the deficient LV apex. There was abnormal apical origin of the papillary muscle

network. There was no significant late gadolinium enhancement seen (Figure 1 and Supplementary Material Videos 3–5). A diagnosis of isolated LV apical hypoplasia was made. The patient’s case was discussed in the device multidisciplinary team meeting and a decision for CRT pacemaker (CRT-P) implantation was made. Although the implantation of a CRT-P led to no significant improvement in effort tolerance, the patient continues to remain stable, has not had any further admissions for decompensated heart failure and has reached the age of 79 years. More recently, she developed difficulty with rate control of AF, resulting in decreased biventricular pacing. Medical therapy, including the addition of amiodarone, was attempted with no beneficial impact on effort tolerance and with unacceptable side-effects for the patient, leading to the need to stop the medication. The patient therefore had atrioventricular nodal ablation for poor rate control, which has improved the biventricular pacing rate and symptoms.

Discussion

Isolated LV apical hypoplasia is a rare condition that was first described in 2004 by Fernandez-Valls et al., who used CMR and cardiac multi-detector CT to show characteristic morphological changes of what appeared to be a previously undiscovered LV congenital abnormality in three patients.1 These patients varied in age from 22 to 46 years, two of whom were women, and none had a relevant family history. They all had an otherwise negative cardiomyopathy screen. Since then, there have been very few cases reported in the literature and very little knowledge currently exists regarding what appears to be a rare congenital disease. The cause is unknown but may be related to inadequate LV–RV dilatation during partitioning, which could lead to a spherical LV and an elongated RV that wraps around the LV apex. A genetic defect may be involved and there has been one case reported in which a mutation of the lamin A/C gene was identified, a gene known to be associated with other forms of cardiomyopathy.2,3 There is currently an ongoing clinical trial with the aim of looking for a genetic basis of the condition by performing genetic testing with whole exome sequencing in seven patients with isolated LV apical hypoplasia (NCT04339582). It is important to distinguish the condition from other congenital conditions. For example, hypoplastic left heart syndrome occurs in 3% of infants with

Isolated LV Apical Hypoplasia Figure 1: Characteristic Appearances of Isolated Left Ventricle Apical Hypoplasia on Cardiac MRI A

A,B: Two-chamber views; C,D: three-chamber views; and E,F: four-chamber views. AFR = anterior front right; AHL = anterior head left; FL = foot, left; HR = head, right; LAH = left, anterior, head; LF = left, foot; LV left ventricle; PFR = posterior, foot, right; PHL = posterior, head, left; RH = right, head; RPF = right, posterior, foot; RV = right ventricle

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Isolated LV Apical Hypoplasia congenital heart disease, and although there is reduction in size in the LV cavity, there are also associated features such as atresia or stenosis of the mitral valve, aortic valve or aorta, which the present patient did not have. Furthermore, hypoplastic left heart syndrome is fatal in the first few weeks of life without intervention.4 Isolated LV apical hypoplasia has a variable phenotype with presentations ranging from asymptomatic to congestive cardiac failure, as seen in the present patient.5–7 A case series of five young patients with the condition describes cyanosis in two of the patients, although these patients had associated persistent ductus arteriosus and severe pulmonary hypertension.8 Indeed, there has been a case report of death on first presentation in a 19-year-old who died of ventricular tachyarrhythmias and multi-organ dysfunction.9 Definitive diagnostic criteria have not yet been established.1,10 The characteristic features on CMR are:

• truncated, spherical and impaired LV with bulging of the interventricular septum towards the RV;

• apical LV fatty material; • papillary muscle/trabecular abnormalities; and • RV elongation wrapping around the deficient LV apex. In the present patient there was a discrepancy in the assessment of LV systolic function using 2D transthoracic echocardiography and CMR. The 2D echocardiographic assessment of LV function is often based on Simpson’s biplane method, which has limitations if the apex is foreshortened or if there is endocardial dropout. This method may not be accurate in the assessment of systolic function of a spherical LV with apical hypoplasia. CMR is a volumetric technique and has a high contrast and spatial resolution, leading to improved accuracy and reproducibility in the assessment of the LV.11 It is the modality of choice in the assessment of LV apical hypoplasia given that it has the benefit of not depending on assumed geometry.12 However, it is noted that there have been reports of characteristic findings of the condition being seen on echocardiography leading to a correct 1. Fernandez-Valls M, Srichai MB, Stillman AE, White RD. Isolated left ventricular apical hypoplasia: a new congenital anomaly described with cardiac tomography. Heart 2004;90:552–5. https://doi.org/10.1136/hrt.2003.010637; PMID: 15084556. 2. Pica S, Ghio S, Raineri C, et al. Mutation of the lamin A/C gene associated with left ventricular apical hypoplasia: a new phenotype for laminopathies? G Ital Cardiol 2014;15:717– 9. https://doi.org/10.1714/1718.18778; PMID: 25533121. 3. Captur G, Arbustini E, Bonne G, et al. Lamin and the heart. Heart 2018;104:468–79. https://doi.org/10.1136/ heartjnl-2017-312338; PMID: 29175975. 4. Grossfeld P, Nie S, Lin L, et al. Hypoplastic left heart syndrome: a new paradigm for an old disease? J Cardiovasc Dev Dis 2019;6:10. https://doi.org/10.3390/jcdd6010010; PMID: 30813450. 5. Sousa A, Pinho T, Almeida P, et al. Left ventricular apical hypoplasia: an unusual diagnosis. Rev Port Cardiol 2013;32:265–7. https://doi.org/10.1016/j.repc.2012.08.011; PMID: 23453257.

