CFR 2022 – Volume 8

Volume 8 • 2022

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Volume 8 • 2022 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

Josip A Borovac

Ersilia M DeFilippis

Acute Heart Failure

Ovidiu Chioncel

University of Medicine Carol Davila, Bucharest, Romania

Sean Lal

Digital Health

Maurizio Volterrani

IRCCS San Raffaele Pisana, Rome, Italy

Cardiogenic Shock

Critical Care Cardiology

University of Copenhagen, Copenhagen, Denmark

Vanderbilt University, Nashville, TN, US

Finn Gustafsson

Aniket S Rali

Editorial Board William T Abraham

Giuseppe Galati

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

San Raffaele Hospital and Scientific Institute (IRCCS), Milan, Italy

Ali Ahmed

Julia Grapsa

Mamas A Mamas University of Keele, Keele, Staffordshire, UK

Theresa A McDonagh

King’s College Hospital, London, UK

Washington DC VA Medical Center, Washington DC, US

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

Fozia Ahmed

David L Hare

St Vincent’s University Hospital, Dublin, Ireland

Sivadasanpillai Harikrishnan

Wayne State University, Detroit, MI, US

Manchester University NHS Foundation Trust, Manchester, UK

Amod Amritphale

University of South Alabama, Mobile, AL, US

John J Atherton

University of Melbourne, Melbourne, Australia Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

Loreena Hill

Royal Brisbane and Women’s Hospital, Brisbane, Australia

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

Feras Bader

Linköping University, Linköping, Sweden

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

Michael Böhm

University of Saarland, Homburg, Germany

Eugene Braunwald

Harvard Medical School, Boston, MA, US

Javed Butler

University of Mississippi Medical Center, Jackson, MS, US

Tiny Jaarsma

Ewa Jankowska

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

Prathap Kanagala

Carmine De Pasquale

Flinders University, Adelaide, Australia

Frank Edelmann

Charité University Medicine, Berlin, Germany

Clara Saldarriaga

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

Simon Stewart

Torrens University, Adelaide, Australia

David Thompson

Wrocław Medical University, Wrocław, Poland

Farrer Park Hospital, Singapore

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

Amina Rakisheva

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

Dipak Kotecha

Alain Cohen-Solal Kevin Damman

Kian Keong Poh

National University Heart Center, Singapore

Queen’s University Belfast, Belfast, Northern Ireland, UK

University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

Université de Paris, Lariboisière Hospital, Paris, France

Ileana L Piña

Liverpool University Hospital NHS Foundation Trust, University of Liverpool and Liverpool Centre for Cardiovascular Science Liverpool, UK

Vijay Chopra

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

Kenneth McDonald

Bernard Kwok

Ekaterini Lambrinou

Cyprus University of Technology, Limassol, Cyprus

Izabella Uchmanowicz Harriette Van Spall

McMaster University, Hamilton, Canada

Raymond Wong

National University Heart Centre, National University Hospital, Singapore

Yuhui Zhang

Lars H Lund

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

Alexander Lyon

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

Karolinska Insitutet and Karolinska University Hospital, Stockholm, Sweden Royal Brompton Hospital, London, UK

Francesco Maisano

University Hospital, Zurich, Switzerland © RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Shelley Zieroth

Robert Zuckermann

Rambam Medical Health Center, Haifa, Israel

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Volume 8 • 2022

Editorial Publishing Director Leiah Norcott | Managing Editor Agnieszka Topolska Production Editors Aashni Shah, Bettina Vine | Senior Graphic Designer Lewis Allen Peer Review Editor Nicola Parsons | Editorial Coordinator Jemima Hegerty-Ward Contact agnieszka.topolska@radcliffe-group.com

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Published by Radcliffe Cardiology.

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© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

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Volume 8 • 2022

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.

• 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, Deputy Editor and Section Editors, 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 Deputy Editor, Section Editors and 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.

Submissions and Instructions to Authors

• Contributors are identified by the Editor-in-Chief, with the support of • • • •

the Deputy Editor, Section Editors, Editorial Board and Managing Editor.

Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, Deputy Editor and Section Editors, formalise the working title and scope of the article.

Instructions for authors and additional submission details are at www.radcliffecardiology.com/guideline/author-guidelines.

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.

Ethics and Conflicts of Interest

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.

Open Access, Copyright and Permissions

Articles published in this journal are gold open access, which means the version of record is freely available, immediately upon publication, without charge. Articles may be published under a CC-BY-NC or CC-BY licence.

CC-BY-NC: Allows users to read, download, copy, redistribute and make derivative works for non-commercial purposes. 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). To support open access publication costs, Radcliffe charges an article publication charge upon acceptance of an unsolicited paper: £1,500 UK | €1,770 Eurozone | $1,970 all other countries. Waivers are available, as specified in the ‘For authors’ section on www.CFRjournal. com. Permission to reproduce an article published under CC-BY-NC for commercial purposes, either in full or part, should be sought from the Managing Editor.

CC-BY: Allows users to read, download, copy, redistribute and make derivative works for any purpose, including commercially. Radcliffe offers publication under the CC-BY 4.0 License (https://creativecommons.org/ licenses/by/4.0/legalcode) to authors funded by UK Research Councils (UKRI) or The Wellcome Trust. The article publication charge is £1,750 | €2,069 Eurozone | $2,299 all other countries. The author retains all rights under this option.

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.

• The manuscript is sent to the Editor-in-Chief for final approval.

Distribution and Readership

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.

Online

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, Journal of Asian Pacific Society of Cardiology and US Cardiology Review.

Reprints

All articles included in Cardiac Failure Review are available as reprints.

Please contact the Sales Director, David Bradbury david.bradbury@radcliffe-group.com.

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Contents Endpoints in Heart Failure Drug Development Aliza Hussain, Arunima Misra and Biykem Bozkurt DOI: https://doi.org/10.15420/cfr.2021.13

T1 and T2 Mapping in Uremic Cardiomyopathy: An Update

Luca Arcari, Giovanni Camastra, Federica Ciolina, Massimiliano Danti and Luca Cacciotti DOI: https://doi.org/10.15420/cfr.2021.19

Extracorporeal Membrane Oxygenation as a Treatment for Branch Pulmonary Artery Rupture Following Right Heart Catheterisation Vineet Agrawal, Kelly A Costopoulos, Mohammed Chowdhary, Keki Balsara, Kelly H Schlendorf, JoAnn Lindenfeld and Jonathan Menachem DOI: https://doi.org/10.15420/cfr.2021.25

Out with the Old and In with the New: Primary Care Management of Heart Failure with Preserved Ejection Fraction Simon Stewart, Amy R Stewart, Laura Waite and Justin Beilby DOI: https://doi.org/10.15420/cfr.2021.27

Clinical and Haemodynamic Effects of Arteriovenous Shunts in Patients with Heart Failure with Preserved Ejection Fraction Medhat Soliman, Nizar Attallah, Houssam Younes, Woo Sup Park and Feras Bader DOI: https://doi.org/10.15420/cfr.2021.12

The Effect of Iron Deficiency on Cardiac Function and Structure in Heart Failure with Reduced Ejection Fraction Pieter Martens DOI: https://doi.org/10.15420/cfr.2021.26

The Impact of Frailty and Comorbidities on Heart Failure Outcomes

Thomas Salmon, Hani Essa, Behnam Tajik, Masoud Isanejad, Asangaedem Akpan and Rajiv Sankaranarayanan DOI: https://doi.org/10.15420/cfr.2021.29

Cell Therapy in Heart Failure with Preserved Ejection Fraction Sabina Frljak, Gregor Poglajen and Bojan Vrtovec DOI: https://doi.org/10.15420/cfr.2021.21

Cardiac Magnetic Resonance in the Evaluation of COVID-19

Daniel E Clark, Sachin K Aggarwal, Neil J Phillips, Jonathan H Soslow, Jeffrey M Dendy and Sean G Hughes DOI: https://doi.org/10.15420/cfr.2021.20

Management of Type 2 Diabetes in Stage C Heart Failure with Reduced Ejection Fraction Anjali Agarwalla, Jadry Gruen, Carli Peters, Lauren Sinnenberg, Anjali T Owens and Nosheen Reza DOI: https://doi.org/10.15420/cfr.2021.31

Telecommunication for Advance Care Planning in Heart Failure Rekha V Thammana and Sarah J Goodlin DOI: https://doi.org/10.15420/cfr.2021.23

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Alberto Aimo, Giosafat Spitaleri, Dario Nieri, Laura Maria Tavanti, Claudia Meschi, Giorgia Panichella, Josep Lupón, Francesco Pistelli, Laura Carrozzi, Antoni Bayes-Genis and Michele Emdin DOI: https://doi.org/10.15420/cfr.2021.30

Clinical Utility of HeartLogic, a Multiparametric Telemonitoring System, in Heart Failure

Juan Carlos López-Azor, Noelia de la Torre, María Dolores García-Cosío Carmena, Pedro Caravaca Pérez, Catalina Munera, Irene Marco Clement, Rocío Cózar León, Jesús Álvarez-García, Marta Pachón, Fernando Arribas Ynsaurriaga, Rafael Salguero Bodes, Juan Francisco Delgado Jiménez and Javier de Juan Bagudá DOI: https://doi.org/10.15420/cfr.2021.35

Mechanical Circulatory Support for Right Ventricular Failure

Ersilia M DeFilippis, Veli K Topkara, Ajay J Kirtane, Koji Takeda, Yoshifumi Naka and A Reshad Garan DOI: https://doi.org/10.15420/cfr.2021.11

© RADCLIFFE CARDIOLOGY 2022 Access at: www.CFRjournal.com

www.CFRjournal.com

Contents Pulmonary Artery Catheter Monitoring in Patients with Cardiogenic Shock: Time for a Reappraisal?

Maurizio Bertaina, Alessandro Galluzzo, Nuccia Morici, Alice Sacco, Fabrizio Oliva, Serafina Valente, Fabrizio D’Ascenzo, Simone Frea, Pierluigi Sbarra, Elisabetta Petitti, Silvia Brach Prever, Giacomo Boccuzzi, Paola Zanini, Matteo Attisani, Francesco Rametta, Gaetano Maria De Ferrari, Patrizia Noussan and Mario Iannaccone DOI: https://doi.org/10.15420/cfr.2021.32

Evidence-based Therapy in Older Patients with Heart Failure with Reduced Ejection Fraction IDavide Stolfo, Gianfranco Sinagra and Gianluigi Savarese DOI: https://doi.org/10.15420/cfr.2021.34

Medical Treatment of Heart Failure with Reduced Ejection Fraction in the Elderly Ivan Milinković, Marija Polovina, Andrew JS Coats, Giuseppe MC Rosano and Petar M Seferović DOI: https://doi.org/10.15420/cfr.2021.14

Aortic Pulsatility Index: A New Haemodynamic Measure with Prognostic Value in Advanced Heart Failure Tania Deis, Kasper Rossing and Finn Gustafsson DOI: https://doi.org/10.15420/cfr.2022.09

© RADCLIFFE CARDIOLOGY 2022 Access at: www.CFRjournal.com

REVIEW

Therapy

Endpoints in Heart Failure Drug Development Aliza Hussain,1 Arunima Misra

1

and Biykem Bozkurt

1,2

1. Winters Center for Heart Failure, Cardiology, Baylor College of Medicine and Michael E DeBakey VA Medical Center, Houston, TX, US; 2. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, US

Abstract

Heart failure (HF) is a major health problem worldwide. The development of effective drug and/or device therapy is crucial to mitigate the significant morbidity, mortality and healthcare costs associated with HF. The choice of endpoint in clinical trials has important practical and clinical implications. Outcomes of interest including mortality and HF hospitalisations provide robust evidence for regulatory approval granted there is sufficiency of safety data. At the same time, it is important to recognise that HF patients experience significant impairments in functional capacity and quality of life, underscoring the need to incorporate parameters of symptoms and patient-reported outcomes in clinical trials. In this review, the authors summarise the evolution and definition of cardiovascular endpoints used in clinical trials, discuss approaches to study design to allow the incorporation of mortality, morbidity and functional endpoints and, finally, examine the current challenges and suggest steps for the development of cardiovascular endpoints that are effective, meaningful and meet the needs of all relevant stakeholders, including patients, physicians regulators and sponsors.

Keywords

Endpoints, heart failure, clinical trials Disclosure: BB has received consulting fees from Bristol Myers Squibb, scPharmaceuticals, Baxter Healthcare, Sanofi-Aventis and Relypsa, and serves on the Clinical Event Committee for the GUIDE HF trial sponsored by Abbott Vascular and the Data Safety Monitoring Committee of the ANTHEM trial sponsored by Liva Nova. All other authors have no conflicts of interest to disclose.

Received: 3 June 2021 Accepted: 16 October 2021 Citation: Cardiac Failure Review 2022;8:e01. DOI: https://doi.org/10.15420/cfr.2021.13 Correspondence: Biykem Bozkurt, Baylor College of Medicine, 2002 Holcombe Blvd, Houston, TX 77030, US. E: bbozkurt@bcm.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.

Heart failure (HF) is a major public health problem, affecting up to 2% of the global population.1,2 HF accounts for significant morbidity and mortality and healthcare costs worldwide.3 Approximately 10% of the elderly population in the western world have HF.2 The prevalence of HF is increasing due to aging of the population and improved treatments for acute cardiovascular (CV) events, despite the efficacy of many therapies for patients with HF with reduced ejection fraction (HFrEF). In the US alone, approximately 1 million new HF cases are diagnosed annually and HF is one of the leading causes of death.4

Evolution of Endpoints in Clinical Trials in Heart Failure

Until the 1970s, treatment options for HF were limited to digitalis and diuretics, with a focus on improvements in symptoms. This was followed by studies with vasodilators that demonstrated improvements in haemodynamics along with symptoms. With the recognition of these haemodynamic benefits, vasodilators were then studied for their effect on mortality in patients with HF.5 The first of these trials, V-HeFT I, was the first major randomised placebo-controlled trial in CV medicine that showed a trend towards mortality reduction with vasodilators.5 However, in the late 1980s the paradigm changed from haemodynamics to neurohormonal blockade with the demonstration of mortality benefit with angiotensin-converting receptor inhibitors in HF patients, the superiority of these agents over vasodilators for survival benefit and their

consistent benefit across different stages of HF.6–8 This was followed by large-scale trials in late 1990s showing survival benefit with beta-blockers, mineralocorticoid receptor antagonists and, more recently, angiotensin receptor–neprilysin inhibitors and sodium–glucose cotransporter 2 inhibitors (SGLT2i) in patients with HFrEF.9–14 In most of these trials, the results were concordant in terms of efficacy for improvement in symptoms, functional and exercise capacity, hospitalisations and safety.

Conversely, historically in studies with inotropic agents, despite improvements in haemodynamic profile, symptoms and functional capacity, there was evidence of adverse outcomes with increased mortality.15,16 The risk for increased mortality with inotropic agents culminated in a regulatory pathway that has required the necessity of clinical trials to address mortality independently or combined with other endpoints.17 With the recognition of HF hospitalisations as one of the strongest markers of mortality, disease severity and healthcare burden, the focus on mortality was followed by an emphasis in recent clinical trials in HF on a reduction in HF hospitalisations as a combined endpoint with mortality or CV mortality.12–14,18–20 It was critical for a drug to demonstrate no increase in mortality but, when the combined endpoint of HF hospitalisations and CV or all-cause mortality was reduced, it also was clinically important to clarify whether the benefit was due to a reduction in HF hospitalisations, mortality or both. As such, drugs such as ivabradine or digoxin, which

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Endpoints in Heart Failure have been shown to reduce HF hospitalisations but not mortality, received a lower class of recommendation (Class II rather than Class I) in practice guidelines for HF.18,21–23 The emphasis on the combined endpoint of CV death and HF hospitalisations has been further enhanced by recent trials with SGLT2i.13,14,24–26 Historically, following the regulatory guidance outlined in 2008 by the Food and Drug Administration (FDA) for new drugs for type 2 diabetes, many large randomised controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycaemic medications on the primary endpoint of major adverse CV events (MACE), defined as CV death, non-fatal MI or non-fatal stroke.27 HF was not specifically mentioned in the FDA guidance.27 However, several trials subsequently showed the strong impact of antihyperglycaemic drugs on HF outcomes, which were not originally specified as the primary endpoint of the trials.28 With the recognition of the consistent risk reduction in HF hospitalisation seen across all trials with SGLT2i in patients with diabetes, new trials have been conducted with SGLT2i in patients with HFrEF with or without diabetes, which again demonstrated the safety and efficacy of these agents in reducing the combined endpoint of CV mortality and HF hospitalisations in patients with HFrEF regardless of the presence of diabetes.13,14 This underscores the importance of HF end-points in all CV trials and that the CV trials should not solely focus on MACE endpoints, which tend to emphasise ischaemic endpoints but not HF events.

Recognising the dynamic changes in the health care delivery models that have resulted in avoidance of hospitalisations and escalation of therapies in the setting of observation units or urgent care, the hospitalisation endpoints have been expanded to include urgent or emergency care or the requirement for intravenous diuretic therapy in addition to hospitalisations for HF. Furthermore, with the expansion of virtual visits, especially in the context of the coronavirus disease 2019 pandemic, other forms of encounters, including home-based therapies or virtual encounters, will likely be included in future endpoints.

HF therapies that theoretically improve congestion and improve haemodynamic changes may also have unintended adverse consequences, such as renal or myocardial injury, that may offset their benefits. This was demonstrated in the ultrafiltration clinical trials. Acute cardiorenal syndrome occurs frequently in patients hospitalised with HF exacerbation and is a predictor of poor outcomes.29 Venous ultrafiltration, due to precise control of the rate and volume of fluid removal and less activation of the neurohormonal axis, was proposed as a potential therapy to improve congestion and treat kidney dysfunction in patients hospitalised with acute decompensated HF and cardiorenal syndrome not responding to medical therapy.30 However, in the CARRESS-HF trial, ultrafiltration, compared with diuretic-based therapy, in patients with acute HF did not demonstrate significant differences in weight loss at 96 hours, 60-day mortality or the rate of hospitalisation, but it significantly worsened serum creatinine.31 Moreover, ultrafiltration was associated with higher rates of adverse events attributed to a higher incidence of kidney failure, bleeding, and intravenous catheter-related complications.32 The endpoints related to devices and interventions have evolved over time. More recent studies entail not only device efficacy and safety endpoints, but also clinical outcomes and patient-reported outcomes, which are addressed in the following section.

However, the strict emphasis on hard endpoints in clinical trials has historically created a predominant focus on mortality and or hospitalisation benefit, with limited recognition of improvements in symptoms, quality of

life and functional and exercise capacity, which are critical parameters for patients and shared decision making. Recently, the FDA provided guidance to make it clear that an effect on symptoms or physical function, without a favourable effect on survival or risk of hospitalisation, can, in fact, be a basis for approving therapies to treat HF.33 Although this complemented focus on patient-centric outcomes and quality of life will be an important paradigm change, the approach for regulatory drug approval in the US will likely require a safety signal, with a requirement for no evidence of an increase in mortality or hospitalisations.17 Of course, one needs to keep in mind that hospitalisations and decompensations requiring intravenous interventions are also important endpoints from patient perspectives because they result in poor quality of life. Despite current treatments, rates of hospital admissions and readmissions for HF have shown little improvement during the past three decades, with substantial healthcare costs attributable to HF hospital admissions.2 Implantable systems for chronic monitoring of pulmonary artery pressures (CardioMEMS Heart Sensor) guide haemodynamictargeted outpatient management of patients with chronic HF and have been shown to result in a significant reduction in hospital admission for HF and to improve quality of life, as assessed by the Minnesota Living with Heart Failure Questionnaire.34–36 Clinical trials with implantable cardiac monitoring systems targeted changes in haemodynamic measurements combined with reductions in HF hospitalisation as endpoints of efficacy and device- and system-related complications as endpoints of safety, providing an example of unique haemodynamic and safety endpoints relevant to device efficacy and safety, combined with clinical endpoints relevant to patients and systems of care, such as quality of life and readmission rates.36,37 Endpoints combining efficacy and safety were also reported in trials with percutaneous valvular interventions in patients with HF. Transcatheterdelivered device therapy known as edge-to-edge leaflet repair (MitraClip) is a promising therapeutic option in patients with HF and severe functional mitral regurgitation. In the COAPT trial, the primary efficacy outcome of HF hospitalisation within 24 months was significantly lower in the MitraClip arm compared to medical therapy (control) group, with no difference in primary safety outcomes of freedom from device-related complications at 12 months.38 Secondary outcomes assessed in the COAPT trial included parameters related to quality of life, including patient-reported changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 6-minute walk test (6MWT), and echocardiographic parameters (changes in left ventricular end-diastolic volume, mitral regurgitation severity and tricuspid regurgitation).38 In the COAPT trial, although mortality was not the primary endpoint, a prominent finding of the clinical trial was a significantly lower rate of mortality at 1 year.38 A second, smaller, randomised controlled trial assessing percutaneous mitral valve repair also evaluated all-cause mortality and HF hospitalisation but did not show a significant difference in these clinical endpoints between percutaneous repair and medical therapy alone.39 Quality of life and functional capacity in secondary mitral regurgitation are important parameters, and percutaneous mitral valve repair has been shown to positively affect both in prospective registries.40,41 Based on the results of the clinical trials, the FDA approved the use of transcatheter mitral valve repair for functional mitral regurgitation.

The differences in endpoints for devices and drugs are also driven, in part, by the differences in FDA approval processes for the two types of

CARDIAC FAILURE REVIEW www.CFRjournal.com

Endpoints in Heart Failure Table 1: Definition of a Heart Failure Hospitalisation A heart failure hospitalisation is defined as an event that meets ALL of the following criteria The patient is admitted to the hospital with a primary diagnosis of HF The patient’s LOS in hospital extends for at least 24 h (or a change in calendar date if the hospital admission and discharge times are unavailable) The patient exhibits documented new or worsening symptoms due to HF on presentation, including at least ONE of the following: • Dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnoea, paroxysmal nocturnal dyspnoea) • Decreased exercise tolerance • Fatigue • Other symptoms of worsened end-organ perfusion or volume overload (must be specified and described by the protocol) The patient has objective evidence of new or worsening HF, consisting of at least TWO physical examination findings OR one physical examination finding and at least ONE laboratory criterion, including: a. Physical examination findings considered to be due to HF, including new or worsened: i. Peripheral oedema ii. Increasing abdominal distension or ascites (in the absence of primary hepatic disease) iii. Pulmonary rales/crackles/crepitations iv. Increased jugular venous pressure and/or hepatojugular reflux v. S3 gallop vi. Clinically significant or rapid weight gain thought to be related to fluid retention b. Laboratory evidence of new or worsening HF, if obtained within 24 h of presentation, including: i. Increased BNP/NT-proBNP concentrations consistent with decompensation of heart failure (e.g. BNP >500 pg/ml or NT-proBNP >2,000 pg/ml). In patients with chronically elevated natriuretic peptides, a significant increase should be noted above baseline ii. Radiological evidence of pulmonary congestion iii. Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or low cardiac output. For example, echocardiographic criteria could include: septal or lateral E/e′ >15 or >12, respectively; D-dominant pulmonary venous inflow pattern; plethoric inferior vena cava with minimal collapse on inspiration; or decreased LVOT minute stroke distance (TVI) OR c. Invasive diagnostic evidence with right heart catheterisation showing a pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) ≥18 mmHg, central venous pressure ≥12 mmHg, or a cardiac index <2.2 l/min/m2 Note: All results from diagnostic tests should be reported, if available, even if they do not meet the above criteria because they provide important information for the adjudication of these events.

The patient receives at least ONE of the following treatments specifically for HF: a. Significant augmentation in oral diuretic therapy (e.g. doubling of loop diuretic dose, initiation of maintenance loop diuretic therapy, initiation of combination diuretic therapy) b. Initiation of intravenous diuretic (even a single dose) or vasoactive agent (e.g. inotrope, vasopressor, vasodilator) c. Mechanical or surgical intervention, including: • Mechanical circulatory support (e.g. IABP, ventricular assist device, ECMO, total artificial heart) • Mechanical fluid removal (e.g. ultrafiltration, haemofiltration, dialysis) BNP = B-type natriuretic peptide; ECMO = extracorporeal membrane oxygenation; HF = heart failure; IABP = intra-aortic balloon pump; LOS = length of stay; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro B-type natriuretic peptide; TVI = time velocity integral.

therapies. Although the FDA requires device trials to demonstrate device safety and efficacy, the level of evidence required for approval is often less rigorous than the hard endpoints required for new drug approval.

healthcare dollars and potentially affecting patient prognosis. Not all HF events are equal, making comparisons across the different drugs and devices difficult.

Data Standards in Cardiovascular Endpoint Definitions

Heart Failure Event

A major limitation in comparing outcomes among trials within and across drug and device development programs has been the lack of uniform definitions for HF and key endpoint events. Attempts have been made to develop definitions that are characterised by objective criteria and reported uniformly, and such definitions have evolved over time.42–45 The standardisation of definitions helps ensure optimal capture of HF events despite differences in the threshold for hospitalisation worldwide and increasing pressure, especially in the US, to reduce the number of HF hospitalisations.

HF events that are not hospitalisations have prognostic significance similar to HF hospitalisations. Because mortality continues to be important for drug or device approval, it is often included as part of the primary endpoint, along with HF hospitalisations and similar events, such as urgent care or emergency department visits, that result in intravenous therapies with diuretics and/or vasoactive agents, which are suggestive of decompensation that may result in hospital visits or therapies, adding to

The most recent Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the FDA, define hospitalised and nonhospitalised HF events as relevant endpoints in HF trials and trials of nonHF therapies in which the therapy may affect the risk of HF.43 An HF event includes hospitalisations for HF and urgent outpatient visits and is defined as a constellation of signs, symptoms, diagnostic testing and HF-directed therapy, as described in Table 1. It is emphasised that HF hospitalisations should be delineated from urgent visits, and that if urgent visits are included in the HF event endpoint, the number of urgent visits needs to be explicitly presented separately from the number of hospitalisations.43

Heart Failure Hospitalisation

To fulfil the criteria for an HF hospitalisation, a patient is required to have an unscheduled hospital admission for a primary diagnosis of HF with a length of stay that either exceeds 24 h or crosses a calendar day.43 The patient should also have typical signs, symptoms and diagnostic testing results consistent with the diagnosis of HF (Table 1). Objective diagnostic

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Endpoints in Heart Failure Table 2: Definition of an Urgent Care Heart Failure Visit An urgent care HF visit is defined as an event that meets ALL of the following criteria The patient has an urgent, unscheduled office/practice or emergency department visit for a primary diagnosis of HF that does not meet the criteria for a HF hospitalisation The patient meets all signs and symptoms, laboratory or diagnostic evidence for HF hospitalisation as indicated in Table 1 The patient receives at least ONE of the following treatments specifically for HF: a.

Initiation of intravenous diuretic or vasoactive agent (e.g. inotrope, vasopressor, or vasodilator) b. Mechanical or surgical intervention, including: i. Mechanical circulatory support (e.g. IABP, ventricular assist device, ECMO, total artificial heart) ii. Mechanical fluid removal (e.g. ultrafiltration, haemofiltration, dialysis) ECMO = extracorporeal membrane oxygenation; HF = heart failure; IABP = intra-aortic balloon pump. Data source: Bozkurt et al.43

findings supporting the diagnosis of HF include elevated natriuretic peptides, radiological evidence of pulmonary congestion and either echocardiographic or invasive evidence of elevated filling pressures. In addition to these signs and symptoms, the patient should be receiving treatment specifically directed at HF, including initiation of intravenous diuretic or vasoactive agents (e.g. vasodilator, vasopressor or inotropic therapy), or mechanical circulatory support or fluid removal (Table 1).43

Urgent Outpatient Visits

To satisfy the criteria for a non-hospitalised HF event, the patient must have an urgent, unscheduled office or emergency visit for HF with signs, symptoms and diagnostic testing similar to those described for HF hospitalisation (Table 2). The patient must also require therapy similar to that described previously for an HF hospitalisation, including initiation of intravenous diuretic or vasoactive agents (e.g. vasodilator, vasopressor or inotropic therapy), or fluid removal.43 It is important to note that clinic visits for the electively scheduled administration of HF therapies or procedures (e.g. IV diuretics, intravenous vasoactive agents or mechanical fluid removal) do not qualify as non-hospitalised HF events.43 Other than HF events, the clinical endpoints described below are reported as safety or efficacy endpoints in HF clinical trials.

Death

Death is usually reported as an efficacy or safety endpoint in clinical trials.

In CV studies, when the specific cause of death is important, adjudication using standardised definitions is recommended.43 The collection of appropriate source documentation is critical for rigorous adjudication of the cause of death. Although death certificates establish that the patient died, reliance on information included in death certificates may be problematic.43 Autopsy reports can be valuable in assessing the cause of death, but may not always be available.46

Cardiovascular Death

CV deaths include deaths that result from an acute MI (AMI), sudden cardiac death, death due to HF, death due to stroke, death due to CV procedures, death due to CV haemorrhage and death due to other CV causes.43 Classification of deaths as CV or non-CV is aimed at capturing the primary cause of death.43 The primary cause as defined here is the underlying disease or injury that initiated the train of events resulting in death. Thus, when an AMI leads to a fatal arrhythmia, the primary cause of death would be the AMI.43 The clinical progression toward a fatal outcome is often manifested by multiple intermediate steps, and identifying the

primary cause requires careful consideration. The primary cause may be distinct from both the mode of death and an intervening cause that is temporally closer and contributes to the death.43 In patients with HFrEF and New York Heart Association (NYHA) Class II and III HF, approximately 90% of deaths are classified as being due to CV causes and 10% are documented as being due to non-CV causes.47 The mode of death is generally regarded as the physiological derangement or the biochemical disturbance produced by the cause of death and should not be substituted for the primary cause. Non-CV causes of death (e.g. renal failure) often ultimately culminate in a CV mode of death (e.g. arrhythmia) that should not be confused with CV death. In addition, the overlap between the primary cause of death and mode of death can also render the subclassification of CV deaths difficult.43

Heart Failure Death

HF death is defined as a death that occurred as a result of worsening symptoms and/or signs of HF, or intractable HF. The death generally occurs during or following hospitalisation but could occur at home, at a long-term care facility or in hospice care. Terminal arrhythmias associated with HF deaths are usually classified as HF death. HF secondary to a recent MI should be classified as an MI death. Patients with worsening HF usually have symptoms and signs of HF and diagnostic evidence of HF, such as an abnormal chest X-ray and a significant increase in natriuretic peptide concentrations.

When sufficient information is available, HF death can be subcategorised as with or without low output and/or congestion. Low output is usually indicated by fatigue, signs of vasoconstriction, prerenal azotaemia, the need for vasopressors, low cardiac output or hypotension. Congestion is usually indicated by symptoms and signs on physical examination, chest X-ray and non-invasive and invasive measurements.

Haemodynamic Endpoints

The device studies, especially percutaneous devices for the management of acute/decompensated HF with cardiogenic shock, also provide a different perspective for endpoints in clinical trials in patients with HF. In refractory circulatory shock, mechanical circulatory support devices, including pulsatile (intra-aortic balloon pump [IABP]), axial continuous (Impella) or centrifugal continuous (TandemHeart) pumps or extracorporeal membrane oxygenation units result in distinct haemodynamic changes and ventricular pressure/volume unloading to improve cardiac output and blood pressure. Unlike drug trials that rely on hard clinical endpoints, most clinical trials studying percutaneous left ventricular assist devices (pLVAD) have relied on demonstrating improvements in specific haemodynamic parameters that the device is designed to achieve, such as cardiac output, arterial pressure, pulmonary capillary wedge pressure, right atrial pressure or systemic vascular resistance.48–51 Given these trials were conducted in shock patients at high risk of mortality, symptoms were not taken into account. However, importantly, because they are highly invasive techniques, procedural complications were considered as endpoints. The measurement of haemodynamic surrogate endpoints in these studies reflected treatment effect that is expected to correlate with clinical benefit. Therefore, surrogate endpoints can be important, as has been the case in certain device trials or small exploratory trials with relatively short follow-up, in which it can be difficult to power for symptom- or survival-based clinical endpoints. This was demonstrated by a meta-analysis of clinical trials comparing pLVAD to IABP showing that although the pLVAD devices significantly improved

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Endpoints in Heart Failure haemodynamics, neither of the two therapies improved 30-day mortality, likely to be due to a small number of patients in all the trials combined.31

Other Evolving Endpoints

In clinical trials, the approach of time to event analyses of clinical endpoints, such as mortality and HF hospitalisations censors hospitalisations after the initial event, discounting the clinical burden of multiple repeated hospitalisations. Conversely, patients with prolonged index hospital stays have less time at risk of rehospitalisation, and patients who die are not at risk of rehospitalisations.

Days Alive and Out of the Hospital

For interventions without an impact on the initial length of stay (LOS), the composite of death and repeat hospital stay may be a better endpoint.

For studies of interventions that may have an effect on the initial LOS, ‘days alive and out of the hospital’, which combines mortality, the LOS of the index hospital stay and the burden of subsequent hospital stays, would be a better endpoint.

Heart Failure Versus All-Cause Hospitalisations

Although HF hospitalisations are of specific interest in drug development in HF, the effect on all-cause hospitalisations would also be of interest, especially for treatment strategies that can affect a variety of comorbidities, such as a medication that may reduce the incidence of AF along with HF events or a glucose-lowering drug that may reduce hospitalisations due to diabetes as well as HF. Due to the cluster of comorbidities and increased prevalence of all-cause hospitalisations in patients with HF with preserved ejection fraction (HFpEF), all-cause hospitalisations may also be of interest in patients with HFpEF.52 All-cause hospitalisations would also be of interest in device- or intervention-related therapies, especially if the intervention has procedural-related risk or complications that may require hospitalisation related to the intervention. However, it should be kept in mind that statistical power and sensitivity are greatly enhanced by examining the specific categories of hospitalisations, such as HF hospitalisations (Table 1), that one expects treatment to affect rather than including insensitive outcomes (e.g. cancer or stroke hospitalisation that is not expected to be affected). A second problem with chiefly focusing on overall hospitalisations is a loss of power when one only counts the first hospitalisation per patient (e.g. as in a time to event analysis).53–55 On the basis of SOLVD trial data, approximately 38% of hospitalisations for HF occurred after hospitalisation for another cause.8 Therefore, using total hospitalisations leads to a loss in statistical power because of the inclusion of a large number of events that are insensitive and a loss in events that are truly sensitive. In the SOLVD trial, the use of first hospitalisation instead of HF hospitalisation would have substantially reduced power.

Global Ranking Approach

The global ranking approach is a strategy for incorporating multiple aspects of the clinical course, including both events and quantitative measures of functional status (e.g. quality of life assessment, 6MWT or biomarkers of cardiac injury), based on a prespecified hierarchical ranking system and may provide many of the advantages of composite endpoints while avoiding pitfalls.56 The basis for using a prespecified hierarchical ranking system lies in the discrepancies often found between Phase II and III studies, where the Phase II study shows improvement in symptoms or congestion but the positive findings do not translate to positive results

when the Phase III study is completed. One possible hypothesis suggested for this is that the improvement in symptoms or congestion occurs at the cost of unintended consequences, such as renal or myocardial injury.57 Biomarkers are commonly used to assess congestion and myocardial injury and include B-type natriuretic peptide, N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponins I and T. Thus, combining biomarkers and clinical endpoints by incorporating continuous data and clinical endpoints, and avoiding the ‘time-to-event’ analyses that are usually used, may be more useful in Phase II studies to provide a better indicator of the success or failure in the Phase III study. A framework that can accomplish this was proposed by O’Brien in 1984.58 In this method, one ranks the endpoints, including both traditional hard endpoints (e.g. mortality) and surrogate endpoints (e.g. biomarkers), as well as subjective endpoints (e.g. dyspnoea). An example of such a global rank list may rank all patients accordingly, with worst outcomes having the lowest score, such that the patient with least time to death would have the lowest score and the patient who avoided death, hospitalisation and had the best improvement in dyspnoea with little myocardial injury (lowest troponin) and no worsening of renal function and best reduction in NT-proBNP would have the highest score.57 This type of global ranking was used in the FIGHT study.59 The primary outcome measures were the global ranking of predefined events from randomisation to 180 days, including time to death, time to hospitalisation and time-averaged proportional change in NT-proBNP. Patients were assigned scores with the shortest time to endpoint or least proportional change to get the lower scores. Secondary outcomes meant to be exploratory included echocardiographic indices, functional assessment and the quality of life score, determined using the KCCQ. This type of endpoint assessment is more global and thought to be more useful in Phase II studies and may provide insights into planning for a Phase III study.

Composite Endpoints

Composite endpoints (e.g. the frequently used ‘death or HF hospitalisation’ endpoint) typically treat all components of the composite equally, despite the fact that clinicians and patients may value specific components of the composite very differently (e.g. death versus hospitalisation). Because nonfatal events tend to occur more frequently than deaths, less severe outcomes (e.g. hospitalisations) tend to drive composite endpoints to a greater degree than less common but more serious outcomes (e.g. death).

Although composite endpoints may provide higher event rates, it may be difficult to interpret whether drug or device effects are similar for all components or whether the effect of treatment is primarily on a more common, less serious component of the composite. From a clinical perspective, composite endpoints reflect the fact that the totality of patient experience with a given therapy may not be captured by mortality alone.

Most long-term studies use ‘time-to-event’ methods, in which patients are followed up until the first ‘event’ of the composite endpoint. This potentially introduces major problems in interpretation, in that less severe events happening earlier in the study (e.g. a brief HF hospitalisation) are counted, whereas more severe events (e.g. death) that happen after an initial event would be censored in the primary analysis of the trial outcomes.56 As an example of this potential discrepancy, using a standard chronic HF composite endpoint of time to death or first HF hospitalisation, a patient who is hospitalised for HF 2 weeks after randomisation but then

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Endpoints in Heart Failure survives and feels well for 5 years would be viewed as having a worse outcome than one who dies 2 months after randomisation. In this sense, the composite endpoint weighs the clinical course in a way that is incongruous with the way it would be viewed by patients and providers.

To overcome this problem, the concept of the win ratio and Finkelstein– Schoenfeld method for reporting composite endpoints has been introduced, the where different components for the composite endpoint are assigned different levels of importance.56 With the Finkelstein–Schoenfeld or the win ratio method, pairwise comparisons are performed and the scores are calculated based on the comparison of the importance of the outcome.60 Consider a primary composite endpoint, such as CV death and HF hospitalisation in an HF trial. Matched pairs of patients are made from the new treatment and control groups based on risk profiles, with patients in the new treatment and matched control groups labelled ‘winners’ or ‘losers’ depending on whoever has a CV death first. If that is not known, only then are they labelled a ‘winners’ or ‘losers’ depending on who had an HF hospitalisation first. Otherwise, they are both considered tied. The win ratio is the total number of winners divided by the total numbers of losers; 95% CIs and p-values for the win ratio are then obtained.

The composite endpoint may actually serve to ‘dilute’ the observed treatment effect and thereby diminish statistical power to detect a difference between treatments if some of the components are affected in a different direction or unaffected altogether, despite an increase in the overall event rate.56 Furthermore, components of the composite may move in different directions, in a divergent manner. It is critical for safety measures, such as an increase in mortality, not to be diluted or masked by improvement in morbidity or hospitalisations in a combined endpoint When composite endpoints are used, data collection for all components should continue until the end of the trial so that each component can be evaluated separately.61

Clinical Status Endpoints

Although mortality is a traditional endpoint for drugs or devices to be approved, a patient-centric approach would argue that the quantity of life lived may not be as meaningful if the patient experiences a poor clinical status, reduced functional capacity and poor quality of life.62 A patient may instead prefer a neutral effect or even a small negative effect on mortality while enjoying an improved quality of life and functionality.63,64 To address this, clinical status composite endpoints have been used in some HF trials. However, clinical status assessments are challenging.

Inherent to intra- and interobserver variation, the reporting of subjective symptoms concerning a specific type (e.g. shortness of breath or fatigue) and type of provocation (at rest versus exertion and amount of exertion) has shown to be problematic and not useful in discerning treatment effect. Similarly, NYHA class has an abundant amount of subjectivity and can be affected by non-HF conditions, such as chronic obstructive pulmonary disease and arthritis. In addition, the physician’s method of categorising the various classes may be different from others because even the definitions of NYHA Classes I–IV are rather subjective. Then, there is global assessment, which is generally performed by the patient without physician input to avoid bias.

In addition, objective assessments of functional capacity through exercise testing have been used to evaluate the ability of the treatment to prolong exercise. However, issues with patient motivation, subjective encouragement introduced by the person administering the test, intra- or

interobserver variability and improved performance with repeated testing are problematic. In addition, a patient’s performance may vary and the standalone exercise assessment may not reflect the general condition or exercise capacity of the patient.65 Finally, there are quality of life assessments that incorporate a range of physical activity, as well as emotional, functional and cognitive, impairments via questionnaires. There are HF-specific questionnaires that are commonly used, including the KCCQ and Minnesota Living with Heart Failure Questionnaire. A combination score incorporating different components of functional status, such as NYHA functional class and global assessment, may be useful.65

Combined Clinical Composite Score

The combined clinical composite score approach combines changes in clinical hard endpoints, such as mortality and hospitalisations, with NYHA functional class and a global assessment. In addition to clinical events, these assessments may also include symptom resolution and biomarker changes.66 The combined clinical composite scores are used to allow for smaller sample size and provide a comprehensive assessment of the trial result. As mentioned previously, when combined endpoints are analysed statistically and the time to the first event is used, subsequent episodes of clinical deterioration may be ignored during statistical analysis. The commonly used clinical composite score combines changes in NYHA functional class and global assessment together with the occurrence of major clinical events. For regulatory purposes, the endpoint used in major clinical trials must be clinically meaningful and must represent a direct assessment of present or future clinical status. Thus, symptoms and functional capacity are commonly used for clinical status, whereas death or hospitalisation are used for major clinical events. In general, clinical investigators have used clinical status for short- and intermediate-term trials and hard events like death and hospitalisation for long-term trials.

However, even in short or intermediate trials, mortality and morbidity data are still included to demonstrate safety. A clinical composite score minimises the exclusion of randomised patients who deteriorated and withdrew due to worsening symptoms.65

Current Applications of Endpoints

When reviewing contemporary clinical trials, it remains clear that the primary endpoints continue to incorporate mortality and HF hospitalisations either in combination or use mortality as the primary endpoint and HF hospitalisations and other MACE events as secondary endpoints. For example, in the PARADIGM trial, the primary outcome was a composite of death from CV causes or first hospitalisation for HF.12 Secondary outcomes were the time to death from any cause, the change from baseline to 8 months in the clinical summary score on the KCCQ, the time to new onset of AF and the time to the first occurrence of a decline in renal function.12 The ADHF RELAX study, examining the efficacy and safety of serelaxin in acutely decompensated HF patients, had two primary efficacy endpoints: death from CV causes at 180 days and worsening HF at 5 days.67 Of note, worsening HF was added to the primary endpoint mid-trial and was originally a secondary endpoint. Worsening HF was defined as worsening signs or symptoms of HF that led to an intensification of treatment for HF, such as initiation or an increased dose of intravenous therapy with a diuretic, nitrate or other medication for HF or the institution of mechanical support, such as mechanical ventilation, ultrafiltration, haemodialysis, an IABP or a ventricular-assist device. The endpoint of worsening HF also included death from any cause or rehospitalisation for HF among patients who had been discharged before Day 5. Secondary efficacy endpoints included death from any cause at 180 days, the index hospital LOS and

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Endpoints in Heart Failure Figure 1: Development and Implementation Steps to Bring New Developments to Patients Public emphasis

Increase awareness Demand advocacy Demand funding Change legislation

R&D

FDA approval

Moonshot funding for CVD

Expedited pathway

Innovative research models

New endpoints (PRO)

Demand payer coverage

According to data and evidence, indications and guidelines Value-based (not cost-based) coverage

Studies with biological insights

Value-based agreements with drug/ device companies

Precision/ targeted therapies Comparative effectiveness

Provider adoption

Patient adoption

Increase education

Education, awareness

Implementation registries

PRO

Incentives

Reduce OOP costs

System integration, appropriate infrastructure data/bioinformatics

Adherence/ medication therapy management programme

Precision/targeted therapies

Medical societies and scientific communities play a critical role in guidance for R&D, guidelines, policy positions, education of their membership, public awareness and advocacy

CVD = cardiovascular disease; FDA = Food and Drug Administration; OOP = out of pocket; PRO = patient-reported outcomes; R&D = research and development.

death from CV causes or rehospitalisation for HF or renal failure at 180 days.67 As one can see, the primary endpoint became diluted with the worsening HF, which was broadly defined, although this did not appear to have altered trial results because all endpoints appeared neutral with regard to drug effect.

Thus, both these chronic and acute HF trials incorporated mortality, either all-cause and CV or both, as well as HF events. In ADHF RELAX, they did not include other endpoints, such as global assessment or quality of life scores, or haemodynamic data despite it being a study in acutely decompensated HF patients.67 In chronic HF, it is important to know whether the treatment prevents multiple events. Recurrent event analyses to determine the treatment effect on recurrent events, such as HF hospitalisations, would be relevant given hospitalisations for HF are the major contributor to healthcare costs.

When only the first event or the time to first events is recorded, the patient’s overall burden of disease may not be accurately represented.

More contemporary trials appear to accept the importance of this analysis.

In the PARADIGM-HF study, evaluating sacubitril/valsartan versus valsartan, the primary endpoint was a composite event of CV death and total (first and recurrent) HF hospitalisations.12 There was also adequate power in this study to enable standard time-to-first-event analysis.61 Another type of analysis is responder analysis, whereby endpoints such as symptoms, functional status, exercise capacity, quality of life measures and haemodynamics can be evaluated based on the clinical relevance of the change as determined by expert consensus.68 This may be helpful when designing patient-centric studies for mainly symptom relief with perhaps a neutral effect on hard endpoints.

Future Directions and Challenges

The appropriate selection of the right endpoints is critical in HF clinical trials to allow the development and approval of therapies with meaningful

outcomes for patients and clinicians. Currently, clinical trials predominantly rely on efficacy endpoints reflecting total and/or cause-specific mortality and morbidity. These endpoints are considered to be scientifically reliable and robust due to our ability to measure objectively with standardised definition, accuracy and reproducibility, with minimal bias or confounding.

However, endpoints must be clinically relevant to both patients and healthcare providers.

Depending on a patient’s perception of their overall HF symptoms and severity of illness, particularly sicker, severely limited or hospitalised patients may choose to trade quality over quantity of life (i.e. a drug therapy that improves symptoms, function and quality of life without a significant effect on survival or even a potential to reduce survival).69 Despite widespread recognition that addressing symptoms, functional capacity and quality of life are important therapeutic goals in HF management, few drugs are currently approved for symptom relief in acute or chronic HF. Endpoints must be tailored to meet the needs of the population under study. Therefore, patient-reported outcomes alone or in combination with measures of functional status may be more relevant to patients, especially those with more advanced stages of the disease. The choice of an endpoint is further influenced by the characteristics of the target patient population, patient phenotype (e.g. HFrEF versus HFpEF), episodes of care (e.g. acute versus chronic HF), stages of HF and treatment objectives (e.g. reductions in morbidity and mortality, safety, symptom management, improvement in haemodynamics) to discriminate between effective and ineffective therapies. A balanced focus on developing therapies that help patients live longer and improve symptoms and quality of life is crucial. Clinical trials must attempt to address the goals of patients and clinicians while addressing the requirements of the regulatory agencies and sponsors.

The FDA has recently issued guidance stating that improvement in patient-centric outcomes that measure a patient’s perception of health

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Endpoints in Heart Failure status (symptoms, functional status, physical function, quality of life), even without demonstration of favourable effects on survival and hospitalisations, can be the basis for approving therapies in development for HF. This guidance is important because it will encourage the development of HF therapies that address the totality of endpoints and meet evolving patient needs. The regulatory approval of drugs for symptom-based indications will allow coverage by third-party payers and improve access to drugs among vulnerable and sicker patients. In addition, although proof of improved survival or morbidity will not be required for approval, there will be consideration of the safety and mortality of these therapies, and studies will still be powered to reasonably rule out an adverse effect on mortality.

and insurance companies, to focus on strategies and clinical trial designs to address these unmet needs in HF therapy trials and ultimately improve patient outcomes (Figure 1).

Robust methods for capturing HF outcomes other than hospitalisation or death must be developed with strategies to reduce variability and improve precision in adjudication. For example, dyspnoea is an important outcome in HF clinical trials. However, consistent measures or standardised instruments for the assessment of dyspnoea need to be developed, validated and adapted consistently across HF research. Furthermore, longitudinal change in dyspnoea over time provides more information than a single point measurement, but the development of a simple instrument sensitive to changes in health status (e.g. dyspnoea) is necessary in order to integrate the change in the severity of dyspnoea over time as an endpoint.

Most long-term drug studies use ‘time-to-event’ methods and composite endpoints. Conventionally, for composite endpoints, all individual components are weighted equally, which is not consistent with real-world practice, where patients and clinicians may value specific components of the composite very differently (e.g. death versus hospitalisation). Because non-fatal events tend to occur more frequently than deaths, less severe outcomes (e.g. hospitalisations) tend to drive composite endpoints to a greater degree than less common but more serious outcomes (e.g. death). Therefore, methods for weighting the relative importance of the individual components must be improved. It is critical for safety measures, such as an increase in mortality, not to be diluted or masked by improvement in morbidity or hospitalisations in the combined endpoint.

Similarly, the development of validated and standardised patient-reported outcome instruments, especially self-administered when possible, will make these instruments acceptable for the basis for drug approval.

Continued improvement in the methodology of HF clinical trials will favourably influence the future direction of HF research and, ultimately, patient outcomes. Finally, studies should be powered to capture mortality in the clinical trial, even if it is not a primary or efficacy endpoint, to establish safety margins. Future collaborative efforts require all stakeholders, including physicians, sponsors, industry, regulatory bodies 1.

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Conclusion

In this review, we summarised the evolution of endpoints used for HF therapies. Currently, large pivotal HF trials rely on demonstrating improvements in hard endpoints, including HF hospitalisation and mortality. In recognition of the fact that the dynamic changes in the health care delivery models have resulted in an avoidance of hospitalisations, the hospitalisation endpoints have been expanded to include urgent or emergency care or the need for IV diuretic therapy.

HF patients experience a high burden of symptoms and functional limitations; therefore, patient-reported outcomes, quality of life and functional capacity are critical parameters for patients and shared decision making. In line with this is a recent paradigm change in regulatory guidance from the FDA allowing the use of measures of functional status or quality of life for regulatory approval in HF trials. Future collaborative and timely efforts are required to provide evidence for CV therapies that are effective, safe and meaningful for patients at different stages of HF.

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19. Teerlink JR, Diaz R, Felker GM, et al. Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: rationale and design of GALACTIC-HF. JACC Heart Fail 2020;8:329–40. https://doi.org/10.1016/j.jchf.2019.12.001; PMID: 32035892.

20. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382:1883–93. https://doi.org/10.1056/ NEJMoa1915928; PMID: 32222134.

21. Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33. https://doi.org/10.1056/ NEJM199702203360801; PMID: 9036306.

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Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure. J Am Coll Cardiol 2012;60:1031–42. https://doi.org/10.1016/j.jacc.2012.01.077; PMID: 22840531.

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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.

Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol 2008;51:1073–9. https://doi.org/10.1016/j.jacc.2007.10.061; PMID: 18342224.

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.

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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.

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Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011–12 Pilot European Sentinel Registry. J Am Coll Cardiol 2014;64:875–84. https://doi.org/10.1016/j.jacc.2014.06.1166; PMID: 25169171.

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Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. J Am Coll Cardiol 2015;66:403–69. https://doi.org/10.1016/j.jacc.2014.12.018; PMID: 25553722.

Hicks KA, Mahaffey KW, Mehran R, et al. 2017 cardiovascular and stroke endpoint definitions for clinical trials. Circulation 2018;137:961–72. https://doi.org/10.1161/ circulationaha.117.033502; PMID: 29495982.

Bozkurt B, Coats AJ, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. Eur J Card Fail 2021;23:352–80. https://doi. org/10.1002/ejhf.2115; PMID: 33605000.

Bozkurt B, Hershberger RE, Butler J, et al. 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards. J Am Coll Cardiol 2021;77:2053–150. https://doi.org/10.1016/j. jacc.2020.11.012; PMID: 33250265.

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Fiuzat M, Lowy N, Stockbridge N, et al. Endpoints in heart failure drug development: history and future. JACC Heart Fail 2020;8:429–40. https://doi.org/10.1016/j.jchf.2019.12.011; PMID: 32278679.

O’Neill WW, Kleiman NS, Moses J, et al. A prospective, randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the PROTECT II study. Circulation 2012;126:1717–27. https:// doi.org/10.1161/CIRCULATIONAHA.112.098194; PMID: 22935569.

Burkhoff D, Cohen H, Brunckhorst C, O’Neill WW. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469. https://doi.org/10.1016/j. ahj.2006.05.031; PMID: 16923414.

Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26:1276–83. https://doi.org/10.1093/ eurheartj/ehi161; PMID: 15734771.

Cheng JM, den Uil CA, Hoeks SE, et al. Percutaneous left ventricular assist devices vs. intra-aortic balloon pump counterpulsation for treatment of cardiogenic shock: a meta-analysis of controlled trials. Eur Heart J 2009;30:2102– 8. https://doi.org/10.1093/eurheartj/ehp292; PMID: 19617601.

Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998– 1005. https://doi.org/10.1016/j.jacc.2011.11.040; PMID: 22402071.

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Anker SD, Schroeder S, Atar D, et al. Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency. Eur J Heart Fail 2016;18:482–9. https://doi.org/10.1002/ejhf.516; PMID: 27071916.

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REVIEW

Diagnosis

T1 and T2 Mapping in Uremic Cardiomyopathy: An Update Luca Arcari ,1 Giovanni Camastra ,1 Federica Ciolina,2 Massimiliano Danti2 and Luca Cacciotti

1

1. Cardiology Unit, Madre Giuseppina Vannini Hospital, Rome, Italy; 2. Radiology Unit, Madre Giuseppina Vannini Hospital, Rome, Italy

Abstract

Uremic cardiomyopathy (UC) is the cardiac remodelling that occurs in patients with chronic kidney disease (CKD). It is characterised by a left ventricular (LV) hypertrophy phenotype, diastolic dysfunction and generally preserved LV ejection fraction. UC has a major role mediating the increased rate of cardiovascular events, especially heart failure related, observed in patients with CKD. Recently, the use of T1 and T2 mapping techniques on cardiac MRI has expanded the ability to characterise cardiac involvement in CKD. Native T1 mapping effectively tracks the progression of interstitial fibrosis in UC, whereas T2 mapping analysis suggests the contribution of myocardial oedema, at least in a subgroup of patients. Both T1 and T2 increased values were related to worsening clinical status, myocardial injury and B-type natriuretic peptide release.

Studies investigating the prognostic relevance and histology validation of mapping techniques in CKD are awaited.

Keywords

Uremic cardiomyopathy, chronic kidney disease, cardiac MRI, native T1 mapping, T2 mapping, fibrosis, oedema Disclosure: The authors have no conflicts of interest to declare.

Received: 21 August 2021 Accepted: 15 November 2021 Citation: Cardiac Failure Review 2022;8:e02. DOI: https://doi.org/10.15420/cfr.2021.19 Correspondence: Luca Arcari, Cardiology Unit, Madre Giuseppina Vannini Hospital, Via di Acqua Bullicante 4, 00177, Rome, Italy. E: luca_arcari@outlook.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.

Chronic kidney disease (CKD) represents a major cardiovascular (CV) risk factor, with the rate of CV events increasing in proportion with the severity of the underlying renal dysfunction.1 CV events in CKD are only partly explained by the clustering of traditional risk factors, such as hypertension or diabetes, and are highly influenced by CKD-related systemic abnormalities, including volume and pressure overload, as well as uremicrelated factors, such as indoxyl sulfate, β2-microglobulin and changes in mineral metabolism.2–4

remodelling in CKD even at subclinical stages and potentially providing surrogate endpoints to better understand the effects of treatments or uremic factors on heart muscle.12 Moreover, native T1 and T2 mapping techniques are especially useful because they can be performed without the need for gadolinium, the use of which raised safety concerns in CKD patients. This review provides a focused update on recent advances and future perspectives of CMR tissue mapping in patients with CKD.

Of note, rates of both atherosclerotic and non-atherosclerotic adverse events are increased in CKD patients, but the share attributable to the latter, especially heart failure and sudden cardiac death, becomes larger with the worsening of CKD.5 Indeed, at higher degrees of renal dysfunction, CV risk is mainly mediated by the hypertrophic cardiac remodelling termed ‘uremic cardiomyopathy’ (UC).6 UC is characterised by left ventricular hypertrophy (LVH) and dilation, with often preserved left ventricular (LV) ejection fraction and increased ventricular stiffness and diastolic dysfunction.7 Histologically, interstitial diffuse myocardial fibrosis is highly prevalent, as observed in postmortem studies performed in patients with end-stage renal disease (ESRD) who have undergone haemodialysis (HD).8 Interestingly, the extent of interstitial fibrosis is correlated with the decline in renal function, indicating that it can be considered a morphological marker of progressive cardiac involvement.9

T1 and T2 mapping can provide accurate and parametric information regarding cardiac tissue composition. T1 mapping measures the course of longitudinal (or spin–lattice) relaxation, which is determined by how quickly protons re-equilibrate their spins after being excited by a radiofrequency pulse. Conversely, T2 mapping measures the course of transverse (or spin–spin) relaxation. Mapping sequences consist of the acquisition of multiple images at the same cardiac phase during multiple heart beats in a single breath hold per slice; the reconstruction of colourcoded maps in which every voxel displays a colour intensity according to its T1 (or T2) value allows for parametric estimation of T1 (or T2) values within a specific region of interest (ROI; Figure 1).

Cardiac MRI (CMR) has the potential to provide a unique assessment of LVH phenotypes, including UC, being the gold standard for LV mass quantification and providing detailed tissue characterisation of myocardial architecture (both myocytes and extracellular space), with useful diagnostic and prognostic information.10,11 In recent years, CMR has helped expand our knowledge of UC, identifying pathological myocardial

T1 and T2 Mapping

Native T1 is an extremely sensitive although non-specific readout that relates to a number of underlying diseases.13 Most of the pathogenic processes involving the heart muscle, including those causing oedema, fibrosis and amyloid infiltration, lead to an increase in native T1 values, whereas the deposition of iron or fat leads to a decrease in T1 value.13 Conversely, an increase in the water content of myocardial tissues is the main cause for longer T2 relaxation times; therefore, myocardial oedema is the main pathology responsible for elevations in T2 values. Normal ranges for T1 and T2 mapping vary according to field strength, machines

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Cardiac MRI Mapping in Chronic Kidney Disease Figure 1: Cardiac Magnetic Resonance Mapping Images in a Patient with Stage 4 Chronic Kidney Disease

Short-axis, mid-slice, region of interest conservatively drawn in the mid-septum. A: Native T1 is increased at 1,067 ms. B: The T2 value is also slightly increased at 50 ms. The left ventricle showed eccentric hypertrophy and dilation; no late gadolinium enhancement was detected. The examination was performed with a 1.5-T scanner (Siemens Aera); in-centre cutt-offs for normality are: 995 ms (native T1) and 49 ms (T2). White arrows indicate pericardial effusion.

and the software used for the evaluation.14,15 Finally, using pre- and postcontrast myocardial and blood pool T1 values, along with the haematocrit, an estimated extracellular volume (ECV) fraction is calculated.16 In principle, calculation of ECV and intracellular volume (ICV) may help understand the underlying nature of LVH, where hypertrophy may, in some cases, be primarily driven by cellular hypertrophy rather than an increase in ECV.17,18 However, given concerns related to the use of gadolinium-based contrast agents (GBCAs) in CKD, scarce data are currently available for ECV assessment in these patients.

Native T1 Mapping

Several studies have investigated native T1 mapping findings in patients with CKD, invariably compared to healthy controls or hypertensive subjects. Of note, T1 values were found to be consistently increased compared with controls.19–22 Interestingly, a significant increase in native T1 values has been observed even in patients with only moderate renal disease (mean estimated glomerular filtration rate 50 ml/min); this finding was unrelated to conventional CV risk factors and was detected in patients who had not developed a significant increase in LV mass compared with a reference control group.23 This suggests a major role of CKD-related factors in driving increases in T1 values, as well as the very sensitive nature of native T1 as an imaging biomarker, able to detect pathological changes even in the absence of identifiable LVH. Observational studies performed in patients with more advanced renal disease are consistent with the ability of native T1 in tracking the progression of cardiac remodelling. In patients with ESRD, native T1 values were increased compared with those in control groups.20,21 In these studies, a correlation was found between increasing T1 values and UC progression (i.e. increasing LV mass and reduced longitudinal and circumferential strain). Further data from a larger, unselected population of patients referred for a clinically indicated CMR study found native T1

values progressively increased across renal disease strata, with higher values in patients with more severe CKD and a significant association between native T1 values and CMR-derived pulse wave velocity as an index of vascular stiffness.24 Moreover, native T1 values were independently associated with clinical variables, such as physical function and cardiac biomarkers.20,25,26 A recent cross-sectional study demonstrated a graded increase in native T1 values that, with declining renal function, was an independent predictor of peak oxygen uptake during cardiopulmonary exercise testing.27 Together, these data suggest that native T1 values can track the progression of adverse remodelling; increases in native T1 values are observed early, even when LV mass is unaffected or the small changes in LV mass are undetectable, and are associated with the progression of UC and deterioration of clinical status.

Some factors should be considered when assessing native T1 values in patients with CKD. The presence of replacement fibrosis, as identified by late gadolinium enhancement (LGE) imaging, is a major confounder when interpreting native T1 as a measure of diffuse fibrosis. Indeed, in this case higher values reflect scarring rather than diffuse disease; hence, LGE areas should be carefully excluded when drawing the corresponding ROIs.28 In patients with CKD this cannot be always done, because many would be offered non-contrast examinations due to concerns related to nephrogenic systemic sclerosis.

Some studies performed before regulatory restrictions regarding the use of GBCAs in CKD investigated the presence of replacement fibrosis.

In these studies, LGE was described in approximately one-third of cases, often of the non-ischaemic type and unrelated to traditional CV risk factors.29,30 It should be noted that the use of newer, stable macrocyclic GBCAs, which have a lower risk of nephrogenic systemic sclerosis, may

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Cardiac MRI Mapping in Chronic Kidney Disease afford patients with CKD the opportunity to have LGE imaging performed.31 A recent study in CKD patients referred with a clinical indication for contrast CMR imaging found that LGE prevalence was similar to that described previously.26 Although in diffuse diseases the method of a conservative mid-septal ROI is suggested for assessing native T1, areas of visually increased signal may be found, suggesting local fibrosis.32,33 A study sought to investigate the ability of native T1 to identify replacement fibrosis in aortic stenosis as a model for use in ESRD, but a defined threshold for the identification of scarred areas could not be identified.34 Another putative factor possibly influencing native T1 assessment is volume overload, although contradictory data are currently available in the literature. One study observed higher native T1 in HD patients compared with controls, with T1 values being positively correlated with pre-HD volume status as assessed by bioimpedance.35 Conversely, another study investigated native T1 in HD patients, also testing interstudy, interobserver and intraobserver variability, finding high reproducibility of the measure and that it was not correlated to detected changes in body weight as a proxy of altered volume status between scans.36 A limitation of both these studies is their small sample size.

In summary, native T1 seems to be invariably increased in patients with CKD, even compared with patients with normal renal function and a similar prevalence of traditional CV risk factors.26 This makes it an effective marker of disease in UC, reflecting the increase in diffuse myocardial fibrosis with worsening renal function. Despite the presence of underlying confounding factors and a lack of histological validation, this hypothesis is largely consistent with results from pathological studies.8,9

T2 Mapping

Fewer studies investigating T2 mapping are available compared with T1 mapping studies. Most reports have highlighted increased T2 values in patients with CKD,22,37–39 whereas others have not.40 Studies investigating T2 mapping values before and after HD sessions revealed a reduction in T2 values after HD, where the reduction in T2 values was put in relation to either the reduction in LV mass or to the volume removed during HD sessions.26,41 Together, these results support the hypothesis that treatment of volume overload can affect myocardial water content, possibly mediating an improvement in cardiac function.42 In contrast, there are some data in which T2 values did not change between HD patients and controls, specifically when CMR examinations were systematically performed the day after dialysis at a time of relative euvolemia.40 These findings indicate that achieving strict control of volume status may help reducing the influence of underlying myocardial oedema on native T1 assessment.

Associations between increased T2 and both troponin and B-type natriuretic peptide in patients with CKD have been described, hypothetically pointing towards a role for myocardial oedema in ongoing cardiac damage in the context of renal disease.26,39 These preliminary observational findings on T2 mapping in CKD need to be confirmed by further studies in order to establish any cause–effect relationship and fully assess whether oedema itself could contribute to myocardial remodelling by inducing structural changes within the interstitium.43

Longitudinal Changes in T1 and T2 Mapping

Several studies have explored longitudinal changes in mapping parameters in patients with CKD. Potentially, T1 and T2 mapping techniques

can provide useful surrogate endpoints to assess the response to any novel treatment approach, as well as to early identify incipient CKDrelated cardiac damage.33,44 In this context, native T1 effectively served as surrogate endpoint in a randomised trial exploring the effect of a program of intradialytic cycling, which was associated with reductions in LV mass, native T1 values and pulse wave velocity.45 In patients with moderate CKD, longitudinal examinations revealed stability of native T1 values, likely explained by the low severity of renal involvement, as well as the relatively short time interval between examinations.23 In ESRD, native T1 has been assessed in patients with incident HD (under HD from <1 year) in which 6 months of standard care was associated with a reduction in LV mass and troponin, albeit unchanged T1 on average; however, the difference in the LV mass index over the duration of the study was greater in those whose T1 time fell, suggesting ongoing positive cardiac remodelling effectively imaged by CMR.46 In addition, CMR provided surrogate endpoints in a study testing different HD modalities.47 Interestingly, nocturnal in-centre HD was associated with positive cardiac remodelling, including reductions in LV mass and native T1.47 Kidney transplantation (KT) has been described to have benefits on cardiac function and UC.48,49 There are only a few studies investigating the longitudinal changes in native T1 in patients undergoing KT, and the data are conflicting. In one study, native T1 was described as increased 2 months after KT.37 Others have described reductions in native T1 at least in a cluster of patients without diabetes and relatively low LV mass.50 Further analysis from that last cohort revealed that T1 values did fall after KT and that cardiac deformation improved.38 More studies with larger sample sizes and longer follow-up times are needed to assess the long-term cardiac effects of KT. Overall, T1 and T2 mapping techniques seem attractive to monitor longitudinal cardiac remodelling in patients with CKD. Combined assessment of native T1 and T2, as well as strict achievement of similar volume status between serial examinations, could be considered to reduce the influence of confounding variables.

Knowledge Gaps and Future Perspectives

Native T1 as a marker of diffuse myocardial fibrosis has been validated in several diseases, including aortic stenosis and dilated and hypertrophic cardiomyopathy.51,52 Although a similar association is highly likely present in UC too, no studies to date have attempted to provide such a validation.

Of note, a trial is underway in which postmortem evaluation of myocardial fibrosis will be compared with CMR mapping (NCT03586518); this assessment would help to further strengthen the concept that native T1 can track the progression of diffuse myocardial fibrosis in patients with renal disease. UC is a diffuse disease, in which, according to currently available data, focal LGE areas may be present but not involved in determining prognosis.29 Conversely, native T1 has been shown to be related to increased N-terminal pro B-type natriuretic and reduced physical function in UC, suggesting that it could potentially be a valuable marker of clinical status in CKD.25,26 Native T1 has been demonstrated to be a prognostic marker in several clinical conditions.28,53–55 However, to date, no study is available investigating the prognostic role of native T1 in UC. Preventing sudden cardiac death in patients with UC is an unmet need.56 Changes in cardiac morphology are associated with ECG abnormalities, further exaggerated by the occurrence of electrolyte imbalance, especially in people undergoing HD.57

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Cardiac MRI Mapping in Chronic Kidney Disease The influence of diffuse fibrosis in the genesis of major arrhythmias is an attractive subject of investigation, and a study deriving post-contrast T1 values from inversion time (TI) scout images of patients undergoing ventricular tachycardia ablation found reduced survival free from recurrence in those patients with lower values, which indicate higher fibrosis burden.58 In patients with CKD, an association between increased native T1 and longer QT interval has been described.20 However, more specific research on this topic is currently lacking.

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Conclusion

CMR T1 and T2 mapping techniques expanded our ability to provide early identification and sensible tracking of disease progression in UC. An increase in native T1 represents the development of diffuse interstitial fibrosis, whereas a contribution of myocardial oedema, identified by increased T2 mapping values, is likely present at least in a subset of patients. Outcome studies are needed to assess the prognostic relevance of T1 and T2 mapping in patients with UC.

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37. Hayer MK, Radhakrishnan A, Price AM, et al. Early effects of kidney transplantation on the heart – a cardiac magnetic resonance multi-parametric study. Int J Cardiol 2019;293:272–7. https://doi.org/10.1016/j.ijcard.2019.06.007; PMID: 31272740.

38. Barbosa MF, Contti MM, de Andrade LGM, et al. Featuretracking cardiac magnetic resonance left ventricular global longitudinal strain improves 6 months after kidney transplantation associated with reverse remodeling, not myocardial tissue characteristics. Int J Cardiovasc Imaging 2021;37:3027–37. https://doi.org/10.21203/rs.3.rs-211311/v1; PMID: 33997925.

39. Han X, He F, Cao, et al. Associations of B-type natriuretic peptide (BNP) and dialysis vintage with CMRI-derived cardiac indices in stable hemodialysis patients with a preserved left ventricular ejection fraction. Int J Cardiovasc Imaging 2020;36:2265–78. https://doi.org/10.1007/s10554020-01942-1; PMID: 32686028.

40. Graham-Brown MPM, Gulsin GS, Poli F, et al. Differences in native T1 and native T2 mapping between patients on hemodialysis and control subjects. Eur J Radiol 2021;140:109748. https://doi.org/10.1016/j.ejrad.2021.109748; PMID: 33962255.

41. Kotecha T, Martinez-Naharro A, Yoowannakul S, et al. Acute changes in cardiac structural and tissue characterisation parameters following haemodialysis measured using cardiovascular magnetic resonance. Sci Rep 2019;9:1388. https://doi.org/10.1038/s41598-018-37845-4; PMID: 30718606.

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LETTER

Therapy

Extracorporeal Membrane Oxygenation as a Treatment for Branch Pulmonary Artery Rupture Following Right Heart Catheterisation Vineet Agrawal ,1 Kelly A Costopoulos,1 Mohammed Chowdhary,1 Keki Balsara,2 Kelly Schlendorf,1 JoAnn Lindenfeld 1 and Jonathan N Menachem 1 1. Division of Cardiology, Department of Medicine, Vanderbilt University Medical Centre, Nashville, TN, US; 2. Department of Cardiothoracic Surgery, Vanderbilt University Medical Centre, Nashville, TN, US

Keywords

Right heart catheterisation, pulmonary artery injury, heart failure, extracorporeal membrane oxygenation, pulmonary hypertension.

Disclosure: The authors have no conflicts of interest to declare.

Received: 12 October 2021 Accepted: 15 November 2021 Citation: Cardiac Failure Review 2022;8:e03. DOI: https://doi.org/10.15420/cfr.2021.25 Correspondence: Jonathan N Menachem, Heart Failure and Transplantation Section, Vanderbilt Heart and Vascular Institute, Medical Centre East, South Tower, 1215 21st Avenue South, 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.

With this letter, the authors would like to express their views to the Editorin-Chief on the use of extracorporeal membrane oxygenation (ECMO) as a treatment for branch pulmonary artery rupture following right heart catheterisation (RHC). Iatrogenic pulmonary artery injury is a rare, but potentially life-threatening, complication of RHC, associated with high mortality due to limited options for acute management. The authors would like to highlight acute considerations in response to iatrogenic pulmonary artery injury after RHC, and identify an effective therapy in veno-arterial ECMO (VA-ECMO) that may help to stabilise patients acutely by decompressing the right ventricle and pulmonary circulation.

We present the case of a 64-year-old woman with dilated non-ischaemic cardiomyopathy, chronic kidney disease and a history of ventricular tachycardia, who was referred for evaluation of candidacy for advanced heart failure (HF) therapies. She was diagnosed with HF in 2006 and had remained clinically stable on guideline-directed medical therapies until 2017, at which time HF symptoms became rapidly progressive and she had multiple HF-related admissions.

Informed consent was obtained from the patient for the presentation of the patient’s data in the current manuscript, and no identifiable information is included. We declare that this work was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).

At the time of her evaluation, echocardiogram was notable for a severely dilated left atrium and left ventricle, with severely depressed function, normal right ventricular function and severe secondary mitral regurgitation (Table 1). She underwent RHC, which demonstrated mild pulmonary hypertension, low cardiac output with a cardiac index of 1.78 l/min/m2, normal pulmonary arterial wedge pressure, elevated pulmonary vascular resistance and elevated systemic vascular resistance (Table 1). Despite attempts to optimise medically with afterload reduction, the patient remained symptomatic and returned for RHC 2 weeks later with a plan for nitroprusside challenge to evaluate the reversibility of her pulmonary

hypertension. Pre-procedural vital signs were normal (Table 2) and cardiac telemetry showed an atrial-sensed, biventricular-paced rhythm. A pulmonary artery (PA) catheter was successfully inserted via the right internal jugular vein, and advanced with the balloon inflated under fluoroscopic guidance through the right atrium, right ventricle and into the PA. Her right atrium pressure was 4 mmHg, and PA pressure was 53/25 mmHg with a mean of 39 mmHg. With deflation of the balloon, the catheter spontaneously advanced into the right posterior basal pulmonary artery and was rapidly withdrawn to the proximal PA without resistance.

Almost immediately, the patient began coughing and had new-onset haemoptysis consistent with presumed iatrogenic branch PA injury.

Under fluoroscopic guidance, the PA catheter balloon was re-inflated and advanced to the site of the suspected injury in an attempt to tamponade the location of the bleeding. The patient was then placed in the right lateral decubitus position, allowing the injured right lung to be in the dependent position. Femoral arterial and venous access were obtained, and fluid resuscitation was begun and blood ordered. Given the inability to control bleeding, leading to airway compromise, left main stem bronchus intubation was performed, followed by double-lumen endotracheal intubation. Despite stable haemoglobin, heart rate and blood pressure, the patient developed a combined respiratory and metabolic acidosis within 20 minutes of branch PA injury (Table 2), and the decision was made to perform peripheral cannulation for VA-ECMO. Notably, heparin was not administered with large bore ECMO cannulation due to ongoing bleeding. With the initiation of ECMO, the patient’s haemoptysis decreased significantly, with subsequent improvement in oxygenation and acidosis (Table 2).

Bronchoscopy was performed through the right endotracheal tube lumen, and approximately 150 ml of blood and clots was suctioned out of the right lung. The patient stabilised on VA-ECMO support over the next 18 hours, and repeat bronchoscopy showed resolution of active bleeding 12 hours after the PA injury. The patient was able to be weaned off inotropic support and decannulated from ECMO. Despite her complicated

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

VA-ECMO as a Treatment for Right Heart Catheterisation-related PA Injury Table 1: Baseline Echocardiographic and Right Heart Catheterisation Measurements Right Heart Catheterisation

Measurements

RA pressure (mmHg)

3

PA pressure (mmHg)

40/16, mean 23

PAWP (mmHg)

13

Fick cardiac output (l/min)

Massive haemoptysis from iatrogenic PA injury

3.9

Fick cardiac index (l/min/m )

1.78

Pulmonary vascular resistance (Wood units)

3.2

Systemic vascular resistance (dynes·s·cm–5)

1,642

2

18

LVIDd (cm)

8.1

LVIDs (cm)

7.71

LV mass index (g/m2)

167.76

LA volume index (ml/m2)

92.78

TR velocity (m/s)

3.02

RVSP (mmHg)

40

TAPSE (cm)

2.5

Haemodynamic management: 1. Advance PA catheter with balloon inflated to site of injury to internally tamponade

Airway management: 1. Suction airway 2. Turn patient to lay injured side down

2. Obtain additional central venous and arterial access (preferably femoral, as this can be used for ECMO)

3. Intubate for airway protection – consider double-lumen endotracheal tube

Echocardiography LVEF, biplane (%)

Figure 1: Proposed Flow Chart for Management of Iatrogenic Pulmonary Artery Injury During Right Heart Catheterisation

3. Fluid resuscitate

4. Monitor oxygenation and ventilation with serial ABGs

4. Reverse coagulopathy

5. Bronchoscopy for visualisation and tamponade of injured PA

LA = left atrial; LV = left ventricular; LVEF = left ventricular ejection fraction; LVIDd = left ventricular internal dimension end diastole; LVIDs = left ventricular internal dimension end systole; PA = pulmonary artery; PAWP = pulmonary artery wedge pressure; RA = right atrial; RVSP = right ventricular systolic pressure; TAPSE = tricuspid annular plant systolic excursion; TR = tricuspid regurgitation.

Table 2: Vital Signs, Laboratory Values, and Haemodynamic Data Before, During and After Right Heart Catheterisation

5. Consider angiography to localise bleed

Patient haemodynamically stable, oxygenating and bleeding controlled?

Yes

Monitor in ICU

No Consider: 1. Balloon tamponade by PA catheter 2. ECMO cannulation for RV/PA decompression and maintenance of end-organ perfusion decompress RV and PA Alternatively, consider percutaneous covered stent versus emergent surgery for definitive management of bleeding

Pre-procedure

Post-PA Injury

Post-ECMO

Heart rate (BPM)

98

105

95

BP (mmHg)

129/79

135/98

106/75

O2 saturation (%)

96

81

99

Haemoglobin (g/dl)

10.1

10.1

10.3

Lactate (mmol/l)

–

6.5

3.6

Arterial pH

–

7.06

7.34

Arterial pO2 (mmHg)

–

61

221

Arterial pCO2 (mmHg)

–

77

38

Arterial HCO3 (mmol/l)

–

22

20

RA (mmHg)

–

4

–

RV (mmHg)

–

48/10

–

PA (mmHg)

–

53/25, mean 39

–

ABGs = arterial blood gases; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; PA = pulmonary artery; RV = right ventricle.

Discussion

Measurement of invasive haemodynamics via RHC is a common procedure for both the diagnosis and management of patients with advanced HF, and is a guideline-recommended procedure for evaluation for heart transplant.1 While generally considered to be a low-risk procedure, PA catheters may lead to complications, including arrhythmia, pneumothorax, heart block, lung infarction, thrombosis, air embolism (either through entrainment of air in the catheter or balloon rupture), infection, catheter knotting and pulmonary artery damage.2

BP = blood pressure; ECMO = extracorporeal membrane oxygenation; PA = pulmonary artery; RA = right atrium; RV = right ventricle.

course, she required only 2 units of packed red blood cell transfusion with a haemoglobin nadir of 9.2 mg/dl, renal function was stable with a creatinine level of 1.3–1.5 mg/dl and estimated glomerular filtration rate of 40–50 ml/min/1.73 m2, and she remained neurologically intact. She was treated with antibiotics for possible hospital-acquired pneumonia versus pneumonitis caused by the PA injury. The patient was ultimately restarted on guideline-directed medical therapies for HF, and discharged to complete rehabilitation therapy. She returned to complete her advanced HF therapy evaluation and was approved for transplant listing, with plans for a left ventricular assist device as a bridge to transplant.

Although branch PA injury is a complication of RHC that is estimated to only occur in approximately 0.5% of cases, mortality associated with this event is as high as 70%.2,3 Risk factors for PA injury during RHC include the presence of pulmonary hypertension, concomitant anticoagulant therapy, advanced age, mitral valve disease and hypothermia.4 Management of branch PA injury requires immediate action, as acute massive haemoptysis will compromise the airway and may quickly lead to haemodynamic instability (Figure 1). Initial management includes identifying the side of bleeding and positioning the patient with the injured lung down. The next step is to establish an airway via either unilateral lung ventilation (through selective contralateral main stem intubation) or double-lumen endotracheal intubation (to allow separate control of both lungs). Accurate measurement of oxygenation is a crucial determinant of stability, and can be accomplished with serial arterial

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VA-ECMO as a Treatment for Right Heart Catheterisation-related PA Injury blood gases. The next step is to ensure adequate venous and arterial access to allow for fluid and blood resuscitation, as well as invasive blood pressure monitoring. If allowable either through the existing PA catheter or through a separate catheter, angiography can be considered to localise the site of bleeding. Finally, reversal of any coagulopathy is necessary, and attempts should be made to control the site of bleeding. Options include endobronchial management with mechanical tamponade or administration of procoagulants, percutaneous balloon tamponade or covered stent placement, emergent surgery and VA-ECMO.5–7 While cannulation of VA-ECMO occurred from femoral sites in our case, the existing internal jugular sheath can also be exchanged for a short, large venous cannula with inflow into the ECMO circuit.

ECMO has been shown to be a life-saving strategy to promote recovery of lung injury, but its utility in the acute treatment of massive haemoptysis has largely only been reported in postoperative management of haemorrhage following pulmonary endarterectomy and patients already being supported by VA-ECMO.8,9 In both the cases of post-endarterectomy or pulmonary haemorrhage while on VA-ECMO support, maximising support through the reduction in blood flow via the right ventricle and pulmonary circulation allowed for successful recovery.8,9 While heparin administration is generally required for large-bore ECMO cannulation, heparin administration in our case was contraindicated due to ongoing 1.

Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update. J Heart Lung Transplant 2016;35:1–23. https://doi.org/10.1016/j. healun.2015.10.023; PMID: 26776864.

2. American Society of Anesthesiologists Task Force on Pulmonary Artery Catheterization. Practice guidelines for pulmonary artery catheterization: an updated report by the American Society of Anesthesiologists Task Force on Pulmonary Artery Catheterization. Anesthesiology 2003;99:988–1014. https://doi.org/10.1097/00000542200310000-00036; PMID: 14508336.

3. Kelly TF, Morris GC, Crawford ES, et al. Perforation of the pulmonary artery with Swan-Ganz catheters: diagnosis and surgical management. Ann Surg 1981;193:686–92. https://doi. org/10.1097/00000658-198106000-00003; PMID: 7018424.

bleeding. At higher flow rates, ECMO circuits can be placed without heparinisation, but carry a risk of spontaneous clotting of the circuit.

Despite this risk, our case report highlights that early deployment of VAECMO may additionally be a valuable treatment in the management of PA catheter-associated iatrogenic PA injury.

VA-ECMO decreases blood flow through the right ventricle and pulmonary circulation by directly removing blood from the right atrium and redirecting it into the aorta after oxygenation. This strategy accomplishes two critical goals in cases of PA rupture. First, it allows for control of bleeding through a reduction in pulmonary blood flow. Second, it preserves adequate circulation to the rest of the body. While these potential benefits must be weighed against the known risks of ECMO, including bleeding and coagulopathy, ECMO may be an effective strategy to stabilise patients with PA injury and massive haemoptysis after having failed more conservative measures (Figure 1).10 In summary, we report the case of a patient with advanced non-ischaemic cardiomyopathy who suffered PA injury due to PA catheterisation and survived after being placed on VA-ECMO. Given the extremely high mortality associated with this rare, but highly lethal, complication of a commonly performed procedure, awareness of immediate management strategies, including the use of ECMO, may lead to improved outcomes.

4. Kearney TJ, Shabot MM. Pulmonary artery rupture associated with the Swan-Ganz catheter. Chest 1995;108:1349–52. https://doi.org/10.1378/chest.108.5.1349; PMID: 7587440.

5. Crawford TC, Grimm JC, Magruder JT, et al. A curious case of acute respiratory distress syndrome. J Surg Case Reports 2015;2015:rjv140. https://doi.org/10.1093/jscr/rjv140 PMID: 26552407.

6. Ejiri K, Ogawa A, Matsubara H. Bail-out technique for pulmonary artery rupture with a covered stent in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. JACC Cardiovasc Interv 2015;8:752– 3. https://doi.org/10.1016/j.jcin.2014.11.024; PMID: 25946450.

7. Bianchini R, Melina G, Benedetto U, et al. Extracorporeal membrane oxygenation for Swan-Ganz induced intraoperative hemorrhage. Ann Thorac Surg 2007;83:2213–

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4. https://doi.org/10.1016/j.athoracsur.2007.01.023; PMID: 17532432.

8. Pretorius V, Alayadhi W, Modry D. Extracorporeal Life support for the control of life-threatening pulmonary hemorrhage. Ann Thorac Surg 2009;88:649–50. https://doi. org/10.1016/j.athoracsur.2008.12.066; PMID: 19632431.

9. Pitcher HT, Harrison MA, Shaw C, et al. Management considerations of massive hemoptysis while on extracorporeal membrane oxygenation. Perfusion 2016;31:653–8. https://doi.org/10.1177/0267659116651484; PMID: 27229004.

10. Thomas J, Kostousov V, Teruya J. Bleeding and thrombotic complications in the use of extracorporeal membrane oxygenation. Semin Thromb Hemost 2018;44:20–9. https://doi. org/10.1055/s-0037-1606179; PMID: 28898902.

EXPERT OPINION

Management

Out with the Old and In with the New: Primary Care Management of Heart Failure with Preserved Ejection Fraction Simon Stewart ,1 Amy R Stewart,2 Laura Waite

3

and Justin Beilby

1,4

1. Torrens University Australia, Adelaide, Australia; 2. Reynella Family Care, Adelaide, Australia; 3. South Eastern Melbourne Primary Health Network, Melbourne, Australia; 4. Highbury Family Practice, Adelaide, Australia

Abstract

Primary care plays an integral role in the management of complex, chronic disease states such as heart failure. However, there is a disconnect between the characteristics of those recruited into clinical trials and those managed in the real world, which means the contribution and consideration of primary care in current guidelines is suboptimal. In this article, the authors explore key issues in the diagnosis and management of heart failure that need to be addressed from a primary care perspective. This article focuses on the issue of heart failure with preserved ejection fraction and the integration of new clinical epidemiology and trial evidence into clinical practice. In response, the authors advocate for dedicated guidelines for the primary care management of heart failure, the development of strategies to facilitate communications between health professionals in acute and community care and a renewed focus on researching optimal models of heart failure care in the community.

Keywords

Heart failure, preserved ejection fraction, expert guidelines, primary care, general practice Disclosure: SS reports financial support from industry relevant to this article in the form of an investigator-led grant from Novartis Australia; is supported by the NHMRC of Australia (GNT 1135894); has received speaking fees or honoraria from Edwards Lifesciences and Novartis; has received consultancy fees from Edwards Lifesciences (UK and Australia) and Novartis Australia; reports participation on a data safety monitoring board or advisory board at Edwards Lifesciences; and is on the Cardiac Failure Review editorial board; this did not influence peer review. LW is a member of Inner South-East Metropolitan Partnership. All other authors have no conflicts of interest to declare.

Received: 11 October 2021 Accepted: 19 November 2021 Citation: Cardiac Failure Review 2022;8:e04. DOI: https://doi.org/10.15420/cfr.2021.27 Correspondence: Simon Stewart, Torrens University Australia, Wakefield Campus, Wakefield Rd, Adelaide, SA 5000, Australia. E: simon.stewart@torrens.edu.au 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.

This article explores the implications of the new European Society of Cardiology (ESC) guidelines for the diagnosis and management of heart failure (HF) from a primary care perspective.1 We specifically discuss the clinical conundrums around accurately identifying and managing patients with HF and preserved ejection fraction (HFpEF) in this context.

We also consider how the latest trial evidence around treating such patients, many of whom are women, will shape contemporary and future clinical practice.

Heart Failure and Primary Care

The overall management of HF, a complex syndrome associated with poor outcomes in all its forms, remains problematic. This particularly applies in the primary care context. As with any other debilitating chronic condition, an individual’s journey with HF, while often punctuated by acute hospital episodes and premature mortality (frequently in winter), typically occurs in a community setting.2 With a broadly informed evidence base, primary care (including general practice) is designed to improve health and wellbeing, prevent disease progression, prolong life and minimise costly hospital episodes in the most vulnerable people. This must include individuals living with HF and the common clusters of other diseases (in the form of multimorbidity) that both drive and exacerbate the syndrome.3

It is from the perspective of the central importance of primary care in the optimal management of chronic HF that a review of the recently published ESC guidelines is concerning.1 These guidelines amount to more than 100 pages of expert opinion supported by 1,001 key references. Surprisingly, however, primary care is specifically mentioned in these guidelines only in respect to:

• The diagnostic value of natriuretic peptides (in the presence of the

typical signs and symptoms of HF) when a threshold of 35 pg/ml for brain-natriuretic peptide (BNP) and 125 pg/ml for NT-proBNP is reached.4,5 • The general follow-up of patients with chronic HF (with no specific evidence from primary care referenced).6 While this does not necessarily mean that these and equivalent guidelines from other learned societies completely discount the role of primary care, it most probably does reflect the specialisation of HF management and a predominant focus on individuals who require acute hospital care.

Notably, with few exceptions, there are no GP authors of these guidelines.

This is of clinical importance, given that it has been shown in a large, realworld patient cohort that the demographic and clinical profile of people diagnosed with HF in primary care is different from that of those diagnosed in hospital, while both have equally poor 5-year survival rates.7

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

HFpEF in Primary Care When one directly compares the demographic and clinical profile of the broader HF population with those recruited into contemporary clinical trials, regardless of the type of HF being treated, HF trial participants are predominantly younger, and more likely to be male and have lower levels of multimorbidity.7–10 The evidence trail and clinical experiences of those writing the guidelines are, therefore, potentially skewed away from a broader and potentially more complex primary care perspective.

Paucity of Primary Care Trials

It is worth highlighting some isolated examples of primary-care-focused HF research relevant to the two topics (diagnostic screening and longterm follow-up) and why, perhaps, few equivalent studies have been reported since.

In the STOP-HF trial, Ledwidge et al. tested the efficacy of a collaborative care model guided by BNP screening in a cohort of 1,374 individuals with cardiovascular risk recruited from 39 primary care clinics in Ireland.11 Overall, the primary endpoint of left ventricular (LV) dysfunction with or without HF occurred in 59 out of 677 (8.7%) patients in the control group versus 37 out of 697 (5.3%) patients in the intervention group (reduced risk of 45%, 95% CI [18–63%]; p=0.003).11 However, as highlighted by a recent position statement from the ESC Heart Failure Association, the primary prevention of HF has remained problematic, with no definitive role articulated for primary care in the decade since this important study was published.12 Similarly, at the genesis of multidisciplinary HF management programmes (now considered a gold-standard component in the care of HF patients discharged from hospital), Doughty et al. reported on the Auckland Heart Failure Management Study conducted in New Zealand.1,13 In a cluster randomised trial, they tested the efficacy of an integrated primary and secondary programme (including alternate GP and HF clinic visits).

Unfortunately, the primary composite endpoint of death or hospital readmission within 12 months was not met.13 This contrasted with the positive results of contemporary trials of nurse-led programmes of care (particularly those with multidisciplinary teams and a component of home visits).1 Once again, therefore, there remains a vacuum in primary-care-focused HF management programmes. For example, a recent systematic review of disease management programmes in primary care revealed that most published trials did not test hard endpoints (hospitalisation or death) and focused on single disease states, such as diabetes and asthma, rather than complex conditions like HF.14 It is well established that a relatively small number of actively managed patients with complex health issues such as HF consume a disproportionate amount of healthcare resources.

For example, in Australia 31–37% of patients visit their GP 4–11 times a year, and 10–14% of patients visit ≥12 times/annum.15 As Koudstaal et al. recently suggested, HF patients predominantly managed within the primary care setting have a very poor prognosis.7 Key research questions remain unanswered, such as how these highcost/high-risk individuals can be readily identified and appropriately managed to improve their quality of life, avoid recurrent hospitalisation and premature mortality via the practical application of gold-standard therapies adapted to the skills and resources of GPs and primary healthcare teams (including pragmatic treatment uptitration and discontinuation protocols).

As the large, multicentre VIPER-BP study demonstrated, it is possible to apply decision-support tools in primary care to safely uptitrate antihypertensive therapy to improve blood pressure control in high-risk

individuals and thereby reduce their future risk of HF.16 This approach applies to most if not all the main antecedents of advanced heart disease.

However, the uptake of such pragmatic and proven strategies often fails when there is no funding mechanism to support their uptake.

As an alternative, the much-supported option of guideline-directed medical therapy for HF should, in theory, be easier to apply in primary care given the availability of subsidised and approved therapies.17 However, as typically occurs in the primary care HF population, this strategy is not so easily applied when a GP is faced with an ‘atypical’ patient who would have been excluded from a clinical trial because of their advanced age, type of HF (e.g. predominantly right sided) and multimorbidity.17 Overall, therefore, there is a paucity of evidence to inform the most costeffective methods to rapidly diagnose and optimally manage HF patients in primary care.

Redefining the Syndrome

The definition of HF continues to evolve as our physiological and clinical understanding of the syndrome increases. In the latest ESC guidelines, three main phenotypes of HF are identified (all or which require the typical signs and symptoms of HF including dyspnoea and signs of congestion):

• Heart failure with reduced ejection fraction (HFrEF): characterised by a left ventricular ejection fraction (LVEF) ≤40%.

• Heart failure with mildly reduced ejection fraction (HFmrEF): characterised by a LVEF of 41–49%.

• HFpEF: characterised by a LVEF ≥50% in addition to structural cardiac abnormalities such as LV hypertrophy and/or diastolic dysfunction/ impaired LV filling.1

It is the last of these – HFpEF – that challenges even the most experienced physicians; it typically requires careful interpretation of an echocardiogram and the patient’s clinical profile. The NEDA study demonstrated that individuals presenting with a LVEF <65% are at increased risk of mortality (with clear sex-based differences evident given women had higher mortality rates at higher LVEF levels).18 However, identifying patients with HFpEF (LVEF ≥50%) who would benefit from the results of trials, such as PARAGON (see below) and EMPEROR-PRESERVED, based on their inclusion criteria, is challenging.8,9 For GPs contending with multiple disease states, there is a clear need to simplify the messaging around who has potentially treatable HF through a streamlined interpretation of BNP levels and subsequent echocardiographic reports, with close consideration of the funding mechanisms and cost implications within different healthcare systems.

For example, in Australia, the recommended BNP screening as the firstline investigation for clinically suspected HF is not reimbursed. Furthermore, GPs need to carefully balance financial constraints with patient care. In particular, people in lower socioeconomic groups and older patients who are more susceptible to HF often cannot afford expensive investigations and multiple new medications, even if these are clinically superior.

Addressing these barriers to applying gold-standard management is becoming increasingly urgent as our understanding and evidence-based approaches to this common condition continues to evolve so rapidly.

Treating HFpEF

In recent years, the management of patients with HFrEF has been transformed with the positive results of the PARADIGM trial of angiotensin

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HFpEF in Primary Care Figure 1: Indicative Clinical Epidemiology and Therapeutic Management of Heart Failure Subtypes 80,000

Men

80,000

60,000

60,000

40,000

40,000

20,000

20,000

0

LVEF

20% 30% 40% 50% 60%

10.5% rEF 10.0% mrEF 24.3% pEF/↑ risk

70%

Women

0

80% High-probability HFrEF

Apply gold standard treatment Potential HFmrEF Consider gold standard treatment Potential for HFpEF/↑ mortality Consider SGLT2 inhibitor

LVEF

20% 30%

4.4% rEF 5.3% mrEF

40% 50% 60% 70%

80%

Regardless of LVEF, consider SGLT2 inhibitor/ neurohormonal agonists

39.9% pEF/↑ risk

This figure shows the frequency distribution of left ventricular ejection fraction levels within the large (>500,000 cases) National Echo Database Australia (NEDA) patient cohort investigated with echocardiography.18 An ongoing project, the Australia-wide, multicentre NEDA study has individually linked cardiac structure and function profiling to long-term mortality among >1 million patients routinely referred for echocardiography (many by their GPs) to investigate potential and existing heart disease. Consistent with the overall epidemiology of heart failure, it shows a preponderance of men with a rEF or mrEF in whom treatment guidelines are more precise. It also highlights the probable difference in the number of men and women (who are older and less represented in randomised controlled trials) with HFrEF and a higher risk of mortality who would benefit from emerging therapies, such as the SGLT2 inhibitors. HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; mrEF = mildly reduced ejection fraction; pEF = preserved ejection fraction; rEF= reduced ejection fraction; SGLT2 = sodium-glucose transport protein 2.

receptor-neprilysin inhibitors (ARNIs) and the EMPEROR-Reduced/DAPAHF trials of sodium–glucose co-transporter 2 (SGLT2) inhibitors.19,20 These agents have now joined angiotensin-converting enzyme inhibitors, betablockers and mineralocorticoid receptor antagonists as the main treatment options for HFrEF – with a continued role for loop diuretics in patients with fluid retention and adjunctive device-based therapies in specific individuals.1 The same principles of management of HFrEF (with the caveat ‘considered’ applied in the guidelines) now largely apply to patients with HFmrEF depending on local therapeutic approvals and authorisation.1 As recently highlighted, any decline in the LVEF among this borderline group is of prognostic importance, with proactive prevention and management of coronary artery disease to preserve an individual’s LVEF critical.1,21 Consistent with a more complex definition and diagnosis algorithm, the therapeutic management of HFpEF remains difficult.1 Compared to those patients presenting with HFrEF/HFmrEF, those with HFpEF are typically women, older and have a higher burden of multimorbidity.1 This includes diabetes, hypertension, AF, chronic kidney disease and non-cardiac conditions, such as chronic lung disease.1,3 To date, management of such cases has been founded on the evidence-based treatment of these conditions rather than of HFpEF per se.

Despite strong evidence of the efficacy of ARNIs and other neurohormonalmodulating therapies in improving outcomes among those with LVEF indicative of HFmrEF (LVEF 40–49%) – as demonstrated by careful analyses of the PARAGON-HF trial and the combined trial evidence – HFpEF has proven to be a graveyard for HF therapies and patients alike.8,22 However, the emergence of SGLT2 inhibitors has finally offered evidence-based, therapeutic options for these patients.20 First,

independent of an individual’s LVEF, SGLT2 inhibitors have been proven to reduce clinical events in patients with diabetes, those at similarly high-risk of experiencing a cardiac event, chronic kidney disease, those with an established form of cardiovascular disease and with a history of hospitalisation for HF (all characteristics of HFpEF).20 Careful analyses of the impact of neurohormonal antagonists according to an individual’s LVEF and the recently completed EMPEROR-Preserved trial provide both encouragement and caveats to the effective scope and treatment of HFpEF.9,22 In this ground-breaking RCT, the efficacy of SGLT2 inhibitor empaglifozin was tested in 5,988 patients with New York Heart Association class II–IV dyspnoea and an LVEF >40%.15 Overall, the SGLT2 inhibitor was associated with a significant 21% reduction (actual rates 13.8% versus 17.1%) in the composite primary endpoint of cardiovascular death or hospitalisation for HF during median 26-month follow-up. The impending results of the equivalent DELIVER trial, which is examining the potential benefits of dapagliflozin therapy among a similar patient cohort, will further clarify the role of SGLT2 inhibitors in treating HFpEF.23 This does not tell the whole story, however. Serious adverse events were reported in around 50% of EMPEROR-Preserved participants with similar rates reported in both treatment arms and treatment being discontinued in 18.4–19.1% of participants. In the treatment arm, there was an increased rate of genital and urinary tract infections and episodes of hypotension.9 Such events would invariably be reported to and managed by a GP in routine clinical practice. Thus, as with any new agent or clinical indication in HF, there is an inherent expectation on primary care to consider and manage complicated issues around the benefits versus risks of continuing agents, such as the SGLT2 inhibitors, while attempting to interpret trial evidence derived from typically younger, less complicated patients.17

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HFpEF in Primary Care As recently posed by Petrie et al. before the EMPEROR-Preserved trial results were reported, the key question is: do SGLT2 inhibitors work across the entire spectrum of HFpEF?20 Critically, the probable answer is a qualified ‘no’. In a prespecified sub-analysis of the EMPEROR-Preserved trial, the greatest benefits occurred in those with an LVEF <50% (HR 0.71, 95% CI [0.57–0.88]) and 50–59% (HR 0.80, 95% CI [0.64–0.99]), but not entirely for those with an LVEF >60% (HR 0.87; 95% CI [0.69–1.10]).9 Moreover, consistent with sex-specific thresholds of mortality at more preserved levels of LVEF, women appeared to derive the greatest benefits from the SGLT2 inhibitor (25% versus 19% hazard reduction in the primary endpoint).22 Assimilating all the available data (from the clinical epidemiology of LVEF levels and associated mortality to contemporary HF guidelines and emerging trial evidence) is not easy from a primary care perspective.

Figure 1, based on the distribution of LVEF observed in the large National Echo Database Australia cohort, provides a broad summary of how the spectrum of HF cases (including those with HFpEF) might be managed from a primary care perspective when considering: the latest ESC classification of HF and the current evidence in favour of neurohormonal blockade according to LVEF levels.1,22

New Solutions for an Old Problem

Despite the encouraging results of the EMPEROR-Preserved trial and 1.

2.

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McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https:// doi.org/10.1093/eurheartj/ehab368; PMID: 34447992.

Loader J, Chan YK, Hawley J, et al. Prevalence and profile of ‘seasonal frequent flyers’ with chronic heart disease: analysis of 1598 patients and 4588 patient-years follow-up.

Int J Cardiol 2019;20:906–20. https://doi.org/10.1016/j. ijcard.2018.12.060; PMID: 30638747.

Stewart S, Riegel B, Boyd C, et al. Establishing a pragmatic framework to optimise health outcomes in heart failure and multimorbidity (ARISE-HF): a multidisciplinary position statement. Int J Cardiol 2016; 212:1–10. https://doi. org/10.1016/j.ijcard.2016.03.001; PMID: 27015641.

Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1349–53. https://doi. org/10.1016/S0140-6736(97)06031-5; PMID: 9365448.

Zaphiriou A, Robb S, Murray-Thomas T, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7:537– 41. https://doi.org/10.1016/j.ejheart.2005.01.022; PMID: 15921792.

Schou M, Gustafsson F, Videbaek L, et al. Extended heart failure clinic follow-up in low-risk patients: a randomized clinical trial (NorthStar). Eur Heart J 2013; 34:432–42. https:// doi.org/10.1093/eurheartj/ehs235; PMID: 22875412.

Koudstaal S, Pujades-Rodriguez M, Denaxas S, et al.

Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-based linked electronic health record cohort study in 2.1 million people. Eur J Heart Fail 2017;19:1119–27. https://doi. org/10.1002/ejhf.709; PMID: 28008698.

Solomon SD, McMurray JJV, Anand IS. Angiotensin-

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attempts to simplify the classification of HF overall, the clinical conundrums posed by HFpEF remain.1,15 This is particularly true for GPs and primary care teams, who continue to interact with and manage those with a potential or established diagnosis of HFpEF. Current guidelines such as those produced by the ESC provide little direction in this regard.1 There is a clear need to rectify this through a specific interpretation of recommendations and pragmatic clinical algorithms that are relevant to primary care. Any such recommendations would need to be supported by dedicated academic detailing and evidence-based translation programmes in the primary care setting.

This is even more urgent with the emergence of novel therapeutic agents, such as the SGLT2 inhibitors. In this context, there is also potential to develop better lines of communication and levels of trust between GPs and cardiologists. This could include easier access to echo investigations and informative diagnoses for GPs to ensure that evidence-based therapeutics are appropriately prescribed, modified and managed in high-risk patients with all forms of HF. Moreover, renewed funding of research focusing on primary care is urgently required to address the critical lack of evidence to guide the optimal management of the growing number of older people with HFpEF and, typically, high levels of multimorbidity who experience poor health outcomes.3

neprilysin inhibition in heart failure with preserved ejection fraction. N Eng J Med 2019;381:1609–20. https://doi. org/10.1056/NEJMoa1908655; PMID: 31475794.

Anker SD, Butler G, Filippatos JP, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Eng J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038; PMID: 34449189.

Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.

Lancet 2020;396:819–29. https://doi.org/10.1016/S01406736(20)31824-9; PMID: 32877652.

Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66–74. https://doi.org/10.1001/jama.2013.7588; PMID: 23821090.

Piepoli MF, Adamo M, Barison A, et al. Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology. Eur J Preventive Cardiol 2022;24:143–68. https:// doi.org/10.1002/ejhf.2351; PMID: 35083829.

Doughty RN, Wright SP, Pearl A, et al. Randomized, controlled trial of integrated heart management: the Auckland Heart Failure Management Study. Eur Heart J 2002;2:139–46. https://doi.org/10.1053/euhj.2001.2712; PMID: 11785996.

Reynolds R, Dennis S, Hasan I, et al. A systematic review of chronic disease management interventions in primary care.

BMC Fam Pract 2018;19:11. https://doi.org/10.1186/s12875-0170692-3; PMID: 29316889.

Australian Institute of Health and Welfare. Primary health care in Australia. 2016. https://www.aihw.gov.au/reports/ primary-health-care/primary-health-care-in-Australia (accessed 10 January 2022).

Stewart S, Carrington MJ, Swemmer CH, et al. Effect of

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intensive structured care on individual blood pressure targets in primary care: multicentre randomised controlled trial. BMJ 2012;345:e7156. https://doi.org/10.1136/bmj.e7156; PMID: 23169801.

Samarendra P. GDMT for heart failure and the clinician’s conundrum. Clin Cardiol 2019;42:1155–61. https://doi. org/10.1002/clc.23268; PMID: 31524968.

Stewart S, Playford D, Scalia GM, et al. Ejection fraction and mortality: a nationwide register-based cohort study of 499 153 women and men. Eur J Heart Fail 2021;23:406–16. https://doi.org/10.1002/ejhf.2047; PMID: 33150657.

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.

Petrie MC, Lee MMY, Docherty KF. Sodium-glucose co-transporter 2 inhibitors – the first successful treatment for heart failure with preserved ejection fraction? Eur J Heart Fail 2021;23:1256–9. https://doi.org/10.1002/ejhf.2108; PMID: 33502794.

Strange G, Playford D, Scalia GM, et al. Change in ejection fraction and long-term mortality in adults referred for echocardiography. Eur J Heart Fail 2021;23:555–63. https:// doi.org/10.1002/ejhf.2161; PMID: 33768605.

Dewan P, Jackson A, Lam CSP, et al. Interactions between left ventricular ejection fraction, sex and effect of neurohumoral modulators in heart failure. Eur J Heart Fail 2020;22:898–901. https://doi.org/10.1002/ejhf.1776; PMID: 32115864.

Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail 2021;23:1217–25. https://doi.org/10.1002/ejhf.2249; PMID: 34051124.

REVIEW

Intervention

Clinical and Haemodynamic Effects of Arteriovenous Shunts in Patients with Heart Failure with Preserved Ejection Fraction Medhat Soliman ,1 Nizar Attallah ,2 Houssam Younes,1 Woo Sup Park1 and Feras Bader1 1. Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; 2. Nephrology and Renal Transplant Department, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates

Abstract

The arteriovenous shunt (AVS) is the most commonly used vascular access in patients receiving regular haemodialysis. The AVS may have a significant haemodynamic impact on patients with heart failure. Many studies have sought to understand the effect of AVS creation or closure on heart structure and functions, most of which use non-invasive methods, such as echocardiography or cardiac MRI. Data are mainly focused on heart failure with reduced ejection fraction and there are limited data on heart failure with preserved ejection fraction. The presence of an AVS has a significant haemodynamic impact on the cardiovascular system and it is a common cause of high-output cardiac failure. Given that most studies to date use non-invasive methods, invasive assessment of the haemodynamic effects of the AVS using a right heart catheter may provide additional valuable information.

Keywords

Arteriovenous shunt, echocardiography, heart failure, heart failure with preserved ejection fraction Disclosure: FB 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: 2 June 2021 Accepted: 21 November 2021 Citation: Cardiac Failure Review 2022;8:e05. DOI: https://doi.org/10.15420/cfr.2021.12 Correspondence: Feras Bader, Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, PO Box 112412, Abu Dhabi, United Arab Emirates.

E: baderf@clevelandclinicabudhabi.ae 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.

Chronic kidney disease (CKD) is a worldwide public health problem. The overall prevalence of CKD in the US adult population was 14.8%, using an estimated glomerular filtration rate of <60 ml/min/1.73 m2 as a definition for CKD.1,2 The prevalence of end-stage renal disease (ESRD) continues to increase. According to the US Renal Data System, the incidence rate is 357 per million per year.3 Of these ESRD patients, 63% were receiving haemodialysis, 7% peritoneal dialysis and 29.6% had a functioning kidney transplant.3 Patients with ESRD need long-term vascular access for haemodialysis.

The most commonly used vascular access is the arteriovenous shunt (AVS). The AVS is a connection between the arterial and venous systems created either using an anastomosis between a limb artery and superficial native vein (arteriovenous fistula; AVF) or insertion of graft (arteriovenous graft) as dialysis access, creating a left-to-right shunt.4 The presence of an AVS has a significant haemodynamic impact on the cardiovascular system – both short- and long-term. It is a common cause of high-output cardiac failure. The mechanism underlying this haemodynamic effect is based on shunting blood from a high-pressure artery via the AVF to a low-pressure vein, thus bypassing capillary beds and decreasing systemic vascular resistance (SVR). These haemodynamic changes stimulate a compensatory increase in heart rate, stroke volume and total plasma volume.5 The elevation in cardiac output (CO) associated with AVS depends upon the size of the shunt and the magnitude of the resultant reduction in SVR. Because blood flowing through the shunt

bypasses the capillary circulation, the total CO increases by the quantity of blood flowing through the shunt to maintain capillary perfusion.6 In high-output heart failure (HF), low SVR results in borderline preserved or depressed systemic arterial blood pressure and elevated cardiac filling pressures. Ineffective blood volume and pressure lead to activation of the sympathetic nervous system and the renin–angiotensin–aldosterone axis along with increased serum vasopressin (antidiuretic hormone) concentrations. This neurohormonal activation results in increased renovascular resistance and reduced renal blood flow and glomerular filtration rate, with retention of salt and water. Chronic volume overload may gradually cause ventricular enlargement, remodelling and HF.6

Definition of Heart Failure with Preserved Ejection Fraction

HF with preserved ejection fraction (HFpEF) is a clinical syndrome in patients with current or prior symptoms of HF with a left ventricular ejection fraction (LVEF) ≥50% and evidence of cardiac dysfunction as a cause of symptoms (e.g. abnormal LV filling and elevated filling pressures).7,8 Patients with HFpEF represent half of all HF patients worldwide. The remaining half have an LVEF <50%, which includes HF with reduced ejection fraction (HFrEF; LVEF ≤40%) and HF with mid-range ejection fraction (LVEF 41–49%).9,10

History of the Arteriovenous Fistula and Relation to Heart Failure

The AVF was first described and used as a reliable form of haemodialysis

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Effects of Arteriovenous Shunts in HFpEF Figure 1: Acute Effects of Arteriovenous Shunt Creation AVS creation

Shear stress NO

Immediate

SVR

Persistent

SVR

Afterload

BP SNS (HR, contractility)

what is considered to be a normal flow may worsen or precipitate HF in patients with pre-existing HF or heart disease.16 The risk of precipitating HF appears to be higher among patients who have an upper-arm AVF compared with forearm AVF.14,15 The higher risk associated with upper-arm AVFs appears to be related to higher blood flow. In an observational study of 562 pre-dialysis patients, the incidence of HF was much higher in patients who had a brachiocephalic AVF compared with those with a radial-cephalic AVF (40% versus 8%).14 Similar rates of HF have been observed among patients with AVFs compared with those with arteriovenous grafts.16 There are no data to assess whether the technique used to create the AVF (direct versus through translocation or transposition) has any relation with the development of HF.

Haemodynamic Changes After Arteriovenous Shunt Creation

The creation of AVS results in acute, sub-acute and chronic cardiovascular changes.

SV and blood flow

Acute Changes CO

VR to RV

RV dilatation AVS = arteriovenous shunt; BP = arterial blood pressure; CO = cardiac output; HR = heart rate; NO = nitric oxide; RV = right ventricle; SNS = sympathetic nervous system; SV = stroke volume; SVR = systemic vascular resistance; VR = venous return.

vascular access by Brescia et al. in 1966.11 Improvements in dialysis technology and the expansion of dialysis eligibility (for example the inclusion of patients with diabetes) resulted in rapid growth of the ESRD population. Many of these patients benefited from the development of prosthetic grafts when autogenous AVFs were not feasible.

In the mid-1980s, the use of permanent catheters (central venous catheters; CVCs) in the internal jugular vein dramatically increased. The cumulative effect was a decrease in AVF use and an increase in graft and CVC use in the 1990s.12 This was associated with increased patient care costs; for example up to 73% of patients were hospitalised to initiate dialysis and almost invariably had a temporary CVC inserted.12,13 This led the Centers for Medicare and Medicaid Services and National Kidney Foundation in the US implementing in 2003 the Fistula First Initiative to increase AVF placement and use to 65% along with lowering costs.13 AVF is still the best choice for dialysis access in terms of patient outcomes/ survival and reducing health care cost, but the approach can be associated with complications.

Incidence of Heart Failure Post-arteriovenous Shunt

Studies have shown that an estimated 17–26% of patients with a functioning AVS develop symptoms of HF.14,15 Factors associated with AVS precipitating HF include development of right ventricular dilatation, left atrial dilation, development of AF, male sex, prior vascular access surgery and high haemodialysis arteriovenous access flow rate.16 The risk of worsening HF is directly proportional to the flow of the haemodialysis arteriovenous access and is greater with pre-existing poor cardiac function.17 There is no threshold access flow rate that defines risk. Even

Acute effects of AVS creation include an immediate decrease in SVR and consequent increases in forward stroke volume, heart rate and CO. The decrease in total SVR is the result of both changes in the vessels associated with the arteriovenous access (called access resistance) and changes in other systemic vessels. In response to increases in blood flow and shear stress, the vascular endothelium releases nitric oxide and other endothelium-dependent relaxing factors that dilate the artery, reducing shear stress towards normal.5,18 The decrease in SVR causes an acute fall in both central and peripheral blood pressure. In response, there is an increase in sympathetic nervous system activity (which increases contractility and heart rate). It is this combination of decreased cardiac afterload and increased sympathetic activation that causes acute increases in CO.5 The CO increases immediately upon creation of the AVS and continues to increase over time.19,20 This increase in CO leads to an increase in venous return to the right side of the heart, leading to right ventricular dilatation in some patients.16 Conversely, acute compression of AVS increases the SVR and blood pressure and decreases CO. The increase in blood pressure leads to baroreceptor-reflex-mediated reduction in heart rate (NicoladoniBranham’s sign; Figure 1).

Subacute and Chronic Changes

Subacute changes occur within days after creation of the AVS. Within 2 weeks of AVS creation, blood volume increases, leading to greater venous return and increased right atrial, pulmonary artery and LV enddiastolic pressures. Both plasma atrial natriuretic peptide and brain natriuretic peptide concentrations increase after AVS creation, peaking 10 days postoperatively.6,21 CO continues to increase over days and weeks after creating of the AVS.19,20 Many studies have sought to understand the effect of AVF creation or closure on heart structure and function. Most use non-invasive methods – mainly echocardiographic parameters – while others use Doppler ultrasound to assess AVF flow and its effect on LV parameters. One study used cardiac MRI as an accurate non-invasive tool for the assessment of cardiac functions and dimensions.4 In 2018, Saleh et al. published a study investigating patients with AVFs and HF.22 The study showed that higher AVF flow is associated with an increased risk of high-outflow HF (HOHF).

Furthermore, the study demonstrated a strong relationship between the

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Effects of Arteriovenous Shunts in HFpEF Table 1: Summary of Key Studies Evaluating Effects of Arteriovenous Shunt on the Heart Authors

n

Aims

Methods

Assessment Method Results

Conclusions

Saleh et al.22

100

Effect of high flow AVF on HF patients

Two groups of patients: • HFA group, Qa >2,000 ml/min • Non-HFA group, Qa <2,000 ml/min

Echo at baseline and after closure of AVF

HFA group showed significant increase in LV and LA volumes compared to non-HFA group

HFA was associated with dilated LV dimensions, impaired LV systolic function

Significant association between high Qa/CO ratio (≥20%) and HOHF

High Qa/CO ratio (≥20%) was an independent predictor of HOHF

Echo did not reveal any significant differences compared with baseline examination

AVF closure does not seem to have a beneficial effect on cardiac function during short-term follow-up

In the AVF-closure group, LVM decreased

AVF closure resulted in significant decrease in LV internal diastolic diameter, IVS and PW thickness with significant improvement in LVEF and significant decrease in LVM

Głowiński et al.31

Movilli et al.

32

Iwashima et al.6

18

61

16

US Doppler for Quantification of AVF flow (Qa)

Effect of AVF closure on heart functions in patients after kidney transplantation

Nine patients after closure Echo baseline and 3 of AVF compared to nine months after AVF closure patients with patent AVF

Evaluate the effect of AVF closure on heart function and structure by Echo

25 patients underwent Echo at baseline and 6 AVF closure-matched with months after AVF closure 36 patients with well-functioning AVF

Patients did not have HF

Serial changes in cardiac Echo before and 3, 7, and functions and hormonal 14 days after AVF creation levels after the AVF creation ANP and BNP concentrations were measured before and 1, 3, 6, 10, and 14 days after the operation

LV EDD and IVS, PW thickness decreased significantly, whereas LVEF increased After AVF creation, there are significant elevations in LV EDD and CO LV DD moved toward restrictive filling pattern with increased LV EDP (highest after 14 days)

AVF creation has significant effects on cardiac systolic and diastolic performance, and ANP release, induced by volume loading. BNP release is stimulated by LV diastolic dysfunction

Increased ANP and BNP (highest after 10 days) Rao et al.33

54

Effect of AVF closure in patients 12 months post-KT

27 patients underwent AVF closure and 27 are the control group.

Cardiac MRI, Echo and NT pro-BNP before and 6 months after AVF closure

The primary outcome was Randomised controlled the change in LVM trial Secondary outcomes: changes in LV, LA, RA volumes, LVEF, NT-proBNP, CI, PA velocity

AVF closure group showed a decrease in LVM compared with a small increase in the control group.

Significant decreases in LV EDV and ESV, CI and NT-pro BNP

Elective ligation of patent AVF in adults with stable KT resulted in clinically significant reduction of LV myocardial mass

No significant changes in LVEF or PA velocity

Unger et al.34

16

Effects of AVF closure on AVF closure in patients ABPM and on LV with stable KT, studied geometry before and 1 month after AVF closure by Echo, ABPM, Qa

Echo, ABPM, Qa at baseline Increase in the mean DBP and 1 month after AVF without significant change in closure SBP The increase in DBP correlated with a reduction in LVM

AVF closure induces an increase in DBP correlated with the reduction in LVM

Cridlig et al.35

76

Effect of persistent AVF in patient post-KT and without previous cardiovascular disease

38 patients with a functioning AVF and a matched group with no AVF

76 Patients underwent Echo for assessment of LVMI, LVH

Patients with AVF have significantly higher LVMI and higher LVH LVMI is higher with higher Qa. Also, LV EDD, ESD are larger in those patients

Persistent functioning AVF resulted in significant increase in cardiac dimensions, LVH and LVMI

Gumus et al.36

81

Effect of AVF creation on right ventricle functions.

Identify new parameters can contribute to the prediction of RVF after AVF creation

81 patients underwent AVF creation divided into two groups: patients with RVF (18.5%) and without RVF (72.5%)

Echo assessment of right ventricle functions including RVLS, TAPSE, RV FAC, TRJV

Increase risk of development of RVF After AVF creation

Independent predictors of developing RVF following AVF creation are RVLS free wall ≤14.2% and TRJV >2.61 m/s

ABPM = ambulatory 24 hours blood pressure monitoring; ANP = plasma atrial natriuretic peptide; AVF = arteriovenous fistula; BNP = brain natriuretic peptide; CI = cardiac index; CO = cardiac output; DBP = diastolic blood pressure; Echo = echocardiogram; HF = heart failure; HFA = high-flow access; HOHF = high-output heart failure; IVS = left ventricle interventricular septum; KT = kidney transplantation; LA = Left atrium; LV = left ventricle; LV DD = left ventricle diastolic functions; LV EDD = left ventricle end diastolic diameter; LV EDP = left ventricle end diastolic pressure; LV EDV = left ventricle end diastolic volume; LV ESV = left ventricle end systolic volume; LVEF = left ventriclular ejection fraction; LVH = left ventricle hypertrophy; LVM = left ventricular mass; LVMI = left ventricle mass index; NT-proBNP = N-terminal pro-brain natriuretic peptide; PA = pulmonary artery; PW = left ventricle posterior wall; Qa = amount of blood flow across the AVF measured by ultrasound Doppler; RA = right atrium; RVF = right ventricular failure; RVFAC = right ventricle fractional area change; RVLS = right ventricle longitudinal strain; SBP = systolic blood pressure; TAPSE = tricuspid annular plane systolic excursion; TRJV = tricuspid regurgitation jet velocity.