diagnosis.13,14 Indeed, in retrospect, the present patient’s echocardiogram in 2006 and 2017 did suggest features of LV apical hypoplasia but these were not fully appreciated due to a lack of awareness of the condition. There is little known about the management or prognosis of LV apical hypoplasia given the relatively low number of cases that have so far been identified. Some cases reported in the literature have responded to recommended first-line heart failure therapy.1 The present patient did respond to these heart failure treatments and remained stable for 11 years before further presentation with heart failure. Our management plan following deterioration involved further up-titration of her heart failure medications and cardiac device therapy. The patient had an LBBB with a QRS duration of 140 ms, impression of severe LV systolic dysfunction on echocardiogram and deteriorating effort tolerance with NYHA class III symptoms. Therefore, a decision was made to proceed with CRT-P despite the higher ejection fraction measured on cardiac MRI. The trials on biventricular pacing are based on echocardiography and not cardiac MRI. A biventricular pacemaker with defibrillator (CRT-D) was not implanted, given that there is very little information on the risk of ventricular tachyarrhythmias in isolated LV apical hypoplasia and there was no significant fibrosis on cardiac MRI. The patient has not had any malignant ventricular tachyarrhythmias since implantation of the CRT-P. This piece describes an interesting case of isolated LV apical hypoplasia in a 79-year-old patient with no family history of cardiovascular disease and two middle-aged daughters with no cardiac disorders. There needs to be increased awareness of this condition to improve diagnostic rates. There were missed early opportunities for diagnosis due to the lack of information about the condition and the low use of cardiac MRI in 2006. The learning points from this case include the importance of continued follow-up and optimisation of heart failure medications and the use of optimised complex cardiac device therapy. Further research is needed to understand the genetic basis of the condition, establish diagnostic criteria and also to understand the natural history of the disease, the risk of tachyarrhythmia and the role of medical and device therapy.

6. Ramamurthy HR, Auti O, Raj V, Viralam K. Isolated left ventricular apical hypoplasia in a young child. BMJ Case Rep 2021;14:e239297. https://doi.org/10.1136/bcr-2020-239297; PMID: 33509886. 7. Choh N, Amreen S, Mir A, et al. Isolated left ventricular hypoplasia: a singularity. Ann Pediatr Cardiol 2020;13:337–9. https://doi.org/10.4103/apc.APC_88_19; PMID: 33311923. 8. Meng H, Li JR, Sun X. Left ventricular apical hypoplasia: a case series and review of the literature. Acta Cardiol 2013;68:339–42. https://doi.org/10.1080/AC.68.3.2983433; PMID: 23882884. 9. Irving CA, Chaudhari MP. Fatal presentation of congenital isolated left ventricular apical hypoplasia. Eur J Cardiothorac Surg 2009;35:368–9. https://doi.org/10.1016/j. ejcts.2008.10.039; PMID: 19070501. 10. Flett AS, Elliott PM, Moon JC. Cardiovascular magnetic resonance of isolated left ventricular apical hypoplasia. Circulation 2008;117:e504–5. https://doi.org/10.1161/ CIRCULATIONAHA.107.746503; PMID: 18574051.

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11. Marwick TH, Neubauer S, Petersen SE. Use of cardiac magnetic resonance and echocardiography in populationbased studies: why, where, and when? Circ Cardiovasc Imaging 2013;6:590–6. https://doi.org/10.1161/ CIRCIMAGING.113.000498; PMID: 23861451. 12. Pennell DJ. Cardiovascular magnetic resonance: twenty-first century solutions in cardiology. Clin Med (Lond) 2003;3:273– 8. https://doi.org/10.7861/clinmedicine.3-3-273; PMID: 12848266. 13. Patrianakos AP, Protonotarios N, Zacharaki A, et al. Isolated left ventricular apical hypoplasia: a newly recognized unclassified cardiomyopathy. J Am Soc Echocardiogr 2010;23:1336.e1–4. https://doi.org/10.1016/j. echo.2010.05.014; PMID: 20591617. 14. Haffajee JA, Finley JJ, Brooks EL, et al. Echocardiographic characterization of left ventricular apical hypoplasia accompanied by a patent ductus arteriosus. Eur J Echocardiogr 2011;12:e17. https://doi.org/10.1093/ejechocard/ jeq170; PMID: 21131656.