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Effects of Arteriovenous Shunts in HFpEF Table 2: Summary of a Suggested Non-invasive Approach to Follow Up Patients After Arteriovenous Shunt Creation and Closure Investigation

Baseline

Follow-up After 3–6 Months

NT-proBNP

Baseline before procedure

Follow-up after creation

Ultrasound Doppler

Quantification of AVS flow (Qa)

Follow-up AVS flow (Qa)

Echocardiography

With following measurements: LVEDV, LVESV, LVEF, LAVI, TAPSE, RV FAC, RVLS, TRJV, RVEF, RAVI, IVC, PASP

Suggested predictors of worsening heart functions: • High Qa/CO ratio (≥20%) predicts development of HOHF27 • Independent predictors of developing RVF following AVS creation are RVLS free wall ≤14.2% and TRJV >2.61 m/s9

AVS = arteriovenous shunt; HOHF = high-output heart failure; IVC = inferior vena cava diameter; LAVI = left atrial volume index; LVEDV = left ventricle end diastolic volume; LVEF = left ventriclular ejection fraction; LVESV = left ventricle end systolic volume; NT-proBNP = N-terminal pro-brain natriuretic peptide; PASP = pulmonary artery systolic pressure; Qa = amount of blood flow through AVS by ultrasound Doppler; Qa/CO = ratio of blood flow through AVS by ultrasound Doppler and cardiac output estimated by echo; RAVI = right atrium volume index; RV FAC = right ventricle fractional area change; RVEF = right ventricluar ejection fraction; RVF = right ventricular failure; RVLS = right ventricle longitudinal strain; TAPSE = tricuspid annular plane systolic excursion; TRJV = tricuspid regurgitation jet velocity.

amount of AVF flow (Qa) in relation to CO and the development of HOHF. A Qa/CO ratio ≥20% was an independent predictor of HOHF.22 Table 1 summarises the key studies evaluating the effects of AVF on the heart.

Cardiac Follow-up After Creation of an Arteriovenous Shunt

Evaluation of all patients following an AVS includes an evaluation for HF. All patients who undergo access placement have markedly reduced kidney function and are at risk for HF. Patients who are at particular risk to develop HF related to the arteriovenous access include those with a large distended AVS, especially in the upper-arm position.20,21

Monitoring Strategies

haemodynamics by right heart catheterisation at rest and with transient fistula occlusion can be helpful. This approach allows the definitive assessment of volume status, direct determination of CO and pulmonary artery pressures and examination of the haemodynamic response to transient fistula occlusion.

Transient fistula occlusion (30 seconds) can provide valuable data when considering management strategies. Transient fistula occlusion should produce a reduction in CO that is often coupled with reduction in central venous pressure. Pulmonary artery and pulmonary capillary wedge pressures may not decrease during transient fistula occlusion because of the acute increase in cardiac afterload.24

Patients should be followed for signs and symptoms of HF as a routine part of every visit to determine whether HF is present. An echocardiogram should be obtained when any new symptoms or signs suggestive of cardiac dysfunction develop, and follow-up echocardiography 3–6 months after creation of the AVS is also recommended. Echocardiographic findings suggesting the development of HF include dilation of the inferior vena cava, new right ventricular dilation or dysfunction and increasing estimated pulmonary artery pressures.16,23

Some studies have suggested assessing the cardio-pulmonary recirculation value, which is the ratio of arteriovenous access flow (Qa) to the CO in patients with arteriovenous access flow >2 l/min. A Qa:CO ratio >0.3 indicates a significant risk of developing high-output cardiac failure.

However, a Qa:CO ratio ≤0.3 or a Qa ≤2 l/min does not exclude accessrelated HF.24

The AVS should be examined at every visit. The presence of a large, distended fistula with very strong thrill is suspicious for high blood flow and should prompt a quantitative evaluation, particularly in the presence of HF signs and symptoms. Patients with a calculated blood flow through the AVS by ultrasound Doppler (Qa) >2 l/min are at increased risk for the development of HF. Blood flow >2 l/min may predict the occurrence of high-output HF.23 However, Qa ≤2 l/min does not exclude AVS-induced HF. Table 2 summarises suggested non-invasive approaches to the follow up of patients after AVS creation or closure.

The presence of a large, distended AVS with very strong pulse augmentation suggests high volume flow and should prompt an evaluation to determine effect of the access on systemic haemodynamics. When the AVS is transiently occluded, the degree of the arterial pulse increase (augmentation) distal to the AVS anastomosis is proportional to the AVS flow.

Approach to Diagnosis of HFpEF After Arteriovenous Shunt Creation

In patients with AVS who are diagnosed with new-onset or worsening HF, it is recommended to obtain a comprehensive echocardiogram (with assessment of ejection fraction and CO) and to non-invasively measure AVS blood flow by ultrasound Doppler. The presence of one or more of the following echocardiographic findings is suggestive of arteriovenousaccess-related HF: dilation of the inferior vena cava, right ventricular enlargement or dysfunction, elevation in estimated pulmonary artery pressures or LV enlargement.6 For patients with an AVS who have new or worsening HF with supportive findings on echocardiography, invasive evaluation of cardiac

Examination and Transient Occlusion of the Arteriovenous Shunt

Transient maximal occlusion (sphygmomanometer inflated to 50 mmHg above systolic pressure for 30 seconds) of a haemodynamically significant arteriovenous access usually decreases heart rate, raises arterial pressure, and lowers venous pressure; this has been termed the Nicoladoni-Branham sign. The Nicoladoni-Branham sign has been shown to be related to arterial baroreceptor activation and increased arterial baroreflex sensitivity.25 In addition to a decrease in heart rate, there is also an increase in arterial blood pressure and increase in SVR, lead to a decrease in CO. Presence of a Nicoladoni-Branham sign was found to be predictive of reduction in LV hypertrophy after AVF ligation.26

Right Heart Catheterisation in Patients with Arteriovenous Shunt

Among patients with AVS, the contribution of the AVS to pulmonary artery hypertension can be initially assessed by manually compressing the AVS under heparinisation and a tourniquet set to at least 30 mmHg above systolic blood pressure for 1 minute, while measuring pulmonary

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Effects of Arteriovenous Shunts in HFpEF haemodynamics on right heart catheterisation. If a significant component of the patient’s pulmonary artery hypertension is related to the AVS, the mean pulmonary artery pressure, right atrial pressure, and possibly the pulmonary capillary wedge pressure and LV end diastolic pressure will significantly decrease (and even normalise) by at least 20% when the arteriovenous access is compressed. However, the definition of what constitutes a significant decrease is not established and is highly subjective. There may be some concern that such compression will lead to thrombosis of the access, particularly if the access is an arteriovenous graft. However, in practice, it is much harder to thrombose an arteriovenous access with manual compression than one would expect.27

Management of HFpEF in Patients with Arteriovenous Shunt

In patients with AVS-related HF, management begins with control of volume status with dialysis and diuretics, correction of anaemia, treatment of hypertension and pharmacological management of HF. If HF remains uncontrolled despite medical therapy, the following approach is suggested: 1. Close any unused AVS. If the patient has more than one arteriovenous access, one should be closed immediately if it is thought to be contributing, with preservation of the shunt with the best blood flow. The patient’s clinical status should then be reassessed.

2. If refractory HF persists with absence of an unused AVS, reduce blood flow of the AVS as close as possible to minimum volume flow necessary for adequate dialysis (600 ml/min). Several different surgical techniques have been used to reduce AVF flow. The goal of surgery is to reduce fistula blood flow while maintaining sufficient 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

United States Renal Data System. 2010 USRDS Annual Data Report: Atlas of Chronic Kidney Disease and End-stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases, 2010.

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United States Renal Data System. 2017 USRDS Annual Data Report: Atlas of Chronic Kidney Disease and End-stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases, 2017.

MacRae JM, Pandeya S, Humen DP, et al. Arteriovenous fistula-associated high-output cardiac failure: a review of mechanisms. Am J Kidney Dis 2004;43:e17–22. https://doi. org/10.1053/j.ajkd.2004.01.016; PMID: 15112194.

Korsheed S, Eldehni MT, John SG, et al. Effects of arteriovenous fistula formation on arterial stiffness and cardiovascular performance and function. Nephrol Dial Transplant 2011;26:3296–302. https://doi.org/10.1093/ndt/ gfq851; PMID: 21317408.

Iwashima Y, Horio T, Takami Y, et al. Effects of the creation of arteriovenous fistula for hemodialysis on cardiac function and natriuretic peptide levels in CRF. Am J Kidney Dis 2002;40:974–82. https://doi.org/10.1053/ajkd.2002.36329; PMID: 12407642.

Paulus WJ, Tschöpe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539–50. https://doi.org/10.1093/eurheartj/ ehm037; PMID: 17428822.

Reddy YN, Borlaug BA. Heart failure with preserved ejection fraction. Curr Probl Cardiol 2016;41:145–88. https://doi. org/10.1016/j.cpcardiol.2015.12.002; PMID: 26952248.

Borlaug BA, Redfield MM. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum.

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Redfield MM. Heart failure with preserved ejection fraction.

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flow for adequate dialysis. These techniques have included access banding and plication or distalisation of the anastomosis to a smaller artery.28–30 In one study of 12 patients with a high-flow AVF and clinical signs of high-output HF, a precision banding procedure was effectively used for access flow reduction.29 Adequacy of access flow restriction was evaluated intraoperative using ultrasound flow measurements, adjusting the banding diameter in 0.5 mm increments to achieve the targeted AVF flow. Mean access flow was reduced to a mean of 598 ml/min (481 to 876) after banding. The clinical signs of HF disappeared, and AVFs remained patent in all patients. Two patients had renal transplant failure and later successfully used the AVS. Follow-up post banding was 1–18 months (mean = 12).29 3. If refractory HF persists, occlude the AVS. If the approach defined above is ineffective, the AVF should be occluded and replaced with a tunnelled catheter or small graft since the resistance is higher in grafts than greatly dilated fistulas. Peritoneal dialysis may also be an option among some patients.29

Conclusion

The presence of AVS in ESRD patients carries a significant impact on cardiac functions, especially in patients with reduced cardiac reserve (HFrEF or HFpEF). It can precipitate HF decompensation in the short term or long term. The available data on the effect of AVS creation on worsening of HFpEF are limited, with most focused on HFrEF and conducted using non-invasive imaging techniques such as echocardiography or cardiac MRI). Using right heart catheterisation – the gold standard for assessment of haemodynamics and intracardiac pressures – to evaluate the haemodynamic effects of AVS creation or closure may provide more valuable information.

N Engl J Med 2016;375:1868–77. https://doi.org/10.1056/ NEJMcp1511175; PMID: 27959663.

Brescia MJ, Cimino JE, Appel K, Hurwich BJ. Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Engl J Med 1966;275:1089–92. https://doi.org/10.1056/NEJM196611172752002; PMID: 5923023.

Lok CE. Fistula first initiative: advantages and pitfalls. Clin J Am Soc Nephrol 2007;2:1043–53. https://doi.org/10.2215/ CJN.01080307; PMID: 17702726.

NKF-K/DOQI clinical practice guidelines for vascular access: update 2000. Am J Kidney Dis 2001;37(Suppl 1):S137–181. https://doi.org/10.1016/S0272-6386(01)70007-8.

Martínez-Gallardo R, Ferreira-Morong F, García-Pino G, et al.

Congestive heart failure in patients with advanced chronic kidney disease: association with pre-emptive vascular access placement. Nefrologia 2012;32:206–12. https://doi. org/10.3265/Nefrologia.pre2011.Dec11223; PMID: 22425802.

Schier T, Göbel G, Bösmüller C, et al. Incidence of arteriovenous fistula closure due to high-output cardiac failure in kidney-transplanted patients. Clin Transplant 2013;27:858–65. https://doi.org/10.1111/ctr.12248; PMID: 24118251.

Reddy YNV, Obokata M, Dean PG, et al. Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease. Eur Heart J 2017;38:1913–23. https://doi.org/10.1093/eurheartj/ehx045; PMID: 28329100.

Amerling R, Ronco C, Kuhlman M, et al. Arteriovenous fistula toxicity. Blood Purif 2011;31:113–20. https://doi. org/10.1159/000322695; PMID: 21228578.

Mitchell GF, Parise H, Vita JA, et al. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension 2004;44:134–9. https://doi. org/10.1161/01.HYP.0000137305.77635.68; PMID: 15249547.

Pandeya S, Lindsay RM. The relationship between cardiac output and access flow during hemodialysis. ASAIO J 1999;45:135–8. https://doi.org/10.1097/00002480199905000-00006; PMID: 10360711.

Beigi AA, Sadeghi AM, Khosravi AR, et al. Effects of the arteriovenous fistula on pulmonary artery pressure and cardiac output in patients with chronic renal failure. J Vasc Access 2009;10:160–6. https://doi.org/10.1177/ 112972980901000305; PMID: 19670168.

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21. Ori Y, Korzets A, Katz M, et al. Haemodialysis arteriovenous access – a prospective haemodynamic evaluation. Nephrol Dial Transplant 1996;11:94–7. https://doi.org/10.1093/ ndt/11.1.94; PMID: 8649659.

22. Saleh MA, El Kilany WM, Keddis VW, El Said TW. Effect of high flow arteriovenous fistula on cardiac function in hemodialysis patients. Egypt Heart J 2018;70:337–41. https:// doi.org/10.1016/j.ehj.2018.10.007; PMID: 30591752.

23. Basile C, Lomonte C, Vernaglione L, et al. The relationship between the flow of arteriovenous fistula and cardiac output in hemodialysis patients. Nephrol Dial Transplant 2008;23:282–7. https://doi.org/10.1093/ndt/gfm549; PMID: 17942475.

24. Roca-Tey R. Permanent arteriovenous fistula or catheter dialysis for heart failure patients. J Vasc Access 2016;17(Suppl 1):S23–9. https://doi.org/10.5301/jva.5000511; PMID: 26951899.

25. Bos WJ, Zietse R, Wesseling KH, Westerhof N. Effects of arteriovenous fistulas on cardiac oxygen supply and demand. Kidney Int 1999;55:2049–53. https://doi. org/10.1046/j.1523-1755.1999.00433.x; PMID: 10231470.

26. Unger P, Wissing KM, de Pauw L, et al. Reduction of left ventricular diameter and mass after surgical arteriovenous fistula closure in renal transplant recipients. Transplantation 2002;74:73–9. https://doi.org/10.1097/00007890200207150-00013; PMID: 12134102.

27. Grossman W (ed). Cardiac Catheterization and Angiography. 4th ed. Philadelphia, PA: Lea and Febiger, 1996.

28. Gkotsis G, Jennings WC, Malik J, et al. Treatment of high flow arteriovenous fistulas after successful renal transplant using a simple precision banding technique. Ann Vasc Surg 2016;31:85–90. https://doi.org/10.1016/j.avsg.2015.08.012; PMID: 26616507.

29. Schneider CG, Gawad KA, Strate T, et al. T-banding: a technique for flow reduction of a hyperfunctioning arteriovenous fistula. J Vasc Surg 2006;43:402–5. https://doi. org/10.1016/j.jvs.2005.11.047; PMID: 16476625.

30. Zanow J, Petzold K, Petzold M, et al. Flow reduction in highflow arteriovenous access using intraoperative flow monitoring. J Vasc Surg 2006;44:1273–8. https://doi. org/10.1016/j.jvs.2006.08.010; PMID: 17145429.

31. Głowiński J, Małyszko J, Głowińska I, Myśliwiec M. To close or not to close: fistula ligation and cardiac function in kidney allograft recipients. Pol Arch Med Wewn 2012;122:348–52.

Effects of Arteriovenous Shunts in HFpEF https://doi.org/10.20452/pamw.1349; PMID: 22743626.

32. Movilli E, Viola BF, Brunori G, et al. Long-term effects of arteriovenous fistula closure on echocardiographic functional and structural findings in hemodialysis patients: a prospective study. Am J Kidney Dis 2010;55:682–9. https:// doi.org/10.1053/j.ajkd.2009.11.008; PMID: 20089339.

33. Rao NN, Stokes MB, Rajwani A, et al. Effects of arteriovenous fistula ligation on cardiac structure and function in kidney transplant recipients. Circulation

2019;139:2809–18. https://doi.org/10.1161/ CIRCULATIONAHA.118.038505; PMID: 31045455.

34. Unger P, Xhaët O, Wissing KM, et al. Arteriovenous fistula closure after renal transplantation: a prospective study with 24-hour ambulatory blood pressure monitoring.

Transplantation 2008;85:482–5. https://doi.org/10.1097/ TP.0b013e318160f163; PMID: 18301341.

35. Cridlig J, Selton-Suty C, Alla F, et al. Cardiac impact of the arteriovenous fistula after kidney transplantation: a case-

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controlled, match-paired study. Transpl Int 2008;21:948–54. https://doi.org/10.1111/j.1432-2277.2008.00707.x; PMID: 18537919.

36. Gumus F, Saricaoglu MC. Assessment of right heart functions in the patients with arteriovenous fistula for hemodialysis access: right ventricular free wall strain and tricuspid regurgitation jet velocity as the predictors of right heart failure. Vascular 2020;28:96–103. https://doi. org/10.1177/1708538119866616; PMID: 31362595.

REVIEW

Comorbidities

The Effect of Iron Deficiency on Cardiac Function and Structure in Heart Failure with Reduced Ejection Fraction Pieter Martens Kauffman Center for Heart Failure Treatment and Recovery, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, US

Abstract

Over the past decade, the detrimental impact of iron deficiency in heart failure with reduced ejection fraction has become abundantly clear, showing a negative impact on functional status, quality of life, cardiac function and structure, exercise capacity and an increased risk of hospitalisation due to heart failure. Mechanistic studies have shown the impact of iron deficiency in altering mitochondrial function and negatively affecting the already altered cardiac energetics in heart failure with reduced ejection fraction. Such failing energetics form the basis of the alterations to cellular myocyte shortening, culminating in reduced systolic function and cardiac performance. The IRON-CRT trials show that ferric carboxymaltose is capable of improving cardiac structure and cardiac performance. This article discusses the effect of iron deficiency on cardiac function and structure and how it can be alleviated.

Keywords

Iron deficiency, cardiac physiology, remodelling, heart failure, ferric carboxymaltose, pharmacology Disclosure: PM is supported by a grant from the Belgian American Educational Foundation and a grant from the Frans Van de Werf Fund and has received consultancy fees from Vifor Pharma.

Received: 5 October 2021 Accepted: 4 December 2021 Citation: Cardiac Failure Review 2022;8:e06. DOI: https://doi.org/10.15420/cfr.2021.26 Correspondence: Pieter Martens, Kauffman Center for Heart Failure Treatment and Recovery, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, US. E: martenp@ccf.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.

Iron deficiency is one of the most common nutritional deficits, affecting more than 2 billion people worldwide.1 Iron deficiency often occurs in children, women, elderly people and patients with chronic inflammatory conditions.1 Iron is an essential element in enzymes and proteins involved in mitochondrial function, oxygen transport and biodegradation and the functioning of proteins.2 The body has no pathway of actively excreting iron and its metabolism is mainly regulated through the intestinal uptake of iron or the buffering of iron within cells.

In the bloodstream, iron is bound to transferrin, which is capable of binding two Fe3+ ions. Intracellularly, iron is bound to ferritin which is capable of binding numerous iron ions.3 Because ferritin carries most of the body’s iron and is also secreted in the blood stream, this reliably reflects a total body iron content in conditions without inflammation. The rate-dependent step in iron uptake is located at the level of ferroportin, which is a protein present at the basolateral site of the enterocyte and is present on spleen macrophages. The expression of this protein is regulated through hepcidin. Hepcidin is upregulated in conditions of inflammation, such as heart failure and excess iron, while it is downregulated in the presence of an iron deficit or hypoxaemia. Hepcidin results in an internalisation of ferroportin, leading to less uptake of intestinal iron from the gut, but also clustering of iron within the reticuloendothelial system.4 This aspect of iron metabolism is important to appreciate because it explains why a functional deficit of iron can occur in heart failure due to reticulo-endothelial system clustering, and why oral

iron therapy is inefficient in the setting of heart failure because of the degradation of ferroportin in enterocytes which hampers intestinal uptake.

Numerous mechanisms result in the high prevalence of iron deficiency in heart failure. Iron deficiency might result from enhanced iron loss, such as from blood loss in patients on antiplatelets or anticoagulants, diminished iron uptake because of malnutrition, intestinal congestion or tea drinking, or reduced iron bio-availability because of reticulo-endothelial clustering.

As iron plays such an important role in numerous important physiological pathways, its presence can worsen the disease trajectory of the patient with heart failure. This review focuses on the role of iron deficiency in aggravating cardiac function and structure and the mitigating role treatment with ferric carboxymaltose plays in patients with heart failure with reduced ejection fraction (HFrEF).5

Definition and Prevalence of Iron Deficiency

Heart failure is associated with chronic inflammation. Ferritin is an acute phase protein, so its levels are elevated in the setting of heart failure.

Therefore, iron deficiency can be diagnosed even in the face of higher levels of ferritin. No formal validation studies have established a definition of iron deficiency in heart failure.6,7 Yet, findings from other medical fields, such as nephrology and haematology, have been used to formulate a definition of iron deficiency in heart failure.

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Iron Deficiency and Heart Failure Figure 1: Prevalence of Iron Deficiency Across NYHA Class and Ejection Fraction

energetic demand, such as the myocardium, skeletal muscle and the central nervous system. Patients with iron deficiency often report having a lack of energy, reduced QoL, headaches, limited concentration, reduced exercise capacity and shortness of breath.18

Prevalence of iron deficiency according to NYHA class Prevalence iron deficiency (%)

100

n = 92

n = 404

n = 531

80 60 40

40%

61%

47%

n = 72 67%

p<0.001

20 0

NYHA I

NYHA II

NYHA III

NYHA IV

Prevalence of iron deficiency according to LVEF category

Prevalence iron deficiency (%)

100

n = 897

80 60

50%

n = 229

n = 72

61%

64%

HFmrEF

HFpEF

The Impact of Iron Deficiency on Cardiac Function

40 20 0

HFrEF

HFmrEF = heart failure with midrange ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association.

The current established definition of iron deficiency in heart failure is a ferritin level below 100 ng/ml irrespective of transferrin saturation (TSAT) or ferritin between 100–300 ng/ml if TSAT is <20%. Importantly, this definition of iron deficiency is capable of identifying heart failure patients with more advanced symptoms, poor quality of life (QoL), diminished exercise capacity and a higher risk of hospitalisation due to heart failure.8–13 Using this definition in intervention trials of IV iron has allowed the identification of patients who show improvement in terms of functional status, exercise capacity and clinical outcome after treatment with ferric carboxymaltose.14–17 This underscores the usefulness of the definition, despite no initial formal validation against the gold standard bone marrow iron staining. Using this definition in patients with stable heart failure, about 50% of patients will be diagnosed with iron deficiency, a prevalence that has been found in numerous observational studies.8,9,11,13,18 Figure 1 shows the prevalence of iron deficiency according to left ventricular ejection fraction (LVEF) strata showing a high prevalence in heart failure with reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction.18 The prevalence of iron deficiency is also higher in patients with a higher New York Heart Association (NYHA) heart failure class. Similarly, in acute heart failure there is a higher prevalence of iron deficiency with about 80% of patients being affected.19 Yet, 30 days after a hospital admission for acute heart failure this prevalence significantly drops, illustrating the difficulty of diagnosing iron deficiency in acute heart failure.20 However, the AFFIRM-AHF trial shows that in the setting of acute heart failure, the classic diagnostic criteria are capable of identifying patients with iron deficiency who benefit from treatment with ferric carboxymaltose showing that this definition of iron deficiency remains useful in selecting patients even in the setting of acute heart failure.16

Clinical Impact of Iron Deficiency

Furthermore, heart failure is associated with a higher risk of hospitalisation for heart failure or dying from a cardiovascular cause. Even in the absence of anaemia, iron deficiency is associated with a reduced exercise capacity and worse clinical outcome as reflected in Figure 2 which also shows that anaemia due to other reasons than iron deficiency has less of an impact on exercise capacity and clinical outcome than iron deficiency does in the absence of anaemia.18

Given the wide range of biological roles that iron plays, it is not surprising that iron deficiency is associated with numerous clinical manifestations.

Iron is an essential co-factor in the first three elements of the electron transport chain and is associated with diminished oxidative phosphorylation and reduced intracellular content of phosphocreatinine and adenosine triphosphate (ATP), which will manifest in tissues with high

According to the Fick equation, peak VO2 is determined by peak exercise cardiac output and the arterial minus mixed venous O2 content (arteriovenous oxygen difference; A-VO2), with the latter being dependent on haemoglobin levels and peripheral oxygen extraction. Theoretically, iron deficiency could affect all elements of the Fick equation while anaemia mainly affects the arterial O2 content component, explaining why isolated iron deficiency (without anaemia) has a stronger relation with peak VO2 than anaemia unrelated to iron deficiency.10,18 We performed a haemodynamic study using invasive cardiopulmonary exercise testing (iCPET) in heart failure patients with reduced ejection fraction.21 We showed that patients with iron deficiency had less ability to increase their cardiac output compared with patients without iron deficiency (see Figure 3). The A-VO2 difference was similar between patients with or without iron deficiency, indicating a similar degree of skeletal muscle oxygen extraction. Nevertheless, the role of iron deficiency in affecting skeletal muscle has been well documented indicating early muscle acidification, lower energy content and slowed recovery kinetics; however, this spans beyond the scope of this article.22–24 Additionally, a similar degree of A-VO2 difference for a lower attained cardiac output could be regarded as abnormal according to the Fick principle of diffusion. This is because a lower cardiac output should be met with a higher A-VO2 difference due to the slower capillary passing time where there is more time to extract oxygen. Therefore, our study points to both cardiac muscle and skeletal muscle involvement in the pathophysiology of iron deficiency.22–24

Cellular Effect of Iron Deficiency

It is important to appreciate the effect of iron deficiency at a cellular level to understand the impact of iron deficiency on the macroscopic cardiovascular system. On a cellular level it is important to remember the intertwining of cellular excitation contraction coupling of cardiomyocytes and energy metabolism.

More than any muscle, the heart consumes ATP with an astonishing rate of 6 kg a day.25 Most myocardial energy is required for either myofilament shortening (the cellular basis of systole) or calcium buffering (the cellular basis of diastole). Once myocytes become activated by a depolarising sodium current, this results in cellular calcium influx from both the extracellular compartment and the endoplasmic reticulum (Figure 4). Such calcium influx results in actin myosin overlap and myofilament shortening.

However, some cytoplasmic calcium is taken up by the mitochondria via the mitochondrial calcium uniporter (MCU).26 Within the mitochondria, calcium plays a role in determining the rate of substrate use in the tricarboxylic acid (TCA) cycle, which is coupled to the rate of oxidative phosphorylation in the electron transport chain (because the TCA cycle

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Iron Deficiency and Heart Failure Figure 2: Impact of Iron Deficiency and Anaemia on Peak VO2 and Clinical Outcome A

B Overall = p<0.001 Between groups = p<0.001

Peak VO2 (ml/kg/min)

20 17.2 ± 4.9 15.4 ± 4.8

15

12.8 ± 3.9 11.0 ± 2.7

10

5

0

100 Freedom from all-cause mortality and heart failure admission (%)

25

80 p=0.001 60 p=0.002 40

0 No anaemia/ no iron deficiency

Anaemia/ no iron deficiency

p<0.001

No anaemia/no iron deficiency Anaemia/no iron deficiency No anaemia/iron deficiency Anaemia/iron deficiency

20

0

No anaemia/ Anaemia/ iron iron deficiency deficiency

1

2

3

4

5

Time (years)

A: The relation between peak VO2 in patients with heart failure (n=867) according to four categories (presence or absence of iron deficiency and/or anaemia). B: The effect on clinical outcome in patients according to the same categories in heart failure patients (n=1,198).

Cardiac Performance and Iron Deficiency

While the Hoes et al. study gives a cellular understanding of the consequences of iron deficiency, it needs to be recognised that the model used is an extreme form of myocardial iron deficiency. However, lesser degrees of iron deficiency might still become relevant in clinical practice.

Indeed, human embryonic stem cell-derived cardiomyocytes contract at a baseline rate of around 30–35 BPM, something known to the clinician as the rate of idioventricular rhythm. Yet the myocardial energy requirement

p=0.045

2 1.5 1 0.5 0 No iron deficiency

Iron deficiency

Change in C(a-v) difference (md/dl)

Hoes et al. explored the role of iron deficiency on myocyte energy metabolism and myocyte shortening and relaxation.27 Human embryonic stem cell-derived cardiomyocytes were incubated with an iron chelator (deferoxamine), resulting in a decrease in intracellular iron content. Iron depletion affected mitochondrial function through reduced activity of the iron–sulphur cluster containing complexes I, II and III, but not complexes IV and V, leading to reduced ATP-linked respiration and respiratory reserve.27,28 This energetic crisis resulted in diminished myocyte shortening and slowed and diminished myocyte relaxation kinetics. As can be expected, myocyte iron deficiency resulted in upregulation of membrane-bound transferrin receptors. Interestingly, administration of soluble transferrin-bound iron allowed for a recovery of the morphological and functional consequences induced by iron deficiency. This indicates that the goal of iron therapy should be to replenish transferrin, which will subsequently lead to intracellular iron repletion. As alluded to in the introduction, this is something that can only be achieved by IV rather than iron taken orally, given the reduced intestinal uptake in the setting of heart failure.17,29

Figure 3: Effect of Iron Deficiency on Components of the Fick Equation

Change in cardiac output (l/min)

provides reducing equivalents). As a result, calcium cycling is fine-tuned to the rate of ATP production. In the cell, ATP is converted to phosphocreatine which is shuttled in the subcellular space through creatinine kinase isoforms to regions of high energy demand, being the myofilaments for shortening or the sarcoendoplasmic reticulum calcium transport ATPase pump for calcium buffering. In this way, excitation coupling is fine-tuned to energy metabolism, forming a streamlined and efficient engine (Figure 4).

p=0.928

5 4 3 2 1 0 No iron deficiency

Iron deficiency

Left panel: The effect of iron deficiency on change in cardiac output from rest to peak exercise.

Right panel: The effect of iron deficiency on the change in peripheral oxygen extraction C(a-v) difference from rest to peak exercise. Data comes from 45 heart failure patients with reduced ejection fraction. C(a-v) = C(a-v) difference.

increases at higher heart rates. Indeed one of several operating mechanisms resulting in an increased cardiac contractility during exercise is the force-frequency relationship.30 This is also known as the Bowditch– Treppe phenomenon and it indicates that at higher heart rates, the myocardium contracts with increased force to meet the enhanced contractile requirements to support the increase in stroke volume during exercise. While such a phenomenon plays in healthy people, as they exhibit a positive force–frequency relationship, illustrated by an increase in force at higher heart rates, this mechanism is deranged in a state of heart failure. Indeed, it has long been recognised that heart failure patients manifest with the reverse, being a negative force-frequency relationship or a decrease in force at higher heart rates.31 The decrease in cardiac force at higher heart rates in patients with heart failure is partially the result of a cellular energetic deficit. Haddad et al. described a mouse model of iron deficiency assessing the impact of iron deficiency on the force-frequency relationship after stimulation with dobutamine.32 Iron-deficient mice showed a similar increase in heart rate to mice without iron deficiency, yet the force (measured invasively as Dp/

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Iron Deficiency and Heart Failure Figure 4: Effect of Iron Deficiency on the Force–Frequency Relationship Coupling of energy metabolism to contraction/relaxation TfRC K+

Beta-oxidation

Glycolysis

NKA INa Na+

Na+

TCA cycle

MCU

Acetyl CoA

PDH

Pyruvate

Oxphos

Ca2+

Ca2+

NCX

Ca2+

CK shuttle Ca2+

SERCA

RyR2

Ca2+

Ca2+ RyR2

ICa

SERCA

T-tubulus

Ca2+

Ca2+

ATP

Ca2+

ADP Ca2+

Cytosol

Abnormalities induced by iron deficiency I

II III

IV V

OXPHOS 1. TfRC upregulation

2. Reduced activity 4. Substrate switch K

+

Beta-oxidation

Glycolysis

NKA

INa Na+

Na+

TCA cycle

MCU

CS

Pyruvate

Acetyl CoA PDH

Lactate LDH

Ca2+

NCX

Ferritin

CK shuttle Ca2+

RyR2

Ca2+

RyR2

T-tubulus

ICa

SERCA Ca2+

2. Energetic crisis

ATP

ADP

Ca2+

Ca

2+

3. Reduced contraction and relaxation (requires 70–90% of all myocardial energy)

Cytosol ADP = adenosine diphosphate; ATP = adenosine triphosphate; Ca2+ = calcium ions; CK = creatine kinase; CoA = coenzyme A; ICa = calcium current; INa = sodium current; K+ = potassium ions; LDH = lactate dehydrogenase; MCU = mitochondrial calcium uniporter; Na+ = sodium ions; NKA = Na+/K+-ATPase; NCX = sodium-calcium exchange; PDH = pyruvate dehydrogenase; RyR2 = ryanodine receptors; SERCA = sarcoendoplasmic reticulum (SR) calcium transport ATPase; TCA = tricarboxylic acid; TfRC = transferrin receptor.

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Iron Deficiency and Heart Failure

We have previously shown that a similar principle occurs in heart failure patients with iron deficiency. By prospectively selecting HFrEF patients with a CRT device, we were able to study the force-frequency relationship in vivo.33 By a stepwise increase in the lower rate of biventricular pacing and simultaneously measuring the non-invasive cardiac contractility index (systolic blood pressure/left ventricular end systolic volume index), we showed that iron-deficient heart failure patients exhibit a negative forcefrequency relationship. Taken together with the invasive iCPET data showing a lower cardiac output during exercise, this clearly documents that iron deficiency negatively affects cardiac performance, especially during exercise or higher heart rates.21,23,33

Cardiac contractility index slope according to treatment assignment 2.9

Group difference p=0.018

2.8 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 1.6 1.5

70

90

110

Legend

The Impact of Iron Deficiency on Cardiac Structure

Follow-up FCM (with 95% CI)

As well as being a co-factor in the first three elements of the mitochondrial electron transport chain, iron is also an essential co-factor in anti-oxidative enzymes.28 Insufficient myocardial capability to defend against oxidative stress has been implicated in the process of progressive cardiac remodelling forming one of the hallmark features of HFrEF.34 Indeed, animal models of iron deficiency (induced by either knockout or with low iron diets) show progressive cardiac remodelling consisting of ventricular dilatation, ventricular hypertrophy, systolic dysfunction and cardiomyocyte apoptosis thereby implicating iron in the process of progressive cardiac remodelling.35,36 In humans, an approach that also clearly documented the involvement of iron deficiency on cardiac remodelling was shown by studying the modulating role of iron deficiency on cardiac reverse remodelling after CRT implant. CRT as a non-pharmacological treatment option for HFrEF patients with electromechanical dyssynchrony can be seen as a clean model allowing a way to study the influences of a covariate on the process of reverse remodelling.

In comparison to drug interventions, which have numerous extra-cardiac effects, CRT selectively induces cardiac reverse remodelling. Before treatment with IV iron was mainstream, we and several other groups showed in a cohort of historically implanted CRT patients, that those with iron deficiency at the time of CRT implantation showed less cardiac reverse remodelling documented by a persistently reduced LVEF and more dilated ventricle.37,38 These studies implicate iron deficiency in the process of cardiac remodelling. However, these observational studies do not resolve the issue of whether iron deficiency directly stimulates cardiac remodelling or both iron deficiency and cardiac remodelling are a sign of another overarching process, such as inflammation.

Effect of Ferric Carboxymaltose on Cardiac Function and Structure

Figure 5: Effect of Ferric Carboxymaltose on the Slope of the Force–Frequency Relationship

Cardiac contractility index

dt) generated dropped at higher heart rates in iron-deficient mice. Using in vivo 31P magnetic resonance spectroscopy, the authors showed that this negative force-frequency relationship was caused by an energetic crisis induced by iron deficiency as documented by a drop in the phosphocreatine/ATP ratio.32

The causal effect of iron deficiency on cardiac function and structure can only be adequately studied in prospective double blind randomised controlled trials (RCTs), as such studies can establish causation. Previous trials have documented the effect of ferric carboxymaltose on patients’ functional status and submaximal exercise capacity shown in the sixminute walk test both at short and long-term follow-up.14,15 Other trials have shown the beneficial effect on maximal exercise capacity and risk for heart failure admissions.16,17 Yet, few randomised studies have assessed the effect of ferric carboxymaltose on cardiac function and structure.

Follow-up SOC (with 95% CI)

FCM = ferric carboxymaltose; SOC = standard of care.

Previous small studies using a different IV iron formulation (iron sucrose) suggested that treatment with IV iron could induce reverse remodelling as documented by an improvement in LVEF.39,40 The Myocardial-IRON trial investigated whether treatment with ferric carboxymaltose is capable of replenishing myocardial iron content.41 Using the feature of the T2* sequence of MRI, investigators estimated myocardial iron content. T2* is often used in clinical practice to examine iron loading, such as for patients undergoing frequent transfusions, with low values indicating myocardial iron loading. However, the reverse has also shown to be true and patients with iron deficiency exhibit an elevated T2* value. In the Myocardial-IRON trial, treatment with ferric carboxymaltose was capable of replenishing myocardial iron content, indicated as a significant decrease in T2* at the 7- and 30-day follow-up.

In a post hoc analysis authors also showed that it was associated with an improvement in biventricular function.42 To determine the effect of ferric carboxymaltose on cardiac function and structure, we designed the IRON-CRT trial. In this double blind prospective RCT we included HFrEF patients who were optimally treated with guideline-directed medical therapy and device-based therapies (CRT), but had a persistently reduced LVEF and had iron deficiency. The CRT device in IRON-CRT needed to work adequately documented by more than 6 months ≥98 biventricular pacing. HFrEF patients with a CRT device were specifically chosen because we are able to assess the force-frequency relationship in these patients. Patients were randomised in a double-blind fashion to either standard of care (IV placebo) or ferric carboxymaltose.43 Cardiac structure was assessed as the change in LVEF, left ventricular end systolic volume (LVESV) and end diastolic volume (LVEDV) from baseline to three months follow-up using 3D echocardiography. The latter is important as in well selected patients, 3D echocardiography has the same variability for LV volumetric measurements as MRI. At baseline and follow-up, patients underwent a detailed force-frequency pacing protocol, in which the noninvasive contractility index was measured at 70, 90 and 110 beats of biventricular pacing, allowing us to determine the slope of the forcefrequency relationship. At 3 months follow-up, the least square mean

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Iron Deficiency and Heart Failure Table 1: Dosing Scheme for Ferric Carboxymaltose Body Weight Haemoglobin (g/dl) <35 kg

35–70 kg

>70 kg

<10

500 mg

1,500 mg

2,000 mg

10 to <14

500 mg

1,000 mg

1,500 mg

≥14

500 mg

500 mg

500 mg

Table 2: Trials Investigating the Effect of IV Iron in Chronic Stable Heart Failure NCT number

FAIR-HF2

IRON-MAN

HEART-FID

NCT03036462

NCT02642562

NCT03037931

Patient population HFrEF >12 months + HFrEF + iron deficiency HFrEF + iron iron deficiency deficiency Design

Multicentre RCT

Multicentre RCT

Multicentre RCT

Randomisation

1:1 FCM versus placebo

1:1 iron (III) isomaltoside 1:1 FCM versus versus placebo placebo

Sample size

1,200

1,300

3,014

Duration trial

>12 months

>2.5 year

12 months

Primary endpoint

HF hospitalisation and CV mortality

HF hospitalisation and CV mortality

HF hospitalisation and CV mortality

Trial status

Actively recruiting

Active, not recruiting

Recruiting

CV = cardiovascular; FCM = ferric carboxymaltose; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; RCT = randomised controlled trial.

change in LVEF from baseline was significantly higher in the ferric carboxymaltose group (4.22%, 95% CI [3.05–5.38]) in comparison to the standard of care group (−0.23%, 95% CI [−1.44, 0.97], p<0.001). Additionally, the change in LVESV from baseline to follow-up was more pronounced in the ferric carboxymaltose group versus the standard of care group (−9.72 ml, 95% CI [−13.5, 5.93] versus −1.83 ml, 95% CI [−5.7, 2.1], p=0.001) However, the change in LVEDV was not different between the two treatment groups (ferric carboxymaltose: −2.5 ml, 95% CI [−5.3, 0.3] versus −1.9 ml, 95% CI [−4.7, 1.0], p=0.784).43 Additionally, treatment with ferric carboxymaltose was capable of improving the force-frequency relationship as documented in Figure 5. In patients treated with ferric carboxymaltose the negative force-frequency relationship was transformed into a positive 1.

2.

3.

4.

5.

6.

7.

Parikh A, Natarajan S, Lipsitz SR, Katz SD. Iron deficiency in community-dwelling US adults with self-reported heart failure in the National Health and Nutrition Examination Survey III: prevalence and associations with anemia and inflammation. Circ Heart Fail 2011;4:599–606. https://doi. org/10.1161/CIRCHEARTFAILURE.111.960906; PMID: 21705484.

Jankowska EA, von HS, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013;34:816–29. https://doi. org/10.1093/eurheartj/ehs224; PMID: 23100285.

Pasricha SR, Flecknoe-Brown SC, Allen KJ, et al. Diagnosis and management of iron deficiency anaemia: a clinical update. Med J Aust 2010;193:525–32. https://doi. org/10.5694/j.1326-5377.2010.tb04038.x; PMID: 21034387.

Camaschella C. Iron-deficiency anemia. N Engl J Med 2015;372:1832–43. https://doi.org/10.1056/NEJMra1401038; PMID: 25946282.

McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https:// doi.org/10.1093/eurheartj/ehab368; PMID: 34447992.

Grote BN, Klip IT, Meijers WC, et al. Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients. Circ Heart Fail 2018;11:e004519. https://doi.org/10.1161/ CIRCHEARTFAILURE.117.004519; PMID: 29382661.

Martens P, Grote BN, van der Meer P. Iron deficiency in

8.

9.

10.

11.

12.

13.

force-frequency relationship. Something that was not observed in patients who were in the standard of care group. This data, together with the preexisting knowledge support the notion that through an improvement in cardiac energy reserve the failing ventricle becomes more efficient and is capable of manifesting reverse cardiac remodelling.

Guidelines for Treating Iron Deficiency

The 2021 ESC guidelines for the diagnosis and treatment of heart failure gave a IIa recommendation supporting the role of ferric carboxymaltose in patients with iron deficiency in order to alleviate heart failure symptoms, improve exercise capacity and QoL in patients with an LVEF <45% (which is a slight change in comparison to the 2016 guidelines which defined HFrEF by an LVEF <40%).5 Additionally, a IIa recommendation is given based on the AFFIRM-HF trial supporting the use of ferric carboxymaltose in patients with a recent heart failure admission and an LVEF <50% to reduce the risk for heart failure admissions. Patients with heart failure need to be periodically screened for the presence of iron deficiency according to the 2021 guidelines (class 1c recommendation) because iron deficiency can reoccur. This is also a slight change in comparison to the 2016 guidelines, which recommended screening for the presence of iron deficiency only in the setting of a new diagnosis of heart failure.44 From a treatment perspective, it is important to adhere to the doses of ferric carboxymaltose as used in the RCTs (and formulated in the summary of product characteristics of ferric carboxymaltose), which is based on the haemoglobin levels and the weight of the patient (Table 1). Indeed, treatment with a too low dose is associated with less improvement in functional status.45 Ongoing studies in patients with stable heart failure will further determine the effect of treatment with IV iron on hard clinical endpoints such as cardiovascular mortality and the risk of hospitalisation for heart failure. Table 2 lists ongoing trials with IV iron in the setting of chronic heart failure.

Conclusion

Iron deficiency alters myocyte and myocardial function and structure.

Data from smaller mechanistic studies and larger RCTs demonstrate a beneficial effect of treatment with ferric carboxymaltose on cardiac function and structure. These mechanistic observations explain the beneficial effect of ferric carboxymaltose on functional status, exercise capacity and the risk of being hospitalised for heart failure.

heart failure-time to redefine. Eur J Prev Cardiol 2021;28:1647–9. https://doi.org/10.1093/eurjpc/zwaa119; PMID: 33624061.

Cleland JG, Zhang J, Pellicori P, et al. Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure. JAMA Cardiol 2016; 1:539–47. https://doi.org/10.1001/jamacardio.2016.1161; PMID: 27439011.

Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872–80. https://doi. org/10.1093/eurheartj/ehq158; PMID: 20570952.

Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail 2011; 17:899– 906. https://doi.org/10.1016/j.cardfail.2011.08.003; PMID: 22041326.

Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82. https://doi.org/10.1016/j. ahj.2013.01.017; PMID: 23537975.

Martens P, Minten L, Dupont M, Mullens W. Prevalence of underlying gastrointestinal malignancies in iron-deficient heart failure. ESC Heart Fail 2018;6:37–44. https://doi. org/10.1002/ehf2.12379; PMID: 30415506.

Yeo TJ, Yeo PS, Ching-Chiew WR, et al. Iron deficiency in a multi-ethnic Asian population with and without heart failure: prevalence, clinical correlates, functional significance and

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prognosis. Eur J Heart Fail 2014; 16:1125–32. https://doi. org/10.1002/ejhf.161; PMID: 25208495.

Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436–48. https://doi. org/10.1056/NEJMoa0908355; PMID: 19920054.

Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al.

Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency dagger. Eur Heart J 2015;36:657– 68. https://doi.org/10.1093/eurheartj/ehu385; PMID: 25176939.

Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895–904. https://doi. org/10.1016/S0140-6736(20)32339-4; PMID: 34838177. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al.

Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency.

Circulation 2017;136:1374–83. https://doi.org/10.1161/ CIRCULATIONAHA.117.027497; PMID: 28701470.

Martens P, Nijst P, Verbrugge FH, et al. Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction.

Acta Cardiol 2017;73:115–123. https://doi.org/10.1080/0001538 5.2017.1351239; PMID: 28730869.

Iron Deficiency and Heart Failure 19. Jacob J, Miro O, Ferre C, et al. Iron deficiency and safety of ferric carboxymaltose in patients with acute heart failure.

AHF-ID study. Int J Clin Pract 2020; 74:e13584. https://doi. org/10.1111/ijcp.13584; PMID: 32533907.

20. Van Aelst LNL, Abraham M, Sadoune M, et al. Iron status and inflammatory biomarkers in patients with acutely decompensated heart failure: early in-hospital phase and 30-day follow-up. Eur J Heart Fail 2017; 19:1075–6. https:// doi.org/10.1002/ejhf.837; PMID: 28516737.

21. Martens P, Verbrugge FH, Nijst P, et al. Limited contractile reserve contributes to poor peak exercise capacity in irondeficient heart failure. Eur J Heart Fail 2018;20:806–8. https://doi.org/10.1002/ejhf.938; PMID: 28925093.

22. Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of Iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation 2019;139:2386–98. https://doi.org/10.1161/ CIRCULATIONAHA.118.038516; PMID: 30776909.

23. Martens P, Claessen G, Van De Bruaene A, et al. Iron deficiency is associated with impaired biventricular reserve and reduced exercise capacity in patients with unexplained dyspnea. J Card Fail 2021;27:766–76. https://doi. org/10.1016/j.cardfail.2021.03.010; PMID: 33838251.

24. Melenovsky V, Hlavata K, Sedivy P, et al. Skeletal muscle abnormalities and iron deficiency in chronic heart failure: an exercise 31P magnetic resonance spectroscopy study of calf muscle. Circ Heart Fail 2018;11:e004800. https://doi. org/10.1161/CIRCHEARTFAILURE.117.004800; PMID: 30354361.

25. Neubauer S. The failing heart – an engine out of fuel. N Engl J Med 2007;356:1140–51. https://doi.org/10.1056/ NEJMra063052; PMID: 17360992.

26. Martens P, Dupont M, Mullens W. Cardiac iron deficiencyhow to refuel the engine out of fuel. Eur J Heart Fail 2018;20:920–2. https://doi.org/10.1002/ejhf.1174; PMID: 29493065.

27. Hoes MF, Grote BN, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail 2018;20:910–9. https://doi.org/10.1002/ejhf.1154; PMID: 29484788.

28. Melenovsky V, Petrak J, Mracek T, et al. Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis. Eur J Heart Fail 2017;19:522–30. https://doi.org/10.1002/ejhf.640; PMID: 27647766.

29. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958–66. https://doi.org/10.1001/jama.2017.5427; PMID: 28510680.

30. Neubauer S. Influence of left ventricular pressures and heart rate on myocardial high-energy phosphate metabolism.

Basic Res Cardiol 1998;93Suppl1:102–7. https://doi. org/10.1007/s003950050231; PMID: 9833137.

31. Just H. Pathophysiological targets for beta-blocker therapy in congestive heart failure. Eur Heart J 1996;17(Suppl B):2–7. https://doi.org/10.1093/eurheartj/17.suppl_B.2; PMID: 8733064.

32. Haddad S, Wang Y, Galy B, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J 2017;38:362–72. https://doi.org/10.1093/ eurheartj/ehw333; PMID: 27545647.

33. Martens P, Dupont M, Dauw J, et al. Rationale and design of the IRON-CRT trial: effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy. ESC Heart Fail 2019;6:1208–15. https://doi.org/10.1002/ehf2.12503; PMID: 31562751.

34. Agnetti G, Kaludercic N, Kane LA, et al. Modulation of mitochondrial proteome and improved mitochondrial function by biventricular pacing of dyssynchronous failing hearts. Circ Cardiovasc Genet 2010;3:78–87. https://doi. org/10.1161/CIRCGENETICS.109.871236; PMID: 20160199.

35. Dong F, Zhang X, Culver B, et al. Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration. Clin Sci (Lond) 2005;109:277–86. https://doi.org/10.1042/CS20040278; PMID: 15877545.

36. Xu HY, Yang ZG, Li R, et al. Myocardial iron deficiency in hemodialysis-dependent end-stage renal disease patients undergoing oral iron therapy. J Am Coll Cardiol 2017;70:2455–6. https://doi.org/10.1016/j.jacc.2017.09.013; PMID: 29096814.

37. Lacour P, Dang PL, Morris DA, et al. The effect of iron deficiency on cardiac resynchronization therapy: results from the RIDE-CRT study. ESC Heart Fail 2020;7:1072–84. https://doi.org/10.1002/ehf2.12675; PMID: 32189474.

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38. Martens P, Verbrugge F, Nijst P, et al. Impact of iron deficiency on response to and remodeling after cardiac resynchronization therapy. Am J Cardiol 2017;119:65–70. https://doi.org/10.1016/j.amjcard.2016.09.017; PMID: 27780556.

39. Toblli JE, Lombrana A, Duarte P, Di GF. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657–65. https://doi.org/10.1016/j. jacc.2007.07.029; PMID: 17950147.

40. Toblli JE, Di GF, Rivas C. Changes in echocardiographic parameters in iron deficiency patients with heart failure and chronic kidney disease treated with intravenous iron. Heart Lung Circ 2015;24:686–95. https://doi.org/10.1016/j. hlc.2014.12.161; PMID: 25666998.

41. Nunez J, Minana G, Cardells I, et al. Noninvasive imaging estimation of myocardial iron repletion following administration of intravenous iron: the Myocardial-IRON trial.

J Am Heart Assoc 2020;9:e014254. https://doi.org/10.1161/ JAHA.119.014254; PMID: 32067585.

42. Nunez J, Monmeneu JV, Mollar A, et al. Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study. ESC Heart Fail 2016;3:293–8. https://doi.org/10.1002/ehf2.12101; PMID: 27867532.

43. Martens P, Dupont M, Dauw J, et al. The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial. Eur Heart J 2021;42:4905–14. https://doi. org/10.1093/eurheartj/ehab411; PMID: 34185066.

44. 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.

45. Martens P, Minten L, Dupont M, Mullens W. The importance of dose optimisation in the treatment of iron deficiency in heart failure. Acta Cardiol 2020;75:520–4. https://doi.org/10.1 080/00015385.2019.1625554; PMID: 31184977.

REVIEW

Comorbidities

The Impact of Frailty and Comorbidities on Heart Failure Outcomes Thomas Salmon ,1 Hani Essa ,1,2 Behnam Tajik ,3 Masoud Isanejad ,2,4 Asangaedem Akpan 1,2 and Rajiv Sankaranarayanan 1,2,5 1. Department of Cardiology, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; 2. Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart & Chest Hospital, Liverpool, UK; 3. Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; 4. Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool UK; 5. National Institute for Health Research, UK

Abstract

Frailty is a multisystemic process leading to reduction of physiological reserve and a reduction in physical activity. Heart failure (HF) is recognised as a global cause of morbidity and mortality, increasing in prevalence over recent decades. Because of shared phenotypes and comorbidities, there is significant overlap and a bidirectional relationship, with frail patients being at increased risk of developing HF and vice versa. Despite this, frailty is not routinely assessed in patients with HF. Identification of these patients to direct multidisciplinary care is key, and the development of a frailty assessment tool validated in a large HF population is also an unmet need that would be of considerable benefit in directing multidisciplinary-team management. Non-pharmacological treatment should be included, as exercise and physical rehabilitation programmes offer dual benefit in frail HF patients, by treating both conditions simultaneously. The evidence for nutritional supplementation is mixed, but there is evidence that a personalised approach to nutritional support in frail HF patients can improve outcomes.

Keywords

Frailty, heart failure, comorbidity Disclosure: RS reports speaker fees from Novartis, Astra Zeneca, Vyfor, Bristol-Myers Squibb, Pfizer and research grants from British Heart Foundation, NHSX and Biotronik UK, outside the submitted work. All other authors have no conflicts of interest to declare.

Received: 19 November 2021 Accepted: 19 January 2022 Citation: Cardiac Failure Review 2022;8:e07. DOI: https://doi.org/10.15420/cfr.2021.29 Correspondence: Rajiv Sankaranarayanan, Liverpool Centre for Cardiovascular Science, Liverpool University Hospitals NHS Foundation Trust, Lower Lane, Liverpool L9 7AL, UK. E: Rajiv.Sankaranarayanan@liverpoolft.nhs.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.

The word frail originates from the French word frêle, meaning ‘of little resistance’, and from the Latin word fragilis, meaning ‘easily broken’. In clinical medicine, frailty is considered one of the significant debilitating medical syndromes commonly associated with ageing and chronic disease that implies a multifactorial decrease in physiological reserve to withstand biological stressors.1 Frailty is thought to be caused by multisystem dysregulations, chronic inflammation, cachexia and sarcopenia, resulting in an increased risk of morbidity and mortality.2 It is estimated that in the UK, the prevalence of frailty in the general population is 8.5% in women and 4.1% in men.3 In the diseased state, mortality risk generally increases with age.4 However, this risk is not uniform and the concept of frailty can be used to describe the heterogeneity of increased risk in people of the same age.5 Frailty is also important in explaining some of the differences in disease presentation.

For example, in a fit individual, a heart attack commonly presents with classic cardiac chest pain, while in the frail individual this presentation is less common and being generally unwell or newly confused is more frequent.6 Heart failure (HF) is a global cause of morbidity and mortality with an estimated 5.7 million cases in the US alone.7 There is substantial and rapidly growing interest at the intersection between frailty and HF, as it has been shown that frailty is a powerful marker of poor prognosis and marker

of outcome in the HF population.8–11 Indeed, there exists significant phenotypic and symptomatic overlap between both conditions (Figure 1).

Furthermore, up to 44.5% of HF patients were considered frail using contemporary measures in a 2017 meta-analysis.12 This is independent of age or New York Heart Association classification.13 The significant bidirectional relationship between frailty and HF is evidenced by the fact that HF patients are 600% more likely to be frail and patients with frailty have a significant increased risk of developing HF.14,15 Furthermore, patients with both conditions are often more complex and have a greater burden of other comorbidities including – but not limited to – chronic obstructive pulmonary disease, chronic kidney disease, dementia and anaemia.1,11,16 Interestingly, frailty appears to be much more common in HF with preserved ejection fraction (HFpEF) than in HF with reduced ejection fraction (HFrEF).17 This is likely to be secondary to the fact that HFpEF patients typically suffer a great burden of comorbidities compared to the HFrEF population.17 Furthermore, HFpEF patients are more likely to suffer non-cardiac hospitalisations.17 Finally, frailty is more likely to be present in those who present to hospital with acute decompensation than in wellcompensated community HF patients.18 The focus of this article is to review the literature with regards to HF and frailty. Specifically, this article will focus on the pathophysiology of frailty, its assessment in HF and its prognostic implications.

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Frailty in Heart Failure Figure 1: Overlap Between Frailty and Heart Failure Heart failure

Frailty

Cognitive impairment Fatigue Cachexia Sarcopenia/weakness Depression/anxiety Poor exercise tolerance Poor nutritional state

Breathlessness Orthopnoea Chest pain Syncope Paroxysmal nocturnal dyspnoea Oedema

Weight loss Diminished reserve Slowness

Weight loss Anaemia Fatigue Sarcopenia

↓ Strength

Cachexia

Decreased activity

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Underlying disease Metabolic syndrome

Chronic inflammation

Finally, the development of anaemia has been identified as a contributing factor to frailty syndrome. Anaemia is more prevalent amongst frail populations and haemoglobin levels negatively correlate with frailty risk.31–33 The anaemia identified in frail patients is commonly found to be normocytic, with haemoglobin levels inversely correlated with interleukin-6, suggesting an interplay between anaemic and inflammatory pathological processes in the development of frailty syndrome.32 Once established, the phenotypical characteristics of frailty feed into each other, leading to a downward spiral in which the patient is perpetually becoming increasingly frail. Key to this cycle are the processes of sarcopenia and cachexia. These conditions often overlap but have distinct definitions. Sarcopenia is typically defined by low muscle mass and function, while cachexia is defined as weight loss in the presence of underlying illness, with chronic inflammation identified as a key pathophysiological mechanism.34,35 Considering the prevalence of markers of chronic inflammation seen in frailty patients, it can be assumed that cachexia plays a role in the pathological cycle amongst a significant proportion of patients with frailty. Figure 1 illustrates the role of abnormal physiology in the cycle of frailty progression, with reference to Fried’s cycle of frailty.36

Figure 2: Processes Involved in the Development of Frailty

Nutritional deficits

folate being associated with frailty independent of total calorie intake.26 Vitamin B12 deficiency has also been identified as more common in prefrail or frail individuals when compared with a non-frail population.28 Healthier diets, such as the Mediterranean diet and high fruit and vegetable intakes, have been associated with decreased risk of frailty in meta-analyses.29,30

Frailty-associated chronic inflammation

Pathophysiology of Frailty

The physiological processes involved in the development of frailty syndrome are predominantly of an immune, endocrine and musculoskeletal nature resulting in a reduction in strength, endurance or cognitive function (Figure 2).19–21 Inflammatory pathways have been elucidated as an important mechanism in the development of frailty syndrome.22,23 Population-based studies have linked elevated levels of the proinflammatory cytokine interleukin-6 to frailty in both community and inpatient populations in addition to identifying higher serum levels of C-reactive protein, tissue necrosis factor-α, and white blood cells in frail members of community and inpatient populations aged ≥70 years.22,24,25 Additionally, lower levels of the negative acute phase reactant albumin correlate with a higher degree of frailty in inpatients aged >75 years.22 Nutritional deficits have also been implicated in the pathophysiology of frailty, with frail patients more likely to have multiple nutritional deficits than non-frail patients.25 High protein intake appears to be protective against frailty in older populations and, conversely, low protein intake has been associated with higher frailty risk.26,27 Micronutrient deficits are also associated with frailty risk, with low intake of vitamins D, E and C, and

Identifying Frailty in Heart Failure

The assessment of frailty in the HF patient is challenging because of the lack of a universal, easily used set of diagnostic criteria or screening tool.

While the term ‘frailty syndrome’ was first described in 1991 in a landmark paper,and has since been adopted into clinical practice and the research environment, as of 2021, there is still no internationally agreed definition or diagnostic criteria.37 Furthermore, frailty is widely recognised and used by the general clinician in guiding treatment decisions and estimating prognosis. This recognition is often performed using a superficial ‘eyeball test’ or the ‘end-of-the-bed-o-gram’ rather than a validated frailty risk assessment. This is because the most well-validated tools can often be cumbersome and resource-intensive in routine medical practice.

Generally, frailty assessment tools are derived from two basic concepts in frailty: a unidimensional/physical model that views frailty as a physical problem, and a multidimensional/holistic model that incorporates both physical problems as well as psychological and social problems.38,39 In a recent review, 67 frailty measurement instruments were identified, and these often-exhibited significant heterogeneity with regards to which parameters were used.40 Table 1 shows the nine most cited frailty assessment tools identified from this review and their individual constituents.40 The frail phenotype/Fried scale is the single most commonly used and validated tool in the cardiovascular disease (CVD) population.36 This was first described over two decades ago and subsequently validated in the in the Women’s Health and Aging study.36,40 The Fried scale consists of five domains: unintentional weight loss, weakness as measured by hand grip strength, self-reported exhaustion, a slow gait speed and low selfreported physical activity. Frailty is defined as three or more criteria being present, and pre-frailty as two or more. The presence of frailty as

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Frailty in Heart Failure Table 1: Most Cited Frailty Assessment Instruments and Their Constituents Frail Phenotype (2001)36

Deficient Gill Frailty Accumulation Measure Frailty Index (2002)86 (2001)40

Clinical Frailty Brief Frailty Scale (2005)87 Instrument (1999)88

Vulnerable Elders Survey (2001)89

Frail Scale (2008)90

Winograd Screen Instrument (1991)37

Physical activity

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Energy

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Social aspect

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Disability

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Medication

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Strength

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Comorbidity

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Health Nutrition

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Continence

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measured on the Fried scale has been demonstrated with worse clinical outcomes and a greater functional impairment in both the HF and non-HF population.41,42 Fried’s criteria is the most used tool to measure frailty, but it can be limited by capturing only the physical frailty, and the requirement for a dynamometer precludes its use without special equipment. Finally, in the context of diuresis it is difficult to accurately assess unintentional weight loss.

The deficient accumulation frailty index is another commonly used frailty tool often used in the CVD population.43 It sums the total number of impairments a patient has during their activities of daily living, comorbid conditions, and abnormal laboratory values. Frailty index categorises the individuals in a quantitative continuum rather than an absolute and can often be assessed from medical records. The disadvantages of this assessment tool are that it is time consuming in routine use and its reliance of the number of deficits rather than the nature of the deficit. Therefore, in certain circumstances it may overestimate the frailty burden.

While a variety of frailty measures and scores have been used in HF, none have been developed and validated in this cohort. These patients are more difficult to assess using contemporary frailty scores for multiple reasons including, but not limited to, the significant overlap between frailty and HF, and the inference of frailty with possible HF treatment. The need for a HF frailty assessment tool prompted the Heart Failure Association of the European Society of Cardiology (ESC) to release a position paper in 2019 on frailty in HF, defining frailty and creating a foundation (based on clinical, psycho-cognitive, functional, and social domains) for the design of a tailored validated score in the HF patient.44,45

Prognostic Implications of Frailty in Heart Failure Patients

+

While there is no single validated frailty assessment tool in the HF population, there is still considerable evidence demonstrating that frailty and its components are correlated with worse HF outcomes. Hand grip strength has consistently been found to be an independent predictor of survival in the HF population, with higher grip strength corresponding with increased survival.46 In a meta-analysis in >2,300 patients with CVD

+

including HF, lower hand grip strength was associated with increased risk of CVD death, all-cause mortality, and admission for HF.47 Poor lowerextremity function at baseline, measured by gait speed or functional assessments such as the 6-minute walk test (6MWT) or the short physical performance battery, has also been associated with increased all-cause and HF mortality.48,49 Additionally, HF patients with decreased gait speed or poorer lower extremity function at follow-up are at higher risk of all-cause mortality when compared with HF patients who maintain gait speed or lower extremity function.48 Higher gait speed or better lower-extremity performance at baseline have also been demonstrated to reliably predict a lower risk of all cause and HF hospitalisation, with improvement in lower-extremity performance or gait speed at follow up reducing risk of all-cause hospitalisation further.48,50,51 Self-reported exhaustion/fatigue is an important component of the frailty phenotype. Fatigue is more challenging to measure objectively, therefore research into its relationship with HF is more limited. However, it has been demonstrated that greater levels of fatigue are linked with worse clinical outcomes after controlling for other prognostic variables.52 Cognitive impairment is a commonly cited feature on many frailty assessment scales and is more prevalent in the HF population, and has been associated with increased hospitalisation in HF patients.53,54 Despite the perceived issues with identifying an existing frailty assessment tool for use in estimating HF prognosis, there have been efforts to validate existing frailty assessments tools for this purpose. Boxer et al. categorised 60 HF patients into three groups based on the frailty phenotype status where the frail patients had the highest mortality at follow-up compared to their counterparts.55 Similarly, in the study by Madan et al. in 40 HF patients, frailty was associated with increased combined endpoint of mortality and all-cause hospitalisation.56 McNallan et al. investigated the relationship between frailty and mortality in HF patients using a the deficit model and a modified version of Fried’s frailty phenotype, differing in patient assessment by using the physical component score of the Short Form 12 health questionnaire as a surrogate for both strength and speed.57,58 This demonstrated that in HF patients defined as frail, the risk of mortality was doubled (HR 2.04; 95% CI [0.99–4.18]). Tanaka et al.

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Frailty in Heart Failure demonstrated that frailty is independently associated with worse clinical outcomes irrespective of age, BMI, ejection fraction and gender.59 In the advanced HF population awaiting a heart transplant, frailty was found to be an independent predictor of all-cause mortality.60 Furthermore, this finding was replicated in patients with HF following CRT with the implication that frailty is an independent predicator of response to CRT.61 In the left ventricular assist device (LVAD) population HF has repeatedly been demonstrated to independently predict outcomes.62,63 Furthermore, in patients with sarcopenia undergoing LVAD therapy, there was a general trend towards increasing hospital stay and mortality.64 In summary, there is significant evidence that both the individual components of frailty and various definitions of frailty as a syndrome can be used to predict prognosis in HF patients.

Management Implications in the Frail Heart Failure Patient

Frailty adds an increasing layer of complexity to the management of the already complex HF patient. Frailty also leaves patients more at risk from guideline-directed medical therapy because of their increased vulnerability to adverse drug effects, such as hypotension and subsequent falls. Therefore, the management of the frail HF patient involves more pragmatism and less rigorous adherence to guidelines. Furthermore, frail patients are more likely to benefit from non-pharmacological interventions than their non-frail counterparts. There are currently two broad categories of intervention for the frail HF patient: exercise and physical rehabilitation and diet and nutritional strategies.

Exercise and Physical Rehabilitation

The 2021 ESC HF guidelines suggest that supervised, exercise-based cardiac rehabilitation programmes should be offered to patients who are frail or with multiple comorbidities. This is based on a class IIa level of evidence.65 Exercise programmes are a promising intervention in frail HF patients as there is evidence of dual benefit, addressing both a patient’s cardiac failure and frailty simultaneously. For HF patients, the positive impact of exercise on physical function, quality of life and exercise capacity is well documented.66–68 Despite these benefits, uncertainty still exits regarding the overall impact on mortality and HF hospitalisations.69,70 Intense exercise therapy has shown that it may improve peak oxygen consumption (VO2).71 Furthermore, exercise training has been shown to reduce serum markers of inflammation in HF patients, suggesting a reduction in the chronic inflammation that acts as a key pathophysiological process in both HF and frailty.72,73 Inflammation may also play a role in predicting benefit from exercise training, as HF patients with higher baseline levels of inflammatory biomarkers have been noted to show poorer improvements in peak VO2 as a result of exercise training when compared with HF patients with lower baseline inflammatory biomarkers.74

Diet and Nutrition Strategies

Dietary support in frailty aims to address the numerous nutritional deficits seen in frail patients. Micronutrient deficiencies common in frailty include vitamins D, E, A, B12, thiamine, iron and folate.75 Long-term vitamin D supplementation in the advanced HF patient has not been demonstrated to reliably improve outcomes or cause harm.76 Thiamine supplementation has been found to be ineffectual in impacting HF progression or physical performance, and while folate supplementation has shown promise in lowering N-terminal pro-brain natriuretic peptide levels, the evidence for this is limited and there is no evidence of clinical benefit in HF populations.77,78 The evidence for micronutrient supplementation (calcium,

magnesium, zinc, copper, selenium, thiamine, riboflavin, folate, vitamins A, B6, B12, C, E, D and coenzyme Q10) is mixed and inconclusive.79,80 Iron replacement in the frail HF patient has a strong evidence base and patients should be regularly screened and treated.65 With regards to macronutrients, high-calorie, high-protein diets in HF patients with significant unintended weight loss have been demonstrated to improve quality of life and 6MWT performance.81 Supplementation with essential amino acids has been shown to improve peak VO2 and 6MWT performance in muscle-depleted HF patients but did not increase muscle mass.82 Conversely, supplementing resistance exercise with branched chain amino acids in HF patients led to no additional improvement in strength or VO2 max when compared with HF patients undertaking exercise without supplementation.83 The future of nutritional support in frail HF patients may lie in a patientpersonalised approach. In a clinical trial of 120 malnourished patients hospitalised with HF, personalised nutritional interventions delivered over a 6-month period led to decreased all-cause mortality (20.3% versus 47.5%; HR 0.37; 95% CI [0.19–0.72]; p=0.003), cardiovascular mortality (16.9% versus 42.6%; HR 0.35; 95% CI [0.17–0.72]; p=0.004) and readmission for HF (10.2 versus 36.1%; HR 0.21; 95% CI [0.09–0.52]; p=0.001).84 Taken together, this suggests that nutritional treatments of frailty in HF should be tailored to the individual patient’s nutritional needs, with or without micronutrient supplementation where appropriate. Further research is required to assess the impact of personalised nutritional support in non-malnourished frail HF patients.

The Role of the Multispecialty Multidisciplinary Team in Heart Failure Management

Recent evidence from Liverpool, UK, has shown that a multispecialty multidisciplinary team approach provides seamless integration of primary care community services with secondary and tertiary care.85 The multispecialty team consists of HF specialists (consultants, specialist nurses), along with a geriatrician, renal physician, diabetes specialist, chest physician, pharmacist, pharmacologist and palliative care physician.

This approach allows for consensus decisions from multidisciplinary team meetings, providing a holistic approach for HF patients with comorbidities, polypharmacy and frailty. This approach can also reduce hospitalisations and inconvenience to patients by preventing the need to attend multiple specialty clinics. This model can also lead to significant cost savings to the healthcare system.

Conclusion

HF is among the high-priority challenges in the field of cardiology. Frailty represents the endpoint of a multitude of complex processes. The incidence of frailty and HF and the combination of both is increasing with an ageing population. The frail HF patient represents the most complex presentation of HF. Routine and meaningful assessment and management of frailty in the HF patient can offer more intensive treatment to improve outcomes. These patients are likely to be more complex than their non-frail counterparts and more likely to benefit from a multidisciplinary HF team approach.

Physical exercise programmes are a useful resource and are recognised in ESC HF guidelines. Further research on personalised nutritional interventions in frail HF patients is recommended to validate the promising evidence available at present. Finally, development and validation of an assessment tool to identify frailty in HF populations is recommended to facilitate delivery of multidisciplinary care to these complex patients.

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REVIEW

Therapy

Cell Therapy in Heart Failure with Preserved Ejection Fraction Sabina Frljak , Gregor Poglajen

and Bojan Vrtovec

Advanced Heart Failure and Transplantation Center, UMC Ljubljana, Slovenia

Abstract

Heart failure with preserved ejection fraction (HFpEF) is the most common cause of hospitalisation for heart failure. However, only limited effective treatments are available. Recent evidence suggests that HFpEF may result from a systemic proinflammatory state, microvascular endothelial inflammation and microvascular rarefaction. Formation of new microvasculature in ischaemic tissues is dependent on CD34+ cells, which incorporate into the newly developing vasculature and produce pro-angiogenic cytokines. In HFpEF patients, worsening of diastolic function appears to correlate with decreased numbers of CD34+ cells. Therefore, it is plausible that increasing the myocardial numbers of CD34+ cells could theoretically lead to improved microvascular function and improved diastolic parameters in HFpEF. In accordance with this hypothesis, recent pilot clinical data suggest that CD34+ cell therapy may indeed be associated with improved diastolic function and better functional capacity in HFpEF patients and could thus represent a promising novel therapeutic modality for this patient population.

Keywords

Heart failure, cell therapy, heart failure with preserved ejection fraction, CD34+ Disclosure: The authors have no conflicts of interest to declare.

Funding: This work was supported by Slovenian Research Agency grant # J3-9283.

Received: 24 August 2021 Accepted: 19 November 2021 Citation: Cardiac Failure Review 2022;8:e08. DOI: https://doi.org/10.15420/cfr.2021.21 Correspondence: Bojan Vrtovec, Advanced Heart Failure and Transplantation Center, Department of Cardiology, Ljubljana University Medical Center, Zaloska 7, MC SI-1000, Ljubljana, Slovenia. E: bvrtovec@stanford.edu; bojan.vrtovec@kclj.si 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.

Nearly one-half of heart failure patients have heart failure with preserved ejection fraction (HFpEF), and the prevalence appears to be rising.1 Today, HFpEF represents the most common cause of hospitalisation for heart failure, surpassing heart failure with reduced ejection fraction (HFrEF).2 Patients with HFpEF experience similar patterns of morbidity and functional decline as those with HFrEF, but few effective treatments are available.3 The effects of medical management in patients of HFpEF are very limited, mainly focusing on treatment of heart failure symptoms and comorbidities. Large clinical trials investigating the effects of candesartan, irbesartan, perindopril, spironolactone and, more recently, sacubitril– valsartan in patients with HFpEF all failed to reach their primary endpoints.4–8 Thus, there is a growing need for the introduction of novel treatment strategies that could potentially improve the outcomes in this large patient population.

Potential Targets for Cell Therapy in HFpEF

Currently, the central paradigm for the pathophysiology of HFpEF is based on the hypothesis that comorbidities lead to a systemic proinflammatory state and coronary microvascular endothelial inflammation.9 Patients with HFpEF have a high prevalence of co-morbidities such as obesity, diabetes, hypertension or renal dysfunction, which can induce the systemic proinflammatory state. In this proinflammatory state, coronary microvascular endothelial cells produce reactive oxygen species, which limits nitric oxide (NO) bioavailability. Reduced NO signalling from dysfunctional endothelium influences adjacent cardiomyocytes and cardiac fibroblasts via the soluble guanylyl cyclase–cyclic guanosine

monophosphate–cGMP-dependent protein kinase pathway, resulting in functional and structural cardiac changes such as delayed myocardial relaxation, increased cardiomyocyte stiffness, cardiac hypertrophy and interstitial fibrosis.10 In addition, NO imbalance affects endothelial progenitor cells (EPCs), leading to impaired endothelial repair and regeneration.11 EPCs are bone-marrow-derived circulating cells able to proliferate and differentiate into functional mature endothelial cells. EPCs are mobilised into the circulation in response to tissue or vessel injury and incorporate into sites of injury. Circulating EPCs can be evaluated by measuring the expression of various surface antigens, including CD34, CD133 and vascular endothelial growth factor receptor 2.12 In ischaemic conditions, EPCs are responsible for the formation of new vessels via direct incorporation into the newly developing vasculature and the production and secretion of angiogenic cytokines.13 Levels of circulating EPCs are significantly reduced in patients with HFpEF and the remaining EPCs have impaired function.12 Furthermore, the numbers of circulating EPCs have been shown to inversely correlate with the degree of diastolic impairment.14 This is in illustrated by findings from autopsy studies demonstrating that HFpEF patients have lower coronary microvascular density and more severe fibrosis than control subjects regardless of the severity of epicardial coronary disease.15 In these subjects, the severity of myocardial fibrosis was inversely associated with microvascular density.

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Cell Therapy in HFpEF More recently, it has been shown that patients with HFpEF have a very high prevalence of microvascular dysfunction, demonstrated by reduced myocardial flow reserve at single-photon emission CT, lower coronary flow reserve, and a higher index of microvascular resistance.16 Together, this evidence strongly supports the hypothesis that coronary microvascular endothelial inflammation in HFpEF may be the key factor leading to impaired angiogenesis, microvascular rarefaction and myocardial fibrosis.

Mechanisms of Action of Cell Therapy in Heart Failure

Different populations of autologous and allogeneic stem cells have been studied in either preclinical or clinical settings of chronic heart failure for their capacity to repair and/or regenerate the failing myocardium.17 Initially, the main reparative mechanism of cell therapy was thought to be a direct replacement of damaged cardiomyocytes with new, cell-derived cardiomyocytes through a process of trans-differentiation.18 While this mechanism has been demonstrated in preclinical models of heart failure, it has never been unequivocally confirmed in the clinical setting. Based on the current evidence, it is believed the main reparative mechanisms of cell therapy on the failing myocardium are mediated through paracrine effects that affect myocardial neurohumoral activation, inflammation, fibrosis, apoptosis, Ca2+ handling and metabolism, stimulation of neovascularisation and activation of endogenous cardiac-resident cells.19,20 These mechanisms may be associated with beneficial effects in HFpEF through improved angiogenesis, decreased fibrosis and reduced inflammation (Figure 1).

Effects of Cell Therapy on Angiogenesis

demonstrated in patients with dilated cardiomyopathy and normal coronary arteries, it is likely that factors other than coronary atherosclerosis may be responsible for the observed changes in myocardial perfusion.23 Evidence suggests that cells may exert their beneficial effects on myocardial angiogenesis through the paracrine secretion of bioactive growth factors, such as vascular endothelial growth factor and fibroblast growth factor.26,27 It has been suggested that stem-cell-derived paracrine factors may further trigger a secretion of other paracrine factors from the host myocardium thus potentiating their effect. This hypothesis may partly explain the apparent discordance between significant clinical effects on the remodelling process caused by a limited number of surviving stem cells in the host myocardium.28

Effects of Cell Therapy on Extracellular Matrix

In addition to exerting positive effects on the microvascular homeostasis, cell therapy has also been associated with reverse remodelling of the extracellular matrix (ECM) in the setting of chronic heart failure. Preclinical data suggest that cell therapy may be associated with a significant reduction in myocardial fibrosis.18,29 These findings have been further corroborated by clinical data, where the intracoronary infusion of cardiosphere-derived autologous stem cells (CDCs) was shown to be associated with a 42% reduction in myocardial scar burden (as assessed by cardiac MRI), and an increase in myocardial viability and regional contractility 12 months after the procedure.30 In accordance with these findings, intramyocardial injection of autologous MSCs was also associated with significant (48%) reduction in myocardial scar burden, improved myocardial perfusion and increased contractile performance.25

Current data suggest that cells transplanted into the failing myocardium likely stimulate angiogenesis and may thus significantly improve myocardial regional perfusion. Kawamoto et al. demonstrated that intramyocardial injections of CD34+ cells are associated with a significantly increased myocardial capillary density in an animal model of heart failure.21 The authors additionally showed that the application of a single cell type (in this case CD34+) may be more advantageous over unfractionated bone marrow mononuclear cells because the latter might cause detrimental changes to the myocardium (haemorrhagic necrosis), thus offsetting the potential benefits of cell therapy.21

Although the exact pathophysiological mechanism of stem cell action on ECM reverse remodelling remains to be clarified, currently available data suggest that stem cell therapy may affect myocardial scar by inhibiting tumour necrosis factor (TNF)-α and the transforming growth factor-β1/ extracellular signal-regulated kinase 1/2 fibrosis pathways and by the direct actions on resident fibroblasts. The latter may result in decreases in transcript levels of matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; collagen I and collagen III and tissue inhibitor of metalloproteinase-1, thereby normalising the turnover of ECM proteins.31

In accordance with these findings, Schuleri et al. demonstrated that intramyocardial injections of mesenchymal stem cells (MSC) likely improve myocardial perfusion (estimated with cardiac MRI) in a preclinical model of ischaemic heart failure.22 These encouraging preclinical findings were subsequently confirmed in a clinical trial in patients with dilated cardiomyopathy, where a significant improvement in myocardial perfusion six months after intracoronary CD34+ cell injections was found.23 Of note, these changes in myocardial perfusion correlated with a significant improvement in contractile performance of the failing myocardium, a decrease in neurohumoral activation, improved exercise capacity and improved overall survival at 5 years follow-up.24

Cell therapy has also been shown to dampen the pro-inflammatory milieu in the failing myocardium by downregulating the expression of proinflammatory cytokines, such as TNF-α, interleukin (IL)-1β, IL-6 and monocyte chemo-attractive protein.32 Furthermore, stem cells (especially MSCs) have been demonstrated to possess immunomodulatory properties that are likely exerted through cell-secreted paracrine factors and direct cell-to-cell interactions, which may affect a wide range of cells involved in the pro-inflammatory response.33 It is further suggested that cell-derived paracrine factors may activate tissue macrophages, which promotes structured angiogenesis and induces a switch from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype, most likely via insulin-like growth factor-1 and IL-10 pathways.34,35 Collectively, these data suggest that the anti-inflammatory properties of cell therapy may have a significant role in stimulating the process of reverse remodelling of the failing myocardium.

In patients with ischaemic heart failure, intramyocardial MSC injections were associated with an improvement of regional perfusion in the injected segments of the failing myocardium, which translated to improved contractility of these segments. Of interest, surgically revascularised segments that were not treated with cell injections did not functionally improve to the same degree.25 These data suggest that the changes in myocardial perfusion after cell therapy appear to occur independently from the status and progression of coronary artery disease.25 Moreover, since the changes in perfusion after cell therapy have also been

Effects of Cell Therapy on Myocardial Inflammation

Preclinical Evidence for Cell Therapy in HFpEF

In contrast to the abundant preclinical evidence on the effects of cell therapy in HFrEF, data on the effects of cell therapy in HFpEF models are very scarce. Using a hypertensive rat model of HFpEF, Gallet et al. investigated the effects of CDCs on left ventricular structure and function.36

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Cell Therapy in HFpEF Figure 1: Potential Effects of Cell Therapy in Heart Failure with Preserved Ejection Fraction

Systemic proinflammatory state (IL-6, TNF-α, sST2, Pentraxin 3, etc.)

↑VCAM ↑E-selectin

Stem cell therapy

Cardiomyocyte

Cardiomyocyte

↑ROS →↓NO ↑Peroxinitrite

Fibroblasts

Obesity Hypertension Diabetes COPD Iron deficiency

Endothelium

HFpEF pathophysiology

↓sGC

↓Hypertrophy ↓Apoptosis

↑Hypertrophy

↓cGMP ↓PKG

Activation

Extracellular Matrix ↓Interstitial and total myocardial fibrosis

↑Myocardial fibrosis

Collagen synthesis

↓Proinflammatory cytokines (TNF-α, IL-lβ, IL-6, etc.)

Paracrine effects

↓Profibrotic pathways (TNF-α, TGFβ1/ERK1/2, etc.)

Endothelial cells Microvasculature ↓Capillary density

↑Capillary density

Smooth muscle cells

Trans-differentiation

Potential mechanisms leading to development and progression of HFpEF are presented in the left panel and the effects of cell therapy are presented in the right panel. In HFpEF, cell therapy may be associated with beneficial effects through its action on microvasculature, cardiomyocytes and extracellular matrix. cGMP = cyclic guanosine monophosphate; COPD = chronic obstructive pulmonary disease; ERK = extracellular signal-regulated kinase; HFpEF = heart failure with preserved ejection fraction; IL = interleukin; NO = nitric oxide; PKG = cGMP-dependent protein kinase; ROS = reactive oxygen species; sGC = soluble guanylyl cyclase; sST = soluble suppression of tumourigenesis; TGF = transforming growth factor; TNF = tumour necrosis factor; VCAM = vascular cell adhesion molecule.

At 13–14 weeks of age the rats were randomly allocated to receive intracoronary infusion of either allogeneic CDCs (n=24) or placebo (n=24).

Follow-up lasted for 4 weeks after randomisation. Before randomisation and at 4 weeks after treatment, echocardiography and invasive haemodynamic measurements were performed. At the end of the followup, CDC therapy was associated with a decrease in E/A ratio and halted left atrial enlargement. The results of haemodynamic measurements demonstrated a twofold higher end-diastolic pressure in placebo-treated animals when compared to those receiving CDC therapy. Furthermore, CDC therapy was associated with decreased lung congestion and improved survival. The histological analysis of the myocardium demonstrated increased capillary density, decreased inflammation and decreased fibrosis in CDC-treated animals. CDC treatment also reversed many transcriptomic changes associated with HFpEF but had no effect on cardiac hypertrophy.

Using a similar rat model of HFpEF, Cho et al. investigated the potential effects of CDC therapy on ventricular arrythmias.37 At 4 weeks after the intracoronary infusion, CDC therapy was associated with shortening of action potential duration and increased action potential duration homogeneity. CDC-treated animals were also less prone to ventricular arrhythmia induction by programmed electrical stimulation. Interestingly, CDC therapy was also associated with a regression of diastolic dysfunction as demonstrated by a decrease in E/e’ ratio and a decrease in left atrial size.

Based on the results of these two studies, there is a positive signal that cell therapy may improve some parameters of diastolic function in HFpEF. Nevertheless, there is a clear need for additional studies to verify and expand these preliminary findings.

Clinical Evidence for Cell Therapy in HFpEF

To date, our group has performed several clinical trials investigating the effects of CD34+ cell therapy in patients with HFrEF. We also evaluated the effects of this approach on diastolic parameters in a group of patients with non-ischaemic dilated cardiomyopathy.38 We enrolled 38 dilated cardiomyopathy patients with New York Heart Association class III and left ventricular ejection fraction (LVEF) <40% who underwent transendocardial CD34+ cell transplantation. Peripheral blood CD34+ cells were mobilised

by granulocyte-colony stimulating factor, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation.

Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e’ ≥15) in 18 patients (Group A), and moderately elevated (E/e’ <15) in 20 patients (Group B). During follow-up there was an improvement in diastolic parameters in Group A (E/e’ from 24.3 ± 12.1 to 16.3 ± 8.0; p=0.005), but not in Group B (E/e’ from 10.2 ± 3.7 to 13.2 ± 9.1; p=0.19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m; p=0.03), and a decrease in N-terminal pro B-type natriuretic peptide (NT-proBNP) from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml (p=0.02).

Based on the results of this trial we next aimed to perform a pilot clinical study of CD34+ therapy in patients with HFpEF.39 In a prospective crossover study, we enrolled 30 patients with HFpEF (LVEF >50%, E/e’ >15, NTproBNP >300 pg/ml). In Phase 1, patients were treated with medical therapy for 6 months. Thereafter, all patients underwent transendocardial CD34+ cell transplantation. They received bone marrow stimulation with filgrastim (10 μg/kg, 5 days); CD34+ cells were collected by apheresis. We performed electroanatomical mapping of the left ventricle and injected the cells transendocardially in the areas of diastolic dysfunction. Patients were followed for 6 months after the procedure (Phase 2). In Phase 1, we found no change in E/e’ (from 18.0 ± 3.5 to 17.4 ± 3.0; p=0.97), global systolic strain (from −11.5 ± 2.4% to −12.8 ± 2.6%; p=0.17), NT-proBNP levels (from 1463 ± 1247 pg/ml to 1298 ± 931 pg/ml; p=0.31), or 6-minute walk test distance (from 391 ± 75 m to 402 ± 93 m; p=0.42). In contrast, in Phase 2, we found a significant improvement in E/e’ (from 17.4 ± 3.0 to 11.9 ± 2.6, p<0.0001), a decrease in NTproBNP levels (from 1298 ± 931 pg/ml to 887 ± 809 pg/ml; p=0.02), and an improvement in 6-minute walk test distance (from 402 ± 93 m to 438 ± 72 m; p=0.02; Figure 1). Although global systolic strain did not change significantly in Phase 2, (from −12.8 ± 2.6% to −13.8 ± 2.7%; p=0.36), we found a significant improvement of local systolic strain in myocardial segments that were targeted with stem cell injections (−3.4 ± 6.8%; p=0.005).

Although these data are encouraging, they should be viewed as preliminary and interpreted with caution, particularly because of the lack of placebo-controlled design. Furthermore, as patients with HFpEF are

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Cell Therapy in HFpEF typically older and present with several comorbidities, the effects of autologous cell therapy in these patient populations may be limited because of decreased cell numbers and impaired cell viability. One approach to improve the therapeutic efficacy of autologous cell therapy in HFpEF may thus be based on strategies to intervene in aspects of the stem cell aging process.40 Alternatively, this limitation could be overcome by the use of allogeneic cell products from healthy donors that could be used as an off-the-shelf therapeutic product. Taking these limitations into account, the results of this trial may serve as a foundation for further, larger trials exploring the potential clinical benefits of cell therapy in patients with HFpEF. 1.

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Kakzanov Y, Sevilya Z, Veturi M, et al. Circulating endothelial progenitor cells in patients with heart failure with preserved versus reduced ejection fraction. Isr Med Assoc J 2021;23:364–8. PMID: 34155850.

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Conclusion

Although complex, the principal underlying mechanisms of HFpEF development and progression appear to be based on endothelial inflammation, leading to microvascular rarefaction and myocardial fibrosis. In various preclinical and clinical settings cell therapies have been consistently associated with anti-inflammatory effects, improved angiogenesis and a decrease in myocardial fibrosis and may thus represent an interesting novel treatment approach for HFpEF. The current preliminary evidence investigating the use of cell therapy in HFpEF shows a positive signal, which should be further validated in future preclinical and clinical studies.

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Poglajen G, Vrtovec B. Stem cell therapy for chronic heart failure. Curr Opin Cardiol 2015;30:301–10. https://doi. org/10.1097/HCO.0000000000000167; PMID: 25827394.

Orlic D, Kajstura J, Chimenti S, et al. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci 2001;938:221–9. https://doi.org/10.1111/ j.1749-6632.2001.tb03592.x; PMID: 11458511.

Monsanto MM, White KS, Kim T, et al. Concurrent isolation of 3 distinct cardiac stem cell populations from a single human heart biopsy. Circ Res 2017;121:113–24. https://doi. org/10.1161/CIRCRESAHA.116.310494; PMID: 28446444.

Tseng CC, Ramjankhan FZ, de Jonge N, Chamuleau SA. Advanced strategies for end-stage heart failure: combining regenerative approaches with LVAD, a new horizon? Front Surg 2015;2:10. https://doi.org/10.3389/fsurg.2015.00010; PMID: 25905105.

Kawamoto A, Iwasaki H, Kusano K, et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation 2006;114:2163–9. https://doi.org/10.1161/CIRCULATIONAHA.106.644518; PMID: 17075009.

Schuleri KH, Feigenbaum GS, Centola M, et al. Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J 2009;30:2722–32. https://doi.org/10.1093/eurheartj/ehp265; PMID: 19586959.

Lezaic L, Socan A, Poglajen G, et al. Intracoronary transplantation of CD34+ cells is associated with improved myocardial perfusion in patients with nonischemic dilated cardiomyopathy. J Card Fail 2015;21:145–52. https://doi. org/10.1016/j.cardfail.2014.11.005; PMID: 25459687.

Vrtovec B, Poglajen G, Lezaic L, et al. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year followup. Circ Res 2013;112:165–73. https://doi.org/10.1161/ CIRCRESAHA.112.276519; PMID: 23065358.

Karantalis V, DiFede DL, Gerstenblith G, et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ Res 2014;114:1302– 10. https://doi.org/10.1161/CIRCRESAHA.114.303180; PMID: 24565698.

Duran JM, Makarewich CA, Sharp TE, et al. Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circ Res 2013;113:539–52. https://doi. org/10.1161/CIRCRESAHA.113.301202; PMID: 23801066.

Payne TR, Oshima H, Okada M, et al. A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts. J Am Coll Cardiol 2007;50:1677–84.

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29. Zhang C, Zhou G, Chen Y, et al. Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF-α and TGF-β1/ERK1/2 signaling pathways.

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30. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895–904. https:// doi.org/10.1016/S0140-6736(12)60195-0; PMID: 22336189.

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REVIEW

Patient Care During the Pandemic and Beyond

Cardiac Magnetic Resonance in the Evaluation of COVID-19 Daniel E Clark ,1 Sachin K Aggarwal ,2 Neil J Phillips ,3 Jonathan H Soslow ,4 Jeffrey M Dendy

1

and Sean G Hughes

1

1. Division of Cardiovascular Medicine, Department of Internal Medicine, Vanderbilt University Medical Centre, Nashville, TN, US; 2. Vanderbilt School of Medicine, Vanderbilt University, Nashville, TN, US; 3. Department of Internal Medicine, Vanderbilt University Medical Centre, Nashville, TN, US; 4. Thomas P Graham Division of Paediatric Cardiology, Department of Paediatrics, Monroe Carell Jr Children’s Hospital at Vanderbilt, Nashville, TN, US

Abstract

Cardiovascular involvement following COVID-19 is heterogeneous, prevalent and is often missed by echocardiography and serum biomarkers (such as troponin I and brain natriuretic peptide). Cardiac magnetic resonance (CMR) is the gold standard non-invasive imaging modality to phenotype unique populations after COVID-19, such as competitive athletes with a heightened risk of sudden cardiac death, patients with multisystem inflammatory syndrome, and people suspected of having COVID-19 vaccine-induced myocarditis. This review summarises the key attributes of CMR, reviews the literature that has emerged for using CMR for people who may have COVID-19-related complications after COVID-19, and offers expert opinion regarding future avenues of investigation and the importance of reporting findings.

Keywords

COVID-19, myocarditis, vaccine myocarditis, multisystem inflammatory syndrome, cardiac magnetic resonance Disclosure: The authors have no conflicts of interest to declare.

Funding: Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number T32HL007411 (DEC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors take full responsibility for the integrity of the data and the accuracy of the data analysis.

Received: 22 August 2021 Accepted: 26 October 2021 Citation: Cardiac Failure Review 2022;8:e09. DOI: https://doi.org/10.15420/cfr.2021.20 Correspondence: Daniel E Clark, 2220 Pierce Avenue, 383 Preston Research Building, Nashville, TN 37237, US. E: daniel.e.clark@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.

Cardiovascular sequelae of COVID-19 include venous and arterial thrombosis, electrical disturbances, and mechanical dysfunction.1–3 As many as 55% of patients with acute COVID-19 have cardiovascular abnormalities detected by echocardiography, and elevations of troponin I and N-terminal pro B-type natriuretic peptide during acute, severe illness are predictors of mortality.4,5 However, among ambulatory patients, traditional cardiovascular diagnostics, such as echocardiography with strain imaging, troponin I and electrocardiography, perform inconsistently as screening tools for COVID-19-related myocarditis.6–8 Myocardial oedema, inflammation and fibrosis have been detected by cardiac magnetic resonance (CMR) in both the acute and late convalescent phases of COVID-19 illness.7–9 Indeed, these cardiovascular sequelae have consistently been detected by CMR among competitive athletes recovering from COVID-19 in the setting of normal echocardiography.6–7 Pathological analysis of the myocardium following COVID-19 remains the gold standard for the diagnosis of direct and indirect myocardial injury, however endomyocardial biopsy is invasive and has limited sensitivity.10 One autopsy study involving 15 patients who had died of COVID-19 revealed nonocclusive fibrin microthrombi in the coronary arteries of 80% (n=12), and active lymphocytic myocarditis in one-third (n=5). No viral particles were identified in the cardiac myocytes, vascular endothelium or interstitial fibroblasts, suggesting an indirect inflammatory process rather than a direct viral invasion of the myocardium.11

CMR has distinct advantages for cardiovascular phenotyping. CMR is not only the reference standard for the assessment of ventricular volumes and function but it can be used to diagnose subclinical myocardial dysfunction using strain analysis. However, its biggest advantage over other imaging modalities is advanced tissue characterisation. Late gadolinium enhancement (LGE) imaging can be used to identify focal areas of oedema and replacement fibrosis, and parametric mapping is extremely sensitive for the detection of diffuse oedema, inflammation, fibrosis, infiltration, and fat. This has made CMR a critical tool for clinicians to understand cardiovascular involvement and for risk stratification of patients recovering from COVID-19.

Advantages of Cardiac Magnetic Resonance Volumes and Function

CMR is the gold standard for assessment of myocardial volumes and function.12 Accurate quantitative assessment of biventricular function, cardiac performance and valvular disease can be reliably obtained with CMR. CMR is particularly beneficial for the accurate assessment of right ventricular (RV) size and function, and multiple studies have shown a reduced RV ejection fraction among patients recovering from COVID-19 compared to controls.9,13,14

Strain

Myocardial strain imaging with CMR may enhance the detection of subclinical functional abnormalities of the myocardium after COVID-19.

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Cardiac Magnetic Resonance in the Evaluation of COVID-19 Table 1: Overview of Studies Involving Competitive Athletes Who Have Had COVID-19 Study

Sample Size

MRI Screening Algorithm

Competition Level

Symptomatic Athletes, n (%)

Myocardial Findings by MRI, n (%)

Myocarditis Suspected, n (%)

Mean Follow-up (days)

Rajpal et al. 202055

26

All inclusive

Collegiate

12 (27)

12 (46)

4 (15)

NA

Brito et al. 2020

54

Selective (48 MRIs performed)

Collegiate

38 (70)

19 (40)

0 (0)

NA

26

All inclusive

Professional

20 (77)

0 (0)

0 (0)

NA

Starekova et al. 2021

145

All inclusive

Collegiate, high school

111 (77)

40 (28)

2 (1.4)

NA

Clark et al. 20216

59 COVID-19positive, 60 COVID-19negative athletes

All inclusive

Collegiate

46 (78% of subjects who tested positive)

2 (3)

2 (3)

NA

Martinez et al. 202159

789

Selective (30 MRIs performed)

Professional

460 (58)

5 (0.6)

5 (0.6)

180

Moulson et al. 20218

3,018

All inclusive (198 MRIs) + selective (119 MRIs)

Collegiate

1,774 (59)

21 (0.7)

21 (0.7)

130

56

Malek et al. 202157 58

Source: Sarma et al. 2021.34 Reproduced with permission from Wolters Kluwer Health.

Strain imaging adds incremental prognostic value to predict major adverse cardiac events (MACE) in comparison to traditional CMR in acute myocarditis.15,16 In particular, CMR strain has been shown to improve diagnostic accuracy in the setting of preserved biventricular systolic function.17–19 Given that patients with COVID-19-related myocarditis tend to have normal biventricular systolic function, investigations of CMR strain may provide further insights into subclinical cardiovascular sequelae after recovery from COVID-19.7,8

Parametric Mapping

Native T1, T2 and extracellular volume (ECV) mapping by CMR can be used for myocardial tissue characterisation, specifically to detect myocardial inflammation, oedema and fibrosis.20 The modified Lake Louise criteria for the detection of myocarditis include the use of these advanced parametric mapping techniques for improved sensitivity.21 Elevation of the native myocardial T1 is non-specific and may be due to any combination of inflammation, oedema, injury and/or infiltration. T2 elevations correspond to myocardial oedema. The resolution of myocardial oedema with persistence of LGE is known to be an unfavourable prognostic marker in viral myocarditis.22 ECV elevations suggest extracellular compartment expansion. Accurate ECV calculation requires a recent haematocrit.

Native T1 and T2 mapping values depend on the magnetic field strength and other unique properties of the individual magnet, pulse sequences and field inhomogeneities in the field of view. Thus, reference to internal magnetic-specific control values is preferred for native T1 and T2 mapping.

On the other hand, ECV is derived from the ratio of native and postcontrast T1 values and is therefore similar between different magnets, allowing for the use of published controls.20

Late Gadolinium Enhancement

Contrasted CMR permits the assessment of myopericardial LGE. The presence, location and extent of LGE relative to the ventricular mass have been shown to be associated with MACE in patients with myocarditis.23–25 The distribution of LGE aids the differentiation of ischaemic versus nonischaemic complications of COVID-19. LGE burden in viral myocarditis often decreases over time with acute phase LGE with myocardial oedema representing inflammation and extracellular expansion, while late phase LGE reflects replacement fibrosis.22,26

Stress Imaging

Vasodilator stress CMR is a highly accurate and useful diagnostic modality for patients with suspected or known coronary artery disease (CAD) and post-orthotopic heart transplantation to assess for coronary allograft vasculopathy.27–31 Because 95% of coronary arterial blood supplying the myocardium returns through the coronary sinus (CS), flow through this vessel is an accurate surrogate for total coronary blood flow.29 The coronary flow reserve (CFR) may be calculated as the ratio of CS flow during vasodilator infusion versus resting conditions. An impaired CFR may indicate either obstructive CAD or coronary microvascular dysfunction.

An autopsy study of COVID-19 patients found an absence of viral particles in the myocardium and thrombosis of the coronary microvasculature during the acute and convalescent stages. This suggests that COVID-19mediated myocardial injury and ischaemia may result from endothelial injury and demand ischaemia from microthrombi.11 COVID-19-related microthrombi and endothelial injury may therefore be detectable by CFR assessment from stress CMR. Thus, stress CMR with CFR may be uniquely suited to explore this mechanism of cardiovascular involvement after COVID-19 and may yield insights into patients with cardiovascular postacute sequelae of COVID-19 (CV-PASC).

Unique Populations Competitive Athletes and Military Personnel

Myocarditis is a known complication of COVID-19 and a leading cause of sudden cardiac death (SCD) among athletes and military recruits in the US.32 The detection of myocarditis in athletes presents unique challenges owing to the heterogeneity of clinical presentation, lack of specific biomarkers for early detection, underlying structural myocardial changes related to dynamic exertion, uncertainty about the true impact of exercise on SCD risk, and downstream training and career implications for athletes who are restricted from activity.33 While the pathophysiology of myocardial injury from COVID-19 is debated, myocarditis remains a primary consideration in decisions to return-to-play among athletes and sports cardiologists.

Contrasted CMR with parametric mapping is uniquely suited as a tool for detection of cardiovascular complications from COVID-19 for the reasons

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Cardiac Magnetic Resonance in the Evaluation of COVID-19 Figure 1: Myocarditis Detected by Cardiac Magnetic Resonance Among Patients with Cardiovascular Post-acute Sequelae of COVID-19

T2 map

Patient 2

Patient 3

Patient 4

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

C

E

G

Native T1 map

Native T2 map D

MIS

A

PSIR LGE (basal) PSIR LGE (mid) A B

H

0 500 1,000 1,500 2,000 20 40

LGE = late gadolinium enhancement. Source: Clark et al. 2021.14 Reproduced from BioMed Central under a Creative Commons (CC BY 4.0) license.

outlined above and has quickly and widely been deployed to understand the cardiovascular complications of COVID-19. Table 1 summarises the findings of key CMR studies among competitive athletes recovering from COVID-19.34 Combined single-centre and multicentre data have shown that the prevalence of myocarditis among competitive athletes is approximately 3% when universal screening with CMR is undertaken (Table 1).

Cardiovascular Post-acute Sequelae of Coronavirus Infection

A study of military personnel with CV-PASC found a higher rate (12%) of myocardial pathology – mostly myocarditis – among this symptomatic cohort.14 For high-performance athletes, employees in high-risk professions (pilots, military personnel and other high-stake professions in which arrhythmias and/or SCD have implications beyond the person affected), and people with underlying cardiovascular abnormalities that make superimposed post-COVID-19 symptoms difficult to discriminate, we propose CMR with parametric mapping with or without stress testing as a crucial tool to improve detection of pathology or provide reassurance of its absence (Figure 1).

Multisystem Inflammatory Syndrome

F

Non-MIS

Native T1 map

Long axis LGE

Short axis LGE

Patient 1

Figure 2: Cardiac Magnetic Resonance Features of COVID-19-related Myocarditis Comparing Multisystem Inflammatory Syndrome (MIS) versus Non-MIS Patients

Multisystem inflammatory syndrome (MIS) has now been reported in both children and adults following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).35,36 Cardiovascular involvement in MIS is variable, with presentations ranging from myocarditis, pericarditis, transient systolic dysfunction, arrhythmias, coronary artery ectasia/ aneurysms and cardiogenic shock.37,38 An inflammatory cardiomyopathy with global elevations in T1 and T2 values has been the characteristic finding in a limited series of MIS patients undergoing CMR, often with mild or no myocardial LGE (Figure 2).39–42 Although echocardiography is often normal, especially after recovery from acute COVID-19, CMR reveals subclinical ventricular dysfunction – evidenced by abnormal strain – that persists as inflammation resolves.40,41 Follow-up CMR in small cohorts of patients reveal that MIS often presents as a transient inflammatory cardiomyopathy, with no residual cardiac abnormalities identified a few months after diagnosis.43,44 Thus, CMR may be a useful tool during the acute phase of MIS to assist with cardiovascular phenotyping and post-acute MIS to identify residual myocardial pathology and resolution of cardiac inflammation.

100

140 180

Top: A 25-year-old man who presented with MIS myocarditis who had elevated troponin I (peaked at 9 ng/ml) and non-specific ST-T changes. Cardiac magnetic resonance showed septal and inferior subepicardial LGE (A, B) and global elevation of T1 (1,245 ms, Z-score 15.6; C) and T2 values (63 ms, Z-score 11.2; D). Bottom: A 24-year-old man with non-MIS myocarditis who had postCOVID-19 dyspnoea on exertion. Cardiac magnetic resonance showed basal inferoseptal and mid-inferolateral LGE (E, F), normal global myocardial T1 (968 ms, Z-score 0.2; G) and mild regional T2 elevation (51 ms, Z-score 3.8) at the location of LGE (H). Yellow arrows point to the locations of LGE. The normal ranges of T1 and T2 were 930–1,010 ms and <50 ms, respectively. The normal range of Z-score was −2 to 2. LGE = late gadolinium enhancement; MIS = multisystem inflammatory syndrome; PSIR = phase sensitive inversion recovery.

Vaccine-associated Myocarditis

Vaccine-associated myocarditis is not a new entity, having previously been reported in 7.8 per 100,000 military service members within 30 days of smallpox vaccination.45 Early reports suggest that vaccine-associated myocarditis is a rare complication of the mRNA COVID-19 vaccine and young men may be at higher risk. Most affected patients present with an acute chest pain syndrome and biomarker evidence of myocardial injury within a week of the second dose of the mRNA vaccine.46–48 These preliminary reports show an incidence of less than 0.001% in comparison to the approximate 3% rate of myocarditis after COVID-19 in competitive athletes. In our experience, mRNA COVID-19 vaccine-associated myocarditis is associated with preserved biventricular systolic function and a modest LGE burden and is similar in appearance to acute COVID-19related myocarditis (Figure 3). Thus, while vigilance for this rare adverse event is advised, there appears to be a much higher likelihood of myocarditis in the acute and convalescent phases after COVID-19 than following mRNA COVID-19 vaccination.

Challenges Associated with CMR Limitations of CMR

CMR is limited by availability, expertise, time constraints (as comprehensive examinations may take more than an hour at some centres) and patientspecific factors, such as claustrophobia, retained leads or non-compatible devices. Despite the common misperception, cost should not be a significant barrier to CMR. In the US, reimbursement for CMR (US$570 for a CMR with contrast) from the Centers for Medicare and Medicaid Services is typically less than single photon emission CT and only slightly greater than echocardiography.49,50 The effective cost of CMR is further diminished after accounting for the cost of downstream consequences of not carrying out these examinations.50

CMR Interpretation Challenges Specific to COVID-19

The Society for Cardiac Magnetic Resonance recommends standardised reporting of parametric mapping in reference to magnet-specific

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Cardiac Magnetic Resonance in the Evaluation of COVID-19 Figure 3: COVID-19 mRNA Vaccine-associated Myocarditis

Figure 4: COVID-19 Myocarditis wth Persistent Myocardial Oedema on Follow-up 1st CMR

2nd CMR E

B

F

C

G

D

H

ECV map

Native T1 map

T2 map

LGE

A

CMR at baseline with inferoseptal acute COVID-19 myocarditis and follow-up CMR 3 months later with ongoing, smouldering myocarditis with residual T2 elevation. CMR = cardiac magnetic resonance; ECV = extracellular volume; LGE = late gadolinium enhancement.

A 25-year-old man with no prior history of heart issues developed an acute chest pain syndrome with angina radiating to the left arm 4 days after receiving a second dose of Pfizer mRNA vaccine.

An ECG revealed ST segment elevations in leads V3–V5 of 1 mm; troponin I peaked at 2.08 (upper limit of normal <0.04). Coronary angiography showed no coronary artery disease. Late gadolinium enhancement images (phase contrast inversion recovery) demonstrated basal-mid inferior late gadolinium enhancement (8.4% myocardial mass, white arrow) with regional T2 elevations meeting modified Lake Louise criteria for myocarditis.

reference values, which often have age- and gender-based normative ranges.20 However, not all centres who are able to offer CMR have collected magnet-specific control data and there are no guidelines to define appropriate selection of regions of interest (ROIs) to define regional parametric abnormalities. While parametric mapping is a highly sensitive technique for the detection of myocardial fibrosis/inflammation, interpretation of these images requires significant experience and may be subject to high inter-observer variability. This variability in parametric ROI reporting may account for some of the wide distribution of prevalence rates of myocarditis after COVID-19 detected by CMR.9 Additionally, interpretation of CMR images may be challenging owing to an apparent predilection of COVID-19 myocarditis to affect the inferior wall and inferoseptum near the RV septal insertion site (Figure 4).6,51 Focal LGE at the inferior RV septal insertion is common among athletes, which may lead to a tendency to over-diagnose pathology in this region without selection of a proper control group.6,52 Furthermore, LVEF tends to be preserved in this population, thereby making it more difficult to discriminate pathological LGE from non-

pathological LGE at this location – especially in the cohort of athletes. All these factors may complicate the accurate diagnosis of myocarditis.

Recommendations for CMR Interpretation

The parametric mapping consensus guidelines recommend the following to standardise parametric mapping use:

• Use magnet-specific age- and gender-assigned controls with normal ranges defined by ±2 standard deviations from the mean.

• Perform basal- and mid-LV short axis mapping along with a fourchamber view for T1, T2 and ECV maps.

• Carefully review the data to ensure adequate motion correction and absence of artefact.

We propose the following additional measures to specifically address issues associated with the interpretation of CMR post-COVID-19:

• Report ROIs that represent no less than a half of a standard segment in the American Heart Association’s 17-segment model.53 • Report methodology, location and value of parametric mapping abnormalities in scientific publications.

We suggest the following characteristics to diagnose pathological LGE in COVID-19 myocarditis:

• LGE encompassing greater than 50% of myocardial thickness.

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Cardiac Magnetic Resonance in the Evaluation of COVID-19 • LGE extending to at least two short-axis slices.

• Associated regional elevations in T2.

• Segmental hypokinesis.

will be necessary to understand the prevalence of smouldering myocarditis and exploring treatment options for this subset of patients.

The first two criteria should always be met; the latter two may help with diagnostic confidence (as a regionally normal T2 in the area of LGE may indicate healing myocarditis). The modified Lake Louise criteria require global or regional T1 and T2 abnormalities to diagnose acute myocarditis

by CMR.21

Cardiovascular involvement following COVID-19 is prevalent and heterogenous in manifestation. CMR accurately diagnoses myocardial inflammation/injury and is the reference standard for the assessment of myocardial structure, function, tissue characterisation and perfusion. CMR should be considered for patients at heightened risk of COVID-19 complications and when the detection of subclinical myocardial inflammation will change medical management or restrict activity. CMR complications after COVID-19 may be subtle and normal findings in athletes may be misconstrued as pathology. Thus, expertise in the acquisition and interpretation of images is critical for accurate diagnosis of acute and post-COVID-19 complications by CMR. Future studies are necessary to determine the long-term implications of myocardial inflammation and injury detected by CMR after recovery from COVID-19.

Future Directions

Comparison to an appropriate control group has been shown to be of critical importance to contextualise CMR findings in COVID-19 and remains a crucial component of ongoing research.6,54 Further investigation is necessary to better understand the utility of CMR for return-to-play screening of competitive athletes and military personnel after COVID-19. Research assessing the clinical yield of CMR for patients in the late convalescent phase of recovery from COVID-19 with CV-PASC will provide insights into the prevalence of detectable myocardial structural, functional and tissue-level changes and their correlation with patient-reported symptoms.

Future studies correlating biomarkers of effector immune response, antigen-presenting cells, cytokines, antibodies and SARS-CoV-2 titres with comprehensive CMR may elucidate which features of COVID-19 and host immune response predispose to the greatest degree of myocardial inflammation and injury. Additionally, large follow-up studies are necessary to understand the clinical significance of subclinical CMR-based myocarditis findings. These analyses should include the following clinical outcomes: quantification of arrhythmia burden, quantification of functional limitations with cardiopulmonary exercise treadmill testing, heart failure, SCD and all-cause death. As the SARS-CoV-2 virus mutates and the pandemic evolves, studies will need to be conducted among different viral variants and in various phases of recovery (acute and chronic convalescent, PASC and late post-recovery). Multicentre collaborations 1.

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Conclusion

Clinical Perspective

• Cardiovascular involvement following COVID-19 is prevalent and heterogenous in manifestation.

• Cardiac magnetic resonance (CMR) is uniquely suited to

comprehensively phenotype high-risk, persistently symptomatic, or otherwise complicated patients who have had COVID-19.

• CMR following COVID-19 may be best suited for specific populations, such as athletes, patients who develop multisystem inflammatory syndrome, and those with suspected COVID-19 vaccine-induced myocarditis.

• Expertise and consistency in image acquisition, analysis, interpretation and reporting is especially critical in the diagnosis of myocarditis by CMR.

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associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 Infection. JAMA Netw Open 2021;4:e2110323. https://doi.org/10.1001/ jamanetworkopen.2021.10323; PMID: 34009351.

Hekimian G, Kerneis M, Zeitouni M, et al. Coronavirus disease 2019 acute myocarditis and multisystem inflammatory syndrome in adult intensive and cardiac care units. Chest 2021;159:657–62. https://doi.org/10.1016/j. chest.2020.08.2099; PMID: 32910974.

Mavrogeni SI, Kolovou G, Tsirimpis V, et al. The importance of heart and brain imaging in children and adolescents with multisystem inflammatory syndrome in children (MIS-C).

Rheumatol Int 2021;41:1037–44. https://doi.org/10.1007/ s00296-021-04845-z; PMID: 33864498.

Blondiaux E, Parisot P, Redheuil A, et al. Cardiac MRI of children with multisystem inflammatory syndrome (MIS-C) associated with COVID-19: case series. Radiology 2020:202288. https://doi.org/10.1148/radiol.2020202288; PMID: 32515676.

Theocharis P, Wong J, Pushparajah K, et al. Multimodality cardiac evaluation in children and young adults with multisystem inflammation associated with COVID-19. Eur Heart J Cardiovasc Imaging 2021;22:896–903. https://doi. org/10.1093/ehjci/jeaa212; PMID: 32766671.

Caro-Dominguez P, Navallas M, Riaza-Martin L, et al.

Imaging findings of multisystem inflammatory syndrome in children associated with COVID-19. Pediatr Radiol 2021;51:1608–20. https://doi.org/10.1007/s00247-02105065-0; PMID: 33904952.

Li DL, Davogustto G, Soslow JH, et al. Characteristics of COVID-19 myocarditis with and without multisystem inflammatory syndrome. Am J Cardiol 2022. https://doi. org/10.1016/j.amjcard.2021.12.031; PMID: 35058054; epub ahead of press.

Bartoszek M, Malek LA, Barczuk-Falecka M, Brzewski M. Cardiac magnetic resonance follow-up of children after pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 with initial cardiac involvement.

J Magn Reson Imaging 2022;55:883–91. https://doi. org/10.1002/jmri.27870; PMID: 34327751.

Webster G, Patel AB, Carr MR, et al. Cardiovascular magnetic resonance imaging in children after recovery from symptomatic COVID-19 or MIS-C: a prospective study. J Cardiovasc Magn Reson 2021;23:86. https://doi.org/10.1186/ s12968-021-00786-5; PMID: 34193197.

Halsell JS, Riddle JR, Atwood JE, et al. Myopericarditis following smallpox vaccination among vaccinia-naive US military personnel. JAMA 2003;289:3283–9. https://doi. org/10.1001/jama.289.24.3283; PMID: 12824210.

Kim HW, Jenista ER, Wendell DC, et al. Patients with acute myocarditis following mRNA COVID-19 vaccination. JAMA Cardiol 2021;6:1196–201.https://doi.org/10.1001/ jamacardio.2021.2828; PMID: 34185046.

Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol 2021;6:1202–6. https://doi.org/10.1001/jamacardio.2021.2833; PMID: 34185045.

Marshall M, Ferguson ID, Lewis P, et al. Symptomatic acute myocarditis in seven adolescents following Pfizer-BioNTech

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COVID-19 vaccination. Pediatrics 2021;148:e2021052478. https://doi.org/10.1542/peds.2021-052478; PMID: 34088762.

Centers for Medicare and Medicaid Services. Physician Fee Schedule Search. https://www.cms.gov/apps/physician-feeschedule/search/search-results.aspx?Y=0&T=0&HT=0&CT=3 &H1=93306&M=12020 (accessed 17 January 2022) Raman SV, Hachamovitch R, Scandling D, et al. Lower ischemic heart disease diagnostic costs with treadmill stress CMR versus SPECT: a multicenter, randomized trial. JACC Cardiovasc Imaging 2020;13:1840–2. https://doi.org/10.1016/j. jcmg.2020.02.020; PMID: 32305477.

Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging 2020;13:2330–9. https://doi.org/10.1016/j.jcmg.2020.05.004; PMID: 32763118.

Domenech-Ximenos B, Sanz-de la Garza M, Prat-Gonzalez S, et al. Prevalence and pattern of cardiovascular magnetic resonance late gadolinium enhancement in highly trained endurance athletes. J Cardiovasc Magn Reson 2020;22:62. https://doi.org/10.1186/s12968-020-00660-w; PMID: 32878630.

Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539–42. https://doi.org/10.1161/hc0402.102975; PMID: 11815441.

Kotecha T, Knight DS, Razvi Y, et al. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur Heart J 2021;42:1866–78. https://doi.org/10.1093/eurheartj/ehab075; PMID: 33596594.

Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol 2021;6:116–8. https://doi.org/10.1001/jamacardio.2020.4916; PMID: 32915194.

Brito D, Meester S, Yanamala N, et al. High prevalence of pericardial involvement in college student athletes recovering from COVID-19. JACC Cardiovasc Imaging 2021;14:541–55. https://doi.org/1031016/j.jcmg.2020.10.023; PMID: 33223496.

Malek LA, Marczak M, Milosz-Wieczorek B, et al. Cardiac involvement in consecutive elite athletes recovered from Covid-19: a magnetic resonance study. J Magn Reson Imaging 2021;53:1723–9. https://doi.org/10.1002/jmri.27512; PMID: 33474768.

Starekova J, Bluemke DA, Bradham WS, et al. Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019 with cardiac magnetic resonance imaging. JAMA Cardiol 2021;6:945–50. https://doi. org/10.1001/jamacardio.2020.7444; PMID: 33443537.

Martinez MW, Tucker AM, Bloom OJ, et al. Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection who received systematic return-to-play cardiac screening. JAMA Cardiol 2021;6:745– 52. https://doi.org/10.1001/jamacardio.2021.0565; PMID: 33662103.

REVIEW

Therapy

Management of Type 2 Diabetes in Stage C Heart Failure with Reduced Ejection Fraction Anjali Agarwalla ,1 Jadry Gruen ,2 Carli Peters ,2 Lauren Sinnenberg ,2 Anjali T Owens 2 and Nosheen Reza 2 1. Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, US; 2. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, US

Abstract

Type 2 diabetes is an increasingly common comorbidity of stage C heart failure with reduced ejection fraction (HFrEF). The two diseases are risk factors for each other and can bidirectionally independently worsen outcomes. The regulatory requirement of cardiovascular outcomes trials for antidiabetic agents has led to an emergence of novel therapies with robust benefits in heart failure, and clinicians must now ensure they are familiar with the management of patients with concurrent diabetes and stage C HFrEF. This review summarises the current evidence for the management of type 2 diabetes in stage C HFrEF, recapitulating data from landmark heart failure trials regarding the use of guideline-directed medical therapy for heart failure in patients with diabetes. It also provides a preview of upcoming clinical trials in these populations.

Keywords

Diabetes, heart failure, antidiabetic agents, clinical trial, sodium–glucose transporter 2 inhibitors, insulin, cardiometabolic risk factors Disclosure: ATO reports consulting for Cytokinetics and Myokardia/Bristol Myers Squibb and has received research support from Cytokinetics, Myokardia/Bristol Myers Squibb and Pfizer. All other authors have no conflicts of interest to declare.

Funding: ATO is supported by the Winkelman Family Fund for Innovation. NR is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Received: 5 November 2021 Accepted: 24 January 2022 Citation: Cardiac Failure Review 2022;8:e10. DOI: https://doi.org/10.15420/cfr.2021.31 Correspondence: Nosheen Reza, Division of Cardiovascular Medicine, 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.

An estimated 38 million people worldwide have heart failure (HF), a clinical syndrome of impaired ventricular filling or ejection defined by fluid retention, effort intolerance and dyspnoea on exertion.1 Left ventricular ejection fraction (LVEF) drives the classification of HF subtypes – HF with reduced ejection fraction (LVEF ≤40%; HFrEF), mid-range (LVEF 41–49%), or HF with preserved ejection fraction (LVEF ≥50%; HFpEF) – because of differences in aetiology, responses to therapy and prognosis among them. Although HFpEF is the most common HF phenotype in the US and globally, the management of HFrEF has the most robust evidence base.2

occurrence of HF and T2D increases mortality 10-fold over those without HF, and 1-year rates of all-cause death, in-hospital death and rehospitalisation for worsening HF are higher in patients with HFrEF and T2D than in those without T2D.8,9

Type 2 diabetes (T2D) is an increasingly common concurrent diagnosis with HFrEF. In total, 60% of Americans with HFrEF have demonstrated insulin resistance and more than 40% of patients with HFrEF carry a concomitant diagnosis of T2D.3 T2D and HF are also independent risk factors for one another. A diagnosis of HFrEF independently raises the incidence ratio of T2D by 2.5-fold over the general population.3 Patients with T2D have a two- to fourfold increased risk of HF, with each 1% increase in HbA1c portending an increase in incident HF by 8–36%.4–6 In addition, the two conditions independently worsen outcomes for one another.

This review seeks to summarise contemporary data regarding available therapies for T2D as well as the evidence for benefit and harms of these therapies in patients with stage C HFrEF.

T2D is an independent predictor of persistently unfavourable quality of life in patients with HFrEF.7 In individuals aged >65 years, the co-

Fortunately, recent trials of novel antidiabetic agents have demonstrated robust benefits on HF, independent of their impacts on glycaemic control.

Therefore, it is imperative for clinicians treating HFrEF to become accustomed to the management of patients with concurrent T2D.

Glycaemic Goals in Stage C HFrEF

The 2021 American Diabetes Association (ADA) guidelines recommend a patient-centred approach to glycaemic goal setting.10 The 2019 guidelines developed by the European Society of Cardiology in conjunction with the European Association for the Study of Diabetes similarly posits a class IA recommendation for a target HbA1c <7% when possible, but with an individualised approach based on age, duration of T2D and comorbidities.11 For patients with pre-existing HF, there are minimal data to guide this

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Diabetes in Stage C Heart Failure Figure 1: Proposed Mechanisms of Cardiovascular Benefits of Sodium–Glucose Cotransporter 2 Inhibitors Glycaemic control Ketogenesis Increased glycosuria

Liver steatosis

Visceral and epicardial adipose tissue

Body mass

Production of advanced glycation end products

Endothelial function and vascular stiffness

Uric acid levels

Oxidative stress Vascular fibrosis

SGLT2 inhibition at proximal tubule

Albuminuria Blood pressure

Increased natriuresis

Initial decrease in effective circulating volume

Haematocrit

Glomerular afferent arteriolar vasoconstriction

Glomerular hyperfiltration

Myocardial Na /H+ exchange +

SGLT2 inhibition at cardiac myocyte

Cardiomyocyte excitation–contraction coupling

SGLT2 = sodium–glucose cotransporter 2.

approach. A U-shaped relationship between HbA1c and mortality in patients with concurrent HF and T2D has been suggested for ambulatory patients with HF and T2D, with the lowest risk of death at HbA1c between 7.1–7.8%.12 More data exist for the impact of glycaemic control in preventing incident HF. The UK Prospective Diabetes Study suggested that in patients with recently diagnosed T2D without HF, a 1% reduction in mean HbA1c was associated with a 16% decrease in incident H=F (95% CI [3–16%]; p=0.016).13 However, these results were not able to be replicated in patients with longer-term T2D diagnoses. In multiple large randomised trials, such as ACCORD, ADVANCE and VADT, intensive glycaemic control did not reduce the risk of HF.14,15,16 Altogether, a moderate approach to glycaemic control may be most appropriate in patients with pre-existing HF. The 2017 American College of Cardiology/American Heart Association (AHA)/Heart Failure Society of America guideline suggests an HbA1c target of 7–8% in patients with stage C HFrEF with individualisation to reflect comorbidity burden.17 In those with longer life expectancy, it is reasonable to pursue a target HbA1c of <7%. In those with limited life expectancy, the risks of symptomatic hypoglycaemia outweigh the benefit of intensive glycaemic control, especially as the majority of the benefit of intensive glycaemic control is based on long-term microvascular complications rather than short-term macrovascular ones.18

Antidiabetic Therapies with Proven Benefit in Stage C HFrEF Sodium–Glucose Cotransporter 2 Inhibitors

In patients with HF, as well as in patients with high atherosclerotic cardiovascular (CV) disease risk or chronic kidney disease, sodium–

glucose cotransporter 2 (SGLT2) inhibitors are recommended for glucose lowering independent of HbA1c or metformin use. Two drugs in this class, dapagliflozin and empagliflozin, have recently been added to the 2021 European Society of Cardiology-Heart Failure Association guidelines as class I, level A recommendation to reduce HF hospitalisations and deaths in all patients with HFrEF.19 This recommendation is based on the class benefit of reduced major adverse cardiovascular events (MACE) and reduced composite CV death or hospitalisation for HF with SGLT2 inhibitors. Three trials of SGLT2 inhibitors, including empagliflozin (EMPEROR-Reduced), dapagliflozin (DAPA-HF), and sotagliflozin (SOLOIST-WHF), an SGLT2 inhibitor that also inhibits gastrointestinal SGLT1, in patients with HFrEF showed a 30–35% reduced risk of HF hospitalisations regardless of T2D status.20–22 Multiple meta-analyses of studies of SGLT2 inhibitor use in patients with HF have reproduced these results, demonstrating that SGLT2 inhibitor use is associated with an approximate 15% relative risk reduction in all-cause mortality and CV mortality and an approximately 30% reduction in the risk of HF hospitalisation.23–26 These benefits are seen across age, sex, ethnicity, renal function and HF functional class. The EMPA-RESPONSE AHF trial showed that in 80 patients randomised to empagliflozin versus placebo for 60 days, an SGLT2 inhibitor initiated during acute HF episodes led to reduced risk of the combined endpoint of in-hospital worsening HF, rehospitalisation for HF or death and had an acceptable safety profile.27 The EMPULSE trial investigated the safety profile and cardiovascular benefits of empagliflozin initiation during a hospitalisation for acute HF. This was the first major trial to evaluate inpatient initiation of an SGLT2 inhibitor and enrolled patients regardless of LVEF and diabetic status. In

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Diabetes in Stage C Heart Failure this population, treatment with empagliflozin led to decreased all-cause mortality, improved quality of life and greater decrease in body weight at 90 days compared to placebo with no associated safety concerns.28 Though the mechanisms by which SGLT2 inhibitors provide these benefits in HF were not specifically studied in the above-mentioned CV outcomes trials (CVOTs), many possibilities have been proposed (Figure 1).29 These possible mechanisms include the direct benefits of SGLT2 inhibition at the proximal convoluted tubule of the glomerulus. SGLT2 inhibitors prevent the reabsorption of glucose through the SGLT2 cotransporter, which is typically responsible for 90% of the glucose reuptake at the level of the glomerulus. This allows for a reduction in plasma glucose levels through glycosuria.30 As such, hypoglycaemia is not a typical side effect of SGLT2 inhibitors, unlike other antidiabetic agents. This increased glycosuria also results in the loss of approximately 200–250 kcal per day, resulting in reduction in body mass.31 Additionally, SGLT2 inhibition prevents sodium reabsorption, resulting in an acute natriuretic effect before the kidney is able to re-equilibrate. This results in reductions in effective circulating volume, blood pressure and glomerular afferent arteriolar vasoconstriction.

Also cited are the less well-studied effects of SGLT2 inhibitors. These include their association with reduced adipose tissue deposition, as epicardial adipose tissue has been associated with increased risks of coronary artery disease, AF and cardiomyopathy.32–34 SGLT2 inhibition also promotes a metabolic shift from glucose oxidation towards ketone body production that may provide an energetic advantage to cardiac myocytes and may reduce the levels of hepatic and cardiac steatosis through increased lipid metabolism. Moreover, SGLT2 inhibitors have been shown to inhibit the myocardial sodium/hydrogen exchanger and potentially improve cardiac myocyte excitation–contraction coupling in animal models.29 Despite our incomplete mechanistic understanding of SGLT2 inhibition, the remarkable benefits of these drugs with their excellent safety profiles make them first-line agents for diabetic control in stage C HFrEF.

Metformin

Metformin is a biguanide that affects glycaemic control through three major mechanisms: decreased hepatic glucose production, decreased intestinal absorption of glucose and improved insulin sensitivity by increasing peripheral glucose uptake and use.35 As such, it does not impact insulin secretion and does not cause hypoglycaemia. It is recommended as first-line antidiabetic therapy in all populations with appropriate renal function (estimated glomerular filtration rate >30 ml/ min/1.73 m2), regardless of HF status.

Within the first year of the approval of metformin by the Food and Drug Administration (FDA) in 1995, there was a notable incidence of lactic acidosis in HF patients receiving the drug, leading to contraindication labelling in this population.36 However, the FDA eliminated this contraindication following two large observational studies that demonstrated lower mortality and fewer hospitalisations with metformin use in HF patients compared with the use of sulphonylureas and thiazolidinediones.37,38 The mechanism behind this benefit is not well understood, though a potential pathway was proposed by a randomised placebo-controlled trial testing metformin treatment in insulin-resistant patients with HFrEF that showed a 20% improvement in myocardial efficiency via reduced myocardial oxygen consumption.39 Though no prospective randomised controlled trials (RCTs) examining metformin use in HF have been performed, numerous observational

studies have replicated the findings of safety and lower mortality in metformin use in HF. In direct comparison with sulphonylurea monotherapy, metformin demonstrated lower morbidity and mortality over an average of 2.5 years when used alone or in combination.38 A 2007 systematic review of eight studies examining the use of available antidiabetic agents at the time that showed that metformin was the only drug not associated with harm in patients with HF and T2D.40 A retrospective cohort study of 6,185 patients treated for HF and T2D in Veterans Affairs clinics demonstrated that metformin therapy was associated with lower rates of mortality in ambulatory HF patients at 2-year follow-up.41 A 2013 meta-analysis of 34,000 patients with T2D and HF across nine cohort studies similarly showed metformin was associated with decreased risk of all-cause mortality and hospitalisations.42 A retrospective cohort study investigating associations between initiation of metformin and sulphonylurea and clinical outcomes among patients with comorbid HF and diabetes showed that metformin initiation was significantly associated with lower risk of composite all-cause mortality or HF hospitalisations at 12 months. However, this was primarily driven by impact on patients with LVEF >40%; when stratified for LVEF <40%, metformin initiation had no statistically significant impact upon HF hospitalisation or mortality.43 Overall, for patients with stage C HFrEF with appropriate renal function, metformin is a safe and effective first-line antidiabetic agent given its relatively benign safety profile and association with improved morbidity and mortality outcomes.

Antidiabetic Therapies to Be Used with Caution in Stage C HFrEF Glucagon-like Peptide-1 Receptor Agonists

In the era of requiring CVOT for new glucose-lowering therapies, multiple society guidelines recommend SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA) as first-line antidiabetic agents in patients with T2D and established CV risk, with a preference for SGLT2 inhibitors for those who have an existing diagnosis of HF.44 GLP-1 RAs work to enhance the action of endogenous GLP-1 on pancreatic cells to increase insulin secretion and decrease glucagon secretion. Currently available GLP-1 RAs include the twicedaily injectable exenatide; once-daily injectable liraglutide and lixisenatide; once-weekly injectable exenatide extended-release semaglutide and dulaglutide; and oral once-daily semaglutide.

Albiglutide was permanently discontinued worldwide by its parent company in 2018 because of limited prescribing of the drug.

Efpeglenatide and tirzepatide (a dual GLP-1 RA and glucose-dependent insulinotropic polypeptide receptor agonist) are not yet approved in the US or Europe.45–47 There are several CVOTs examining the effects of GLP-1 RA use in patients with T2D and varying levels of CV risk. However, none of the eight major GLP-1 RA CVOT to date (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, REWIND, PIONEER 6 and AMPLITUDE-O) included HF in the primary composite outcome.45,48–54 The proportions of trial participants with a history of HF at enrolment ranged from 8.6% in REWIND (dulaglutide) to 23.6% in SUSTAIN-6 (semaglutide). Information about participants’ HF subtype and baseline LVEF were not uniformly provided or standardised in these trials.

Hospitalisation for HF was examined as a separate secondary endpoint in ELIXA (HR 0.96; 95% CI [0.75–1.23]; p=0.75); LEADER (HR 0.87; 95% CI

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Diabetes in Stage C Heart Failure [0.73–1.05]; p=0.14); SUSTAIN-6 (HR 1.11; 95% CI [0.77–1.61]; p=0.57); EXSCEL (HR 0.95; 95% CI [0.78–1.13]); REWIND (HR 0.93; 95% CI [0.77– 1.12]; p=0.46); PIONEER 6 (HR 0.86; 95% CI [0.48–1.55]); and AMPLITUDE-O (HR 0.61; 95% CI [0.38–0.98]) and as a composite secondary endpoint in HARMONY (HR 0.85; 95% CI [0.70–1.04]; p=0.113).45,48–54 Among these trials, AMPLITUDE-O was the only trial associated with a significant reduction in risk of HF hospitalisation.

Recent meta-analyses of the major GLP-1 RA trials have demonstrated a 12% reduction in all-cause mortality and an approximately 10% reduction in HF hospitalisation with use of this drug class.55–57

Insulin

However, little data regarding the use of GLP-1 RA in patients with established HF exist. Subgroup analyses of the aforementioned trials demonstrated no reduction in all-cause mortality in patients with HF.44 Post-hoc analysis of the SUSTAIN-6 and PIONEER 6 trials showed that semaglutide had no effect on MACE in patients with baseline HF.58 Trials specifically designed to target this question have enrolled relatively few patients. These include the LIVE trial, an RCT of 241 patients with chronic stable HFrEF randomised to placebo versus liraglutide for 24 weeks; and the FIGHT trial, an RCT of 300 patients with HFrEF with a recent decompensation randomly assigned to liraglutide or placebo for 6 months.59,60 In LIVE, there were no significant improvements in LVEF (p=0.24), quality of life (p=0.39) or functional class for those randomised to liraglutide. However, patients in the intervention arm were noted to have a mean 7 BPM increase in heart rate (p<0.0001), a finding which may be clinically significant as increased heart rate has been associated with worsened outcomes in HFrEF. Additionally, there were significantly more serious adverse cardiac events in patients on liraglutide than on placebo (10% versus 3%, p=0.04), including sustained ventricular tachycardia, AF requiring intervention and aggravation of ischaemic heart disease. In FIGHT, there were again no differences in HF-related outcomes or functional capacity; however, there was a signal for increased composite outcome of death and HF hospitalisation in patients on liraglutide.

In patients with established HF, there is little evidence about the safety and efficacy of insulin use. No RCTs have been conducted with insulin use in patients with HF, and observational studies are often confounded by indication, as insulin is more likely to be used in patients with more advanced T2D or severe comorbidities. The ORIGIN trial showed no impact of basal insulin glargine on CV outcomes and HF events in patients with CV risk factors in comparison to standard of care.63 Given insulin’s correlation with hypoglycaemia and weight gain and lack of demonstrable CV benefit with use, other agents, such as metformin and SGLT2 inhibitors should be used preferentially unless appropriate glycaemic control cannot be achieved solely with these agents.

As such, in patients with pre-existing HF, GLP-1 RA may not offer the same cardioprotective effects compared with those in patients without HF and may have a worse safety profile in this population. Further inquiry into the clinical significance of these findings is necessary before incorporation of GLP-1 RA into standard therapy for patients with diabetes and HFrEF.

Sulphonylureas

Sulphonylureas, such as glipizide and glimepiride, increase insulin release from pancreatic β-cells. There are no RCTs that examine sulphonylurea use in HF. A cohort study in the Veterans Affairs system showed a higher risk of HF and CV death with sulphonylurea use compared with metformin, but this was likely confounded by indication as those who could not take metformin due to comorbidities were more likely to be on sulphonylureas.61 A retrospective cohort study of clinical outcomes following sulphonylurea initiation in patients with HF and concurrent diabetes showed that sulphonylurea initiation was associated with a nominally statistically significant excess risk of allcause mortality (HR 1.24; 95% CI [1.00–1.52]; p=0.045). Initiation was also associated with higher risk of composite all-cause mortality and HF hospitalisation (HR 1.17; 95% CI [1.00–1.37]; p=0.047) and HF hospitalisation alone (HR 1.22; 95% CI [1.00–1.48]; p=0.050). This was consistent when stratified for LVEF >40% and <40%.43 Given the lack of data of any demonstrable benefit, sulphonylureas are not recommended as initial therapy in patients with stage C HFrEF.

Insulin is the main anabolic hormone that promotes glucose uptake into the liver, adipose and skeletal muscle tissue and was the original mainstay of diabetes management. Cardiac insulin resistance has become an increasingly recognised factor in the development of HF. As cardiac myocytes develop insulin resistance, they become metabolically inflexible, resulting in energy deficiency which further leads to diastolic dysfunction, myocardial cell death and fibrosis.62 Hyperinsulinaemia has also been implicated in worsening HF, through progressive insulin resistance and oxidative stress, increased obesity and fluid retention.

Antidiabetic Therapies to Avoid in Stage C HFrEF Thiazolidinediones

Thiazolidinediones act on PPAR-γ, a nuclear transcription regulator, to increase insulin action and insulin sensitivity in muscle and fat and decrease hepatic gluconeogenesis. A 2003 consensus statement from the AHA and ADA recommended that thiazolidinediones be avoided in patients with New York Heart Association (NYHA) class III and IV HF and used with caution in those with class I or II symptoms.64 This statement was in response to reports of increased fluid retention with thiazolidinedione use. A meta-analysis by Lago et al. showed a 1.7-fold increase in the relative risk of HF with thiazolidinedione use (95% CI [1.2– 2.42]; p=0.002), with slightly greater risk with rosiglitazone than pioglitazone.65 Lincoff et al. similarly demonstrated a 1.4-fold increase in the risk of HF with pioglitazone (95% CI [1.14–1.76]; p=0.002).66 The RECORD study showed that addition of rosiglitazone to metformin or a sulphonylurea significantly increased the risk of HF death or hospitalisation (HR 2.1; 95% CI [1.30–3.27]; p=0.001).67 A 2007 Canadian meta-analysis of three RCTs and four observational studies estimated a number needed to harm of approximately 50 over a 2.2 year period (OR 2.10; 95% CI [1.08– 4.08]; p=0.03).68 Of note, these studies did not show an increase in the risk of CV death. In a 2007 RCT of 224 patients with T2D and NYHA class I and II HF were randomised to 52 weeks of treatment with rosiglitazone versus placebo, the rosiglitazone group had improved glycaemic control without adverse impact on LVEF.69 While more congestion-related events occurred with thiazolidinedione treatment, the events generally did not result in study withdrawal and were managed with diuretics. As such, the clinical significance of the fluid retention with thiazolidinedione use is not welldefined. This is especially notable as the PROactive study, an RCT of over 5,000 patients with T2D comparing pioglitazone use versus placebo, demonstrated that pioglitazone is associated with reduced all-cause death, non-fatal MI and non-fatal stroke without difference in mortality.70 Overall, though the fluid retention associated with thiazolidinediones may not have long-term mortality consequences, thiazolidinediones should not be prescribed to patients with stage C HFrEF given the availability of medications with more definitively favourable safety and efficacy profiles.

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Diabetes in Stage C Heart Failure Table 1: Considerations for Use of Antidiabetic Agents for Type 2 Diabetes in Patients with Heart Failure Therapy

Average HbA1c Contraindications Reduction

Adverse Effects

Guideline Recommendations

Biguanides Metformin

1.0–1.3%

Nausea, diarrhoea, lactic acidosis

•

Sulphonylureas Glimepiride Glipizide Glyburide

0.4–1.2%

Insulin

Variable

Thiazolidinediones Pioglitazone Rosiglitazone

0.4–1.4%

eGFR <30 ml/min/1.73 m2

• •

Sulpha allergy, pregnancy

NYHA Class III or IV HF

Hypoglycaemia, weight gain

• • •

AHA/ACC: NA ESC: NA ADA: NA

Hypoglycaemia, weight gain

• • • •

AHA/ACC: NA ESC: NA ADA: NA

Weight gain, oedema

• •

SGLT2 inhibitors Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Sotagliflozin

0.5–0.9%

GLP-1 receptor agonists Albiglutide Dulaglutide Exenatide Liraglutide Lixisenatide Semaglutide

0.8–2.0%

DPP-4 inhibitors Alogliptin Linagliptin Saxagliptin Sitagliptin

0.5–0.9%

eGFR <30 ml/min/1.73 m2

AHA/ACC: Recommended as first-line therapy for glycaemic control in all populations (Class IIa) ESC: NA ADA: In patients with HF, metformin may be used for glucose lowering if eGFR >30 ml/min/1.73 m2 (Class B)

Urinary tract infections, genital infections, increased LDL cholesterol

• • •

Exenatide not recommended Nausea, vomiting, weight loss, for eGFR <30 ml/min/1.73 m2 pancreatitis

• • •

Diabetic ketoacidosis, dose Headache, pancreatitis adjustments are needed for renal insufficiency

• • •

AHA/ACC: Should be avoided in patients with NYHA Class II through IV HF (Class III) ESC: Not recommended in patients with HF due to increasing risk of HF worsening and HF hospitalisation ADA: Should be avoided inpatients with symptomatic HF AHA/ACC: Recommended for patients with T2D who require glucose-lowering therapy despite lifestyle modifications and metformin (Class IIb) ESC: Recommended in patients with T2D and HFrEF to reduce hospitalisations for HF and CV death (class I) ADA: Recommended in patients with T2D and HFrEF to reduce the risk of HF and CV death AHA/ACC: Recommended for patients with T2D who require glucose-lowering therapy despite lifestyle modifications and metformin (class IIb) ESC: NA ADA: NA

AHA/ACC: NA ESC: Saxagliptin is not recommended in patients with HF (class III) ADA: NA

ACC = American College of Cardiology; ADA = American Diabetes Association; AHA = American Heart Association; CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; ESC = European Society of Cardiology; ESRD = end stage renal disease; eGFR = estimated glomerular filtration rate; GLP-1 = glucagon-like peptide 1; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; NA = not applicable; NYHA = New York Heart Association; SGLT2 = sodium–glucose cotransporter 2; T2D = type 2 diabetes.

Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin mimetics. They act by inhibiting DPP-4, an enzyme that limits insulin release by inactivating incretins such as GLP-1 and gastric inhibitory polypeptide. This medication class has a mixed evidence base in HFrEF. The FDA recommends discontinuation of saxagliptin and alogliptin in patients who develop HF, supported by evidence from SAVOR-TIMI 53, which demonstrated a 27% increased risk of HF hospitalisations in patients receiving saxagliptin versus placebo (95% CI [1.07–1.51]; p=0.007).71 However, the EXAMINE trial was more equivocal, showing no statistically significant increase in the risk of HF hospitalisations in all patients (HR 1.07; 95% CI [0.79–1.46]). In a post-hoc subgroup analysis, when stratified for previous history of HF, treatment with alogliptin in those without a previous history of HF was associated with increased risk of HF hospitalisation (HR 1.76; 95% CI [1.07–2.90] p=0.026). Conversely, in

patients with an established history of HF, there was no statistically significant increase in hospitalisation for HF (HR 1.00; 95% CI [0.71–1.42]; p=0.996). There was no significant interaction between treatment and history of HF (p=0.068).72 Additionally, this does not appear to be a class-wide effect. A 2015 RCT randomising 14,671 patients with established CV disease to adding sitagliptin or placebo to their existing therapy showed no increase in MACE or hospitalisation for HF in the intervention arm.73 The CARMELINA trial, a multicentre study of 6,979 patients with and without a history of HF, showed no increased incidence of HF hospitalisations over the 2.2-year follow up period, regardless of LVEF.74 The mechanism by which saxagliptin and alogliptin impart a seemingly greater risk of HF is largely unknown. Regardless of the demonstrated safety of other members of the DPP-4 inhibitor class in HF, their relatively

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Diabetes in Stage C Heart Failure Figure 2: HRs for Hospitalisation for Heart Failure Endpoint of Cardiovascular Outcomes A SGLT2 inhibitor trial

HR

dapagliflozin following a HF admission affects subsequent admissions, urgent care visits, and mortality for patients with HF (NCT04249778). The DICTATE-AHF trial will test the efficacy of dapagliflozin along with protocolised diuretic therapy during hospitalisation for acute HF in patients with T2D (NCT04298229). Other studies will use observational data to examine the real world efficacy and safety of SGLT2 inhibition. The EMPRISE study, for example, is comparing CV endpoints for over 230,000 people with T2D who take empagliflozin, DPP-4 inhibitors or GLP-1 RAs (NCT03363464).

95% CI

EMPA-REG OUTCOME* 0.65

0.50–0.85

CANVAS Program*

0.67

0.52–0.87

DECLARE-TIMI 58*

0.73

0.61–0.88

CREDENCE*

0.61

0.47–0.80

VERTIS CV*

0.70

0.54–0.90

SCORED*

0.67

0.55–0.82

SOLOIST-WHF*

0.64

0.49–0.83 0.25

0.50

0.75

1.0 1.25

Hospitalisation for heart failure

B GLP-1 RA trial ELIXA

HR

95% CI

0.96

0.75–1.23

LEADER

0.87

0.73–1.05

SUSTAIN-6

1.11

0.77–1.61

EXSCEL

0.95

0.78–1.13

REWIND

0.93

0.77–1.12

PIONEER 8

0.86

0.48–1.55

AMPLITUDE-O*

0.61

0.38–0.98

HARMONY

0.85

0.70–1.04 0.25

0.50

0.75

1.0 1.25 1.5

Hospitalisation for heart failure

C DPP-4 inhibitor trial

HR

95% CI

TECOS

1.00 0.83–1.20

CAROLINA

1.21

CARMELINA

0.90 0.74–1.08

SAVOR-TIMI 53*

1.27 1.07–1.51

0.92–1.59

0.50

0.75

1.0

1.25 1.5

2.0

Hospitalisation for heart failure

Trials are grouped by drug class. *Trials with significant HRs. A: SGLT2 inhibitors; B: GLP-1 RAs; C: DPP-4 inhibitors. DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide 1 receptor agonists; SGLT2 = sodium–glucose cotransporter 2.

high cost and the lack of strong CV benefit make metformin and SGLT2 inhibitors comparatively superior options. Additionally, saxagliptin should be avoided in patients with HF and clinicians should be aware of the risk of HF in patients taking alogliptin.

Considerations for the use of antidiabetic agents for patients with T2D and HF are summarised in Table 1. HRs for the endpoint of hospitalisation for HF in CVOTs of SGLT2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors are shown in Figure 2.

Anticipated Trials in Diabetes and Heart Failure

Many on-going and future trials aim to better elucidate the safety and efficacy of the newer antidiabetic therapies, while others plan to study available drugs to better understand the physiological interplay between T2D and HFrEF (Table 2). The majority of SGLT2 inhibitor CVOTs to date have enrolled patients with chronic, stable disease who are on optimal guideline-directed medical regimens for HF.20,21 Upcoming trials will further investigate the effect of SGLT2 inhibitor initiation in acute HF. The Dapagliflozin HF Readmission trial will investigate whether initiating

In addition to studying the timing of initiation and efficacy of SGLT2 inhibitor therapy, imaging and invasive strategies are being employed to better understand the pleotropic mechanisms of benefit. The DAPAMEMRI study investigators theorise that dapagliflozin improves calciumhandling in patients with HF, and enrolled patients will be randomised to receive dapagliflozin or placebo with manganese-enhanced cardiac MRI at baseline and 6 months to quantify the potential mechanistic benefit of SGLT2 inhibition in HF (NCT04591639). Investigators of the DAPA-MEMS trial plan to utilise the CardioMEMS device to study invasive pulmonary pressure measurements in ambulatory patients. This trial aims to study changes to pulmonary artery pressures, diuretic dosing and functional capacity for patients with HFrEF and a CardioMEMS sensor after 12 weeks of therapy with dapagliflozin (NCT04570865).

Other studies are examining whether available antidiabetic agents may also positively affect cardiac function. The MEASURE-HF trial is investigating whether the DPP-4 inhibitors saxagliptin and sitagliptin improve cardiac dimensions and function in patients with T2D and HF (NCT02917031). In a pilot study called Metformin in Heart Failure Without Diabetes, patients with HF but without diabetes will be randomised to receive metformin or placebo and will receive on-going functional testing and follow-up for HF symptoms and hospitalisation (NCT03331861). A similar study from the Danish Heart Foundation plans to test the efficacy and safety of metformin for patients with HFrEF and a diagnosis of diabetes or prediabetes (Met-HeFT; NCT03514108). With an estimated 1,500 participants, this will be the largest prospective RCT to date testing the recommendation that metformin should be first-line therapy for most patients with diabetes and HF.75 Finally, there are on-going trials that focus on non-pharmacological interventions for patients with HF and diabetes. The TARGET-HFDM trial will leverage consumer mobile health technology to improve medication adherence and physical activity in subjects with HF and diabetes (NCT02918175). Another trial will test whether a multi-model exercise programme will affect cardiorespiratory function and exercise capacity in patients with HF and diabetes (NCT04888390). The majority of these studies have target end-dates in 2022–2024, highlighting the rapidly evolving landscape of therapies for patients with diabetes and HF.

Guideline-directed Medical Therapy for Heart Failure in Patients with Diabetes

There are no RCTs assessing the efficacy of guideline-directed medical therapy (GDMT) of HFrEF specifically in patients with diabetes. However, enrolled participants in the original landmark trials had a high prevalence of diabetes, allowing for many subsequent subgroup analyses. The evidence suggests consistent benefits of GDMT when comparing patients with and without diabetes. As a result, the general recommendations for HF management remain the same regardless of diabetes status.17,76 Detailed landmark trial outcomes and diabetes status treatment effects are summarised in Supplementary Material Table 1.

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Diabetes in Stage C Heart Failure Table 2: Upcoming Clinical Trials Investigating the Intersection of Type 2 Diabetes and Heart Failure Trial

Intervention

Primary Outcome

n

Expected Trial Completion Date

EMPRISE (NCT03363464)

Observational study of the safety and effectiveness of empagliflozin versus DPP-4 inhibitor and GLP-1 receptor agonist

3-point MACE (admission for MI, admission for stroke, CV, mortality), hospital admission rate, all-cause mortality

232,000

June 2022

Dapagliflozin HF Readmission (NCT04249778)

Double-blind, randomised, placebo-controlled trial of dapagliflozin versus placebo in patients with HFrEF with or without diabetes being discharged after hospital admission with clinical diagnosis of acute decompensated HF

Composite number of hospital admissions, emergency department visits, urgent clinic visits for HF and death after admission with acute decompensated HF

392

July 2023

DICTATE-AHF (NCT04298229)

SGLT2 inhibitor therapy with protocolised diuretic therapy versus protocolised diuretic therapy alone

Cumulative change in weight per 40 mg intravenous furosemide equivalents from enrolment to day 5 or discharge

240

March 2022

DAPA-MEMS (NCT04570865)

Administration of dapagliflozin for patients with HFrEF (NYHA II–IV) with or without diabetes who have CardioMEMS implanted after 12 weeks of therapy

PA diastolic pressure change, PA pressure changes

100

February 2022

DAPA-MEMRI (NCT04591639)

Administration of dapagliflozin for patients with HFrEF with or without diabetes

Rate of change in myocardial T1 values with manganese enhanced cardiac MRI

160

August 2024

Metformin in Heart Failure Without Diabetes (NCT03331861)

Placebo-controlled trial for metformin versus placebo in HF patients without diabetes

Change in minute ventilation to carbon dioxide production slope

50

February 2022

Met-HeFT (NCT03514108)

Placebo-controlled trial for hydralazine ISDN + metformin versus hydralazine alone versus metformin alone versus placebo in HF patients with diabetes or prediabetes

Death or hospitalisation with worsening HF or acute MI or stroke

1,100

September 2023

TARGET-HFDM (NCT02918175)

Mobile health behavioural intervention to increase physical activity and improve medication adherence in patients with HF and diabetes

Change in mean weekly step count

187

September 2020

Exercise Intervention on Cardiorespiratory Function in HF with DM (NCT04888390)

The multi-model exercise intervention includes aerobic exercise training by ergometer or treadmill, resistance exercise by using elastic band and flexibility exercise by active stretch

Change in NT-proBNP and oxygen consumption

80

December 2024

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; ISDN = isosorbide dinitrate; MACE = major adverse cardiovascular events; NYHA = New York Heart Association; PA = pulmonary artery; SGLT2 = sodium–glucose cotransporter-2.

Conclusion

Individuals with concomitant T2D and stage C HFrEF have an increased risk for adverse cardiovascular outcomes, and aggressive cardiometabolic risk factor modification is imperative to combat the growing global burden of these diseases. The past decade has seen a paradigm shift in the management of these comorbid diseases with a proliferation of novel antidiabetic agents with broad cardiovascular benefits. Current data emphasise that for patients with stage C HFrEF, clinicians should aim for moderate glycaemic control with an HbA1c target 7–8%, guided by the 1.

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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.

Giugliano D, Scappaticcio L, Longo M, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs. Cardiovasc Diabetol 2021;20:189. https://doi.org/10.1186/s12933-021-01366-8; PMID: 34526024.

Giugliano D, Maiorino MI, Bellastella G, et al. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: an updated meta-analysis including the REWIND and PIONEER 6 trials. Diabetes Obes Metab 2019;21:2576–80. https://doi.org/10.1111/dom.13847; PMID: 31373167.

Husain M, Bain SC, Jeppesen OK, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab 2020;22:442–51. https://doi.org/10.1111/ dom.13955; PMID: 31903692.

Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE) – a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail 2017;19:69–77. https://doi.org/10.1002/ejhf.657; PMID: 27790809.

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.

Roumie CL, Min JY, D’Agostino McGowan L, et al.

Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J Am Heart Assoc 2017;6:e005379. https://doi.org/10.1161/ JAHA.116.005379; PMID: 28424149.

Aroor AR, Mandavia CH, Sowers JR. Insulin resistance and heart failure: molecular mechanisms. Heart Fail Clin 2012;8:609–17. https://doi.org/10.1016/j.hfc.2012.06.005; PMID: 22999243.

ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319–28. https://doi. org/10.1056/NEJMoa1203858; PMID: 22686416.

Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004;27:256– 63. https://doi.org/10.2337/diacare.27.1.256; PMID: 14693998.

Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370:1129–36. https:// doi.org/10.1016/S0140-6736(07)61514-1; PMID: 17925165.

Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.

JAMA 2007;298:1180–8. https://doi.org/10.1001/ jama.298.10.1180; PMID: 17848652.

Komajda M, McMurray JJV, Beck-Nielsen H, et al. Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J 2010;31:824–31. https://doi.org/10.1093/eurheartj/ehp604; PMID: 20118174.

Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 2007;30:2148–53.

Diabetes in Stage C Heart Failure https://doi.org/10.2337/dc07-0141; PMID: 17536074.

69. Dargie HJ, Hildebrandt PR, Riegger GAJ, et al. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association functional class I or II heart failure. J Am Coll Cardiol 2007;49:1696–704. https://doi.org/10.1016/j. jacc.2006.10.077; PMID: 17448371.

70. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. https://doi. org/10.1016/S0140-6736(05)67528-9; PMID: 16214598.

71. 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.

72. 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.

73. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.

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74. 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

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2019;321:69–79. https://doi.org/10.1001/jama.2018.18269; PMID: 30418475.

75. Wiggers H, Køber L, Gislason G, et al. The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): a 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT). Am Heart J 2021;231:137–46. https://doi.org/10.1016/j.ahj.2020.09.020; PMID: 33039340.

76. Yancy, CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.

Circulation 2013;128:e240–327. https://doi.org/10.1016/j. jacc.2021.05.019; PMID: 23747642.

REVIEW

Patient Care During the Pandemic and Beyond

Telecommunication for Advance Care Planning in Heart Failure Rekha V Thammana

1,2

and Sarah J Goodlin

1,3

1. Geriatrics and Palliative Care, Rehabilitation and Long Term Care, Veterans Affairs Portland Health Care System, Portland, OR, US; 2. School of Medicine, Hematology and Medical Oncology, Oregon Health and Sciences University, Portland, OR, US; 3. School of Medicine, Geriatrics, Oregon Health and Sciences University, Portland, OR, US

Abstract

Heart failure is a chronic illness that carries a significant burden for patients, caregivers and health systems alike. The integration of palliative care and telehealth is a growing area of interest in heart failure management to help alleviate these burdens. This review focuses on the incorporation of advance care planning for complex decision-making in heart failure in the setting of increasing virtual care and telehealth.

The review will also consider the role of virtual education for advance care planning and serious illness communication. Telecommunication for clinical care and clinical education are both described as non-inferior to in-person methods. Nevertheless, more research is needed to discern best practices and the optimal integration of methods.

Keywords

Telehealth, palliative care, advance care planning, communication, heart failure, virtual education Disclosure: The authors have no conflicts of interest to declare.

Received: 13 September 2021 Accepted: 10 January 2022 Citation: Cardiac Failure Review 2022;8:e11. DOI: https://doi.org/10.15420/cfr.2021.23 Correspondence: Sarah J Goodlin, Geriatrics and Palliative Care, Rehabilitation and Long Term Care, Veterans Affairs Portland Health Care System, 3710 SW US Veterans Hospital Rd, P3PRMS, Portland, OR, 97239, US. E: sarah.goodlin@va.gov 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 variable, chronic, progressive and life-limiting illness with significant impacts on quality of life (QOL), use of acute care and family and caregiver burden.1,2 Palliative care is described by the WHO as an approach that “improves the quality of life of patients and that of their families who are facing challenges associated with life-threatening illness.”3 Palliative care includes management of suffering (including physical, psychosocial and spiritual domains), communication of prognosis, assessment of prognostic awareness and advance care planning (ACP).3–5 Professional bodies now recommend the integration of palliative care into HF therapy.2,6 Significant barriers remain, including access to palliative care resulting from geographical barriers and workforce shortages.1 Telehealth is a rapidly growing means for providing palliative care.7–9 In fact, while telehealth has grown organically over the past two decades, COVID-19 has precipitated a 38-fold growth in telehealth in the US from 2020 to 2021.10 This review will describe the role of telehealth in ACP for HF, as well as the role of virtual education for training clinicians in ACP communication.

Advance Care Planning

ACP includes discussions of life values, goals for treatment and the periodic revisiting of these wishes to integrate with appropriate treatment as underlying diseases advance.11,12 Communication between patients, their loved ones or decision-makers and clinicians is at the core of ACP. Because of a variety of factors, many individuals would like to control decisionmaking around healthcare, particularly choices at the end of life.13 The advance directive (AD) is a written, legal document that serves as a guide for a patient’s decision-makers.14 The AD developed as a result of landmark US court cases, including those of Karen Quinlan and Nancy Cruzan, regarding the ability of patients or their surrogate or representative to refuse or

withdraw medical care.15,16 While prevalence varies, AD are present in North America, Europe, Australia and parts of Asia.12,16,17 These are distinct from decisions regarding resuscitation and CPR, which are transmitted in orders for life-sustaining treatment, for example the physician order for lifesustaining treatment (POLST) or do not resuscitate (DNR) orders (Table 1).12,17,18 The AD developed as a way to enact ethical principles of autonomy and individual control over the dying process, but often do not delve to the level of detail required for individualised medical care.13,15,19 A proportion of patients with AD do not have their wishes followed.13 The advent of POLST or DNR orders increased the frequency of goal-concordant care.13,18,20 However, in addition to AD and/or POLST, given the growing complexity of modern medical care and increasingly nuanced medical decision making, patient–provider communication is the mainstay of ACP. Communication for ACP has been found to be most effective when initiated by a provider well known to patients over multiple visits (Table 2).15 ACP conversations can involve discussions of prognosis, deciding surrogate decision makers, expected disease trajectories, life-sustaining treatments, interventions and procedures along with general attitudes towards care. Barriers to effective communication for ACP are numerous, and include patient and clinician hesitancy to discuss, lack of training and comfort in ACP discussions, time constraints and access to specialty palliative care.1

Advance Care Planning in Heart Failure

Discussion of ACP in cardiac disease and HF has grown significantly in the past two decades, but palliative care and hospice care remain underused

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Telecommunication for Advance Care Planning in HF Table 1: Key Differences Between Advanced Directives and Physician Order for Life-sustaining Treatment Advance Directive

POLST

A voluntary legal document

A voluntary medical order

For all adults regardless of health status at any age, starting at 18 years old

For those with serious illness, or frailty, or a limited prognosis at any age, depending on health status

significant event (e.g. following hospitalisations), multiple interventions over time, involvement of family or surrogate decision makers and participation of the multidisciplinary team.27 In ACP discussions, exploring goals and values prior to discussing particular preferences for treatment decisions leads to more effective and focused communication (Table 2).

Mixed evidence quality is noted in multiple reviews because of heterogenous populations studied and small samples sizes, implying the need for additional high-quality studies.25–27

Appoints a healthcare representative

Is a specific medical order and is signed by a healthcare professional

Telehealth in Heart Failure

Memorialises values and preferences Is signed by the principal Provides for theoretical situations in which a person may not have capacity for decision-making

Provides for likely events that can be foreseen

Specific medical orders addressing defined Guidelines for imagined future situations medical interventions for situations that are that may arise and for which a person may likely to arise given the patient’s health have preferences for a particular kind of status and prognosis care plan POLST = physician order for life-sustaining treatment.

Table 2: Communication Techniques in Advance Care Planning Communication Techniques

Explanation

Ask–tell–ask

First, provider asks patient questions to confirm the meaning and intent of the patient’s questions. Then, provider answers specific question and addresses other underlying concerns.

Lastly, provider confirms patient’s understanding

Hope for the best, Exploring a patient’s hopes for care and treatment helps to prepare for the worst build rapport and partner with the patient. Later, exploring worries and preparing for the worst allows patients to explore their fears and potential complications of treatment Naming emotions

Responding to emotions, verbal and non-verbal, helps patients feel supported and move past emotional barriers to communication

in these populations.21,22 Previous models of ACP and communicating around serious illness centred around oncologic disease, despite the morbidity and mortality associated with HF.19 HF is the final common pathway of a variety of health conditions, each with their own illness trajectories and comorbidities, making prognostication notoriously difficult.4,23 However, because of the variability of exacerbations and decompensations, early ACP is a crucial piece of an effective intervention (Figure 1).24 In addition, assessing prognostic awareness – defined as awareness of having an incurable disease and shortened life expectancy – sets the stage for ACP conversations.5 Key decisions in HF include life-sustaining treatments (e.g. CPR, other resuscitative efforts), interventions (e.g. placement of an ICD or left ventricular assist device), level of care (e.g. transfers to hospital or an intensive care unit), and intensity of medication treatment and adverse effect management, among many others.24 ACP in advanced HF also involves discussions of deactivation (e.g. of an ICD or left ventricular assist device), ideally occurring at the time of intervention or implantation.

ACP interventions in HF show improvement in QOL and improvement in depression, but mixed findings regarding quality of death and site of death.25–27 Effective ACP interventions involve tying discussions to a

HF care involves specialised, multidisciplinary, highly coordinated care with frequent monitoring.28,29 The growth of chronic diseases, such as HF, and the concomitant growth of personal devices creates a space for innovative technology, including telehealth.29,30 Telehealth is defined broadly as the delivery of healthcare from a distance, either provided synchronously or asynchronously.30,31 The applications of telehealth in HF are far reaching, spanning from remote patient monitoring with wearable technology to direct consultations with HF providers.29 Telehealth has many facilitators for adoption in HF. These include the provision of care to remote or under-resourced settings, patient-centred and personalised care, improved coordination of care for high-cost conditions such as HF and increased decision support for complex populations.29 Nevertheless, there are also many barriers to telehealth.

These include access to personal electronics, acceptance of new technology (particularly in older people), limitations in clinician reimbursement (which received a temporary reprieve during COVID-19), lower quality of patient–provider relationships, the learning curve for staff involved and regulatory constraints.29,30,32 COVID-19 advanced the use of telehealth exponentially because of the need to rapidly reduce in-person contact for prevention of transmissible disease. However, the field had grown significantly prior to 2020 because of the facilitators listed above.30,31 Multiple studies show that telehealth is non-inferior to in-person, direct patient care for direct consultation with providers.31,33,34 Telemonitoring and structured telephone interventions reduce hospitalisations and death in HF.28,35,36 Additional findings show telemonitoring can also improve depression severity and QOL in HF.37

Telecommunication in Heart Failure: Approaches to Shared Decision-making

Telehealth interventions have the possibility of expanding the reach of palliative care in all disease entities, including HF.7,9,38–41 Given the potential benefits of palliative care and overall shortages of palliative care providers, the question arises whether telehealth is an appropriate venue for ACP communication. Studies of telehealth interventions are varied, with many focused on symptom monitoring and caregiver support in addition to ACP and serious illness communication.7,38,40 Tele-hospice care has an evidence base of >20 years and has been generally well accepted by patients, caregivers and hospice staff.42–44 COVID-19 provided a natural experiment for rapid transition to telehealth and telecommunication. Lally et al. describe that documentation of goals of care – which is tightly linked to ACP – increased with transitions to telehealth.8 In an editorial, Lee notes that a Zoom family meeting improved coordination of care and provided a patient- and family-centred approach to care.45 The frequency, intensity, and modality of effective ACP interventions are debatable.

Hoek et al. describe a weekly teleconsultation intervention for palliative

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Telecommunication for Advance Care Planning in HF care in advanced cancer patients that led to increased distress, suggested to be related to excess attention to suffering during the intervention.39 They also describe an unknown component of the possible negative effect of technology on patient’s well-being.39

Figure 1: The Disease Trajectory in Advanced Heart Failure Excellent Supportive care

ACP conversations can occur between any member of a healthcare team and patients at any stage of health. A team-based approach helps to share the workload, using nursing and social work team members as available to prepare for the visit and follow-up with questions and resources. Pre-planning with ACP tools can help guide discussions, as well as planning to spend a visit on the topic (Table 3). In virtual care, mailing or electronic communication of these tools, as well as ACP documentation (e.g. blank advance directives) can facilitate more specific conversations. Screen-sharing capability can also help with viewing documents, such as previously completed advance directives or other ACP documentation. ACP conversations take multiple conversations and should be revisited over time.

Concerns for a digital divide based on age with moves to telehealth present a genuine challenge to ACP conversations. ACP tools such as PREPARE for Your Care have been shown to be effective for increasing ACP documentation in diverse and elderly populations.46 Other tools, such as The Conversation Project and Five Wishes, provide multiple electronic resources that can be printed and mailed or provided to patients.47,48 Other innovations include ACP group visits, which provide a space for group discussions of ACP and also increases completion of ACP documentation.49 These have migrated to virtual platforms during COVID-19 and can be an additional resource for continuing ACP conversations.

Discussion of life-sustaining treatments, including cardiopulmonary resuscitation and forms of life support, can also benefit from telehealth interventions. Regardless of the platform, discussions of resuscitation will benefit from being normalised (e.g. “I talk to all my patients about this topic”) and using clear and simple language to introduce the topic (e.g.

“When the time comes that your heart and breathing stop, we can allow you to die naturally or try to revive you”). Video and virtual reality interventions providing education on life-sustaining treatments and ACP have been effective in increasing comfort with ACP and discussing ACP

2 3

Heart failure care 4

1

5

Death Time Sudden death event Transplant or ventricular assist device Schematic course of stage C and D HF. 1. Initial symptoms of HF develop and HF treatment is initiated. 2. Plateaus of variable length may be reached with initial medical management, or following mechanical support or heart transplant. 3. Functional status declines with variable slope, with intermittent exacerbations of HF that respond to rescue efforts. 4. Stage D HF, with refractory symptoms and limited function. 5. End of life. Sudden death may occur at any point along the course of illness. HF = heart failure. Source: Reproduced with permission from PC-HEART, Patient-centered Education and Research.

Figure 2: Trends in Advance Care Planning Documentation During a Virtual Education Intervention Completed ACP documentation by month 400 350

ACP documents (n)

A common theme across relevant literature for palliative care in telehealth is the challenge of attuning to interpersonal cues and non-verbal communication.8,39,41 Tips for improved communication include using verbal rather than non-verbal cues to express empathy, acknowledging the awkwardness of the medium and the loss of in-person interaction (particularly during COVID-19), positioning equipment appropriately, looking at the camera rather than the screen to approximate eye contact, and also leaving time for small-talk and rapport-building.41 It also may be appropriate to offer subsequent in-person visits or visits with interdisciplinary team members to continue conversations.

Functional status

ENABLE CHF-PC built on a previously-established nurse-led telehealth intervention in palliative care populations.40 Findings showed no difference in QOL and mood between intervention and usual care groups, which the authors believed to be related to higher pre-existing QOL and mood symptoms. In addition, a large percentage of participants were unable to complete the telehealth intervention and attend in-person visits, believed to be an under-‘dose’ of the intervention. While it is difficult to draw broad conclusions regarding telecommunication for ACP, telehealth interventions require selection of appropriate patients and level of intervention, particularly when discussing challenging topics.

300 250 200 150 100 50 0

June

September Intervention 2020

December 2019

The educational intervention was conducted during the COVID-19 pandemic at eight primary care clinics in the Portland Veterans Affairs Healthcare System. Documentation included advance directives, advance directive discussion notes and physician order for life-sustaining treatment.

Numbers of ACP documents are shown for before, during and after the intervention. The previous year, 2019, is provided as comparison. ACP = advance care planning.

decisions.50,51 While there has been no comparison of virtual reality to video interventions in ACP, virtual reality is speculated to be more immersive, although this intervention was not performed in a seriously ill population and may not be generalisable.51

Virtual Clinical Education for Communication

Communication of difficult topics is at the core of ACP, regardless of the underlying diagnosis. One area of growth in the integration of palliative care in HF is communication training for cardiologists. The goals of these interventions are to improve the comfort of cardiologists in having conversations regarding serious illnesses and begin ACP earlier, potentially preventing the need for additional specialty palliative care in light of palliative care workforce shortages.52 Cardiology-specific

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Telecommunication for Advance Care Planning in HF Table 3: Preparation of Advance Care Planning Discussions in Heart Failure ACP in HF Discussion Points

• • • • •

Choosing surrogate decision-maker Preferences surrounding life-sustaining treatments (resuscitation, life support) Preferences surrounding hospitalisation and intensity of care Preferences for assistance with self-care and level of independence Decisions around procedures and interventions

ACP Discussion Support Tools Five Wishes47 PREPARE for Your Care60 The Conversation Project48 ACP = advance care planning; HF = heart failure.

communication training includes CardioTalk, which is a well-received adaptation of VitalTalk.53 The training is often multi day and involves standardised patients and guided communication feedback.54 Alternatives include using serious illness communication guides and training programs focused on using these guides.54 Other approaches to ACP education involve a focus on AD completion, such as completion of one’s own AD or that of a loved one.55 This approach allows participants to consider their own goals and values for medical care and encourages empathy for patients and caregivers as they embark on challenging discussions. However, this method focuses on ACP documentation and particular interventions rather than the process of eliciting goals and values for medical care. A more values-based approach for ACP education includes using conversation starter guides as a starting point for discussions (Table 3).55 Communication training sessionss similar to VitalTalk have been converted to a virtual format during COVID-19, yielding high satisfaction and comparable self-reported communication preparedness to in-person training.56 Prior to COVID-19, approaches to virtual clinical education were found to be non-inferior if they included direct communication and coaching by clinical educators.57 Wilcha describes a variety of virtual adaptations to medical education during COVID-19, with the overall finding that virtual interventions are effective.58 However, one major caveat is that students described declining mental health during the period studied, which is – in part – attributed to social isolation and fatigue with virtual platforms.

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Hill L, Prager Geller T, Baruah R, et al. Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper. Eur J Heart Fail 2020;22:2327–39. https://doi. org/10.1002/ejhf.1994; PMID: 32892431.

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The authors of this current review performed virtual education regarding ACP during COVID-19 to eight primary care clinics in the Portland Veterans Affairs Healthcare System. This education developed out of a scarce resource allocation committee and an initiative to increase ACP discussions in the setting of COVID-19. Sessions were virtual lectures via Microsoft Teams and included physicians, advance practice providers, nurses and social workers. Given the newness of virtual platforms and limited time allotted for sessions, the authors adapted prior serious illness communication training programmes and a conversation guide developed by the authors into a 40-minute interactive case-based discussion of a man with coronary artery disease and HF. Beyond training participants in the basics of serious illness communication, we strongly encouraged completing ACP documentation given the risk of serious illness and hospitalisation with COVID-19. Documentation recommended included the AD and POLST. In addition, we encouraged completing AD discussion notes, which describe narrative discussions of ACP, and life-sustaining treatment plans, which are a Veterans Affairs approximation of POLST.59 Of note, life-sustaining treatment plans were not included in comparisons because of adoption in November 2019 by Portland Veterans Affairs Healthcare System.

Documentation of AD, POLST, and AD discussion notes spiked during the intervention (Figure 2). This is particularly impressive, given the degree of virtual care and overall decrease in patient volume seen during the autumn of 2020 compared to prior years. The decline in ACP documentation seen in December 2020 is difficult to interpret, but may imply that on-going interventions will be needed to increase ACP documentation during periods of high-volume virtual care.

Conclusion

With a globally ageing population and increasing prevalence of HF, ACP will continue to be a focus of high-quality HF management in the coming decades. ACP communication empowers patients and providers alike to focus on the goals and values that patients prioritise, and these discussions are particularly beneficial earlier in a patient’s course. The growing use of telehealth is likely to facilitate improved ACP discussions in HF, although some challenges with technology platforms may interfere with the quality of these discussions. Lastly, communication training in HF and cardiology is an emerging area of interest that will push ACP discussions upstream. Transitions to virtual communication education appear non-inferior to in-person discussions thus far. The impact of COVID-19 on all of these trends is continuously evolving, and opportunities exist to accelerate ACP in HF care via telecommunication.

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19. Schellinger S, Sidebottom A, Briggs L. Disease specific advance care planning for heart failure patients: implementation in a large health system. J Palliat Med 2011;14:1224–30. https://doi.org/10.1089/jpm.2011.0105; PMID: 21870958.

20. Fromme EK, Zive D, Schmidt TA, et al. Association between physician orders for life-sustaining treatment for scope of treatment and in-hospital death in Oregon. J Am Geriatr Soc 2014;62:1246–51. https://doi.org/10.1111/jgs.12889; PMID: 24913043.

21. Yim CK, Barrón Y, Moore S, et al. Hospice enrollment in patients with advanced heart failure decreases acute medical service utilization. Circ Heart Fail 2017;10:e003335; https://doi.org/10.1161/CIRCHEARTFAILURE.116.003335; PMID: 28292824.

22. von Schwarz ER, He M, Bharadwaj P. Palliative care issues for patients with heart failure. JAMA Netw Open 2020;3:e200011. https://doi.org/10.1001/ jamanetworkopen.2020.0011; PMID: 32101301.

23. Pantilat SZ, Steimle AE. Palliative care for patients with heart failure. JAMA 2004;291:2476–82. https://doi.org/10.1001/ jama.291.20.2476; PMID: 15161899.

24. Goodlin SJ. Palliative care in congestive heart failure. J Am Coll Cardiol 2009;54:386–96. https://doi.org/10.1016/j. jacc.2009.02.078; PMID: 19628112.

25. Diop MS, Rudolph JL, Zimmerman KM, et al. Palliative care interventions for patients with heart failure: a systematic review and meta-analysis. J Palliat Med 2017;20:84–92. https://doi.org/10.1089/jpm.2016.0330; PMID: 27912043.

26. Nishikawa Y, Hiroyama N, Fukahori H, et al. Advance care planning for adults with heart failure. Cochrane Database Syst Rev 2020;2:CD013022. https://doi.org/10.1002/14651858.

CD013022.pub2; PMID: 32104908.

27. Schichtel M, Wee B, Perera R, et al. The effect of advance care planning on heart failure: A systematic review and meta-analysis. J Gen Intern Med 2020;35:874–84. https://doi. org/10.1007/s11606-019-05482-w; PMID: 31720968.

28. Kotb A, Cameron C, Hsieh S, Wells G. Comparative effectiveness of different forms of telemedicine for individuals with heart failure (HF): a systematic review and network meta-analysis. PLoS One 2015;10:e0118681. https:// doi.org/10.1371/journal.pone.0118681; PMID: 25714962.

29. Silva-Cardoso J, Juanatey JRG, Comin-Colet J, et al. The future of telemedicine in the management of heart failure patients. Card Fail Rev 2021;7:e11. https://doi.org/10.15420/ cfr.2020.32; PMID: 34136277.

30. Dorsey ER, Topol EJ. State of telehealth. N Engl J Med 2016;375:154–61; https://doi.org/10.1056/NEJMra1601705; PMID: 27410924.

31. Snoswell CL, Chelberg G, De Guzman KR, et al. The clinical effectiveness of telehealth: a systematic review of metaanalyses from 2010 to 2019. J Telemed Telecare 2021. https:// doi.org/10.1177/1357633X211022907; PMID: 34184580; epub

ahead of press.

32. Tersalvi G, Vicenzi M, Kirsch K, et al. Structured telephone support programs in chronic heart failure may be affected by a learning curve. J Cardiovasc Med (Hagerstown) 2020:231–7. https://doi.org/10.2459/ JCM.0000000000000934; PMID: 32004244.

33. Albritton J, Ortiz A, Wines R, et al. Video teleconferencing for disease prevention, diagnosis, and treatment: a rapid review. Ann Intern Med 2022;175:256–66. https://doi. org/10.7326/M21-3511; PMID: 34871056.

34. Tersalvi G, Winterton D, Cioffi GM, et al. Telemedicine in heart failure during COVID-19: a step into the future. Front Cardiovasc Med 2020;7:612818. https://doi.org/10.3389/ fcvm.2020.612818; PMID: 33363223.

35. Koehler F, Koehler K, Deckwart 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.

36. Kao DP, Lindenfeld J, Macaulay D, et al. Impact of a telehealth and care management program on all-cause mortality and healthcare utilization in patients with heart failure. Telemed J E Health 2016;22:2–11. https://doi. org/10.1089/tmj.2015.0007; PMID: 26218252.

37. 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 202;23:186–94. https://doi.org/10.1002/ejhf.2025; PMID: 33063412.

38. Hancock S, Preston N, Jones H, Gadoud A. Telehealth in palliative care is being described but not evaluated: a systematic review. BMC Palliat Care 2019;18:114. https://doi. org/10.1186/s12904-019-0495-5; PMID: 31835998.

39. Hoek PD, Schers HJ, Bronkhorst EM, et al. The effect of weekly specialist palliative care teleconsultations in patients with advanced cancer -a randomized clinical trial. BMC Med 2017;15:119. https://doi.org/10.1186/s12916-017-0866-9; PMID: 28625164.

40. Bakitas MA, Dionne-Odom J, Ejem DB, et al. Effect of an early palliative care telehealth intervention vs usual care on patients with heart failure: the ENABLE CHF-PC randomized clinical trial. JAMA Intern Med 2020;180:1203–13. https://doi. org/10.1001/jamainternmed.2020.2861; PMID: 32730613.

41. Allen Watts K, Malone E, Dionne-Odom JN, et al. Can you hear me now?: Improving palliative care access through telehealth. Res Nurs Health 2021;44:226–37. https://doi. org/10.1002/nur.22105; PMID: 33393704.

42. Cameron P, Munyan K. Systematic review of telehospice telemedicine and e-health. Telemed J E Health 2021;27:1203– 14. https://doi.org/10.1089/tmj.2020.0451; PMID: 33512303.

43. Oliver DP, Demiris G, Wittenberg-Lyles E, et al. A systematic review of the evidence base for telehospice. Telemed J E Health 2012;18:38–47. https://doi.org/10.1089/tmj.2011.0061; PMID: 22085114.

44. Demiris G, Oliver DRP, Fleming DA, Edison K. Hospice staff attitudes towards telehospice. Am J Hosp Palliat Care 2004;21:343–7. https://doi.org/10.1177/104990910402100507; PMID: 15510570.

45. Lee TH. Zoom family meeting. N Engl J Med 2021;384:1586– 7. https://doi.org/10.1056/NEJMp2035869; PMID: 33914438.

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46. Scheerens C, Gilissen J, Volow AM, et al. Developing eHealth tools for diverse older adults: lessons learned from the PREPARE for Your Care Program. J Am Geriatr Soc 2021;69:2939–49. https://doi.org/10.1111/jgs.17284; PMID: 34081773.

47. Five Wishes. https://fivewishes.org/ (accessed 25 February 2022).

48. The Conversation Project. https://theconversationproject. org/ (accessed 25 February 2022).

49. Lum HD, Sudore RL, Matlock DD, et al. A group visit initiative improves advance care planning documentation among older adults in primary care. J Am Board Fam Med 2017;30:480–90. https://doi.org/10.3122/ jabfm.2017.04.170036; PMID: 28720629.

50. Toraya C. Evaluation of advance directives video education for patients. J Palliat Med 2014;17:942–6. https://doi. org/10.1089/jpm.2013.0585; PMID: 24773190.

51. Hsieh WT. Virtual reality video promotes effectiveness in advance care planning. BMC Palliat Care 2020;19:125. https:// doi.org/10.1186/s12904-020-00634-w; PMID: 32799876.

52. Gelfman LP, Kavalieratos D, Teuteberg WG, et al. Primary palliative care for heart failure: what is it? How do we implement it? Heart Fail Rev 2017;22:611–20. https://doi. org/10.1007/s10741-017-9604-9; PMID: 28281018.

53. Berlacher K, Arnold RM, Reitschuler-Cross E, et al. The impact of communication skills training on cardiology fellows’ and attending physicians’ perceived comfort with difficult conversations. J Palliat Med 2017;20:767–9. https:// doi.org/10.1089/jpm.2016.0509; PMID: 28437212.

54. Paladino J, Kilpatrick L, O’Connor N, et al. Training clinicians in serious illness communication using a structured guide: evaluation of a training program in three health systems. J Palliat Med 2020;23:337–45. https://doi.org/10.1089/ jpm.2019.0334; PMID: 31503520.

55. Lum HD, Dukes J, Church S, et al. Teaching medical students about “the conversation”: an interactive valuebased advance care planning session. Am J Hosp Palliat Care 2018;35:324–9. https://doi.org/10.1177/1049909117696245; PMID: 28273761.

56. Frydman JL, Gelfman LP, Lindenberger EC, et al. Virtual geritalk: Improving serious illness communication of clinicians who care for older adults. J Pain Symptom Manage 2021;62:e206–12. https://doi.org/10.1016/j. jpainsymman.2021.02.024; PMID: 33631324.

57. Quail M, Brundage SB, Spitalnick J, et al. Student selfreported communication skills, knowledge and confidence across standardised patient, virtual and traditional clinical learning environments. BMC Med Educ 2016;16:73. https://doi. org/10.1186/s12909-016-0577-5; PMID: 26919838.

58. Wilcha R. Effectiveness of virtual medical teaching during the COVID-19 crisis: systematic review. JMIR Med Educ 2020;6:e20963. https://doi.org/10.2196/20963; PMID: 33106227.

59. Levy C, Ersek M, Scott W, et al. Life-sustaining treatment decisions initiative: early implementation results of a National Veterans Affairs program to honor veterans’ care preferences. J Gen Intern Med 2020;35:1803–12. https://doi. org/10.1007/s11606-020-05697-2; PMID: 32096084.

60. PREPARE for Your Care. https://prepareforyourcare.org/ (accessed 25 February 2022).

REVIEW

Treatment

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond Alberto Aimo ,1,2 Giosafat Spitaleri ,3 Dario Nieri,4 Laura Maria Tavanti,4 Claudia Meschi,5 Giorgia Panichella,1 Josep Lupón ,3,6,7 Francesco Pistelli ,4 Laura Carrozzi,4,5 Antoni Bayes-Genis 3,6 and Michele Emdin 1,2 1. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy; 2. Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 3. Heart Failure Clinic and Cardiology Service, University Hospital Germans Trias i Pujol, Badalona, Spain; 4. Pulmonary Unit, Cardiothoracic and Vascular Department, Pisa University Hospital, Pisa, Italy; 5. Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy; 6. Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 7. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain

Abstract

Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug.

Keywords

Pirfenidone, idiopathic pulmonary fibrosis, lung, heart, animal models, clinical trials Disclosure: The authors have no conflicts of interest to declare.

Received: 28 October 2021 Accepted: 15 February 2022 Citation: Cardiac Failure Review 2022;8:e12. DOI: https://doi.org/10.15420/cfr.2021.30 Correspondence: Alberto Aimo, Scuola Superiore Sant’Anna and Fondazione Toscana Gabriele Monasterio, Piazza Martiri della Libertà 33, 56124, Pisa, Italy.

E: a.aimo@santannapisa.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.

Pirfenidone (PFD) is an oral drug with antifibrotic properties.1 Its modes of action are not completely understood.2 The first results from studies using animal models support to the use of PFD in lung diseases primarily characterised by progressive fibrosis, and PFD is currently one of the two conditionally recommended drugs for the treatment of idiopathic pulmonary fibrosis (IPF).3,4 IPF is the most common and by far the most aggressive type of the idiopathic interstitial pneumonias, being associated with a severe prognosis with a median survival of 2–5 years for patients not receiving antifibrotic drugs.5,6 PFD has been recently evaluated in fibrosing lung diseases other than IPF, such as unclassifiable progressive fibrosing interstitial lung disease, and is under investigation for other interstitial pneumonias.7–9 It has also been regarded with interest as a possible treatment for cardiac disorders where fibrosis plays an important pathogenetic role, such as heart failure with preserved ejection fraction (HFpEF). This review provides an update on current and possible novel applications of pirfenidone.

Pharmacokynetics and Pharmacodynamics

PFD is a small synthetic molecule rapidly absorbed in the gastrointestinal tract, with a half-life of about 3 hours.10,11 It is metabolised in the liver, mainly by cytochrome P450, and mostly excreted as the metabolite 5-carboxy-pirfenidone, either through the urine (80%) or in faeces (20%).

PFD inhibits fibroblast proliferation and collagen synthesis by interfering

with transforming growth factor-β (TGF-β) signalling and other growth factors, such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor.12,13 PFD also upregulates several matrix metalloproteinases (MMPs) that attenuate extracellular matrix (ECM) accumulation.14 PFD also modulates acute inflammation by reducing the expression of inflammatory cytokines, most notably tumour necrosis factor (TNF)-α, interleukin (IL)-4 and IL-13, and by inhibiting the formation of the nucleotide-binding oligomerisation domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome, a protein complex responsible for the recognition of stress signals and involved in the onset and maintenance of inflammatory responses.10,15 Finally, PFD may modulate the activity and proliferation of both T and B lymphocytes.10

Idiopathic Pulmonary Fibrosis: Possible Disease Mechanisms

The exact pathogenesis of IPF is still unknown, but its histopathological hallmarks have been well identified. This condition is characterised by areas of fibrosis alternating with relatively spared zones, honeycombing, and architectural distortion.16 Repeated microinjuries combined with an inability of alveolar epithelium to effectively repair wounds and epigenetic alterations lead to an aberrant activation of alveolar endothelial cells, which produce many profibrotic growth factors, chemokines, MMPs and procoagulant factors (such as tissue factor, activated factor VII, factor X

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Pirfenidone for Lung and Cardiac Disorders and thrombin), all inducing the proliferation of fibroblasts and their differentiation into myofibroblasts. These last cells play a key role in the abnormal wound healing process, causing an exaggerated production of ECM, tissue scarring and irreversible lung fibrosis.17,18 TGF-β is probably the most important factor in IPF as it stimulates alveolar endothelial cells and fibroblasts, also through several microRNAs (miRNAs).19 Moreover, extracellular vesicles (small vesicles released by virtually all eukaryotic cells upon different stimuli and which can transport miRNAs), play an active role in intercellular communication, promoting the fibrotic response.20 Finally, some cells belonging to both innate and adaptive immune systems, such as dendritic cells, monocytes/ macrophages, T and B lymphocytes, with their associated cytokines, can still play a role in IPF pathogenesis.21

Pirfenidone in the Treatment of Idiopathic Pulmonary Fibrosis: Possible Mechanisms Antifibrotic Effects

Iyer et al. reported a protective effect of oral PFD towards bleomycininduced lung fibrosis.1 Although bleomycin-induced fibrosis does not represent an accurate model of IPF, this was the first demonstration of potential antifibrotic activity of PFD in vivo. PFD was shown to effectively inhibit fibronectin and the production of α-smooth muscle actin (α-SMA) which is an important factor in fibroblast-to-myofibroblast transition, by human lung fibroblasts, when incubated with TGF-β. PFD also suppressed fibrotic changes, mediated by TGF-β, in human fetal lung fibroblasts.22,23 Another study confirmed that PFD reduced TGF-β-mediated α-SMA production by primary human lung fibroblasts and it effectively impaired phosphorylation of SMAD3 and phospho-p38 mitogen-activated protein kinase (p38 MAPK), two key effectors in the downstream of TGF-β signalling, thus providing a possible explanation for PFD antifibrotic effects in IPF.24 PFD can also act on heat shock proteins (HSP) and collagen overproduction. Indeed, PFD significantly inhibited HSP-47 and collagen I mRNA expression in a human type II alveolar epithelial cell line stimulated

by TGF-β; moreover, cellular expression of fibronectin was reduced after pre-treatment with PFD.25 PFD has also been shown to be able to inhibit collagen fibril formation and assembly as well as inhibiting both PDGF and basic fibroblast growth factor, thus influencing myofibroblast differentiation or collagen I overproduction.26–28 Overall, these data show some potentially relevant mechanisms for the antifibrotic action of PFD, mainly focused on the inhibition of the TGF-β pathway.

Anti-inflammatory Effects

In a study using an orthotopic mouse lung transplant model, PFD treatment suppressed the activation of dendritic cells (DCs), which present antigens to T-cells, by several mechanisms including a PFD-mediated reduced response to Toll-like receptors agonists, PFD significantly reduced the production of several cytokines and chemokines, such as CCL2, TNF-α, CCL12 and IL-10, from stimulated DCs in vitro.29 In another study, PFD blunted T-cell proliferation and production of inflammatory cytokines.30 PFD has been shown to reduce the polarisation of alveolar macrophages (AMs) towards the M2 phenotype in rats; since M2-type AMs have profibrotic properties, mainly by secreting cytokines able to promote fibroblast proliferation, these findings could support a possible alternative mode of action for PFD. In another murine model, PFD reduced airway responsiveness, inflammatory cytokines and cells in the bronchoalveolar fluid after pre-

sensitisation with an allergen.21,31,32 Another study has demonstrated that PFD could reduce the production of proinflammatory cytokines by inhibiting p38 MAPK in B lymphocytes, thus representing a novel potential mechanism of action of PFD in lung fibrosis, since the inflammatory milieu induced by B-cell-derived cytokines can cause the activation and migration of fibroblasts.33

Clinical Trials on Pirfenidone for the Treatment of Idiopathic Pulmonary Fibrosis

In 1999, Raghu et al. conducted the first open-label study to evaluate the efficacy and safety of PFD for patients with IPF.34 An open-label treatment was administered in terminally ill patients who had failed or not tolerated conventional therapy. The mortality observed was 22% at 1 year and 37% at 2 years, and PFD arrested the further decline of lung function in most patients. The drug was well tolerated with minimal side-effects that disappeared after it was discontinued or its dosage was decreased.34 A second open-label study was conducted in 2002 in patients with advanced IPF.35 Over 1 year of treatment, the deterioration in terms of chest radiographic scores, pulmonary function and arterial blood oxygen partial pressure (PaO2) appeared to stabilise, but survival was not significantly prolonged, probably because of the short treatment duration.

As in the previous study, PFD was well tolerated.35 In 2005 a double-blind, placebo-controlled, randomised, phase II trial tested the efficacy of PFD at a maximum dose of 1,800 mg/day in 107 patients with IPF.36 The primary endpoint – the change in the lowest oxygen desaturation (SpO2) during a 6-minute walking test (6MWT) – did not reach statistical significance (p=0.072), but PFD treatment demonstrated its efficacy in a few secondary endpoints, showing a significantly smaller decline in vital capacity (VC) (p=0.037) and preventing acute exacerbation of IPF at 9 months (p=0.003). The trial was prematurely stopped due to an excess of acute IPF exacerbations in the placebo group. Treatment with PFD was associated with more adverse events, not affecting the adherence to treatment.

In 2010, a phase III trial evaluated high doses (1,800 mg/day) and low doses (1,200 mg/day) of PFD in 275 patients with IPF.37 This trial demonstrated the efficacy of high-dose PFD treatment in slowing down VC deterioration (−90 ml versus −160 ml; p=0.042) and increasing the progression-free survival time (p=0.028) over 1 year. A lower but significant difference in VC decline was also seen in the PFD low-dose group (p=0.039). No statistically significant difference was detected in the mean change of the lowest SpO2 during a 6MWT. The incidence of adverse events was higher in the PFD treatment groups, without differences in treatment discontinuation.

Two Phase III international randomised double-blind placebo trials (CAPACITY 004 and CAPACITY 006), involving 779 patients with IPF, were performed in North America, Europe and Australia.38 The primary endpoint of both studies was the change in percentage predicted forced vital capacity (FVC%pred) from baseline to week 72. The CAPACITY 004 study included 435 patients treated with high-dose PFD (2,403 mg/day), lowdose PFD (1,197 mg/day) or placebo while the CAPACITY 006 study included 344 patients treated with exclusively high-dose PFD or placebo.

The CAPACITY 004 trial showed a significant difference in FVC%pred from baseline over 72 weeks between high-dose PFD and the placebo arm (−8% versus −12.4%; p=0.001). In the low-dose PFD group the mean change in FVC%pred was intermediate to that in the high-dose PFD and

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Pirfenidone for Lung and Cardiac Disorders placebo groups. The high-dose PFD group also showed a positive result against placebo in terms of prolongation of progression-free survival.

Instead, the CAPACITY 006 study recorded a significant difference in reduction in FVC%pred rate of decline up to week 48 in PFD group (p=0.005), but this difference was not maintained to week 72 (p=0.501).

No significant effect was reported on progression-free survival, but highdose PFD significantly reduced decline in 6MWT distance at week 72. The adverse effects, mainly gastrointestinal and skin-related events, were generally mild to moderate in severity, without any significant clinical consequence or reduction in therapy adherence.

Since the CAPACITY 006 study failed to meet its primary endpoint, another randomised, double-blind, placebo-controlled Phase III trial was requested by US regulatory authorities, which was performed in 2014 to support the approval of PFD for IPF treatment.39 In the ASCEND trial, 555 patients with IPF were randomly assigned to receive PFD (2,403 mg/day) or placebo over 1 year. The PFD group showed a 50% reduction compared with the placebo group (17% versus 32%, respectively) in primary endpoint, which was a decline of at least 10% of the FVC%pred or death at week 52 compared to baseline. Furthermore, the proportion of patients with no decline in FVC increased by 133% in the PFD group (p<0.001). PFD-treated patients also displayed a relative reduction of 28% (p=0.04) in the decline of the 6MWT distance and a 43% longer progression-free survival (p<0.001). Gastrointestinal and skin-related side-effects were more common in the PFD group, but rarely caused discontinuation.39 In a pre-specified analysis of the pooled population of CAPACITY and ASCEND trials (1,247 patients), PFD significantly reduced the relative risk of all-cause mortality at 1 year by 48% (p<0.01) and the risk of IPF-related mortality at 1 year by 68% (p=0.006).40 Similarly, treatment with PFD at 2,403 mg/day reduced the proportion of patients with a decline of 10 percentage points or more in the FVC%pred or death by 44% and increased the proportion of patients with no lung function decline by 59%.

PFD efficacy seemed to be independent of baseline disease severity.40,41 Even if the inclusion criteria for clinical trials do not necessarily reflect real-world patients and practices, emerging real-world data has shown that the tolerability and the overall efficacy of PFD on reducing FVC decline in patients with IPF were consistent with findings from the clinical trials.42–44

Pirfenidone and Progressive Fibrosing Interstitial Lung Diseases

Diffuse interstitial lung diseases (ILDs) represent a large heterogeneous group of rare pulmonary disorders. ILDs arise from a large spectrum of distinctive aetiologies. They can be a pulmonary complication of connective tissue disease, such as rheumatoid arthritis, systemic sclerosis and polymyositis, or result from the exposure to environmental antigens, such as chronic hypersensitivity pneumonitis, or through occupational exposure, such as asbestosis, or due to unknown cause, such as idiopathic interstitial pneumonia and sarcoidosis.5 A variable proportion of patients with ILDs may have clinical features similar to IPF characterised by the decline of lung function, worsening of respiratory symptoms and healthrelated quality of life and higher mortality. In this case, they are termed progressive fibrosing ILDs or fibrosing ILDs with a progressive phenotype.45 Pharmacological studies with antifibrotic drugs have been conducted in patients with progressive fibrosing ILDs; both PFD and nintedanib have been used in fibrosing diseases secondary to connective tissue diseases,

such as rheumatoid arthritis associated with ILD and systemic sclerosis associated with ILD (SSc-ILD), as well as in unclassifiable fibrosing ILDs. In 2016, the LOTUSS study evaluated the safety profile of PFD in patients with SSc-ILD, demonstrating an acceptable tolerability profile that improved as titration time increased.46 In 2020, Acharya et al. published a double-blind, randomised, placebo-controlled pilot study, where 34 subjects with SSc-ILD and an FVC%pred of 50–80% were randomised 1:1 to receive PFD (2,400 mg/day) or placebo for 6 months. Stabilisation/ improvement in FVC was observed in 94% and 77% subjects in the PFD and placebo groups, respectively (p=0.33). The changes in FVC%pred, 6MWD, dyspnoea scores, modified Rodnan skin score (MRSS), and TNF-α and TGF-β levels did not differ significantly.47 Among chronic fibrosing ILDs, chronic hypersensitivity pneumonitis may represent a diagnostic challenge with respect to IPF and its incidence is probably underestimated.48 An open-label study evaluated the efficacy and safety of PFD associated with prednisone and azathioprine with 22 people with chronic hypersensitivity pneumonitis enrolled and divided into two groups: 9 patients received only prednisone and azathioprine and the remaining 13 received combining PFD with prednisone and azathioprine. After 1 year of treatment, patients in the PFD arm did not show a significant improvement in FVC but they did have an improved quality of life with an acceptable safety profile.49 PFD has also been proposed in the treatment of COVID-19, both for the acute phase and the fibrotic sequelae.50 Four clinical trials on PFD and COVID-19 are currently recruiting new patients (NCT04653831, NCT04607928, NCT04856111 and NCT04282902).

Fibrosis in Cardiac Disease

Myocardial fibrosis is a common pathophysiological process in most heart diseases, defined as an excess of ECM deposition by cardiac fibroblasts.51 The activation of profibrotic pathways is a compensatory mechanism in response to myocardial damage and necrosis. Nonetheless, excessive ECM deposition may trigger a vicious cycle eventually leading to heart failure (HF).52 Fibrosis can be divided into two distinct forms: reparative or replacement fibrosis and reactive or interstitial fibrosis.53 While the first is generally observed in the development of an organised fibrotic scar after MI, the latter is a typically perivascular or interstitial fibrosis, as part of progressive pathological cardiac remodelling.53 Although the pathophysiological mechanisms leading to fibrotic remodelling differ according to the underlying disease, the cellular effectors are shared.

Cardiomyocyte death or injurious stimuli, such as inflammation, often trigger fibrosis.54 Activation and conversion of fibroblasts into myofibroblasts are crucial points. The ECM proteins produced by myofibroblasts, such as collagens, glycoproteins and proteoglycans, offer local mechanical support to the failing heart in a multi-step process involving the degradation of damaged existing ECM, and the production, secretion and maturation of new ECM.53 Monocytes, macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting profibrotic factors, such as inflammatory cytokines and chemokines, reactive oxygen species, proteases, endothelin-1, the renin–angiotensin– aldosterone system (RAAS), and matrix proteins, such as TGF-β and PDGF.54 Following MI, the necrosis of cardiomyocytes triggers an inflammatory reaction, ultimately leading to replacement of dead myocardium with a

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Pirfenidone for Lung and Cardiac Disorders Figure 1: Cardiac Protective Effects of Pirfenidone Pirfenidone N O Inflammation Pressure overload ↑ NLRP3 inflammasome formation ↑ Vascular permeability ↑ Probiotic factors (TGF-β)

Myocardial fibrosis

Diabetes

Anthracyclines

↑ TGF-β ↑ Fibronectin ↑ Perivascular and interstitial collagen deposition

↑ Lipid peroxidation ↑ Hydroxyproline production Disorganisation of myofibrils and vacuolistion of the myofibers

Oxidative stress Atrial fibrillation ↑ TGF-β ↑ TNF-α ↑ MMP-9 ↓ LTCC expression

Duchenne muscular dystrophy Myocyte degeneration ↑ TGF-β ↑ Deposition of collagenous extracellular matrix

LTCC = L-type calcium channel; MMP-9 = matrix metalloproteinase 9; NLRP3 = NLR family pyrin domain containing 3; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α.

reparative fibrotic scar.54,55 Ageing is associated with progressive fibrosis that may contribute to the development of increased wall stress, and diastolic and systolic ventricular dysfunction.56,57 Pressure overloadrelated fibrosis, caused by hypertension or aortic stenosis, is progressively associated with increased stiffness, diastolic dysfunction, ventricular dilation and HF.58 Volume overload due to valvular regurgitant lesions may also result in cardiac fibrosis.54 Chronic mitral regurgitation can result in left atrial enlargement and atrial fibrotic remodelling, which is one of the fundamental causes of persistent AF.59

Pirfenidone as a Possible Cardiac Protective Drug

As myocardial fibrosis is a key mechanism in the development of structural and functional cardiac alterations, therapeutic strategies targeting this process are becoming increasingly important. The heart diseases that will benefit most from anti-fibrotic therapies are the same where fibrosis plays a major pathogenic role, such as MI, AF and HF. A notable example is HFpEF. Following the systematic failure of trials on neurohormonal antagonists, researchers’ attention has shifted to the phenotypic heterogeneity of HFpEF, with the ultimate goal of developing therapies tailored on individual patient phenotypes.60 The new HFpEF paradigm states that coronary microvascular inflammation and myocardial fibrosis can be considered the central theme in the HFpEF conundrum, and antifibrotic drugs, such as PFD, may be effective tools in blocking this pathological mechanism.61 The following section summarises evidence about PFD’s antifibrotic activity in various animal models of cardiac disease, including pressure overload, diabetes and anthracycline-induced cardiomyopathies, MI, AF and Duchenne muscular dystrophy (DMD; Figure 1).

Cardiac Protection in Animal Models Pressure Overload

proliferation and fibrotic tissue deposition in pressure-overloaded rats.64 Additionally, inflammatory cells are found in the perivascular spaces of hypertensive hearts, suggesting that pressure overload might trigger an inflammatory response through inflammatory chemokines, such as monocyte chemoattractant protein-1, followed by reactive fibrosis.62 Multiple studies have shown that PFD might reduce vascular permeability in the acute phase and reduce the development of chronic fibrosis in pressure-overloaded hearts.15,65–67 Wang et al. investigated PFD in a mouse model of hypertensive left ventricular (LV) remodelling induced by transverse aortic constriction.15 They demonstrated that PFD attenuated myocardial fibrosis by inhibiting inflammation and fibrosis caused by NLRP3, a protein induced by pressure overload and involved in NLRP3 inflammasome formation. Furthermore, mice treated with PFD showed a higher survival rate compared with the control group.15 PFD was also studied in a rat model of hypertensive cardiomyopathy induced by unilateral nephrectomy followed by administration of salt and deoxycorticosterone acetate. Treatment with PFD for 2 weeks prevented cardiac remodelling by attenuating LV hypertrophy and reducing diastolic stiffness without lowering systolic blood pressure or reversing the increased vascular responses to norepinephrine.65 Similarly, PFD administration in a mouse model of cardiac hypertrophy induced by angiotensin II infusion reduced LV hypertrophy and inhibited perivascular and interstitial tissue fibrosis.67 PFD reduced the expression of atrial and B-type natriuretic peptides, which are closely related to cardiac hypertrophy, and the levels of TGF-β1 and monocyte chemoattractant protein-1. Furthermore, PFD inhibited the expression of mineralocorticoid receptors, which implies it may prevent cardiac remodelling also by inhibiting the aldosterone signalling pathways.67

Myocyte hypertrophy and myocardial fibrosis are two key mechanisms of hypertensive cardiomyopathy. The increased deposition of collagen type I and III by cardiac fibroblasts in hypertensive hearts allows the force generated by hypertrophied myocytes to be transmitted to the entire ventricle.62 However, the excessive deposition of fibrotic tissue causes increased myocardial stiffness and diastolic dysfunction.63

Another study investigated the effects of PFD on cardiac fibrosis in a pressure-overloaded HF mouse model, achieved by transverse aortic constriction.66 PFD reduced TGFβ-induced collagen 1 expression and increased the expression of claudin 5, a tight junction protein that regulates vascular permeability. These effects resulted in reduced fibrosis and reduced serum albumin leakage into the interstitial space.

TGF-β plays a crucial role because its increased expression is associated with an increased synthesis of collagen type I and III. The administration of an anti-TGF-β monoclonal antibody was reported to reduce fibroblast

The role of PFD in models of right ventricular (RV) pressure overload is controversial. PFD reduced RV fibrosis in a Sugen-hypoxia model of pulmonary hypertension.68 Conversely, Andersen et al. found that PFD did

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Pirfenidone for Lung and Cardiac Disorders Table 1: Results from Preclinical Studies Involving Pirfenidone for Lung and Cardiac Disorders Study

Model

Intervention

Findings

Miric et al. 200172

Rat model of STZ-induced diabetic cardiomyopathy

PFD (200 mg/day) from week 4 to week 8 after STZ treatment

•

Mirkovic et al. 200265

Rat model of hypertensive cardiomyopathy by single kidney removal

DOCA-salt or no further treatment for 2 weeks PFD (0.4% in powdered rat food) for further 2 weeks

Giri et al. 200474

DXR-induced rat model of cardiac and renal toxicity

Saline + regular diet; DXR + regular diet; • saline + the same diet mixed with 0.6% PFD; DXR + the same diet mixed with 0.6% PFD for 25 days •

PFD suppressed DXR-induced increases in hydroxyproline content in the heart and kidney, lipid peroxidation of the kidney and plasma and protein content of the urine PFD minimised the DXR-induced histopathological changes of heart and kidney

Lee et al. 200681

Dog model of congestive heart failure PFD (800 mg 3 times per day) for 3 weeks

•

PFD attenuated arrhythmogenic left atrial remodelling, left atrial fibrosis, AF duration PFD reduced TGF-β, TNF-α and metalloproteinase-9 and increased TIMP-4 levels

• •

•

PFD attenuated LV perivascular and interstitial collagen deposition and diastolic stiffness increase induced by STZ PFD did not normalise cardiac contractility PFD attenuated LV hypertrophy and reduced collagen deposition and diastolic stiffness

Van Erp et al. 200686

Dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy

PFD for 7 months

•

PFD improved cardiac contractility and decreased TGF-β expression but did not reduce extracellular matrix deposition

Yamazaki et al. 201267

Mouse model of angiotensin II-induced cardiac hypertrophy

PFD (300 mg/kg/day) for 2 weeks

•

PFD inhibited angiotensin II-induce LV hypertrophy, decreased heart weight, attenuated mRNA expression of ANP, BNP, TGF-β1 and mineralocorticoid receptors

Wang et al. 201315

Mouse model of TAC-induced LV hypertrophy

PFD (200 mg/kg) every 2 days from day 10 after surgery

•

PDF increased survival rate and reduced fibroblast proliferation and the expression of TGF-β1 and hydroxyproline PFD attenuated myocardial inflammation by regulating the NLRP3 inflammasome-mediated IL-1β signalling pathway

Yamagami et al. 201566 Mouse model of TAC-induced LV hypertrophy

PFD (400 mg/kg) twice daily from week 4 to week 8 after surgery

•

Andersen et al. 201969

Rat model of pressure overload RV failure by pulmonary trunk banding

PFD (700 mg/kg/day) for 6 weeks

•

PFD did not reduce RV fibrosis or improve RV haemodynamics

Poble et al. 201968

Sugen/hypoxia rat model of severe pulmonary hypertension

PFD (30 mg/kg/day) three times a day for 3 weeks

•

PFD reduced proliferation of pulmonary artery smooth cells and extracellular matrix deposition in lungs and RV

•

•

PFD improved systolic function and suppressed LV dilation and fibrotic progression induced by pressure overload PFD inhibited changes in the collagen 1 and CLDN5 expression levels resulting in reduced fibrosis and vascular permeability

ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; CLDN5 = claudin 5; DOCA = deoxycorticosterone acetate; DXR = doxorubicin; LV = left ventricle; PFD = pirfenidone; TAC = transverse aortic constriction; TGF-β = transforming growth factor-β; TNF-α = tumour necrosis factor-α; RV = right ventricle; STZ = stretpozocin.

not reduce fibrosis or improve RV haemodynamics when the RV pressure overload was induced by pulmonary artery banding in a rat model.69

Diabetic and Anthracyclineinduced Cardiomyopathies

Diabetic cardiomyopathy is characterised by structural and functional abnormalities, including systolic and diastolic dysfunction and LV hypertrophy.70 In this setting, cardiac fibrosis is partially due to increased expression of TGF-β1 caused by RAAS activation, oxidative stress, advanced glycation end-products, hyperglycaemia and hyperinsulinaemia, although the specific mechanisms remain elusive.71 In a rat model of diabetic cardiomyopathy, streptozotocin administration promoted interstitial collagen deposition in the kidney and the aorta, increased LV fibrosis and diastolic stiffness and reduced the maximum positive inotropic responses to norepinephrine and a calcium sensitiser in papillary muscles.72 PFD treatment reversed cardiac and renal fibrosis and improved diastolic function but did not normalise cardiac contractility or renal function.72 Cardiotoxicity is a well-recognised side-effect of several cancer therapies, especially anthracyclines, which are associated with myocardial oedema

and fibrosis.73 Giri et al. investigated the protective role of PFD in a rat model of anthracycline-induced toxicity.74 PFD therapy attenuated the doxorubicin-induced increase in hydroxyproline content and the histopathological changes in the heart characterised by disorganisation and vacuolisation of cardiac myofibrils.74

MI

Cardiac fibrosis is a primary event following MI, which impairs cardiac function eventually leading to HF and may also act as a substrate for ventricular tachyarrhythmias.10,75,76 PFD therapy has shown to reduce fibrosis in a rat model of post-MI remodelling.66 Treatment was started 1 week after ischaemia-reperfusion injury and continued for 4 weeks.

PFD-treated rats showed smaller infarct scars compared with controls, less total LV fibrosis, a reduced decline in LV ejection fraction (LVEF) and lower rates of ventricular tachycardia inducibility.77 In another rat model of MI, PFD administration by gavage for 4 weeks after permanent ligation of the left anterior descending artery reduced cardiac fibrosis and infarct size.75 The cardioprotective effects may be due, in large part, to an inhibition of the angiotensin II type 1 receptor (AT1R)/p38 MAPK/RAS axis through the activation of liver X receptor-α

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Pirfenidone for Lung and Cardiac Disorders (LXR-α).75 Similarly, in two different in vivo mice models of acute myocardial injury (induced by diphtheria toxin and closed-chest ischaemia-reperfusion injury), PFD attenuated LV remodelling and improved survival rates.78 Treatment with PFD had no effect on diphtheria toxin-induced cardiomyocyte cell death and the infiltration of neutrophils, monocytes or macrophages, but decreased CD19+ lymphocytes. B-cell depletion abrogated the beneficial effects of PFD. In vitro studies demonstrated that stimulation with lipopolysaccharide and extracts from necrotic cells activated B lymphocytes and PFD blunted this activation; therefore, PFD may also exert cardioprotective effects by modulating cardiac B lymphocytes.78

AF

Atrial interstitial fibrosis is a crucial element of structural and electrical remodelling, which plays a crucial role in the onset and perpetuation of AF.79,80 Indeed, fibrosis prolongs conduction times, leading to the creation of macro-reentrant circuits that increase susceptibility to AF and maintains AF.79 In a canine model of HF, PFD treatment reduced TGFβ, TNF-α and MMP-9 levels and increased the levels of an endogenous cardio-specific inhibitor of MMP, tissue inhibitor of MMP 4 (TIMP-4).81 These changes reduced atrial remodelling and AF development.70 PFD could also prevent AF by modulating the electrical properties of atrial tissue. Indeed, chronic treatment with PFD increased the expression of L-type calcium channels in adult rat cardiomyocytes. These channels are typically downregulated in AF; their increased expression by PFD prolongs both the action potential duration and the refractory period, thus lowering the susceptibility to AF.82

Duchenne Muscular Dystrophy

DMD is a severe, progressive, muscle-wasting disease caused by mutations in the DMD gene that abolish the expression of dystrophin in the skeletal muscle. Patients with DMD often develop systolic and diastolic dysfunction and myocardial fibrosis, often progressing to clinical HF.83,84 Indeed, dystrophin deficiency also causes cardiomyocyte degeneration and an increased deposition of ECM resulting in a progressive impairment of cardiac function.85 Van Erp et al. randomised 36 dystrophin-deficient mice to PFD or placebo for 7 months. PFD reduced TGF-β expression and improved cardiac contractility, but did not cause a significant reduction in myocardial fibrosis.86 The beneficial effects of PFD in this setting might then derive from a reduced synthesis of inflammatory cytokines and less oxidative stress more than an antifibrotic effect. Results from preclinical studies are summarised in Table 1.

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Evidence of Cardiac Protection

Two clinical studies have retrospectively examined the effects of PFD on echocardiographic parameters of LV function. In the first, PFD treatment did not improve parameters of LV structure, diastolic function, systolic function and global longitudinal strain.87 In the second, PFD was associated with decreased indexed LV end diastolic and end systolic volumes, although no significant changes in LV diastolic, systolic function and strain were observed.88 However, both studies included only IPF patients and were limited by their small size and retrospective design.

To date, only one randomised, double-blind, placebo-controlled trial included patients with a cardiac condition. The PIROUETTE phase 2 trial evaluated the safety and efficacy of a 52-week treatment with PFD in 94 patients with HFpEF (LVEF ≥45%) and myocardial fibrosis (defined as an ECM volume ≥27% measured by cardiac MRI [CMR]).89 At 52 weeks, the extracellular volume displayed an absolute decrease by 0.7% in the PFD group and an increase by 0.5% in the placebo group, with a betweengroup difference that was very small (also considering the variability in extracellular volume measurements by CMR), but still achieved statistical significance (between-group difference −1.21%; 95% CI [−2.12 to −0.31]; p=0.009). A limited but significant reduction in N-terminal pro-B-type natriuretic peptide values was also found. Conversely, no significant differences in measures of diastolic function, 6MWT nor Kansas City Cardiomyopathy Questionnaire summary score values were observed.79 These findings suggested that PFD may be beneficial but further trials are needed to determine the clinical effectiveness and safety in a broader population.

Conclusion

PFD is an antifibrotic drug mostly studied in lung models. Solid evidence based on clinical trials and real-life studies shows that PFD improves the outcomes of IPF, slowing down or blocking the decline of respiratory function and improving survival. The therapeutic role of PFD in fibrosing ILDs, including SARS-CoV-2, is being evaluated. Furthermore, the antifibrotic and anti-inflammatory activities of PFD provide a rationale for the evaluation of PFD for the treatment of chronic cardiovascular or renal diseases where fibrosis plays a crucial role. Following some promising results in animal models of several disorders, a phase II trial has recently reported a beneficial effect of PFD in patients with HFpEF, though limited to small changes in extracellular volume on repeated CMR scans.10 PFD was well tolerated, confirming the good safety profile emerging from studies on IPF.89 Further clinical studies on the efficacy and safety of PFD for the treatment of cardiac disease in humans are warranted.

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Burlew BS. Diastolic dysfunction in the elderly--the interstitial issue. Am J Geriatr Cardiol 2004;13:29–38. https:// doi.org/10.1111/j.1076-7460.2004.00059.x; PMID: 14724399.

Horn MA, Trafford AW. Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. J Mol Cell Cardiol 2016;93:175–85. https://doi.org/10.1016/j. yjmcc.2015.11.005; PMID: 26578393.

Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart.

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Zhang D, Li B, Li B, Tang Y. Regulation of left atrial fibrosis induced by mitral regurgitation by SIRT1. Sci Rep 2020;10:7278. https://doi.org/10.1038/s41598-020-64308-6; PMID: 32350389.

Senni M, Paulus WJ, Gavazzi A, et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014;35:2797–815. https://doi. org/10.1093/eurheartj/ehu204; PMID: 25104786.

Graziani F, Lillo R, Crea F. Rationale for the use of pirfenidone in heart failure with preserved ejection fraction.

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Kai H, Kuwahara F, Tokuda K, Imaizumi T. Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res 2005;28:483–90. https://doi.org/10.1291/hypres.28.483; PMID: 16231753.

Ma ZG, Yuan YP, Wu HM, et al. Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci 2018;14:1645–57. https:// doi.org/10.7150/ijbs.28103; PMID: 30416379.

Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.

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Mirkovic S, Seymour AM, Fenning A, et al. Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats. Br J Pharmacol 2002;135:961–8. https:// doi.org/10.1038/sj.bjp.0704539; PMID: 11861324.

Yamagami K, Oka T, Wang Q, et al. Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts.

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Yamazaki T, Yamashita N, Izumi Y, et al. The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice. Hypertens Res 2012;35:34–40. https:// doi.org/10.1038/hr.2011.139; PMID: 21866107.

Poble PB, Phan C, Quatremare T, et al. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. FASEB J 2019;33:3670–9. https:// doi.org/10.1096/fj.201801659R; PMID: 30481487.

Andersen S, Birkmose Axelsen J, Ringgaard S, et al.

Pressure overload induced right ventricular remodeling is not attenuated by the anti-fibrotic agent pirfenidone. Pulm Circ 2019;9:1–13. https://doi.org/10.1177/2045894019848659; PMID: 30997866.

Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res 2018;122:624–38. https://doi.org/10.1161/ CIRCRESAHA.117.311586; PMID: 29449364.

Yue Y, Meng K, Pu Y, Zhang X. Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract 2017;133:124–30. https://doi.org/10.1016/j.diabres.2017.08.018; PMID: 28934669.

Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol 2001;133:687– 94. https://doi.org/10.1038/sj.bjp.0704131; PMID: 11429393.

Farhad H, Staziaki PV, Addison D, et al. Characterization of the changes in cardiac structure and function in mice treated with anthracyclines using serial cardiac magnetic resonance imaging. Circ Cardiovasc Imaging 2016;9. https:// doi.org/10.1161/CIRCIMAGING.115.003584; PMID: 27923796.

Giri SN, Al-Bayati MA, Du X, et al. Amelioration of doxorubicin-induced cardiac and renal toxicity by pirfenidone in rats. Cancer Chemother Pharmacol 2004;53:141–50. https://doi.org/10.1007/s00280-003-0703-z; PMID: 14564477.

Li C, Han R, Kang L, et al. Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarctioninduced cardiac fibrosis. Sci Rep 2017;7:40523. https://doi. org/10.1038/srep40523; PMID: 28091615.

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Nguyen DT, Ding C, Wilson E, et al. Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm 2010;7:1438–45. https://doi.org/10.1016/j.hrthm.2010.04.030; PMID: 20433946.

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88. AlAnsari S, Southern BD, Sharma V, et al. Pirfenidone is associated with decreased indexed end diastolic and systolic volumes in patients with HFpEF and a known history of idiopathic pulmonary fibrosis. J Card Fail 2020;26(10 Suppl):S25. https://doi.org/10.1016/j.cardfail.2020.09.080.

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REVIEW

Diagnosis

Clinical Utility of HeartLogic, a Multiparametric Telemonitoring System, in Heart Failure Juan Carlos López-Azor ,1,2 Noelia de la Torre ,1 María Dolores García-Cosío Carmena ,1,2 Pedro Caravaca Pérez ,1,2 Catalina Munera,1 Irene Marco Clement ,1,2 Rocío Cózar León ,3 Jesús Álvarez-García ,2,4 Marta Pachón ,5 Fernando Arribas Ynsaurriaga ,1,2 Rafael Salguero Bodes ,1,2 Juan Francisco Delgado Jiménez 1,2,6 and Javier de Juan Bagudá 1,2 1. Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain; 2. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; 3. Cardiology Service, University Hospital Virgen Macarena, Seville, Spain; 4. Cardiology Service, University Hospital Ramón y Cajal, Madrid, Spain; 5. Cardiology Service, Unidad de Arritmias, Hospital Universitario de Toledo, Toledo, Spain; 6. Faculty of Medicine, Complutense University, Madrid, Spain

Abstract

Telemonitoring through multiple variables measured on cardiac devices has the potential to improve the follow-up of patients with heart failure. The HeartLogic algorithm (Boston Scientific), implemented in some implantable cardiac defibrillators and cardiac resynchronisation therapy, allows monitoring of the nocturnal heart rate, respiratory movements, thoracic impedance, physical activity and the intensity of heart tones, with the aim of predicting major clinical events. Although HeartLogic has demonstrated high sensitivity for the detection of heart failure decompensations, its effects on hospitalisation and mortality in randomised clinical trials has not yet been corroborated. This review details how the HeartLogic algorithm works, compiles available evidence from clinical studies, and discusses its application in daily clinical practice.

Keywords

Heart failure, remote monitoring, ICD, cardiac resynchronisation therapy, hospitalisation, HeartLogic Disclosure: RCL declares fees for consultancy work from Boston Scientific. FAY declares fees for consultancy work and presentations from Boston Scientific, Medtronic and Abbott. RSB declares fees for consultancy work from Boston Scientific. JdJB declares fees for consultancy work and presentations from Boston Scientific. All other authors have no conflicts of interest to declare.

Acknowledgements: The authors appreciate the help of Carlos Briz with the critical revision of this article.

Received: 5 December 2021 Accepted: 8 February 2022 Citation: Cardiac Failure Review 2022;8:e13. DOI: https://doi.org/10.15420/cfr.2021.35 Correspondence: Javier de Juan Bagudá, Cardiology, Heart Failure Transversal Program, Hospital Universitario 12 de Octubre, Avenida de Córdoba s/n, 28041, Madrid, Spain. E: javierdejuan166@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.

Chronic heart failure (HF) is a major health problem that affects approximately 64 million people worldwide. It is estimated that 1–3% of the general population in developed countries lives with HF and one in five individuals will be diagnosed with HF at some point in their lives. The burden of HF increases with age: HF affects 10% of individuals >70 years old, and more than 80% of cases are diagnosed in people >65 years old.1,2 Higher baseline cardiovascular risk and lower mortality due to improved treatment of major cardiac and non-cardiac diseases are responsible for the progressive rise in the incidence of HF. The impact of HF on healthcare is also growing. HF is the first cause of admission among the older population, is a leading cause of death (3% of men and 10% of women die from HF) and consumes 1–3% of healthcare spending in developed countries.3–5 The natural history of HF is characterised by periods of stability interrupted by episodes of acute decompensation. Decompensation is defined as the clinical and haemodynamic deterioration caused by an increased cardiac filling pressure leading to systemic and/or pulmonary congestion and, in

severe cases, peripheral hypoperfusion. Decompensation becomes more frequent as the disease progresses and is a marker of poor prognosis. In addition, most of episodes of decompensation require hospital admission, which is the main healthcare cost related to the disease.6–8 In this context, it is necessary to develop strategies to diagnose and treat episodes decompensation at early stages to prevent hospital admissions and other adverse events. This is not easy, because the symptoms and signs of decompensation usually appear late in the pathophysiological chain that leads to an HF decompensation (Figure 1).9 Since the early 2000s, several telemonitoring (TM) strategies have been developed in an attempt to detect preclinical deterioration in HF. A distinction can be made between non-invasive and invasive TM modalities, as discussed below.

Non-invasive Telemonitoring

Non-invasive TM primarily uses two strategies: structured periodic telephone calls conducted by a trained clinical team; and the automatic registration of symptoms and vital signs, such as blood pressure, heart

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Utility of HeartLogic in Heart Failure Figure 1: Changes in Different Parameters Throughout Heart Failure Decompensation Up Until the Need for Hospital Admission Pathophysiology of congestion Hospitalisation

Intrathoracic impedance changes Autonomic adaptation

Filling pressure increase

−30

Symptoms

Weight change

−20

−10

0

Days

Source: Adamson. 2009.9 Reproduced with permission from Springer Science Business Media.

Figure 2: HeartLogic Algorithm

Heart rate Night 3%

9%

3%

Activity Respiration Rate and volume Time spent active 12%

Impedance Thoracic 6%

7%

8%

Heart sounds S1 and S3

Combined into a single, simple index with alert HeartLogic heart failure index

100

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3 March 2013

75 50 25 0

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Oct 2012

Nov 2012

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Issues alert when index crosses threshold

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Percentages inside the arrows reflect the mean sensor variations (all p<0.01) between baseline (20–60 days) and the days (1–3) prior to hospitalisation. Source: Boehmer et al.26

rate, cardiac rhythm, peripheral saturation and weight using remotely connected medical devices. The first strategy is proactive because it requires contacting the patient directly. The second strategy allows passive monitoring, with no need for direct interaction if not indicated.

The aim in both cases is the early detection of symptoms and signs of decompensation. Both strategies have been tested in several randomised clinical trials with conflicting results. Although these strategies improve self-care and adherence, they have not consistently been shown to reduce hospital admission and mortality in HF patients.10 Alternatively, percutaneous non-invasive devices that can measure the intrathoracic water in various ways as a surrogate of pulmonary congestion have been developed. Even though some of these devices showed promising results in observational studies, to date they also have failed to demonstrate a prognostic impact in randomised clinical trials.11–13

Invasive Telemonitoring Strategies

Invasive TM strategies require the implantation of intravascular devices, such as haemodynamic TM devices and cardiac implantable devices.

Haemodynamic TM devices directly measure the pressure of cardiac chambers or arteries using small manometers. Their potential usefulness is based on detecting the increase in intracardiac pressure that precedes an episode of HF decompensation. The most relevant advance in the field of haemodynamic TM has been CardioMEMS, a wireless device that monitors pulmonary artery pressure. In the CHAMPION-HF clinical trial, CardioMEMS was shown to reduce mortality and hospital admissions in patients with HF with reduced ejection fraction, New York Heart Association (NYHA) class III and a previous hospitalisation.14 However, these results could not be validated in a more heterogeneous cohort in the GUIDE-HF study.15 Devices implanted in other chambers, such as the left atrium or left ventricle, have not demonstrated efficacy in preventing episodes of decompensation or have presented an unacceptable incidence of procedure complications.16–18 Although more technologically advanced haemodynamic monitoring devices are in development, to the best of our knowledge none is currently under clinical evaluation.

With regard to cardiac implantable devices, additional functionalities have been developed to implement the follow-up of HF patients with reduced ejection fraction that carry an ICD, a cardiac resynchronisation therapy (CRT) defibrillator (CRT-D) or a CRT pacemaker (CRT-P). The first algorithms tried to associate one parameter, such as changes in heart rate, rhythm or thoracic impedance, with clinical worsening. One of the most well-known algorithms is Optivol (Medtronic), an index that quantifies daily changes in thoracic impedance as a surrogate for lung congestion. Although Optivol and some other one-parameter algorithms have been shown to improve the follow-up of HF patients, none has reduced hospitalisation or mortality in clinical trials.19–21 More complex detection systems, combining multiple variables as surrogates for volume status, have been developed in an attempt to impact HF prognosis.22–24 In the PARTNERS-HF observational study, an algorithm combining patient activity, heart rate, atrial fibrillation burden, Optivol index and proportion of CRT pacing proved to be useful in selecting patients with HF at higher risk of HF decompensation.25 In this paper, we focus on HeartLogic (Boston Scientific), a novel multiparametric algorithm that potentially will have a complementary role to guideline-directed management of patients with HF with reduced ejection fraction.

The HeartLogic Algorithm

HeartLogic is a multiparametric algorithm implemented in certain ICDs (with or without CRT) from Boston Scientific, which allows stratification of the risk of decompensation in HF patients. HeartLogic is an automatic, remotely monitored system that combines trend analysis from different sensors implanted in the generator, namely nocturnal heart rate, intensity of the first and third sounds of the cardiac cycle, intrathoracic impedance, respiratory rate, tidal volume and physical activity, integrating them to generate a single numerical indicator, the HeartLogic index. When a patient is at risk of HF decompensation there will usually be a progressive rise in the heart rate and the intensity of the third sound, a decrease in the first sound of the cardiac cycle, breathing will become shallower and faster, diminishing inspiratory volume, pulmonary congestion will reduce intrathoracic impedance and physical activity will be limited by a deterioration in the functional class.26 It is through the combination of information from the different measures that the HeartLogic index estimates the risk of HF decompensation (Figure 2).

The HeartLogic index is specific for each patient and depends on the value of each parameter at steady state. Its lower value, called the baseline HeartLogic index, is calculated over a 3-month rolling window of

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Utility of HeartLogic in Heart Failure each patient evolution. An increase in the index reflects a deviation from the baseline situation towards the decompensation in HF. HeartLogic measurements of each parameter are automatically updated on a daily basis, as is the HeartLogic index. This makes it possible to describe a trend in the patient’s evolution that can be represented on a graph over time. The HeartLogic index remains stable if the clinical situation of the patient does not change acutely. When the HeartLogic index exceeds a prespecified numerical value, the device issues an alarm, the HeartLogic alert, indicating a higher risk of decompensation. This value is predefined at 16, because this value demonstrated the best sensitivity and specificity ratio for detecting an HF event in the MultiSENSE study, but it can be adjusted individually for each patient or group of patients.27 If the patient improves and approaches the baseline condition again, as may happen after a patient has been prescribed diuretics, the HeartLogic index decreases (Figure 3). When the index falls below 6, the alert will be resolved.

The information from the HeartLogic algorithm is transmitted via a communicator to the Latitude NXT system, a remote monitoring virtual platform that can be accessed by the medical team, allowing for the follow-up of multiple patients and their stratification according to the risk of decompensation. A patient will only be aware of a HeartLogic alert status if they are directly contacted by their healthcare professional. Of note, the HeartLogic has a minimal effect on the longevity of the on the ICD (±CRT). The reduction in battery durability with HeartLogic sensor data collection and daily alert checks is approximately 2 months.

Figure 3: Evolution of the HeartLogic Index in a Patient with an Alert Health Most recent daily measurement (30 Sep 2021)

Blood pressure

HeartLogic heart failure index

128/94 mmHg (9 Jan 2021)

OK 0 Sleep incline N/R 16.5/min Respiratory rate 34 events/h AP Scan Activity level 0.2 h 69 BPM Mean heart rate Total time in AT/AF 0h Heart rate variability (SDANN) 41 ms

View: 1m 3m 6m 1y 1 Jul 2021

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Evidence

The HeartLogic index not only changes throughout a patient’s evolution and predicts HF decompensation, as described above, but its baseline value also seems to select patients with a higher risk of decompensation. Patients that decompensate tend to have higher baseline HeartLogic index values than those who remain stable.28 In addition, the HeartLogic index has been shown to have a prognostic value independent of N-terminal pro B-type natriuretic peptide (NT-proBNP). An increase in the HeartLogic index above 16 is an indicator of risk of admission in patients with and without elevated NT-proBNP. Moreover, patients who are in alert and have elevated NTproBNP seem to be at higher risk of decompensation.29 In a subanalysis of the MultiSENSE study, patients in the HeartLogic alert state had a 24- and 50-fold higher risk of HF decompensation by at the 12-month follow-up if their NT-proBNP concentrations were <1,000 pg/ml and >1,000 pg/ml, respectively, compared with patients with NT-proBNP <10,00 pg/ml and a negative HeartLogic index.29

External sensors

Implanted device measures

Thoracic impedance

The usefulness of the HeartLogic algorithm has so far been evaluated in observational studies. The MultiSENSE study was the first to evaluate the usefulness of HeartLogic in predicting HF decompensation.27 That study included 900 patients with a COGNIS (Boston Scientific) CRT-D with HF with reduced ejection fraction, NYHA class II–IV or with an admission for HF or need for IV diuretic administration within the past 6 months. The study used one cohort for development of the HeartLogic algorithm and another for its validation. In the MultiSENSE study, the HeartLogic algorithm demonstrated a maximum sensitivity of 70% with an index value of 16 for predicting HF decompensation, defined as a hospital admission or unplanned visit requiring intravenous therapy. Its specificity was 86% and its negative predictive value was 99.9%. The median time from alert (exceeding an index value of 16) to HF decompensation was 34 days, and, of note, there was a low incidence of false alarms (1.47 per patient per year).27

Most recent daily measurement

Note: Shaded portion indicates degree of worsening on 21 Aug 2021 Trend graphs

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Note how the contribution of the different sensors to the index can be identified for each specific day. AT = atrial tachycardia; N/R = not recorded; SDANN = standard deviation of the averages of NN.

Few observational studies have shown how HeartLogic performs in reallife clinical practice (Table 1). In general, these studies demonstrated that the algorithm allows the identification of relevant HF-related conditions with high sensitivity and specificity and enables effective clinical action to be taken remotely, with a low incidence of false alarms.30–32 One multicentre study compared 1-year HF hospitalisation before and after activation of the HeartLogic algorithm in 68 patients, showing a 66% reduction in HF admissions, a >50% decrease in the hospitalisation length of stay and a significant reduction in overall health economic costs after

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Utility of HeartLogic in Heart Failure Table 1: Performance of HeartLogic in the MultiSENSE and Real-world Studies Study

Year of No. Patients Follow-up Sensitivity (%) Specificity (%) Positive Unexplained Time in Alert Publication (Months) Predictive Alert Rate (% Observation Value (%) (/Patient-year) Period)

MultiSENSE (validation dataset)27

2017

400

12

70

87.5

11

1.47

17

Capucci et al.30

2019

58

5

100

N/A

58

0.41

12

Santini et al.

2020

104

13

69

N/A

60

0.37

15

2021

68

12

90

89

73

0.16

N/A

Blinded phase

2021

101

10

100

93

27

0.52

8

Unblinded phase

2021

267

16

98

90

57

0.39

11

31

Treskes et al.

33

De Juan Bagudá et al.34

Figure 4: RE-HEART Registry Follow-Up Protocol Based on the HeartLogic Algorithm HF nurse: weekly remote revision of HeartLogic Patient in alert state for exceeding the HeartLogic index threshold (>16) No medical action taken and alarm revision 1 week later

Alarm persists

Alarm has ended

Telephone consultation with patient

Routine follow-up

No clinical changes

Clinical worsening

Actions: • Remember warning signs, recommendations and therapy • Ensure patients have the HF unit contact details • Remind patients that contact is needed upon decompensation signs Re-evaluate: in 2 and 6 weeks If index persists raised, consider modifying alarm threshold

Notify the treating physician, who acts according to own criteria Clinic visit appointment

HF = heart failure. Source: de Juan Bagudá et al. 2021.34 Adapted with permission from Elsevier.

activation of the HeartLogic algorithm.33 In a prospective study in 366 ICD patients recruited from 22 centres, at the 11-month follow-up HeartLogic alerting was associated with a 24.5-fold increased risk of hospital admissions.32 In addition, in that study, alarms followed by a clinical intervention were associated with a lower incidence of events at followup.32 In another multicentre study conducted in 102 patients who were followed for a median of 13 months, 100 alerts were recorded, 60% of which were of clinical interest.31 The incidence of non-insignificant alerts has been reported to be only 0.37 per patient-year, and the rate of hospitalisations not preceded by an alert is very low (0.05 per patientyear).21,22 We have recently published an ambispective study with the first data from the RE-HEART registry, which included 288 patients from 15 centres across Spain.34 In that study, the HeartLogic algorithm was shown to predict a HF decompensation or clinically relevant event in more than half of the alerts, on average 20 days in advance. Sensitivity and negative predictive value were close to 100%, with a specificity of over 90%.34 The

HeartLogic was demonstrated to be useful in identifying events and individualising patient follow-up, knowing that decompensation outside the alert state is unlikely. It is also of note that the reported rate of unexplained alerts was low (0.39 alerts per patient-year) and that in more than 80% of cases alerts could be resolved by telephone.34 However, these promising results have not yet been validated in a randomised study. MANAGE-HF (NCT03237858), currently in the inclusion phase, is the first randomised clinical trial designed to assess the impact of HeartLogic on hospitalisation and mortality in symptomatic (NYHA functional class II–III) HF patients with either a previous decompensation or elevated natriuretic peptides. It is planned that MANAGE-HF will include 2,700 patients with a Boston ICD, CRT-D or CRT-P who will be randomised 1:1 to a guideline-directed follow-up with HeartLogic monitoring on versus off. If the results of MANAGE-HF are positive, HeartLogic would be the first algorithm of implantable devices to demonstrate a prognostic impact in HF.

Application of HeartLogic in Daily Clinical Practice

The HeartLogic algorithm allows daily TM of patients with HF and the detection of those at increased risk of decompensation. Its simplicity and the encouraging results of the observational studies described above have motivated its incorporation into the protocols of centres with HF units. Figure 4 shows the follow-up protocol based on monitoring with the HeartLogic algorithm in the centres included in the Spanish RE-HEART registry.34 When the HeartLogic index enters the alert state, it does so early enough to that the precipitating factors of an HF admission can be addressed.

Through telematic or face-to-face contact three possible scenarios are defined:

• If the patient is symptomatic, medication can be adjusted, possible

precipitating factors can be detected and corrected and early targeted treatment can be administered before the patient exhibits admission criteria. Subsequent follow-up can be done on an individual basis.

• If the patient is asymptomatic but has an active precipitating factor, the precipitating factor can be addressed and the response to the intervention can be assessed with individualised follow-up. Some precipitating factors are low adherence to medical treatment or dietary restrictions, the use of deleterious medications, such as non-steroidal anti-inflammatory drugs, the incidence of arrhythmias, such as AF and the loss of cardiac resynchronisation.

• If the patient is asymptomatic and no precipitating factor is evident,

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Utility of HeartLogic in Heart Failure considering that this is a higher-risk patient, closer remote follow-up can be performed.

In our experience, the threshold value of 16 for the HeartLogic alert performs well in most patients and its individual adjustment is rarely needed. However, we have seen a small group of patients with a worse prognostic profile who are persistently above this value, like those with persistent congestion, diuretic resistance, low adherence to treatment or in advanced HF; in such patients, raising the alert threshold could be considered. Other very rare conditions could be patients with HF events but whose HeartLogic index does not reach the in-alert status (false negatives), for whom a lower threshold value would make sense.

Most HeartLogic alerts can be resolved via telephone by trained nursing staff with low time consumption. In the RE-HEART registry, only 60 minutes of clinical care time per week was consumed for every 30 patients monitored with HeartLogic.34 HeartLogic also selects low-risk patients based on its high negative predictive value. These patients are defined as those with a stable and negative HeartLogic index. In this case, the algorithm makes follow-up more flexible, minimising in-clinic contact with the healthcare environment.

This factor is particularly relevant in the current epidemiological context, influenced by the COVID-19 pandemic.

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10.

11.

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.

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.

Conrad N, Judge A, Tran J, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet 2018;391:572–80. http://doi. org/10.1016/S0140-6736(17)32520-5; PMID: 29174292.

Tsao CW, Lyass A, Enserro D, et al. Temporal trends in the incidence of and mortality associated with heart failure with preserved and reduced ejection fraction. JACC Heart Fail 2018;6:678–85. https://doi.org/10.1016/j.jchf.2018.03.006; PMID: 30007560.

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.

Gheorghiade M, De Luca L, Fonarow GC, et al.

Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol 2005;96(Suppl 6A):11G–7. https://doi.org/10.1016/j.amjcard.2005.07.016; PMID: 16196154.

Delgado JF, Oliva J, Llano M, et al. Costes sanitarios y no sanitarios de personas que padecen insuficiencia cardiaca crónica sintomática en España. Rev Esp Cardiol (Engl Ed) 2014;67:643–50. https://doi.org/10.1016/j.rec.2013.12.014; PMID: 25037543.

Farré N, Vela E, Clèries M, et al. Medical resource use and expenditure in patients with chronic heart failure: a population-based analysis of 88 195 patients. Eur J Heart Fail 2016;18:1132–40. https://doi.org/10.1002/ejhf.549; PMID: 27108481.

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.

Zhu Y, Gu X, Xu C. Effectiveness of telemedicine systems for adults with heart failure: a meta-analysis of randomized controlled trials. Heart Fail Rev 2020;25:231–43. https://doi. org/10.1007/s10741-019-09801-5; PMID: 31197564.

Shochat MK, Shotan A, Blondheim DS, et al. Non-invasive lung IMPEDANCE-guided preemptive treatment in chronic heart failure patients: a randomized controlled trial (IMPEDANCE-HF trial). J Card Fail 2016;22:713–22. https://doi. org/10.1016/j.cardfail.2016.03.015; PMID: 27058408.

Among the limitations of the HeartLogic system, it should be noted that this system only allows the monitoring of patients with a Boston Scientific ICD. Implantation is due to the presence of specific indications in HF, and therefore excludes many patients with a diagnosis of HF without indication for this therapy, such as those with a left ventricular ejection fraction >35% or those in NYHA functional class I. Furthermore, although the HeartLogic system has been shown to select patients at higher risk, it is not yet known whether it has an effect on hard clinical events, such as hospital readmission or mortality in the demanding setting of HF with reduced ejection fraction under optimal prognostic treatment. The MANAGE-HF clinical trial will resolve this issue. Finally, although initial data are promising, the role of the HeartLogic system in reducing direct and indirect costs in the follow-up of HF needs to be further evaluated.

Conclusion

HeartLogic seems to be a useful tool in the daily practice of an HF program. It can help to both identify patients at increased risk of decompensation, to enable prompt action to try to avoid an impending decompensation, and reassure patients out of alert, who can be followed in a more lenient way. Most patients can be managed by telephone, thus avoiding unnecessary visits to the clinic, improving patient experience.

This proactive way of following patients is promising and will hopefully lead to improvements in the prognosis of HF.

12. Wheatley-Guy CM, Sajgalik P, Cierzan BS, et al. Validation of radiofrequency determined lung fluid using thoracic CT: findings in acute decompensated heart failure patients. Int J Cardiol Heart Vasc 2020;30:100645. https://doi.org/10.1016/j. ijcha.2020.100645; PMID: 33024812.

13. Uriel N, Sayer G, Imamura T, et al. Relationship between noninvasive assessment of lung fluid volume and invasively measured cardiac hemodynamics. J Am Heart Assoc 2018;7:e009175. https://doi.org/10.1161/JAHA.118.009175; PMID: 30571493.

14. Givertz MM, Stevenson LW, Costanzo MR, et al. Pulmonary artery pressure-guided management of patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2017;70:1875–86. https://doi.org/10.1016/j.jacc.2017.08.010; PMID: 28982501.

15. Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamicguided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet 2021;398:991–1001. https://doi.org/10.1016/S0140-6736(21)01754-2; PMID: 34461042.

16. Ritzema J, Melton IC, Richards AM, et al. Direct left atrial pressure monitoring in ambulatory heart failure patients: initial experience with a new permanent implantable device.

Circulation 2007;116:2952–9. https://doi.org/10.1161/ CIRCULATIONAHA.107.702191; PMID: 18056531.

17. Abraham WT, Adamson PB, Costanzo MR, et al.

Hemodynamic monitoring in advanced heart failure: results from the LAPTOP-HF trial. J Card Fail 2016;22:940. https:// doi.org/10.1016/j.cardfail.2016.09.012; PMID: 30588319.

18. Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure. The COMPASS-HF study. J Am Coll Cardiol 2008;51:1073–9. https://doi.org/10.1016/j.jacc.2007.10.061; PMID: 18342224.

19. Hindricks G, Taborsky M, Glikson M, et al. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014;384:583–90. https://doi.org/10.1016/S01406736(14)61176-4; PMID: 25131977.

20. Guédon-Moreau L, Lacroix D, Sadoul N, et al. A randomized study of remote follow-up of implantable cardioverter defibrillators: safety and efficacy report of the ECOST trial.

Eur Heart J 2013;34:605–14. https://doi.org/10.1093/eurheartj/ ehs425; PMID: 23242192.

21. 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.

22. Arya A, Block M, Kautzner J, et al. Influence of home

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23.

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28.

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monitoring on the clinical status of heart failure patients: design and rationale of the IN-TIME study. Eur J Heart Fail 2008;10:1143–8. https://doi.org/10.1016/j. ejheart.2008.08.004; PMID: 18805053.

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.

Auricchio A, Gold MR, Brugada J, et al. Long-term effectiveness of the combined minute ventilation and patient activity sensors as predictor of heart failure events in patients treated with cardiac resynchronization therapy: results of the clinical evaluation of the physiological diagnosis function in the PARADYM CRT device trial (CLEPSYDRA) study. Eur J Heart Fail 2014;16:663–70. https:// doi.org/10.1002/ejhf.79; PMID: 24639140.

Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heart failure device diagnostics identify patients at higher risk of subsequent heart failure hospitalizations. Results from PARTNERS HF (Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol 2010;55:1803–10. https://doi.org/10.1016/j.jacc.2009.11.089; PMID: 20413029.

Boehmer JP, Sriratanasathavorn C, Fisher J, et al. Heart failure diagnostics sensor measurements change prior to heart failure decompensation events. J Card Fail 2017;23(8 Suppl):S65. https://doi.org/10.1016/j.cardfail.2017.07.182.

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;5:216–25. https://doi.org/10.1016/j. jchf.2016.12.011; PMID: 28254128.

Gardner RS, Thakur P, Hammill EF, et al. Multiparameter diagnostic sensor measurements during clinically stable periods and worsening heart failure in ambulatory patients.

ESC Heart Fail 2021;8:1571–81. https://doi.org/10.1002/ ehf2.13261; PMID: 33619893.

Gardner RS, Singh JP, Stancak B, et al. HeartLogic multisensor algorithm identifies patients during periods of significantly increased risk of heart failure events: results from the MultiSENSE study. Circ Heart Fail 2018;11:e004669. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004669; PMID: 30002113.

Capucci A, Santini L, Favale S, et al. Preliminary experience with the multisensor HeartLogic algorithm for heart failure monitoring: a retrospective case series report. ESC Heart Fail 2019;6:308–18. https://doi.org/10.1002/ehf2.12394; PMID: 30632306.

Santini L, D’Onofrio A, Dello Russo A, et al. Prospective

Utility of HeartLogic in Heart Failure evaluation of the multisensor HeartLogic algorithm for heart failure monitoring. Clin Cardiol 2020;43:691–7. https://doi. org/10.1002/clc.23366; PMID: 32304098.

32. Calò L, Bianchi V, Ferraioli D, et al. Multiparametric implantable cardioverter-defibrillator algorithm for heart failure risk stratification and management: an analysis in

clinical practice. Circ Heart Fail 2021;14:e008134. https://doi. org/10.1161/CIRCHEARTFAILURE.120.008134; PMID: 34190592.

33. Treskes RW, Beles M, Caputo ML, et al. Clinical and economic impact of HeartLogicTM compared with standard care in heart failure patients. ESC Heart Fail 2021;8:1541–51.

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https://doi.org/10.1002/ehf2.13252; PMID: 33619901.

34. de Juan Bagudá J, Gavira Gómez JJ, Pachón Iglesias M, et al. Remote heart failure management using the HeartLogic algorithm. RE-HEART registry. Rev Española Cardiol (Engl Ed) 2021. https://doi.org/10.1016/j.rec.2021.09.015; PMID: 34896031; epub ahead of press.

REVIEW

Treatment

Mechanical Circulatory Support for Right Ventricular Failure Ersilia M DeFilippis ,1 Veli K Topkara ,1 Ajay J Kirtane ,1 Koji Takeda,2 Yoshifumi Naka2 and A Reshad Garan

3

1. Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, US; 2. Division of Cardiothoracic Surgery, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, US; 3. Beth Israel Deaconess Medical Center, Boston, MA, US

Abstract

Right ventricular (RV) failure is associated with significant morbidity and mortality, with in-hospital mortality rates estimated as high as 70–75%.

RV failure may occur following cardiac surgery in conjunction with left ventricular failure, or may be isolated in certain circumstances, such as inferior MI with RV infarction, pulmonary embolism or following left ventricular assist device placement. Medical management includes volume optimisation and inotropic and vasopressor support, and a subset of patients may benefit from mechanical circulatory support for persistent RV failure. Increasingly, percutaneous and surgical mechanical support devices are being used for RV failure. Devices for isolated RV support include percutaneous options, such as micro-axial flow pumps and extracorporeal centrifugal flow RV assist devices, surgically implanted RV assist devices and veno-arterial extracorporeal membrane oxygenation. In this review, the authors discuss the indications, candidate selection, strategies and outcomes of mechanical circulatory support for RV failure.

Keywords

Right ventricle, mechanical circulatory support, right ventricular assist device, veno-arterial extracorporeal membrane oxygenation Disclosure: EMD is on the Cardiac Failure Review editorial board; this did not influence peer review. AJK has received institutional grants from Abbott, Medtronic, Boston Scientific, Abiomed, CSI, Siemens and Philips. YN is a consultant for Abbott. ARG has previously received honoraria from Abiomed and is an unpaid consultant to Abiomed. None of these organisations had any role in the drafting of this manuscript. All other authors have no conflicts of interest to declare.

Funding: ARG is supported by National Institutes of Health grant number UL1 TR001873.

Received: 27 May 2021 Accepted: 19 November 2021 Citation: Cardiac Failure Review 2022;8:e14. DOI: https://doi.org/10.15420/cfr.2021.11 Correspondence: A Reshad Garan, Advanced Heart Failure and Mechanical Circulatory Support, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, Boston, MA 02215, US. E: agaran@bidmc.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.

Right ventricular (RV) failure is associated with significant morbidity and mortality, with in-hospital mortality rates estimated as high as 70–75%.1–3 RV failure may occur following cardiac surgery, in conjunction with left ventricular (LV) failure (e.g. in acute decompensated heart failure), or isolated in circumstances, such as inferior MI with RV infarction, pulmonary embolism (PE) or following left ventricular assist device (LVAD) placement.4–10 Medical management includes volume optimisation, inotropic therapy and vasopressor support; a subset of patients may benefit from mechanical circulatory support (MCS) for persistent RV failure.9,11,12 Increasingly, percutaneous and surgical mechanical support devices are being used for RV failure.1,13–15 Devices for isolated RV support include percutaneous options, such as micro-axial flow pumps and extracorporeal centrifugal flow right ventricular assist devices (RVADs), surgically implanted RVADs and venoarterial extracorporeal membrane oxygenators (VA-ECMO). In this review, we will discuss the indications, candidate selection, strategies and outcomes of MCS for RV failure.

Pathophysiology

The primary mechanisms of cardiogenic shock secondary to RV failure include pump failure, volume overload and pressure overload.9 Pump

failure leads to a reduction in contractility in the setting of primary myocardial injury (e.g. myocarditis or RV ischaemia). A decreased stroke volume leads to dilation of the RV. This exacerbates tricuspid regurgitation, which may lead to further RV dilation.9 Volume overload can also lead to RV failure. A typical example of this is RV failure following LVAD implantation. When the left ventricle (LV) is unloaded with an LVAD, there is increased venous return to the right side of the heart, which can worsen pre-existing RV failure.16–20 This may be exacerbated by altered position of the interventricular septum, resulting in diminished RV stroke volume. Finally, RV pressure overload may result from decompensated left-sided heart failure, pulmonary hypertension or acute PE.14,21 Medical therapy often involves optimisation of preload with volume expansion or diuretic therapy, reduction of afterload with pulmonary vasodilators and inotropic therapy.9,11 However, the main focus of this review will be on MCS options for patients who have RV failure refractory to medical therapy.

A reason for optimism regarding MCS options for the RV arises from the ability of the RV to recover from various insults relatively quickly. This makes it an attractive target for short-term circulatory support devices.

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Mechanical Circulatory Support for RV Failure Table 1: Commercially Available Right Ventricular Assist Devices Device

Mechanism/Configuration

Advantages

Disadvantages

Optimal Use

ProtekDuo RVAD (LivaNova)

• •

Centrifugal flow, extracorporeal Percutaneously implanted (coaxial dual-lumen cannula) RA/RV to PA blood flow

• • •

Percutaneously deployed Single access site Blood flow up to 4–5 l/min

•

May cause SVC syndrome with larger cannula size

RV failure following durable LVAD implantation

Microaxial-flow Percutaneously implanted RA/IVC to PA blood flow

• • • • •

Percutaneously deployed Single access site Blood flow up to 4-5 l/min

• •

Obligate femoral venous access RV infarct or RV failure following Risk of thrombosis at lower levels durable LVAD implantation of anticoagulation

Blood flow up to 7 l/min Lower rate of red blood cell destruction

•

Surgical implantation

In combination with Centrimag LVAD use

Centrifugal flow, extra-corporeal Percutaneously or surgically implanted RA/IVC/SVC to aorta blood flow

• • •

Percutaneous deployment possible Emergent/bedside deployment Blood flow up to 3–5 l/min

• • •

Increases LV afterload Systemic arterial embolic events Risk of limb ischaemia

Massive pulmonary embolus or decompensated pulmonary hypertension

Centrifugal flow Surgically implanted RA/RV to PA blood flow

•

Fully implantable device (i.e. dischargeable) Blood flow up to 4–6 l/min

•

Surgical implantation

In combination with durable LVAD implantation for dischargeable patient

Impella RP (Abiomed) Surgical CentriMag RVAD (Abbott) Veno-arterial ECMO

HeartMate 3 (Abbott)

• • • • • • • • • • • • •

Centrifugal flow, extracorporeal Surgically implanted RA/IVC/SVC/RV to PA blood flow

•

IVC = inferior vena cava; LVAD = left ventricular assist device; PA = pulmonary artery; RA = right atrium; RV = right ventricle; SVC = superior vena cava.

For example, because it has a lower myocardial oxygen demand than the LV, the RV often recovers from ischaemic insults following an acute coronary syndrome.22 In addition, while some patients will experience RV failure after LVAD implantation and require RVAD implantation, interventions designed to improve RV performance often allow for timely wean from these short-term devices.

Patient and Device Selection

Given the availability of both percutaneous and more invasive surgical options, an interdisciplinary approach is necessary when choosing the most appropriate therapy for each patient.23–25 Vital perspectives are provided from shock team, including from advanced heart failure specialists, interventional cardiologists, cardiac surgeons and intensive care physicians.

Patients should be identified early to avoid potentially irreversible endorgan injury. The choice of device will depend on whether the underlying process is a primary RV insult, valvular pathology or biventricular insult (Table 1).9 Considerations include the haemodynamic impact of the device and technical aspects, as well as the exit strategy for these patients, including their candidacy for durable ventricular assist devices and organ transplantation (Figure 1).

Percutaneous Mechanical Support Devices Intra-aortic Balloon Pump

Intra-aortic balloon pumps (IABPs) are commonly employed in LV failure due to MI or cardiomyopathy. However, they are less effective in situations of acute RV failure. IABPs help to reduce LV afterload. By unloading the LV, they may reduce right-sided filling pressures and/or increase right coronary perfusion, but these effects are indirect.1 However, studies have shown minimal haemodynamic benefit, especially in RV failure, and suggest many patients will require escalation of mechanical support.26,27

Microaxial Flow Transvalvular RVAD

The Impella RP (Abiomed) is a micro-axial pump that can be inserted percutaneously via the femoral vein. The pump head is 23 Fr and is mounted on an 11 Fr catheter. It provides up to 5 l/min of flow and is approved for use for up to 14 days.1 When it is in the correct position, blood

is drawn into the pump from the inferior vena cava-right atrial junction and ejected into the main pulmonary artery (PA). Its appearance on chest radiography is shown in Figure 2, along with other RV support devices.

In the RECOVER RIGHT study, 30 patients with refractory right heart failure prospectively received the Impella RP device. Approximately half of the cohort had developed RV failure following LVAD implantation while the remaining patients had RV failure following cardiotomy or MI.28 A followup study ultimately expanded this cohort to 60 patients.29 Haemodynamics improved rapidly with an increase in cardiac index and a decrease in central venous pressure.

In 2019, the Food and Drug Administration (FDA) warned about the increased mortality observed in patients supported by the device. This was likely due to use of the device outside the indications described and the severity of illness of patients supported by it. An interim analysis of the post-approval study showed that the survival rate for the patients who would have met the enrollment criteria for the clinical trials was 72.7%, which is similar to the survival rate in the premarket clinical study (73.3%).30 The Impella RP has also shown beneficial haemodynamic effects in patients with acute RV failure in the setting of PE.31,32 In patients who were refractory to volume expansion and inotropic support due to a massive or submassive PE, support with the Impella RP device lowered mean heart rate, increased mean systolic blood pressure and improved the cardiac index.31 During the COVID-19 pandemic, the FDA issued an emergency use authorisation for Impella RP for patients experiencing RV failure or decompensation due to complications of COVID-19 infection, including PE.33 The Impella RP should be used with caution in patients with tricuspid valve regurgitation. According to the manufacturer, tricuspid valve regurgitation is a contraindication. However, functional tricuspid regurgitation caused by dilation of the valvular annulus may improve with Impella RP treatment.34 Pulmonary regurgitation, however, is a major contraindication for the use of this device.

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Mechanical Circulatory Support for RV Failure Figure 1: Management of Right Ventricular Failure with Cardiogenic Shock Right ventricular failure with cardiogenic shock

Eligibility for MCS: • Multidisciplinary shock team evaluation, including CT surgery, interventional cardiology and intensivist input • Identify goal of therapy (e.g. bridge to recovery, durable VAD or transplant) • Consider palliative care consultation if none of these destinations feasible Other surgical intervention requiring sternotomy planned?

Yes

• CentriMag* • HVAD† • HeartMate 3 LVAD†

Evidence of right ventricle failure: 1. CVP >15 mmHg 2. Cardiac index <2.2 l/min/m2 3. CVP/pulmonary capillary wedge pressure >0.63 4. Vasopressor or inotrope use to maintain systolic blood pressure >90 mmHg

Yes

Untreated left ventricular failure present?

No

No

Impaired gas exchange?

Yes

• VA-ECMO • Bi-pella

• PD-RVAD‡ • VA-ECMO

No

• Impella RP • PD-RVAD • VA-ECMO

This algorithm is proposed for the management of patients with right ventricular failure with cardiogenic shock. It considers the need for sternotomy, concurrent left ventricular failure and/or presence of impaired gas exchange. *Consider graft to pulmonary artery to allow for less invasive device removal. †If durable LVAD planned and durable RVAD support anticipated. ‡With use of oxygenator.

CVP = central venous pressure; LVAD = left ventricular assist device; MCS = mechanical circulatory support; PD = ProtekDuo; RVAD = right ventricular assist device; VAD = ventricular assist device; VA-ECMO = veno-arterial extracorporeal membrane oxygenation.

Figure 2: Mechanical Circulatory Support Devices for Right Ventricular Failure

percutaneous venous cannulation that withdraws blood from the right atrium and ejects into the main PA.14 An example of this is the TandemHeart used with the ProtekDuo cannula (LivaNova). Cannulation may be from bilateral femoral venous access, internal jugular access (if the ProtekDuo cannula is used) or a combination of the two sites. This percutaneous configuration has been employed in a variety of scenarios including MI, severe pulmonary hypertension, severe mitral regurgitation, allograft failure following heart transplantation and post-LVAD implant.14,35–39 The THRIVE registry studied 46 patients receiving a TandemHeart RVAD in eight centres.40 The TandemHeart RVAD was used in myocarditis, MI and chronic left heart failure, and following valve surgery, coronary artery bypass grafting, orthotopic heart transplant and LVAD implantation. Within 48 hours of RVAD deployment, haemodynamics, including mean arterial pressure, right atrial pressure, PA systolic pressure and cardiac index, were all significantly improved.

Radiographic appearance of options for short- and long-term mechanical circulatory support devices for right ventricular failure. A: Percutaneous micro-axial right ventricular assist device (RVAD; Impella RP). B: Coaxial dual lumen cannula (ProtekDuo) with extra-corporeal centrifugal-flow RVAD. C: Durable RVAD (HeartWare) with RV inflow. D: Durable RVAD (HeartWare) with right atrial inflow.

A significant advantage of the Impella RP is its need for only a single venous access site as well as its percutaneous placement, although only femoral access is possible. Haemolysis has been reported for other Impella devices but less is known about its incidence with Impella RP.

Extra-corporeal Centrifugal Flow Percutaneous RVAD

This device configuration employs an extracorporeal centrifugal-flow pump (e.g. TandemHeart [LivaNova] or CentriMag [Abbott]) with

More recently, the ProtekDuo cannula has allowed percutaneous RVAD support to be established with a single venous access cannulation. The ProtekDuo cannula is a dual-lumen cannula that can be placed via the jugular vein and may be positioned in such a way that its distal port enters the PA. When used with an extracorporeal centrifugal blood pump, it can deliver blood from the right atrium to the main PA.41 It is capable of providing 4–5 l/min of flow and allows for ambulation given the lack of femoral cannulation.

In one dual-centre experience, involving 17 patients with RV failure supported by ProtekDuo-RVAD, 23% of patients were successfully weaned.42 However, more than 40% of patients died even with adequate pump flow. Twelve of these patients already had a durable LVAD in place.

The benefits of this device configuration include the avoidance of sternotomy, particularly in patients who may have had prior surgery or may be transplant candidates. In certain cases, these devices have been used pre-emptively for RV support in patients undergoing durable LVAD implantation.43

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Mechanical Circulatory Support for RV Failure An analysis at our centre compared 19 patients with percutaneous RVADs (both Impella RP and ProtekDuo-RVAD) with 21 patients with surgical RVADs.44 Both percutaneous and surgical support systems provided immediate improvements in haemodynamic profiles despite higher overall flows with surgical RVADs. In addition, percutaneous RVAD use was associated with less morbidity including decreased blood transfusion requirement and a shorter time being mechanically ventilated.

Surgically Implanted Support Devices CentriMag

The CentriMag (Abbott) is an extracorporeal centrifugal pump that is approved for use as an isolated RVAD for up to 30 days in patients with cardiogenic shock.45 It has also been used as part of an ECMO circuit.46 It lacks mechanical bearings or seals, and its magnetically levitated rotor is thought to reduce blood trauma and mechanical failure.47 The device can be used as an RVAD with inflow and outflow cannulas. The inflow cannula may be positioned in the right atrium through direct insertion via the superior vena cava (or internal jugular, for example) or the inferior vena cava (or femoral vein, for example); alternatively, it may be inserted directly into the RV. The outflow is typically anastomosed to the PA, though reports have included connection through a graft sewn to the PA which allows the RVAD to be removed without reopening the chest.48 For patients with concomitant respiratory failure, an oxygenator may be added to the configuration.

A meta-analysis of 999 patients supported with the CentriMag found that it was used as a ventricular assist device in 72% of cases and as part of an ECMO circuit in 25%.46 Those included had experienced post-cardiotomy shock, post-transplant allograft rejection, RV failure following LVAD placement, as well as some pre-cardiotomy states. At 30 days, survival was 66% in pre-cardiotomy cardiogenic shock, 61% in post-LVAD placement, 54% in post-transplant allograft failure and 41% in postcardiotomy cardiogenic shock.46

Biventricular Support Strategies Surgical Biventricular Assist Device

Full biventricular support can be established with the use of a centrifugal flow extracorporeal pump, such as CentriMag used as an RVAD (described above), or in combination with an extra-corporeal LVAD configuration (typically with cannulation of the LV and aorta). Such a configuration may provide up to 7 l/min of circulatory support with full unloading of both ventricles.

Percutaneous Biventricular Assist Device

The use of the Impella RP device in combination with a percutaneous LVAD from the same manufacturer has been reported in patients with biventricular failure.49–52 The degree of circulatory support with this configuration depends on the maximum flow provided by the percutaneous LVAD, which is in the range of 3.5–5 l/min.

Extracorporeal Membrane Oxygenation

VA-ECMO has become an increasingly used method of short-term haemodynamic support in cardiogenic shock.53 It simultaneously provides extracorporeal gas exchange and circulatory support in the setting of left, right or biventricular failure.54 The circuit consists of a venous inflow cannula, centrifugal flow pump, oxygenator, heat exchanger and outflow arterial cannula. VA-ECMO can be employed centrally or with peripheral access (e.g. by the femoral vein and artery).

Typically, central VA-ECMO is used in patients unable to be weaned from cardiopulmonary bypass whereas peripheral VA-ECMO can be initiated

percutaneously.54,55 It has become increasingly used specifically in cases of fulminant myocarditis, allograft failure after cardiac transplantation, acute RV failure due to PE, RV failure during LVAD support and severe decompensated heart failure.53,56–61 It is important that these patients have an exit strategy, which may include bridge to recovery, durable LVAD or heart transplantation.

VA-ECMO can provide 3–5 l/min of flow depending on cannula size. Since it drains blood directly from the central venous system, it decreases RV preload and therefore can be helpful in cases of RV failure secondary to volume and pressure overload. A distinction should be made, however: while VA ECMO provides circulatory support irrespective of RV or LV function, it differs from a traditional RVAD in that it establishes a parallel circulation as opposed to being an actual ventricular assist device.

Because of this, when used for RV support after LVAD implantation, VAECMO decreases flow through the LVAD, potentially increasing the risk of device thrombosis.

One disadvantage of VA-ECMO is the increase in afterload with the potential for LV distension and overload.62 The increase in left atrial pressure can induce or worsen pulmonary oedema and lead to stasis within the LV and aortic root.54 Therefore, many clinicians will initiate a ‘venting’ strategy to prevent the complications of LV pressure overload.

Options include percutaneous LVAD, such as Impella, IABP, atrial septostomy or direct cannulation of the left atrium or LV.54 A minimally invasive surgical approach combining an extracorporeal LVAD with extracorporeal membrane oxygenation (Ec-VAD) for short-term biventricular circulatory support has been used as a bridge to durable LVAD or recovery.63,64 A minithoracotomy is performed for direct LV apical cannulation, which is combined with femoral venous inflow and outflow cannulation of the right or left axillary artery. Compared to conventional extracorporeal surgical LVAD implantation, Ec-VAD patients have shorter cardiopulmonary bypass times and significantly lower incidences of bleeding events with similar flow rates. The 30-day survival was similar between groups.63 Other potential complications of peripheral VA-ECMO include lower extremity ischaemia, which has been shown to occur in 12–22% of patients.65 To obviate this risk, a 6–8 Fr vascular introducer can be placed to provide antegrade distal perfusion to the cannulated extremity. In addition, roughly 25% of all VA-ECMO patients have major bleeding complications.66 This can occur even in patients who are not on anticoagulation therapy.54 Bleeding complications may be reduced by the use of smaller arterial cannulas.67

Durable Biventricular Assist Devices

A significant proportion of individuals require RV MCS following durable LVAD placement and fewer than half of these patients can be weaned from temporary RVAD support.68,69 Therefore, various strategies of durable biventricular support have been employed and described.68,70–72 According to the INTERMACS registry, 618 durable continuous-flow BiVAD procedures have been performed.73 Shebab et al. have described the use of the HeartWare ventricular assist device (HVAD; Medtronic) as a biventricular assist device for patients awaiting cardiac transplantation.71 Six patients underwent right HVAD implantation in the RV free wall while seven patients had it implanted in the RA free wall. RVAD pump thrombosis occurred in three of six RV pumps and one of seven RA pumps. This series demonstrates one of the

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Mechanical Circulatory Support for RV Failure difficulties in using assist devices in the RV; the heavily trabeculated RV and dense tricuspid subvalvular apparatus can predispose patients to suction events. Implantation in the RA may be more favourable.68 In another series, 11 patients with biventricular failure underwent implantation of an LVAD as well as an HVAD in the RA.68 Still, pump thrombosis occurred in four patients, who required treatment with bivalirudin and cannula-directed tissue plasminogen activator.68 One reason for the elevated incidence of device thrombosis may be related to the need to maintain lower pump speeds to avoid generating excessive flow through the low-resistance vascular bed. Of note, in August 2021, because of increasing incidences of adverse neurological events and pump thrombosis, the FDA issued a class I recall for the HeartWare HVAD system.74 More recently, the HeartMate 3 (Abbott) has been used in a biventricular configuration.75 Given the low incidence of thrombosis recorded with the HeartMate 3, it is an appealing device to use in the highly trabeculated RV.76 In the first experience described, which involved 14 patients, eight patients underwent simultaneous RVAD and LVAD implant while the others underwent RVAD implantation following LVAD implant.75 The RVAD was implanted into the RA in 12 patients. Nine patients were still alive at the time of publication.

McGiffin et al. also describe 12 patients who underwent similar biventricular HeartMate 3 implantation as a bridge to cardiac transplantation.77 The right-sided pump was implanted in the right atrium. Three cases of right VAD thrombosis were reported: one was managed medically, one required surgical pump exchange and one was intraoperatively treated with clot retrieval. By 18 months after implantation, five patients had undergone cardiac transplantation, five were alive on biventricular support, one had died and one had the VAD explanted for myocardial recovery.

right heart.78 An IABP balloon is then placed inside so that, during balloon inflation, blood flows into the pulmonary arteries. The device has been shown to achieve flow rates of 3.5 litres per min in vitro. In a sheep model of acute pulmonary embolism, the device increased cardiac output by 59%.79 However, future studies are needed to determine its efficacy and outcomes in humans.

Gaps in Knowledge

While different mechanical support platforms hold great potential for improving patient outcomes related to RV failure, it is important to acknowledge the absence of randomised trial data to guide the use of this technology. Furthermore, the difference between outcomes with the Impella RP device in a study population and the post-market experience highlights the importance of careful patient selection and the need for more high-quality data to support the use of these technologies.

While the focus of durable RVAD investigation has been on patients with RV failure following durable LVAD implantation, interest is growing in the use of isolated durable RVAD use for patients with other disease processes that typically affect the RV and spare the LV. HVAD use has been reported in isolated RV failure secondary to WHO group 1 pulmonary hypertension when lung transplantation is not feasible.80 In addition, the optimal use of durable RVADs for patients with durable LVADs remains unclear. The optimal timing of percutaneous RVAD insertion for patients at high risk of RV failure following LVAD insertion is unknown, with some centres initiating RVAD support before implanting an LVAD. Lastly, the relative benefit of one short-term RV MCS device over another is also unclear and may vary according to the underlying aetiology of RV failure.

Conclusion

Future Directions

RV failure portends a poor prognosis across a spectrum of cardiovascular disease states including RV infarction and post-cardiotomy shock as well as following LVAD implantation, among other situations.

The chamber is implanted in the inferior vena cava and the outlet tube attached to its distal part has its tip in the pulmonary trunk, bypassing the

The ability of the RV to recover from a variety of pathophysiologic insults makes it an attractive target for short-term circulatory support devices.

Recent advances in percutaneous therapies for short-term RV circulatory support offer promise to improve upon these historically poor outcomes.

However, the long-term use of RV MCS devices remains limited, and outcomes are variable. Early recognition of RV failure and implementation of RV MCS devices are important steps to optimising outcomes for this patient population.

PERkutane KATheterpumptechnologie RV (PERKAT RV, NovaPump) is a newer device, designed with the aim of creating a minimally invasive mechanical right heart support device that modifies the pulsatile support technology of IABP therapy. It is meant for rapid percutaneous deployment requiring an 18 Fr sheath. The device is composed of a nitinol chamber covered by foil that contains inflow valves.

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center experience with HeartMate 3 in a biventricular configuration. J Heart Lung Transplant 2021;40:193–200. https://doi.org/10.1016/j.healun.2020.12.006; PMID: 33423854.

78. Kretzschmar D, Lauten A, Schubert H, et al. PERKAT RV: first in vivo data of a novel right heart assist device.

EuroIntervention 2018;13:e2116–21. https://doi.org/10.4244/EIJD-17-00899; PMID: 29360066.

79. Kretzschmar D, Schulze PC, Ferrari MW. Concept, evaluation, and future perspectives of PERKAT® RV-A novel right ventricular assist device. J Cardiovasc Transl Res 2019;12:150–4. https://doi.org/10.1007/s12265-018-9834-9; PMID: 30267328.

80. Rosenzweig EB, Chicotka S, Bacchetta M. Right ventricular assist device use in ventricular failure due to pulmonary arterial hypertension: lessons learned. J Heart Lung Transplant 2016;35:1272–4. https://doi.org/10.1016/j. healun.2016.07.010; PMID: 27569986.

REVIEW

Clinical Syndromes

Pulmonary Artery Catheter Monitoring in Patients with Cardiogenic Shock: Time for a Reappraisal?

Maurizio Bertaina ,1 Alessandro Galluzzo ,2 Nuccia Morici ,3,4 Alice Sacco ,3 Fabrizio Oliva,3 Serafina Valente ,5 Fabrizio D’Ascenzo ,6 Simone Frea ,6 Pierluigi Sbarra,1 Elisabetta Petitti,1 Silvia Brach Prever,1 Giacomo Boccuzzi ,1 Paola Zanini,1 Matteo Attisani ,7 Francesco Rametta ,2 Gaetano Maria De Ferrari ,6 Patrizia Noussan1 and Mario Iannaccone 1 1. Department of Cardiology, San Giovanni Bosco Hospital, ASL Città di Torino, Turin, Italy; 2. Department of Cardiology, Sant’Andrea Hospital, Vercelli, Italy; 3. Intensive Cardiac Care Unit and De Gasperis Cardio Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 4. IRCCS S. Maria Nascente – Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy; 5. Department of Cardiovascular Diseases, University of Siena, Siena, Italy; 6. Division of Cardiology, Department of Medical Sciences, University of Turin, Città della Salute e della Scienza Hospital, Turin, Italy. 7. Department of Cardiac Surgery, San Giovanni Bosco Hospital, ASL Città di Torino, Turin, Italy

Abstract

Cardiogenic shock represents one of the most dramatic scenarios to deal with in intensive cardiology care and is burdened by substantial shortterm mortality. An integrated approach, including timely diagnosis and phenotyping, along with a well-established shock team and management protocol, may improve survival. The use of the Swan-Ganz catheter could play a pivotal role in various phases of cardiogenic shock management, encompassing diagnosis and haemodynamic characterisation to treatment selection, titration and weaning. Moreover, it is essential in the evaluation of patients who might be candidates for long-term heart-replacement strategies. This review provides a historical background on the use of the Swan-Ganz catheter in the intensive care unit and an analysis of the available evidence in terms of potential prognostic implications in this setting.

Keywords

Swan-Ganz catheter, cardiogenic shock, invasive monitoring, pulmonary artery catheter, review Disclosure: The authors have no conflicts of interest to declare.

Received: 16 November 2021 Accepted: 19 January 2022 Citation: Cardiac Failure Review 2022;8:e15. DOI: https://doi.org/10.15420/cfr.2021.32 Correspondence: Maurizio Bertaina, Cardiology Department, San Giovanni Bosco Hospital, ASL Città di Torino, Donatore di Sangue Square, 3 – 10154 Turin, Italy.

E: maurizio.bertaina@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.

Cardiogenic Shock: Epidemiology, Aetiology and Prognostic Considerations

Notably, apart from the well-established benefit of early revascularisation of the culprit lesion in CS complicating ST-elevation MI, no further interventions to date have proven any survival benefit.8 In particular, the adoption of mechanical circulatory support (MCS) devices has been tested in randomised controlled trials (RCTs) among heterogeneous populations of CS patients without survival improvement.9,10

CS complicates up to 13% of acute coronary syndromes (ACS), which are traditionally considered the most prevalent cause.2 However, the increasing burden of chronic heart failure (HF) worldwide has changed the aetiological epidemiology in recent years. For example, recent data from the Critical Care Cardiology Trial Network underline the rising incidence of CS complicating acutely decompensated heart failure (ADHF), which represented up to half of that CS cohort.3 The timely identification of progression to overt CS in this group of patients may be more challenging. This is because of their chronically compensated lowoutput state and the more subtle manifestation of typical signs and symptoms.4 Moreover, even if significant heterogeneity has been described according to the aetiology and the severity at presentation, the prognosis of this acute condition remains very poor, with a short-term death rate of up to 50%.5–7

Many concerns about device-related complications have been highlighted.

Nevertheless, many issues may negatively influence these results. These include the advanced impairment of included patients, the risk of preselection bias and difficulties in conducting large RCTs in such critical scenarios. Moreover, the complexity of the disease itself may deserve a comprehensive and prespecified management protocol.

The term cardiogenic shock (CS) refers to a series of complex and heterogeneous clinical scenarios characterised by primary myocardial dysfunction leading to the inability to maintain adequate tissue perfusion, resulting in progressive irreversible multi-organ failure.1

Accordingly, some observational evidence suggests that the use of a ‘shock team’ approach using a pre-established therapeutic protocol is associated with significantly reduced short-term mortality.11–14 All these studies have strengthened the prognostic implications of early diagnosis, early adoption of MCS (when indicated) and continuous and dynamic reevaluation of whether to upgrade, wean or move to a palliation strategy.

Furthermore, the studies have largely adopted invasive haemodynamic

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PAC Monitoring in Cardiogenic Shock monitoring with extensive use of the Swan-Ganz catheter to guide the different phases of the proposed protocols.

Historical Background of the Swan-Ganz Catheter

The Swan-Ganz catheter recently reached its fiftieth anniversary since the first use in a human body in 1969.15 Jeremy Swan firmly pursued its ideation and development – with the help of Willie Ganz and other colleagues – in the belief that bedside invasive haemodynamic monitoring of patients admitted for an acute MI (AMI) may assist in better therapy selection and, consequently, improved survival.

The pioneering study of Forrester et al. on bedside invasive haemodynamic monitoring in AMI patients demonstrated the effect of medical therapy according to the patient’s haemodynamic phenotype and led to the development of the well-known Forrester classification.16 This classification relates pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) to categorise the patient according to their congestion and perfusion status with well-demonstrated prognostic and therapeutic implications.

In the decades that followed, the pulmonary artery catheter (PAC) became a hallmark of intensive care monitoring despite the lack of data on safety, accuracy and benefits of this technique. However, after an initial moratorium on PAC use in the mid 1980s, a propensity-matched analysis in the SUPPORT study in 1996 found higher mortality in a heterogeneous cohort of intensive care unit (ICU) patients receiving PAC.17,18 The same ominous prognosis was also described in the setting of AMI, namely the subject of the Forrester classification.19,20 In 2003, the first of several RCTs found no benefit of PAC on surgical patients.21 The publication of the ESCAPE trial in 2005 represented a cornerstone in the history of the Swan-Ganz catheter in HF: 433 patients with severe symptomatic decompensated HF, excluding those with CS, were randomised to receive therapy guided by clinical assessment alone or with the addition of PAC in order to target decongestion.22 Both groups experienced a reduction in symptoms and signs of congestion, although patients with PAC were more likely to receive vasodilator therapy and showed a faster time to resolution of symptoms. However, a neutral result was found in terms of the primary endpoint of days alive out of hospital in the first 6 months. Interestingly, patients screened but not randomised and receiving PAC monitoring were included in a separate registry, which reported a significantly higher mortality rate than those in the trial, underlining the clinicians’ common belief that invasive monitoring was necessary for more severe patients.23 Following these negative study results, many authors discouraged the routine use of PAC in the ICU and surgical settings.24 Many limitations of the tool were suggested to justify this, including the risk related to the invasive procedure itself (although inversely related to the centre’s experience), the challenge in obtaining accurate data, and – likely most importantly – the difficulty in correctly interpreting this information and responding with appropriate and standardised medical treatment, along with the advances in non-invasive diagnostic techniques.

Nonetheless, even if there was an initial progressive reduction in PAC use for the HF setting in general hospitals, it was followed by an increasing trend of usage, especially in large academic centres in the United States.25,26 One potential explanation for this paradox may be a shift in the clinical profile of patients admitted for HF towards more severe stages, leading clinicians to search for more accurate haemodynamic monitoring, in particular when considering advanced HF strategies.27

Limitations of Noninvasive or Minimally Invasive Techniques in the Cardiogenic Shock Setting

The use of echocardiography in the critical care setting – as opposed to the PAC – has burgeoned over the last decades. There are many potential benefits of this technique that may explain the trend. Firstly, echocardiography has a complementary role to invasive monitoring because it allows rapid evaluation of biventricular function and identification of severe valvular, pericardial and large-vessel disease or mechanical complications, helping to put in place adequate aetiological treatments. Moreover, thanks to its wide availability and easy handling, it has been largely proposed and used to non-invasively estimate haemodynamic data.28 It is well established that echo-derived haemodynamic estimators have prognostic implications even in the critical care setting.

Jentzer et al. recently published a large retrospective cohort of CS patients, showing how high E/e’ ratio and low echo-derived indexed stroke volume correlated with Society for Cardiovascular Angiography and Interventions (SCAI) stages and short-term mortality.29 However, the dynamic and rapidly changing nature of CS requires continuous monitoring techniques to provide reliable and fast estimation of haemodynamic parameters in each critical phase in order to promptly select the therapeutic strategy. Time-consuming averages of several echo-derived parameters are needed to get a raw range of value. Indeed, several practical problems may limit the suitability of echo-dynamics in the critical care setting and very few studies with small sample sizes have demonstrated reliability in this setting.30 Ultrasound windows may not always be permissive in clinical practice, especially in mechanically ventilated patients forced to the supine position. For example, inferior vena cava diameter and its respiratory variations, used to determine right atrial pressure (RAP), may not be obtained in up to 22% of cases – even in the hands of expert clinicians.31 Moreover, there may be suboptimal correlation with central venous pressure and many situations (e.g. right ventricular dysfunction or pulmonary hyperinflation) make this value unreliable for predicting fluid responsiveness.32,33 Further issues have to be acknowledged when estimating left filling pressures with echocardiography: the E/A ratio is dependent on diastolic function and it is not available in cases of AF; conflicting data have been published on the correlation between E/e’ and invasive PCWP, particularly in the setting of ADHF and if left bundle branch block or CRT stimulation is present; and the feasibility of pulmonary venous flow velocity evaluation is demonstrated only in an ambulatory setting, as are the majority of the correlation studies published on this theme since now.30,34–36 Finally, echoderived cardiac output (CO) from the continuity equation has shown good correlation with the invasively-derived one in older observational cohorts.37,38 Notably, this technique is not reliable in cases of significant aortic regurgitation because of over estimation and is highly limited by inter-operator accuracy in the measurement of left-ventricular outflow tract diameter. Additionally, when a trans-aortic ventricular assistance device such as the Impella is used, it is further limited by significant beatto-beat variability and device-related artefact.

Likewise, minimally invasive techniques have been proposed as alternatives to PAC monitoring. Those based on arterial waveform to estimate CO rely on external calibration (e.g. PiCCO [Pulsion], LiDCO [LiDCO], EV-1000 [Edwards Lifesciences]), internal calibration (e.g.

Pulsioflex [Pulsion Medical Systems], LiDCO Rapid [LiDCO], FloTrac Vigileo

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PAC Monitoring in Cardiogenic Shock [Edwards Lifesciences], Retia [Retia Medical]), or no calibration (MostCare Up PRAM [Vygon, Vytech]). Despite increasing interest in these devices in recent years following technological improvements, results in terms of CO estimation are controversial and further studies are still in progress (e.g.

NCT04955184).39–41 Notably, the derived measures are significantly influenced by vascular impedance and are therefore less reliable in estimating haemodynamic data in the unstable CS setting: tachycardia, arrhythmias or MCS devices may interfere with the inferential models used to predict CO from pulsatory pressure curve, making these values less reproducible.42 In addition, these tools may require time-consuming multiple recalibrations, limiting their practical applicability in this context.

Finally, transpulmonary thermodilution methods are limited by the inability to discriminate between right- and left-heart dysfunction or to accurately estimate left filling pressures.

Indications and Implications of the SwanGanz Catheter in Cardiogenic Shock

To date, the use of PAC monitoring in the CS setting is only recommended if there are uncertainties on diagnosis or for the most severe cases that are unresponsive to the first therapeutic attempts.43 Potential practical uses in CS were proposed in the SCAI/Heart Failure Society of America 2017 expert consensus document on invasive haemodynamics for the diagnosis and management of cardiovascular disease (Figure 1).44

The Role of the Pulmonary Artery Catheter in the Diagnosis and Classification of Cardiogenic Shock

The diagnosis of CS is usually made when the combination of clinical signs and symptoms of low CO and tissue hypoperfusion are matched in the presence of adequate intravascular volume.45 The most commonly used definition is the presence and persistence of systolic blood pressure (SBP) <90 mmHg, along with clinical or laboratory evidence (i.e. lactate elevation) of tissue hypoperfusion or the need for pharmacological or mechanical support to reverse it. However, it has been shown that the clinically estimated haemodynamic profile is comparable to the invasively derived one in the critical care setting in only half of cases, and noninvasive techniques have several limitations in this setting as previously mentioned.46 Therefore, invasive evaluation by right heart catheterisation (RHC) remains the gold standard for diagnosis.

A CI ≤2.2 l/min/m2 associated with a PCWP of at least 15 mmHg has been the traditional haemodynamic criterion for left-sided CS since the pioneering SHOCK trial in the AMI setting; furthermore, nowadays it is well known that CS is an evolving and multifaceted haemodynamic scenario.8 Invasive haemodynamic data from sub-studies of the SHOCK trial registry demonstrated that – beyond the criterion of reduced CI – the relationship between PCWP and systemic vascular resistance (SVR) can define different entities.47 The most frequent is the ‘wet and cold’ scenario in which both are elevated, accounting for up to two-thirds of AMI-related CS. ‘Dry and cold’ CS is characterised by hypoperfusion along with reduced filling pressure values or those within the upper range of normal.

This represented up to 28% of post-MI CS in the SHOCK trial registry.

Moreover, the loss of the compensatory increase in SVR caused by the cytokine storm resulting from systemic inflammatory response syndrome and/or ischaemic gut bacterial transmigration represents the dramatic scenario of ‘mixed vasodilatatory CS’.5 There has been growing interest in recent years in the spectrum of the pre-shock and non-hypotensive shock conditions characterised by normotension or relative hypotension with reactive tachycardia and initial – but often subtle – signs of end-organ hypoperfusion.44,48,49 For example,

Figure 1: Potential Implications of Swan-Ganz Catheter Monitoring in Cardiogenic Shock •

Diagnosis and haemodynamic classification

•

Continuous haemodynamic monitoring for management in patients receiving therapy with MCS

•

Guide pharmacological and MCS withdrawal in patients with myocardial recovery

•

Assess candidacy for advanced heart failure therapies (LVAD or heart transplantation) in case of no recovery

Recommendations for invasive hemodynamic monitoring in patients with cardiogenic shock from the Society for Cardiovascular Angiography and Interventions/Heart Failure Society of America.44 LVAD = left ventricular assist device; MCS = mechanical circulatory support.

Swan-Ganz catheter, 2022. Catheter image reproduced with permission from Edwards Lifesciences LLC, Irvine, CA. Edwards, Edwards Lifesciences, Swan and Swan-Ganz are trademarks of Edwards Lifesciences Corporation.

in the SHOCK trial registry it was demonstrated that up to 5% of patients had SBP >90 mmHg without any therapeutic support despite similar PCWP and CI values at RHC when compared to those of the classic CS haemodynamic phenotype. This was the consequence of higher compensatory vasoconstrictive tone as demonstrated by the higher SVR values.50 Considering the 43% rate of short-term mortality described in this subgroup of patients, under recognition or late recognition may have dramatic consequences.

Evaluation of Right Ventricle Dysfunction Using a Pulmonary Artery Catheter

The use of the PAC provides a unique opportunity to finely characterise the presence and the degree of right ventricle (RV) dysfunction alone or in combination with the left-sided dysfunction.

Up to 40% of AMI-CS patients show some degree of RV failure and up to 15% have severe dysfunction. A recent CS registry demonstrated that up to 16% of these patients had RV failure as the primary cause, with shortterm survival similar to those with predominantly left-sided failure despite a better admission profile.51,52 Several haemodynamic predictors have been proposed to identify the failing RV. Among them, evidence of a pulmonary artery pulsatility index (PAPi) <0.9 has been described as the strongest indicator of severe RV failure and worse prognosis after MI.53

Guiding Supportive Pharmacological Therapeutic Interventions, Mechanical Circulatory Support Device Selection, Up-titration and Weaning

The accurate identification of the patient’s haemodynamic profile may help in better selection and dynamic titration of the therapeutic interventions for CS. Observational studies on heterogenous populations with circulatory shock showed that in up to 60% of cases, invasive haemodynamic assessment led to modification of the therapeutic intervention compared to clinical evaluation alone.54 Similarly, as described above, in the PAC group of the ESCAPE trial in ADHF patients, higher rates of vasodilator therapy were reported, resulting in lower filling pressures at discharge.22 The ultimate treatment goal in patients with CS should be to restore endorgan perfusion without exacerbating the vicious circle of increased myocardial oxygen demand and ischaemia. Unfortunately, because of their intrinsic mechanism of action, neither vasopressors nor inotropes

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PAC Monitoring in Cardiogenic Shock Table 1: Studies Evaluating Association Between Pulmonary Artery Catheter Use and Short-term Outcomes in Cardiogenic Shock Patients Study

Study Design

Enrolment Period

Included Population

n

CS Aetiology

MCS Use

Outcome

Ranka et al.

202168

Retrospective data from the Nationwide Readmissions Database US registry

January 2016– November 2017

ICD-9-CM codes corresponding to CS diagnosis.

Further analysis of patients with ICD-9 procedure codes for RHC

23,6156 (9.6% RHC)

MI 44.1% Other 65.9%

IABP 16.3% Percutaneous VAD 4.8% ELS 2.5%

In-hospital propensitymatched mortality PAC 25.8% versus no-PAC 33.1% (adjusted OR 0.69; 95% CI [0.66–0.72]; p<0.001)

Garan et al.

202067

Retrospective data from the first eight sites contributing to the Cardiogenic Shock Working Group registry in the US

2016–2019

CS definition: sustained episode of SBP <90 mmHg for at least 30 min or use of vasoactive agents and/or cardiac index <2.2 l/min/m2 determined to be secondary to cardiac dysfunction, in the absence of hypovolaemia; or use of an MCS device for clinically suspected CS

858 (69.7% complete PAC)

MI 34.9% HF 50.4% Other 12.6%

IABP 54.5% Impella 29% ECMO 23.6% Multiple MCS 21.8%

In-hospital mortality complete PAC assessment 25% versus no-PAC 33.8% (adjusted OR 0.64; 95% CI [0.43–0.94])

Hernandez et al. 201966

Retrospective data from the National Inpatient Sample database in the US

2004–2014

ICD-9-CM codes corresponding to HF and CS diagnosis.

Further analysis of patients with ICD-9 procedure codes for PAC monitoring

91,5416 (8.7% PAC)

Not specified

MCS (not further specified) 26.2%

In-hospital propensitymatched mortality PAC 34.9% versus no-PAC 37% (adjusted OR 0.91; 95% CI [0.87–0.97]; p=0.001)

Sionis et al.

201970

Subanalysis of the prospective European CardShock study

October 2010– December 2012

Consecutive patients ≥18 years old within 6 hours from identification of CS, defined as evidence of an acute cardiac cause and: 1. SBP <90 mmHg for 30 min or need for vasopressor therapy to maintain SBP >90 mmHg; 2. symptoms and/or signs of systemic and/or pulmonary congestion; and 3. symptoms and/or signs of hypoperfusion Exclusion criteria: shock after cardiac or noncardiac surgery or on-going haemodynamically significant arrhythmia

219 (62.6% PAC)

MI 80.8% Mechanical complication 8.7% Chronic HF 10.5%

IABP 55.7% ECMO 1.8% LVAD 4.1%

30-day mortality PAC 42% versus no-PAC 24% (p=0.2)

O’Neill et al.

201871

Subanalysis of the Impella IQ US prospective registry

2009–2016

AMICS defined as SBP <90 mmHg, or need for vasopressors to maintain SBP >90 mmHg, in the setting of prolonged chest discomfort and associated with ST segment elevation, new left bundle branch block, or ST T-wave changes compatible with non-ST-elevation MI

13,984 (37.3% PAC)

MI 100%

Impella 100%

Mortality before explantation PAC 37% versus no-PAC 51% (p<0.0001).

Multivariate analysis OR 0.60; 95% CI [0.53–0.68]; p<0.0001

Rossello et al.

201769

Prospective cohort investigation of a single-centre Spanish ICCU

December 2005–May 2009

All consecutive patients presenting with a first admission of CS, defined as: SBP <90 mmHg for 30 min or the need for vasopressor therapy to maintain adequate perfusion pressure and signs of hypoperfusion

129 (64.3% PAC)

MI 50% CMP 22% Other 28%

IABP 32% LVAD 2%

30-day mortality with PAC 55% versus no PAC 78% (p=0.010; adjusted HR 0.55; 95% CI [0.35–0.86]; p=0.008)

Propensity-matched 30-day mortality 46% versus 42% (adjusted HR 1.17; 95% CI [0.59–2.32]; p=0.66)

Long-term mortality (median follow-up 63 months) lower (HR 0.57; 95% CI [0.37–0.86]; p=0.007; adjusted HR 0.63; 95% CI [0.41–0.97]; p=0.035

AMICS = acute MI cardiogenic shock; CMP = cardiomyopathy; CS = cardiogenic shock; ECMO = extracorporeal membrane oxygenation; ELS = extracorporeal life support; HF = heart failure; IABP = Intra-aortic balloon pump; ICCU: Intensive Cardiac Care Unit; ICD-9-CM = ICD-9 Clinical Modification; LVAD = left ventricular assist device; MCS = mechanical circulatory support; PAC = pulmonary artery catheter; RHC = right heart catheterisation; SBP = systolic blood pressure; VAD = ventricular assist device.

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PAC Monitoring in Cardiogenic Shock alone can ensure this. Detrimental effects on survival have been shown if recovery is not reached soon after aetiological therapy has been established and higher doses and numbers of drugs are needed to maintain perfusion.55 In this context, there seems to be a pathophysiological rationale for the use of MCS devices to unload the heart and maintain end-organ perfusion in CS. Experimental and pioneering human studies have shown the safety and the potential benefit of a ‘first unload’ strategy in the setting of AMI-CS. The adoption of timely mechanical unloading may reduce myocardial oxygen consumption and the infarct area, increasing the opportunity for recovery.56,57 In this scenario, the directly and indirectly derived haemodynamic parameters from PAC may finely identify the presence of isolated left-, right- or biventricular failure to define the type of MCS needed.49 In particular, a value of cardiac power output <0.6 W and a PAPi <1 are used in many recent shock management flowcharts as predictors of left ventricular and right ventricular failure, respectively.11,12 Through close monitoring of lung function data and according to the presence and degree of respiratory failure, the clinician may decide if an isolated pump or a combined pump and oxygenator support is needed.58 Notably, multiparametric evaluation including PAC assessment must be approached in a dynamic and prospective way. After the initial profiling, frequent prospective re-evaluation of the aforementioned parameters will allow the identification of patients who are responding or those who are failing and needing an up-titration or palliation strategy. Likewise, considering the well-known risk of time-dependent complications, the duration of MCS should be long enough to achieve effective myocardial recovery or stabilisation toward long term replacement therapies, but adequately short to limit the unwanted consequences of these devices.6,9,59 Continuous monitoring of how the filling pressure and native CO modify while reducing MCS flow during a weaning trial may help determine the timing of safe removal. Adequate device selection in the right patient and timely removal may be the keys to the expected prognostic benefits of MCS in CS patients.

Assessing Candidacy for Long-term Replacement Therapies or Palliation Strategies in Non-responders

Patients who cannot be permanently weaned from their device and/or inotrope or vasopressor therapies must be considered for a long-term heart-replacement strategy, i.e. heart transplantation or left ventricular assist device (LVAD) implantation.

According to the International Society of Heart and Lung Transplantation and the recently published European Society of Cardiology Heart Failure guidelines, RHC maintains a Class I indication as a mandatory screening tool during candidacy assessment.60,61 Evaluation of the presence of pulmonary hypertension (PH) and its severity and reversibility are mandatory before heart transplantation listing. In cases of severe and irreversible PH, the implantation of a LVAD as a bridge to candidacy – or even as a destination therapy – can be considered. Moreover, evaluation of the degree of RV dysfunction through well-validated predictors of post implantation RV failure, such as a reduced PAPi or an increased RAP-toPCWP ratio, are relevant parameters to be considered before implantation.62 Finally, in cases of irreversible end-organ damage, advanced sarcopenia, lack of a caregiver support or other contraindications for both these rescue strategies, palliation must be considered and undertaken, with patients and their families adequately supported in the end-of-life period.63

Prognostic Implications of Swan-Ganz Catheter Monitoring in Cardiogenic Shock

When evaluating studies investigating the potential prognostic impact of PAC in CS it is important to stress the concept that the presence of a catheter in the pulmonary artery per se does not improve prognosis.

Derived haemodynamic data need to be accompanied by appropriate clinical responses to determine the effect on the patient’s clinical course.

No monitoring device can improve patient-centred outcomes unless it is coupled with treatment that itself improves outcomes. This is especially true in the extremely heterogeneous and unstable setting of CS. The lack of uniform practice, together with the absence of RCTs, makes it difficult to draw definite conclusions from previous works. Therefore, some researchers have called for future studies testing standardised protocols to effectively assess how PAC influences in-hospital therapeutic interventions and outcomes.64 While acknowledging these important limitations, it is noteworthy that the majority of previous studies focusing on PAC in HF report better results in the most severe subgroups of patients presenting with hypotension or shock.19 In particular, in a sub-analysis from the historical GUSTO IIb and III trials in over 26,000 ACS patients, those who underwent PAC insertion (2.8%) experienced higher 30-day mortality, with the exception of those presenting in shock for whom the outcome was neutral.65 Similar results were reported in the biggest registry available to date from National Inpatient Sample database.66 In this 10-year retrospective analysis of more than 9 million patients with HF, PAC use was associated with significantly higher mortality (9.9% versus 3.3%) and in-hospital cardiac arrest (2.7% versus 0.6%), although declining with time.66 However, paradoxically, the same study showed that the use of PAC in the CS subgroup correlated with a reduction in both outcomes (9% and 23% decreases, respectively), which was confirmed in the propensity-matched analysis. The authors reported that since 2007 the mortality trend for CS with and without PAC has separated and speculated that this may be in part because of advances of HF therapy and the adoption of MCS where invasive monitoring was largely used.

Several observational studies focusing on the CS population have been published in recent years, with all but one of them showing a protective association between PAC use and short-term mortality after adjusted analysis.67–71 An overview of these studies is reported in Table 1. The Cardiogenic Shock Working Group performed a 3-year retrospective analysis on over 1,400 CS patients from eight tertiary care institutions who had undergone a complete (42%) or a partial (40%) PAC assessment, or no invasive evaluation at all (18%) during the index hospitalisation.67 The main cause for CS in the cohort was decompensation of HF followed by AMICS. The complete PAC assessment group had the lowest in-hospital mortality compared to the other groups across all SCAI stages. This result was more pronounced for more advanced stages (stage D and E) and remained significant after adjustment for comorbidities, cause of shock and PAC usage per site.

Ranka et al. recently reported a retrospective evaluation of the Nationwide Readmissions Database (NRD), selecting more than 25,000 patients who had received RHC among the total CS population (9.6%). This subgroup experienced a 31% reduction in adjusted in-hospital mortality and a 17% reduction in adjusted 30-day rehospitalisation, while being six times more likely to receive invasive advanced treatment for HF during rehospitalisation compared to the non-RHC group.68

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PAC Monitoring in Cardiogenic Shock A smaller, single-centre prospective study by Rossello et al. confirmed that CS patients receiving PAC monitoring (64% of the total) experienced 45% lower adjusted 30-day mortality and 37% lower adjusted long-term mortality.69 The authors underlined that the benefit was only significant in the non-ACS group in their subgroup analysis, but the small sample size clearly limits any reliable interpretation on this point. Moreover, in the previously cited largest NRD cohort, a similar benefit from invasive pulmonary artery monitoring was noted irrespective of the aetiology.68 Another focused analysis of 219 CS patients in the prospective, multicentre European CardShock study showed that only 37.4% of patients had PAC monitoring. They had worse baseline profiles and were treated more aggressively and more frequently with MCS. The authors did not find any survival impact of the PAC implementation in a small propensity-matched cohort of two sets of 50 matched patients.70 Finally, a larger cohort of AMI-CS patients treated with the Impella device found a benefit in terms of survival to device removal for those who had received invasive monitoring during support.71 As previously underlined, the context of CS patients needing MCS seems to be an interesting window of opportunity for Swan-Ganz monitoring to improve ability in device selection, upgrading and timely weaning. It may reduce the risk of related complications and lead to the much-awaited survival improvement.

Association of PAC Monitoring and Therapeutic Interventions in Cardiogenic Shock

Patients with CS undergoing invasive monitoring are usually those receiving more aggressive therapeutic approaches because of their worse clinical condition as demonstrated by baseline characteristics. Few studies in this setting reported details on the rate and type of inotrope/ 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

Marini M, Battistoni I, Lavorgna A, et al. Cardiogenic shock: from early diagnosis to multiparameter monitoring. G Ital Cardiol (Rome) 2017;18:696–707 [in Italian]. https://doi. org/10.1714/2790.28259; PMID: 29105684.

Aissaoui N, Puymirat E, Tabone X, et al. Improved outcome of cardiogenic shock at the acute stage of myocardial infarction: a report from the USIK 1995, USIC 2000, and FAST-MI French Nationwide registries. Eur Heart J 2012;33:2535–43. https://doi.org/10.1093/eurheartj/ehs264; PMID: 22927559.

Berg DD, Bohula EA, Van Diepen S, et al. Epidemiology of shock in contemporary cardiac intensive care units. Circ Cardiovasc Qual Outcomes 2019;12:e005618. https://doi. org/10.1161/CIRCOUTCOMES.119.005618; PMID: 30879324.

Brener MI, Rosenblum HR, Burkhoff D. Pathophysiology and advanced hemodynamic assessment of cardiogenic shock.

Methodist deBakey Cardiovasc J 2020;16:7–15. https://doi. org/10.14797/mdcj-16-1-7; PMID: 32280412.

Jentzer JC, van Diepen S, Barsness GW, et al. Cardiogenic shock classification to predict mortality in the cardiac intensive care unit. J Am Coll Cardiol 2019;74:2117–28. https:// doi.org/10.1016/j.jacc.2019.07.077; PMID: 31548097.

Iannaccone M, Albani S, Giannini F, et al. Short term outcomes of Impella in cardiogenic shock: a review and meta-analysis of observational studies. Int J Cardiol 2021;324:44–51. https://doi.org/10.1016/j.ijcard.2020.09.044; PMID: 32971148.

Bertaina M, Ferraro I, Omedè P, et al. Meta-analysis comparing complete or culprit only revascularization in patients with multivessel disease presenting with cardiogenic shock. Am J Cardiol 2018;122:1661–9. https://doi. org/10.1016/j.amjcard.2018.08.003; PMID: 30220420.

Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999;341:625–34. https:// doi.org/10.1056/NEJM199908263410901; PMID: 10460813.

Thiele H, Jobs A, Ouweneel DM, et al. Percutaneous shortterm active mechanical support devices in cardiogenic shock: a systematic review and collaborative meta-analysis of randomized trials. Eur Heart J 2017;38:3523–31. https:// doi.org/10.1093/eurheartj/ehx363; PMID: 29020341.

Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon

11.

12.

13.

14.

15.

16.

17.

18.

19.

vasopressor used in the PAC and no-PAC groups, confirming a higher adoption rate in the first group.69,70 In terms of MCS used, all of them but one showed a higher MCS implantation rate within the cohort monitored with Swan-Ganz catheter.56

Safety of Swan-Ganz Monitoring

Invasive monitoring with PAC insertion is associated with a small incidence of complications. Previous studies suggested that the most frequent complications are related to the site of catheter insertion (up to 3.6%) and strictly depend on the specific centre’s experience.72 Rarely, severe complications such as heart block (0.3–3.8%) and pulmonary artery rupture (<1 case per 1,000 insertions) may occur.72 Among previously cited studies focusing on the critical CS setting, only three describe data on the incidence of complications related to use of the Swan-Ganz catheter.66,69,70 Overall the incidence ranged between 5% and 10%, but few details on the type and clinical impact were provided.

Conclusion

CS is still burdened by very high short-term mortality despite therapeutic and technological improvements in recent years. The key for improving prognosis probably relies on an integrated approach with timely diagnosis and phenotyping, a shock team and a management protocol. The SwanGanz catheter, whose use has clearly dropped in the last 50 years, is being rediscovered as a valuable tool and may play a role in steps from diagnosis to weaning from MCS. Few studies on its prognostic implications in this setting have been published to date. Considering the intrinsic limitations of observational studies, further prospective evidence is needed to better clarify whether the theoretical usefulness of this diagnostic tool will help in achieving the – as yet unmet – goal of improving survival in this disease.

support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287–96. https://doi.org/10.1056/ NEJMoa1208410; PMID: 22920912.

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Forrester JS. A tale of serendipity, ingenuity, and chance: 50th anniversary of creation of the Swan-Ganz catheter. J Am Coll Cardiol 2019;74:100–3. https://doi.org/10.1016/j. jacc.2019.04.050; PMID: 31272535.

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34. Mullens W, Borowski AG, Curtin RJ, et al. Tissue Doppler imaging in the estimation of intracardiac filling pressure in decompensated patients with advanced systolic heart failure. Circulation 2009;119:62–70. https://doi.org/10.1161/ CIRCULATIONAHA.108.779223; PMID: 19075104.

35. Nagueh SF, Bhatt R, Vivo RP, et al. Echocardiographic evaluation of hemodynamics in patients with decompensated systolic heart failure. Circ Cardiovasc Imaging 2011;4:220–7. https://doi.org/10.1161/ CIRCIMAGING.111.963496; PMID: 21398512.

36. Jensen JL, Williams FE, Beilby BJ, et al. Feasibility of obtaining pulmonary venous flow velocity in cardiac patients using transthoracic pulsed wave Doppler technique. J Am Soc Echocardiogr 1997;10:60–6. https://doi.org/10.1016/S08947317(97)80033-8; PMID: 9046494.

37. Lewis JF, Kuo LC, Nelson JG, et al. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation 1984;70:425–31. https://doi. org/10.1161/01.CIR.70.3.425; PMID: 6744546.

38. Dubin J, Wallerson DC, Cody RJ, Devereux RB. Comparative accuracy of Doppler echocardiographic methods for clinical stroke volume determination. Am Heart J 1990;120:116–23. https://doi.org/10.1016/0002-8703(90)90168-W; PMID: 2360495.

39. Hattori K, Maeda T, Masubuchi T, et al. Accuracy and trending ability of the fourth-generation FloTrac/Vigileo system in patients with low cardiac index. J Cardiothorac Vasc Anesth 2017;31:99–104. https://doi.org/10.1053/j. jvca.2016.06.016; PMID: 27612931.

40. Phan TD, Kluger R, Wan C, et al. A comparison of three minimally invasive cardiac output devices with thermodilution in elective cardiac surgery. Anaesth Intensive Care 2011;39:1014–21. https://doi. org/10.1177/0310057X1103900606; PMID: 22165352.

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EXPERT OPINION

Cardiogeriatrics

Evidence-based Therapy in Older Patients with Heart Failure with Reduced Ejection Fraction Davide Stolfo ,1,2 Gianfranco Sinagra

2

and Gianluigi Savarese

1,3

1. Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 2. Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina and University Hospital of Trieste, Trieste, Italy; 3. Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden

Abstract

Older patients are becoming prevalent among people with heart failure (HF) as the overall population ages. However, older patients are largely under-represented, or even excluded, from randomised controlled trials on HF with reduced ejection fraction, limiting the generalisability of trial results in the real world and leading to weaker evidence supporting the use and titration of guideline-directed medical therapy (GDMT) in older patients with HF with reduced ejection fraction. This, in combination with other factors limiting the application of guideline recommendations, including a fear of poor tolerability or adverse effects, the heavy burden of comorbidities and the need for multiple therapies, classically leads to lower adherence to GDMT in older patients. Although there are no data supporting the under-use and under-dosing of HF medications in older patients, large registry-based studies have confirmed age as one of the major obstacles to treatment optimisation. In this review, the authors provide an overview of the contemporary state of implementation of GDMT in older groups and the reasons for the lower use of treatments, and discuss some measures that may help improve adherence to evidence-based recommendations in older age groups.

Keywords

Heart failure, medical therapy, age, older patients, guidelines, reduced ejection fraction Disclosure: DS reports personal fees from Novartis, Merck, GSK and Acceleron. G Sinagra reports consulting fees from Novartis, Impulse Dynamics and Biotronik, and speaker fees and honoraria from Novartis, Bayer, AstraZeneca, Boston Scientific, Vifor Pharma, Menarini and Akcea Therapeutics. G Savarese reports grants from Vifor, Boehringer Ingelheim, AstraZeneca, Novartis, Boston Scientific, Bayer and Merck; personal fees from Vifor, Societá Prodotti Antibiotici, AstraZeneca, Roche, Servier, GENESIS, Cytokinetics and Medtronic; and non-financial support from Boehringer Ingelheim outside the submitted work. G Savarese received financial support from Boehringer Ingelheim (via a grant to his institution) for the present work.

Received: 5 December 2021 Accepted: 15 February 2022 Citation: Cardiac Failure Review 2022;8:e16. DOI: https://doi.org/10.15420/cfr.2021.34 Correspondence: Davide Stolfo, Division of Cardiology, Department of Medicine, Karolinska Institutet, Heart and Vascular Theme, Karolinska University Hospital, Norrbacka S1:02, 171 76 Stockholm, Sweden. E: davide.stolfo@ki.se 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 estimated to affect more than 64 million people worldwide, and its prevalence continues to grow.1 Among the reasons for the increasing prevalence of HF, the ageing of the population is probably one of the most important and is one explanation for the persistently poor prognosis and increasing burden of HF-related hospitalisations.2–8 Broadly speaking, the results of randomised control trials (RCTs) are poorly generalisable to daily clinical practice, limiting the implementation of their findings.9 Older patients are not explicitly excluded from RCTs, but the median age of patients included in such studies is systematically below 70 years and thus poorly representative of the general HF population.10 According to the current European HF guidelines age is not a contraindication to guideline-directed medical therapy (GDMT), and data do not demonstrate a lack of benefit of evidence-based medications in older adults.11–16 Nevertheless, under-implementation of treatment in older individuals is extensively encountered in the literature, which could be explained by routine clinical considerations, such as perceived contraindications or low tolerability, the risk of drug–drug interactions in

polytherapy, patients’ preferences and clinical inertia.17–22 The fear of sideeffects or the perceived lack of benefit derived from a focus on symptoms rather than prognosis also limits treatment implementation in older patients.23 Moreover, weaker evidence supporting the incremental prognostic effect of dose optimisation in older patients may lead to a reluctance on the part of clinicians to consider dose titration.24–26 In this review, we provide an overview of the treatment of HF with reduced ejection fraction (HFrEF) in older patients and summarise the evidence regarding the efficacy of these HF treatments.

Real-world and Randomised Clinical Trials: Two Distinct Entities

Phenotypic classification of HF remains anchored to the categorisation of ejection fraction (EF).11 Among the three categories of HF, only HFrEF has established treatments based on solid evidence derived from multiple RCTs. However, poor generalisability is one of the major limitations to the applicability of RCT results in real-world practice, with age being a typical example. The mean age of HF patients in most developed countries is >70 years and the prevalence of HF increases with age, ranging from 2% in

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Heart Failure Therapy in Older Patients Figure 1: Adherence to Guideline-directed Medical Therapy in Octogenarians with Heart Failure with Reduced Ejection Fraction: Preliminary Data from the SwedeHF Registry Use of GDMT

Target concentration

100

100

88 80

30

78

Combination therapy 9

25

3% 26% 18%

60

%

% 50 40

31

35

71

35 53% 39

20

40 20

7 0

0 RAS inhibitor

ARNI

β-blockers

MRA

RAS inhibitor/ β-blockers ARNI

<50%

MRA

50–99%

≥100%

No drugs

1 drug

2 drugs

3 drugs

ARNI = angiotensin receptor–neprilysin inhibitors; GDMT = guideline-directed medical therapy; MRA = mineralocorticoid receptor antagonists; RAS = renin–angiotensin system. Source: Stolfo et al.

2022.40

the general population to >10% among people aged >70 years.6,19 Moreover, a considerable portion of the general HF population is aged ≥80 years; for example, up to 30% of the SwedeHF HFrEF population was aged >80 years and 15% of patients enrolled in the GTWG-HF were aged >85 years.27,28 However, the scenario in RCTs is completely different. In one large meta-analysis of the results from major RCTs on β-blockers, the median age was 64 years.14 In the only study designed to assess the efficacy of β-blockers in older HF patients, namely the SENIORS trial, one inclusion criterion was age ≥70 years, and the mean subject age was 76 years.24 Similarly, in former RCTs on renin–angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRA), the mean age was well below 70 years.26,29–33 The progressive aging of the general HF population should have been translated into a change in the patients eligible for inclusion in RCTs. Instead, in the most recent studies, the mean age at enrolment ranged from 63 years in the PARADIGM-HF trial to 67 years in the VICTORIA study.34–37 When not specified by exclusion criteria, the low rate of inclusion of older populations in RCTs could be explained by a reduced rate of referral of older individuals for cardiology specialist care and the frequent coexisting conditions that may preclude or discourage the inclusion of these individuals in RCTs (i.e. cardiovascular and non-cardiovascular comorbidities, frailty issues, polypharmacy).19,20,38 Whatever the cause, the widening discrepancy between RCTs and the real world opens up the debate of the generalisability of trial results in the routine management of HF, particularly in older patients.

Adherence to Guideline-directed Medical Therapy in Older Patients: Data from Registries

Age is a recognised major determinant of low adherence to GDMT in HFrEF.17,18,20,21 In the CHAMP-HF registry, older age was associated with the lower use of β-blockers, MRAs and angiotensin receptor–neprilysin inhibitor (ARNI), and, at the 12-month follow-up, dose maximisation was less likely with increasing age.18,39 Similarly, in the US GWTG-HF registry, there was a decreasing gradient in the use of GDMT with increasing age, although the authors correctly highlighted that the prescription rate was high overall also in the oldest category (i.e. 79% and 83% of patients >85 years old were on angiotensin-converting enzyme inhibitors [ACEi] and β-blockers, respectively).28

There is a similar apparent reticence in Europe to implement treatments in older patients. For example, in 2009, octogenarians in the Euro Heart Failure Survey II were less likely to be treated compared with younger age classes, with only 76% of those aged >80 years treated with a RAS inhibitor, 53% treated with β-blockers and 38% treated with an MRA.19 Octogenarians had a heavier burden of comorbidities, including anaemia, chronic obstructive pulmonary disease and chronic kidney disease, more frequent indicators of frailty and less favourable socio-demographic conditions.19 All these aspects should be considered as partial explanations for the lower adherence to GDMT among patients in older age categories.

However, recent data collected in the CHECK-HF registry attested to an overuse of diuretics in older patients, with under-prescription of evidencebased drugs for the treatment of HFrEF.17 The inverse association between age and the use of medication was confirmed for ACEi, β-blockers and MRA even after extensive adjustment, supporting that, beyond the obvious higher prevalence of comorbidities or socio-demographic factors limiting treatment implementation, age per se limits the application of GDMT in HFrEF.17 Recent data from the SwedeHF Registry provided a comprehensive overview of the current treatment approach in older (i.e. ≥80 years) patients with HFrEF.40 Of 27,430 patients with HFrEF, 35% were aged ≥80 years. The use of treatments decreased progressively with increasing age: for example, the use of RAS inhibitor/ARNI, β-blockers and MRA, was 95%, 95% and 54%, respectively, for those aged <70 years, compared with 80%, 88% and 35%, respectively, for those aged ≥80 years (Figure 1).

Devices were similarly underused in older patients, and older patients were less likely to be treated with target doses of GDMT or to receive multiple drugs in combination (only 26% among those aged ≥80 years).40 There are several reasons that may explain the lower use of treatments among older patients. With aging, the increasing burden of comorbidities may hamper the implementation of treatments. Chronic kidney disease, for example, may be perceived as a potential contraindication for treatment with an RAS inhibitor or ARNI. However, in a previous analysis from the SwedeHF Registry, 66% of HFrEF patients with severe impairment of renal function were treated with RAS inhibitors, suggesting that trial criteria for a low estimated glomerular filtration rate are not a strong deterrent for the use of RAS inhibitors.41 Potential reasons for β-blocker

CARDIAC FAILURE REVIEW www.CFRjournal.com

Heart Failure Therapy in Older Patients underuse in the older population may be related to safety concerns, in particular the risk of hypotensive or bradyarrhythmic events. However, in a former study from the SwedeHF Registry, no increased risk of hospitalisation for syncope, which may be a consequence of hypotension or bradyarrhythmia, was observed in older subjects.27 Moreover, dedicated studies have shown good tolerability of β-blockers in older people with HF and, in a meta-analysis of 11 HFrEF RCTs, older age was not associated with treatment discontinuation, although the median age in the RCTs was lower compared with the real-world HFrEF population.14,42,43 Other reasons for the underuse and underdosing of HF treatments in older patients may include lower socio-economic status, lower education levels and fewer referrals to specialty care. Finally, polypharmacy, which is typical of older individuals with multimorbid conditions, is another deterrent to treatment use and dose maximisation, with potential negative effects on outcome.44

Effect of Evidence-based Therapy in Older Patients with HFrEF

Although guidelines do not recommend age-related differences in medical approaches, the evidence supporting the efficacy of GDMT in older patients is weak.11 Most of the landmark RCTs generating the evidence forming the basis of the contemporary medical approach to HF, including the most recent RCTs on ARNI and sodium–glucose cotransporter 2 (SGLT2) inhibitors, enrolled younger patients, and there are very few examples of studies specifically designed for older age categories. In a meta-analysis of four RCTs enrolling patients with left ventricular dysfunction, ACEi did not affect survival or the composite risk of death/MI/ HF hospitalisation in patients >75 years.13 However, only 1,066 patients were aged >75 years, compared with 11,674 aged ≤75 years, and there was no significant interaction between age and the effect of ACEi.13 Similarly, in post hoc analyses of RCTs, including the most novel classes of ARNI and SGLT2 inhibitors, age did not impact on the treatment effect.12,14,15,45,46 Post hoc analysis data from the DAPA-HF trial reported consistent (i.e. no significant interaction) effects across age categories for all the study outcomes; interestingly, the magnitude of the effect of dapagliflozin in reducing the composite endpoint of death/HF hospitalisation and the secondary endpoint of urgent HF visit/HF hospitalisation was numerically higher in those aged >75 years compared with younger age categories.45 The only study designed to assess the efficacy of β-blockers in older HF patients was the SENIORS trial (inclusion criteria age ≥70 years; mean age 76 years), which showed a significant reduction in the combined risk of death or cardiovascular rehospitalisation, but no significant effect on survival, in patients receiving β-blockers versus the placebo arm.24 Of note, most of that study cohort was aged <80 years, and approximately one-third had a left ventricular EF >35%. It is contentious whether age per se can explain the different effects of nebivolol on mortality observed in SENIORS compared with the largest benefit of β-blockers observed in other RCTs. A recent large meta-analysis of RCTs including patients with HFrEF and sinus rhythm showed a significant benefit of β-blocker therapy in terms of all-cause mortality that was consistent across all age groups, but age attenuated the effect of β-blockers on the risk of HF hospitalisation (p for interaction<0.05).14 Similar results were observed for HF hospitalisation, albeit with a smaller effect of β-blockers in older patients.14 In older patients, the benefit of treatments in terms of improvements in symptoms and quality of life can be apparently reduced, being frequently affected by concomitant comorbid conditions and limited mobility. However, data

from the DAPA-HF study demonstrated similar changes in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQTSS) in older (i.e. ≥75 years) and younger patients (i.e. <55 years).45 The existing knowledge gap between selected cohorts included in RCTs and the real world can be filled, at least in part, by observational studies that have reproduced similar prognostic effects of GDMT for both RAS inhibitors and β-blockers in patients in older age categories.27,47 The complexity of older individuals with HFrEF can lead to a more cautious approach to the dose titration of GDMT. Moreover, the additional benefit of increasing dosing is less well-established in patients in older age categories.

In the two largest RCTs comparing low (50 mg daily of losartan, 2.5–5.0 mg daily of lisinopril) versus high dose (150 mg daily of losartan, 32.5–35 mg daily of linisopril) of ACEi/angiotensin receptor blockers (ARB), patients assigned to higher doses had significantly improved outcomes than those being treated with lower doses, with no effect of age, with older (>65 years) patients having similar outcomes to younger patients.25,26 However, in clinical trials of older HFrEF patients, there is some evidence suggesting that there may not be incremental benefit from achieving target doses of β-blockers compared with lower doses. For example, in the SENIORS trial, patients on 50% of the target dose had similar outcomes to those on 100% of the target dose.24 Such observations were confirmed by the multicentre European cohort BioStat-CHF study, which demonstrated additional benefit for higher doses of RAS inhibitors in both older (≥70 years) and younger (<70 years) groups, whereas the improvements in outcome obtained with higher doses of β-blockers were limited to the younger group.20 The existence of multiple comorbidities that enhance the risk of adverse reactions, the perception of low tolerance and the concomitant polytherapy for extracardiac conditions may limit the sequential combination of evidence-based treatments in older patients. In the SwedeHF Registry, less than 20% of octogenarians were on a triple-drugs combination (Figure 1).40 No specific studies have assessed the incremental prognostic benefit of comprehensive evidence-based HFrEF therapy in older groups. However, in an indirect comparison of three of the major RCTs, the estimated gain in HF hospitalisation-free survival provided by comprehensive diseasemodifying pharmacological therapy (ARNI, β-blocker, MRA and SGLT2 inhibitor) compared with conventional therapy (RAS inhibitor and β-blocker) in a hypothetical 80-year-old patient was 2.7 years, although this was less than the gain in younger patients.48

Unmet Needs and Future Directions

Older patients are rapidly becoming prevalent in the overall HF population.

Older patients are associated with enormous complexity that is determined by several factors, including a greater burden of cardiac and non-cardiac comorbidities, frailty, a lower tolerance to medications and a higher risk of drug–drug interactions because of polypharmacy. All these aspects can lead to lower adherence to GDMT, even though these patients are at higher risk of poor cardiovascular and non-cardiovascular outcomes, further contributing to increasing pressures on healthcare systems, with considerable effects on financial costs.

There is a persistent mismatch between the characteristics of populations enrolled in RCTs and those of patients seen in regular daily practice. In particular, older patients have been classically excluded or largely underrepresented in RCTs, questioning the evidence that supports the adoption of GDMT for HFrEF and the achievement of target doses of HF medications

CARDIAC FAILURE REVIEW www.CFRjournal.com

Heart Failure Therapy in Older Patients in the older population. Guidelines recommend a standard approach to the treatment of HFrEF, regardless of age.11 However, in current practice, as confirmed by large international HF registries, older age is a strong deterrent to the initiation and titration of treatment in HFrEF. Stronger efforts are needed to improve strategies for treatment implementation in older patients. Enrichment strategies for the inclusion of older patients in RCTs and studies specifically designed for older patient age categories could provide solid evidence on the benefit of HF treatments in this group.

Moreover, the incorporation of measures of quality of life or frailty, such as the Rockwood Clinical Frailty Scale, could be helpful in estimating treatment benefit and the risk of poor tolerance/limited adherence in older patients.49 Real-world practice may benefit from a broad range of interventions encompassing all parts of the healthcare system. Structured, active recruitment to follow-up after hospital discharge and planned systematic outpatient visits, including support for home-to-clinic transport when required, could overcome physicians’ clinical inertia and facilitate the 1.

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assessment of tolerability. Multidisciplinary teams including geriatric specialists, or dedicated cardiologists with a background in geriatrics, are needed to holistically approach the complexity of older patients, including management of multimorbid conditions and frailty. Referral to nurse-led clinics has been demonstrated to provide additional survival benefit in real-world practice, and this can be even reinforced in older age categories.50 Additional strategies, such as remote monitoring, home delivery of medications, and nursing support at home, could promote adherence to treatment and facilitate early variations and treatment intensifications to limit episodes of HF worsening. Socio-economic interventions are also part of the holistic care of older patients, who more frequently experience poor social and economic conditions. Consistent consideration of these different aspects may help achieve the complete implementation of HF treatments in older patients, with important consequences in terms of prognostic benefit. Finally, a more individualised approach could allow better tailoring of treatment strategies for individual patients, according to their needs and wishes, to balance quality of life and longevity.

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Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation 2004;110:2618–26. https://doi.org/10.1161/01.

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Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009;30:478–86. https://doi.org/10.1093/eurheartj/ehn539; PMID: 19106198.

Mordi IR, Ouwerkerk W, Anker SD, et al. Heart failure treatment up-titration and outcome and age: an analysis of BioStat-CHF. Eur J Heart Fail 2021;23:436–44. https://doi. org/10.1002/ejhf.1799; PMID: 32216000.

Savarese G, Bodegard J, Norhammar A, et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur J Heart Fail 2021;23:1499–511. https:// doi.org/10.1002/ejhf.2271; PMID: 34132001.

Rosano GMC, Moura B, Metra M, et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021;23:872–81. https://doi.org/10.1002/ejhf.2206; PMID: 33932268.

Ahmed A, Weaver MT, Allman RM, et al. Quality of care of nursing home residents hospitalized with heart failure. J Am Geriatr Soc 2002;50:1831–6. https://doi. org/10.1046/j.1532-5415.2002.50512.x; PMID: 12410902.

Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–25. https:// doi.org/10.1093/eurheartj/ehi115; PMID: 15642700.

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REVIEW

Therapy

Medical Treatment of Heart Failure with Reduced Ejection Fraction in the Elderly Ivan Milinković,1,2 Marija Polovina ,1,2 Andrew JS Coats ,3 Giuseppe MC Rosano

4

and Petar M Seferović

1,5

1. Faculty of Medicine, University of Belgrade, Belgrade, Serbia; 2. Department of Cardiology, Clinical Centre of Serbia, Belgrade, Serbia; 3. University of Warwick, Coventry, UK; 4. IRCCS San Raffaele Pisana, Rome, Italy; 5. Serbian Academy of Sciences and Arts, Belgrade, Serbia

Abstract

The aging population, higher burden of predisposing conditions and comorbidities along with improvements in therapy all contribute to the growing prevalence of heart failure (HF). Although the majority of trials have not demonstrated age-dependent heterogeneity in the efficacy or safety of medical treatment for HF, the latest trials demonstrate that older participants are less likely to receive established drug therapies for HF with reduced ejection fraction. There remains reluctance in real-world clinical practice to prescribe and up-titrate these medications in older people, possibly because of (mis)understanding about lower tolerance and greater propensity for developing adverse drug reactions. This is compounded by difficulties in the management of multiple medications, patient preferences and other non-medical considerations. Future research should provide a more granular analysis on how to approach medical and device therapies in elderly patients, with consideration of biological differences, difficulties in care delivery and issues relevant to patients’ values and perspectives. A variety of approaches are needed, with the central principle being to ‘add years to life – and life to years’. These include broader representation of elderly HF patients in clinical trials, improved education of healthcare professionals, wider provision of specialised centres for multidisciplinary HF management and stronger implementation of HF medical treatment in vulnerable patient groups.

Keywords

Heart failure, heart failure with reduced ejection fraction, elderly, medical treatment, pharmacotherapy Disclosure: AJSC is Editor-in-Chief and GMCR is Deputy Editor-in-Chief of Cardiac Failure Review; this did not influence peer review. All other authors have no conflict of interests to declare.

Received: 7 June 2021 Accepted: 26 November 2021 Citation: Cardiac Failure Review 2022;8:e17. DOI: https://doi.org/10.15420/cfr.2021.14 Correspondence: Petar M Seferović, University of Belgrade Faculty of Medicine and Heart Failure Center, Belgrade University Medical Center, Koste Todorovica 8, 11 000 Belgrade, Serbia. E: seferovic.petar@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.

The incidence of heart failure (HF) has remained stable over recent decades. However, the prevalence of HF is on the rise, presumably as a result of the progress made in its management with the introduction of several life-saving medical and device therapies.1 The overall aging of the population – together with the cumulative burden of predisposing conditions and comorbidities – also contributes to the growing prevalence of HF. After the age of 65 years, there is a twofold increase in the prevalence of HF in men and a threefold increase in women.2 Rates of all-cause mortality, all-cause hospitalisation and HF hospitalisation significantly increase with advancing age in both sexes.3,4 Aging is associated with a higher risk of morbidity and mortality because of a greater impact of comorbidities, higher risks of complications, and possible underuse of guideline-directed treatments (GDT). The latter is likely the result of difficulties imposed by polypharmacy, frailty, cognitive impairment, poor tolerance and adherence, along with limited social support that ultimately hinder the quality of care.5 The term ‘elderly’ has up until recently been applied to patients aged over 65 years, but with the population becoming older, this limit has shifted to over 70–80 years. The HF population aged over 75 years has been largely underrepresented in randomised clinical trials (RCTs) assessing therapies for HF with reduced ejection fraction (HFrEF). Elderly patients typically

comprise approximately 30% of participants in trials, and individuals with the severe or advanced comorbidities frequently observed in the realworld elderly patients are excluded.6,7 Although the majority of trials have not demonstrated heterogeneity in the efficacy or safety of treatments in different age groups, there remains uncertainty about tolerability, dosing and the risk–benefit ratio in older patients.8 This can make decisions about initiation or up-titration of GDT in elderly HF patients challenging.

The purpose of this review is to provide a summary of evidence from clinical trials and real-world registries regarding the medical treatment of HFrEF in the elderly population.

Potential Reasons for Underuse of Guideline-directed Treatment in the Elderly

There are several reasons for the underuse and/or under-dosing of GDT in the elderly. These can be broadly grouped into the following categories: patient-associated factors, treatment-related aspects and healthcare system characteristics. Patient-associated factors of particular concern for the elderly include lower blood pressure, lower heart rate and lower BMI, greater severity of HF, and the burden of multiple comorbidities, frailty, cognitive impairment, polypharmacy and limited social support.9,10 Treatment-related aspects, such as poor tolerability, contraindications and adverse effects are also more commonly encountered in elderly and

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Medical Treatment of HFrEF in the Elderly frail patients.11 Healthcare system characteristics that may adversely impact on GDT prescription include regional and international differences in healthcare system organisation, service availability and quality of care.

A recent Heart Failure Association Atlas survey on the epidemiology of HF and resources for its management showed significant differences in reimbursement of standard HF medications and disparities in the availability of specialised centres for the multidisciplinary HF management in the European Society of Cardiology countries.12 These factors may have critical impact on the provision of HF medications and the availability of follow-up by cardiologists or HF specialists, who may be more experienced and confident to engage in GDT optimisation in the elderly compared with general practitioners, geriatricians or internal medicine specialists.13

Evidence from Clinical Trials Patient Characteristics

Accumulating data suggest that elderly patients have distinct clinical characteristics compared with younger participants of RCTs. Elderly patients are more often female and tend to have more comorbidities, including coronary artery disease, hypertension, AF and chronic kidney disease, as well as higher baseline natriuretic peptide levels despite higher average left ventricular ejection fraction.14–16 They also tend to have a worse prognosis, but it seems that the mortality gradient across the age span has become less steep in the most recent clinical trials compared with earlier studies, most likely reflecting evolving benefits of more comprehensive contemporary care. However, even the latest trials demonstrate notable differences in background medical therapies between younger and the older participants, with the older participants being less likely to receive established disease-modifying drug therapies for HFrEF. There is also a tendency for older patients to obtain lower doses of study medications that require up-titration (Supplementary Material Table 1).14–16

Drug Therapies β-blockers

Age-stratified analyses of data from RCTs on the efficacy and safety of β-blockers are sparse because of the underrepresentation of the oldest patients. A post hoc analysis of MERIT-HF participants aged ≥65 years showed a 37% reduction in all-cause mortality (RR 0.63; 95% CI [0.48–0.83]) among patients treated with metoprolol succinate, with a trend toward benefit in patients aged ≥75 years (RR 0.71; 95% CI [0.42–1.19]).17 The rates of adverse events (bronchospasm, depression and dizziness) that would be the cause of drug discontinuation were not higher in the elderly.18 The SENIORS trial has specifically addressed the efficacy and safety of the β-blocker nebivolol in the treatment of individuals with HF aged ≥70 years.8 The study showed a significant reduction in the combined outcome of all-cause mortality and cardiovascular (CV) hospitalisation in the nebivolol arm (HR 0.86; 95% CI [0.74–0.99]) but without a significant effect on all-cause mortality (HR 0.88; 95% CI [0.71–1.08]).8 A meta-analysis of the major trials with β-blockers including 13,833 HFrEF patients in sinus rhythm (median age 64, interquartile range 55–71) demonstrated a 24% risk reduction in all-cause mortality with β-blockers and an absolute risk reduction of 4.3% (number needed to treat 23; 95% CI [18–32]).19 β-blockers were superior in comparison to placebo across the range of age groups (p for interaction=0.1). There was also a reduction in the risk of hospitalisation for HF, although this effect was slightly attenuated at older ages (p for interaction=0.05). Likewise, there was an attenuation of the effect on CV mortality with aging (p for interaction=0.04), although there remained a trend toward a reduction in event rates even

in the oldest patient group. Drug discontinuation rates were comparable regardless of age (14.4% in those receiving a β-blocker and 15.6% in those receiving placebo).

Post hoc analyses of clinical trials with β-blockers demonstrate that uptitration to the target doses may not provide incremental benefit over the mid-range doses. In the SENIORS trial, attaining 50% of the target dose of nebivolol had a similar impact on outcome as the target dose of 10 mg daily.20 However, patients in a low-dose group (1.25–2.5 mg daily) and those unable to tolerate any dose of nebivolol had an increased risk of death or CV hospitalisation.20 The MERIT-HF trial also showed similar reduction in total mortality with low (≤100 mg daily) or high-dose (>100 mg daily) metoprolol compared with placebo, which may be explained by a similar reduction in the heart rate.21 This notion is further supported by the CIBIS-ELD study, which demonstrated that the achieved heart rate after up-titration, rather than the dose of bisoprolol, was a significant predictor of lower mortality.22

Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers

Despite strong evidence about the benefits of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in the general population of patients with HFrEF, without evidence of agerelated heterogeneity in major RCTs, none of the trials has specifically enrolled only older individuals and therefore data are limited in patients aged >75 years.23 A meta-analysis of five RCTs with ACEIs in patients with ischaemic aetiology of HF or left ventricular systolic dysfunction has documented a significantly lower risk of mortality (OR 0.74; 95% CI [0.66–0.83]), as well as lower risk of the composite endpoint of death, HF hospitalisation or MI in patients treated with ACEIs. Importantly, there was a nonsignificant age-by-treatment interaction for both outcomes (p=0.47 and p=0.95, respectively).24 In another meta-analysis of RCTs with ACEI in HFrEF, total mortality and hospitalisation for worsening HF were significantly reduced with ACEI treatment, with an OR of 0.72 (95% CI [0.59–0.89]) in patients aged <60 years and a favourable trend in those aged >60 years (OR 0.94; 95% CI [0.78–1.13]).25 A subgroup analysis of the CHARM-Overall trial has also reported a significant mortality benefit with candesartan in patients aged 65–75 years as well as in those aged >75 years, with a nonsignificant age-bytreatment interaction (p=0.26).26 Another sub-analysis of the CHARM programme assessed the efficacy of candesartan treatment across five age groups: <50 years (8% of all study patients), 50–59 years (19%), 60– 69 years (31%), 70–79 years (33%), and ≥80 years (9%).14 The risk of CV death or HF hospitalisation increased from 24% in the youngest age group to 46% in the oldest age group, and there was a gradient in the risk of death (from 13% to 42%) across the age span. Relative risk reduction (15% in the overall study population) in CV death or HF hospitalisation with candesartan was similar regardless of age. Because of the higher morbidity and mortality in the elderly, the benefit increased with advancing age (event-rate reduction 3.8/100 treated patients in the youngest age group compared with 6.8/100 treated patients in the oldest age group). Of note, adverse events leading to drug discontinuation (hyperkalaemia, increase in serum creatinine and hypotension) occurred more frequently in the older age categories. However, the relative increment in the risk of adverse events with candesartan compared with placebo was similar regardless of age, except for an increase in serum creatinine, which was less frequent with candesartan in the elderly.14

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Medical Treatment of HFrEF in the Elderly A post hoc analysis of Val-HeFT, in which almost 50% of patients were aged >65 years, has demonstrated similar risk reduction in the co-primary endpoint of the first morbid event (death, sudden death, HF hospitalisation or urgent HF treatment) regardless of age.27 Accordingly, there was an 11.8% risk reduction (p=0.07) in morbidity in patients aged >65 years and a 14.6% risk reduction in those aged <65 (p=0.09). In addition, valsartan also had a beneficial effect on left ventricular function and size, quality of life and levels of natriuretic peptides, regardless of age.

Mineralocorticoid Receptor Antagonists

In the three pivotal RCTs of mineralocorticoid receptor antagonists (MRAs) in patients with HFrEF or post-MI, the treatment effects of spironolactone and eplerenone were similar, regardless of age. In the RALES trial spironolactone conferred a significant mortality reduction in patients ≥67 years compared with placebo, while eplerenone demonstrated no ageby-treatment interactions in the EMPHASIS-HF and EPHESUS trials.28–30 A meta-analysis of RCTs with MRAs that included 1,756 patients ≥75 years of age demonstrated a 26% risk reduction in CV death or HF hospitalisation with an MRA compared with placebo (HR 0.74; 95% CI [0.63–0.86]; p<0.001; heterogeneity p=0.52), without significant between-trial or agerelated heterogeneity.31 Worsening renal function and hyperkalaemia were more frequent in patients taking MRAs, and worsening renal function – but not hyperkalaemia – occurred more frequently in elderly patients.

Sacubitril/valsartan

PARADIGM-HF enrolled almost 20% of patients aged ≥75 years, including 7.0% aged ≥80 years and 1.4% aged ≥85 years. A sub-analysis of this trial according to age categories (<55 years, 55–64 years, 65–74 years and ≥75 years) demonstrated consistent risk reduction in the primary endpoint of CV mortality or hospitalisation for HF (overall HR 0.80; 95% CI [0.73– 0.87]; p<0.001) regardless of age, with a HR <1.0 in all age categories (p for interaction between age category and treatment=0.94). Age-bytreatment interactions were also non-significant for risk reduction in HF hospitalisation, CV and all-cause mortality. The rates of hypotension, renal impairment and hyperkalaemia increased with advancing age, irrespective of the treatment allocation. However, hypotension was more frequent, whilst renal impairment and hyperkalaemia were less frequent with sacubitril/valsartan compared with enalapril, and these findings were consistent across age categories.15

Sodium-glucose Cotransporter 2 Inhibitors

A sub-analysis of the DAPA-HF trial according to age groups (<55 years, 13.4% of participants; 55–64 years, 26.2%; 65–74 years, 36.2%; and ≥75 years, 24.2%) demonstrated similar risk reduction across the age span, with the corresponding HRs for the primary endpoint of risk reduction in CV death or hospitalisation for HF being <1.0 in all age groups (i.e. HR 0.87; 95% CI [0.60–1.28], HR 0.71; 95% CI [0.55–0.93], HR 0.76; 95% CI [0.61–0.95], and HR 0.68; 95% CI [0.53–0.88], respectively; p for interaction=0.76).16 There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, including elderly individuals. Predefined subgroup analysis of EMPEROR-Reduced with empagliflozin and SOLOIST WHF with sotagliflozin have also found no evidence of heterogeneity in treatment effects according to age.32,33

Ivabradine

A sub-analysis of the SHIFT trial stratified by age categories (<53 years, 53 years to <60 years, 60 to <69 years and ≥69 years), has shown that the relative risk of the primary endpoint (CV death or hospitalisation for worsening HF) was significantly reduced with ivabradine in all age groups

(i.e. by 38% in the patients <53 years (HR 0.62; 95% CI [0.50–0.78]; p<0.001) and by 16% in patients ≥69 years (HR 0.84; 95% CI [0.71–0.99]; p=0.035).34 Up-titration of ivabradine resulted in similar reduction in heart rate in all age groups (by 11 BPM). Bradycardia, AF and phosphenes occurred at a similar rate regardless of age but were more frequently observed in patients receiving ivabradine.34

Digoxin

Available evidence indicates that digoxin improves functional status and quality of life in patients with HF and reduces total and hospitalisations for HF but has no favourable effects on mortality.35 Post-hoc analysis of the DIG trial suggested that digitalis may be less effective in the elderly HF patients and that they may experience greater risk of adverse effects because of lower lean body mass, which may cause higher concentrations of the drug in the myocardium. In addition, the adverse effects of digitalis can be worsened by renal impairment and electrolyte imbalance.36 Accordingly, keeping serum digoxin levels in a narrow range between 0.5 and 0.9 ng/dl may result in a significant 23% reduction in all-cause mortality, including patients aged ≥70 years.37 However, this requires careful titration and monitoring of serum digoxin levels, which may be challenging in clinical practice.37

Vericiguat and Omecamtiv Mecarbil

A prespecified subgroup analysis of the VICTORIA trial has suggested that vericiguat may be less effective in patients aged >75 years compared with younger individuals, but this observation may need to be further explored before reaching conclusions.38 The GALACTIC-HF trial has not suggested differences in treatment effects of omecamtiv mecarbil according to age.39

IV Iron

Elderly patients are at risk of developing anaemia because of the higher prevalence of comorbidities (e.g. renal dysfunction and malignancies), poor diet (low iron, folate, B12 intake) and concomitant use of medications that increase the risk of bleeding (aspirin, oral anticoagulants, nonsteroidal anti-inflammatory drugs). Anaemia is associated with worse prognosis in HF and is responsible for reduced exercise tolerance and worsening of myocardial ischaemia.40,41 The FAIR-HF trial showed that treatment with ferric carboxymaltose in HF and iron deficiency improves New York Heart Association Class, 6-minute walk test and quality of life in patients aged ≥69.7 and <69.7 years, with no difference in adverse events and mortality between the two groups.42

Real-world Data on Drug Treatments

Real-world data from registries and observational studies underscore the significantly higher mortality and hospitalisation rates in older individuals with HFrEF.43,44 Indeed, the European EORP LT-HF registry has shown that all-cause mortality and all-cause hospitalisation increase with advancing age in both sexes.45 Similarly, the OPTIMIZE and GWTG registries in the US indicate that older age is independently associated with higher in-hospital and post-discharge mortality.46,47 Notably, registries confirm the findings of clinical trials that beneficial effects of GDT, including β-blockers and ACEI/ARB are not attenuated by age. In the propensity-matched analysis of the SwedeHF registry, renin–angiotensin–aldosterone inhibitor (RAASI) and β-blocker therapy was associated with a similar reduction in morbidity and mortality and no apparent association with risk of syncope-related hospitalisation in HFrEF patients aged >80 years, compared with younger individuals.48,49 Similarly, the Spanish RICCA registry has shown that β-blockers and ACEI/ARB therapy significantly reduced mortality in the elderly.50 This observation is in keeping with the results of the OPTIMIZE

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Medical Treatment of HFrEF in the Elderly Table 1: Guideline-directed Therapy in Elderly Patients in Registries Registry

HF Type/Age

ACEI/ARB Use in Elderly Group

β-blocker Use in Elderly Group

MRA Use in Elderly Group

Outcome Analysed

OPTIMIZE-HF46 US, 48,612 patients, 2003–2004

More than half HFpEF Median 80 years (25% aged >85 years)

ACEI 37%, ARB 12.0%

52.2%

5.8%

Older age (≥75) independently associated with in-hospital and post-discharge mortality risk increases (76% and 62%, respectively; p<0.001 for both)

IMPROVE-HF54 US, 15,381 patients, 2005–2007

CHF outpatients (4,791 patients aged >76 years)

ACEI/ARB 73.3%

80.3%,

26.4%

NA

ADHERE64 US, 82,074 patients, 2001–2006

AHF patients ≥65 years (average age 79 ± 6 years)

ACEI/ARB 61.8%

65.8%

16.4%

Slightly lower unadjusted mortality in ADHERE patients (4.4% versus 4.9% in-hospital, 11.2% versus 12.2% at 30 days, 36.0% versus 38.3% at 1 year [p<0.001]) and all-cause readmission (22.1% versus 23.7% at 30 days, 65.8% versus 67.9% at 1 year; p<0.001)

IN-CHF65 Italy, 3,327 patients, 1995–1998

CHF (32.6% LVEF >40%) 1,033 patients aged >70 years

ACEI 74.9%

6.9%

N/A

1-year mortality rate significantly higher in patients ≥70 years (22% versus 13.7%; p<0.001)

RICCA50 Spain, 1,772 patients, 2008–2015

Hospitalised HF patients (average age 78 ± 8.7 years)

ACEI or ARB 79.9%, 72.4% (ACEI in 61%, ARB in 25.5%)

32.8%

β-blocker and ACEI/ARB therapy reduced mortality (RR 0.58; 95% CI [0.48–0.75]; p<0.001; RR 0.59 95% CI [0.46–0.78]; p<0.001, respectively)

SwedeHF48 Sweden, 2,416 patients, 2000–2012

HF patients, LVEF <40% Age >80 years, median age 86 years (IQR: 83–91).

20% of patients aged >80 versus 6% of those aged <80 years did not receive RAASI

Propensity-score matching, RAASI use associated with HR 0.78 (95% CI [0.72–0.86]) for all-cause mortality and HR 0.86 (95% CI [0.79–0.94)] for all-cause mortality/HF hospitalisation

Get With The Guidelines– AHF, mean age 73 ± 14 Heart Failure47 years US, 57,937 admissions, 18.7% >85 years 2005–2007

ACEI/ARB 81.8%

88%

20.5%

NA

EORP45 Europe, 9,428 patients, 2011–2016

845 patients ≥75 years

ACEI/ARB 80.4%

82.3%

45.6%

Age an independent predictor of all cause death (referent age >75 years): • <55 years HR 0.48; 95% CI [0.32–0.71]; p=0.0003 • 55–64 years HR 0.70; 95% CI [0.52–0.96]; p=0.0260 • 65–75 years HR 0.65 95% CI [0.49–0.86]; p=0.0025)

CHECK-HF5 The Netherlands; 8,351 patients; 2013–2016

4,040 patients ≥75 years

ACEI/ARB 76.1%

78.6%

51.8%

NA

ACEI = angiotensin-converting enzyme inhibitors; AHF = acute heart failure; ARB = angiotensin receptor blockers; CHF = congestive heart failure; eGFR = estimated glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; LVEF = left ventricular ejection fraction; NA = not applicable; RAASI = renin–angiotensin–aldosterone system inhibitors.

registry, which have shown a 23% lower mortality in elderly HFrEF patients receiving a β-blocker without evidence of an age-by-treatment interaction (p=0.87).46 The issue of potentially lower tolerability of β-blockers in the elderly was addressed in the COLA II observational study, in which over 1,000 patients aged ≥70 years were followed after initiating treatment with carvedilol. The study has shown that >80% of participants continued treatment for ≥3 months, without evidence of significant adverse effects that would require drug discontinuation.51 Attaining evidence-based target doses of HF medications in the elderly is often challenging because of the limitations discussed above. In a recent US registry, most eligible HFrEF patients did not receive target doses of medical therapy at any point during the follow-up, and few patients had doses increased over time.52 This study demonstrated that advancing age was not an obstacle to the use or up-titration of ACEI/ARBs, but older age

was independently associated with a lower likelihood of initiation or dose intensification of β-blockers and angiotensin receptor–neprilysin inhibitors at 12-month follow-up.52 A recent sub-analysis of the BIOSTATCHF trial on the association between the achieved dose of HF medications and mortality and/or HF hospitalisation across the age spectrum demonstrated that attaining higher doses of ACEI/ARBs was associated with improved outcomes, regardless of age.53 However, achieving higher doses of β-blockers was only associated with improved outcome in those aged <70 years, but not in older patients (≥70 years).

Despite the encouraging results, registries also reveal a more concerning side of under-prescription and underuse of GDT among elderly patients for reasons that remain poorly understood (Table 1). In the EORP LT-HF registry, crude GDT utilisation rates were lower in women than in men (all differences p ≤0.001) at all ages, but age >75 years was identified as an

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Medical Treatment of HFrEF in the Elderly Figure 1: Specificities in Proposed Medical Treatment Algorithm of Chronic Stable HFeEF Elderly Patients

I

II

Lower starting doses with gradual increases until the RCT recommended

III

Monitoring of serum creatinine and potassium levels at intervals according to starting values.

Regular monitoring of BP and HR

IV

HFrEF elderly

Assessment of serum creatinine and potassium levels before initiating ACEI/ARB, ARNI, SGLT2I and MRAs

All patients without contraindications/intolerance β-blocker

ARNI/ACEI

• Lower to mid-range doses sufficient/or titration according to HR

• Lower risk of renal impairment and hyperkalaemia with ARNI versus ACEI/ARB • Easier introduction and up-titration of MRAs

For ACEI/ARB, ARNI, SGLT2I and MRA: eGFR up to 30% K+ >5.5 mmol/l or eGFR <30 ml/ min/1.73 m2 TRANSIENT DOSE ADJUSTMENT K+ >6.0 mmol/l or eGFR <20 ml/min/1.73 m2 REFFERAL TO A HF SPECIALIST

MRA

SGLT2I

• Same incidence of gynaecomastia with eplerenone and spironolactone

• Lower risk of renal impairment and hyperkalaemia • Easier up-titration of MRAs

Subgroups

ARNI/ACEI intolerance

SR, HR >70 BPM

Higher HR and symptoms

AF

Congestion

Anaemia

ARB

Ivabradine

Digoxin

Anticoagulation

Diuretics

Diuretics

Lower starting doses with gradual increases until the RCT recommended

Lower starting dose (2 × 2.5 mg) with gradual increases until the RCT recommended

Up to 0.125 mg/day (plasma concentration up to 1 ng/ml).

Monitoring of electrolytes, dehydration and drug–drug interactions

DOAC preferred (lower doses for apixaban ≥80 years and renal impairment/low BMI and dabigatran ≥75 to 80 years and/or low eGFR)

Doses adjusted to improve to keep NYHA class and keep euvolaemic state, avoid volume depletion, worsening renal function and mental confusion

To improve NYHA class and QoL

ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; ARNI = angiotensin receptor–neprilysin inhibitor; BP = blood pressure; COPD = chronic obstructive pulmonary disease; DOAC = direct oral anticoagulant; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; HR = heart rate; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; QoL = quality of life; RCT = randomised controlled trial; SBP = systolic blood pressure; SGLT2I = sodium–glucose cotransporter 2 inhibitors; SR = sinus rhythm.

independent predictor of GDT underuse.45 In the OPTIMIZE registry, all GDT were prescribed less frequently at discharge to eligible patients >75 years than to those <75 years.46 Similar findings were observed in the IMPROVE-HF and GWTG registries.54,47 Likewise, in the Dutch CHECK-HF registry, each 10-year increase in age was associated with a decline in the probability of receiving MRAs, β-blockers, RAASI or ivabradine, by 10%, 12%, 29% and 21%, respectively.5 At the same time, the probability of receiving diuretics increased by 32% with each decade of age. Of note, patients of older age were less likely to receive the recommended target doses of GDT medications compared with younger individuals.5

excellent negative predictive value for exclusion of reduced left ventricular systolic function.57

Practical Approaches to Pharmacotherapy of HFrEF in Older Patients Natriuretic Peptide Testing

Despite the proven benefits of medical therapies for HFrEF (except, perhaps, vericiguat) and reassuring safety profile of most drugs, there remains a reluctance in the real-world clinical practice to prescribe and up-titrate these medications in older people. This may be the result of (mis)understanding that elderly individuals have lower tolerance and greater propensity for developing adverse drug reactions, in particular in the presence of comorbidities that interfere with drug metabolism. It may also reflect issues around access to specialised care, difficulties in the management of multiple medications, patient preferences, and other non-medical considerations. In order to overcome these issues, it is prudent to commence HF medications in older patients at lower doses then to slowly and carefully up-titrate to target doses to prevent intolerance and adverse drug reactions.62 (Figure 1 and Table 2).

Current guidelines recommend the use of natriuretic peptide testing – B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) – in the diagnostic assessment of patients with HF regardless of age.55 However, interpretation of test results may be challenging in the elderly given that natriuretic peptide levels tend to increase with aging, and the presence of comorbidities, such as AF or renal dysfunction. Indeed, in patients aged >80 years with acute dyspnoea, BNP was shown to be of limited clinical utility in discriminating cardiac versus respiratory origin of dyspnoea when added to the multifactorial prediction model.56 Agespecific cut-off values have been suggested to increase the predictive value of natriuretic peptides in the elderly. A study has shown that using age-stratified NT-proBNP cut off values (i.e. 50 pg/ml in patients <50 years, 75 pg/ml in those aged 50–75 years, and 250 pg/ml in those aged >75 years) considerably improved diagnostic performance, with an

The use of natriuretic peptides to guide or intensify GDT remains controversial as clinical trials did not demonstrate improved outcomes with this strategy.58–60 In particular, the TIME-CHF trial failed to show benefits for overall survival or HF-free survival with NT-proBNP guided medical therapy compared with standard care in individuals ≥75 years of age.61

Guideline-directed Medical Therapy

Assessment of serum creatinine and potassium levels is recommended before initiating ACEI/ARB and MRAs and monitoring is needed at intervals set according to baseline renal function and potassium concentration.

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Medical Treatment of HFrEF in the Elderly Table 2: Selected Contraindications of Medical Treatment of Chronic Stable HFrEF Elderly Patients ACEI/ARB

ARNI

β-Blocker

MRA

SGLT2I

Contraindications: • Previous angioedema • Bilateral renal artery stenosis • SBP <90 mmHg • Severe hyperkalaemia (K+ >5.5 mmol/l)

Contraindications: • SBP <100 mmHg • eGFR <30 ml/min/1.73 m2 • Previous angioedema

Contraindications/precautions: • HR <60 BPM • SBP <100 mmHg • Signs of peripheral hypoperfusion • PR interval >0.24 s • Second- or third-degree atrioventricular block • Severe COPD/history of asthma • Severe peripheral vascular disease

Contraindications: • K + >5.5 mmol/l or eGFR <30 ml/min/1.73 m2

Contraindications: • eGFR <20 (30)* ml/ min/1.72 m2

*For dapagliflozin. ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blockers; ARNI = angiotensin receptor–neprilysin inhibitor; COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; HFrEF = heart failure with reduced ejection fraction; HR = heart rate; MRA = mineralocorticoid receptor antagonist; SBP = systolic blood pressure; SGLT2I = sodium–glucose cotransporter 2 inhibitors.

Monitoring should be intensified in face of changes in clinical status that may increase the risk of worsening renal function and hyperkalaemia. An acute decline in estimated glomerular filtration rate is frequent following initiation of ACEI/ARB and should not be the reason to discontinue treatment, but transient dose adjustment may be required. Given that sacubitril/valsartan carries a lower risk of renal impairment and hyperkalaemia it may be the preferred drug choice over ACEI/ARB. This may also allow for easier introduction and up-titration of MRAs. Digoxin should only be considered in select patients for symptom relief and prevention of repeat HF hospitalisations, but only if careful up-titration and monitoring of serum drug levels can be performed. Diuretic doses also need to be adjusted to keep a euvolemic state whilst avoiding volume depletion, worsening renal function and mental confusion.

Since polypharmacy is frequent among the elderly, simplification of the treatment scheme is highly recommended. It is advisable to review prescribed medications and discontinue drugs that may precipitate worsening HF symptoms (e.g. thiazolidinediones, Class I antiarrhythmic medications, dronedarone, calcium channel blockers expect amlodipine and felodipine, etc.) and substitute them with safer choices. Patients also need to be warned about caveats of over-the-counter drugs (e.g. nonsteroidal anti-inflammatory drugs) and herbal remedies that may 1.

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5.

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Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994–2003.

Arch Intern Med 2008;168:418–24. https://doi.org/10.1001/ archinternmed.2007.80; PMID: 18299498.

Veenis JF, Brunner-La Rocca HP, Linssen G, et al. Age differences in contemporary treatment of patients with chronic heart failure and reduced ejection fraction. Eur J Prev Cardiol 2019;26:1399–407. https://doi. org/10.1177/2047487319835042; PMID: 30866680.

McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur Heart J 2012;33:1787–847. https://doi.org/10.1093/eurheartj/ehs104; PMID: 22611136.

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9.

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aggravate HF symptoms and cause severe drug interactions. Cognitive impairment and HF frequently coexist and a multidisciplinary team approach is recommended. The use of adherence aids and greater involvement of family members and caregivers could improve self-care and adherence to HF treatment.63

Call for Action

With the aging global population and the growing burden of HF, future research should focus on providing more granular analyses on how to best approach medical and device therapies in elderly patients. These should take into account biological differences, difficulties in care delivery and issues relevant to patients’ values and perspectives. Over the past decades, the number of old and very old patients enrolled in RCTs has increased, but their broader representation should be encouraged to obtain better insights into the efficacy and safety of investigated treatments. In addition, more information is needed from real-world practice on reasons for underuse of the available treatment options in older populations. Improved education of healthcare professionals, wider provision of specialised centres for multidisciplinary HF care and stronger implementation of GDT in vulnerable patient groups, may prove to be the way to ‘add years to life – and life to years’ in elderly patients with HF.42

from 14,713 patients in the Swedish Heart Failure Registry.

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ORIGINAL RESEARCH

Pathophysiology

Aortic Pulsatility Index: A New Haemodynamic Measure with Prognostic Value in Advanced Heart Failure Tania Deis ,1 Kasper Rossing1 and Finn Gustafsson

1,2

1. Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; 2. Department of Clinical Medicine, University of Copenhagen, Denmark

Abstract

Aim: To test if the newly described haemodynamic variable, aortic pulsatility index (API), predicts long-term prognosis in advanced heart failure (HF). Methods: A single-centre study on 453 HF patients (median age: 51 years; left ventricular ejection fraction [LVEF]: 19% ± 9%) referred for right heart catheterisation. API was calculated as pulse pressure/pulmonary capillary wedge pressure. Results: Log(API) correlated significantly with central venous pressure (CVP; p<0.001) and cardiac index (p<0.001) in univariable regression analysis. CVP remained associated with log(API) in a multivariable analysis including cardiac index, heart rate, log(NT-proBNP [N-terminal proB-type natriuretic peptide]), LVEF, New York Heart Association (NYHA) class III or IV and sex (p=0.01). In univariable Cox models, log(API) was a significant predictor of freedom from the combined endpoint of death, left ventricular assist device implantation, total artificial heart implantation or heart transplantation (HR 0.33; (95% CI [0.22–0.49]); p<0.001) and all-cause mortality (HR 0.56 (95% CI [0.35–0.90]); p=0.015). After adjusting for age, sex, NYHA class III or IV and estimated glomerular filtration rate in multivariable Cox models, log(API) remained a significant predictor for the combined endpoint (HR 0.33; 95% CI [0.20–0.56]; p<0.001) and all-cause mortality (HR 0.49; 95% CI [0.26–0.96]; p=0.034). Conclusion: API was strongly associated with right-sided filling pressure and independently predicted freedom from the combined endpoint and all-cause mortality.

Keywords

Aortic pulsatility index, heart failure with reduced ejection fraction, haemodynamics, prognosis Disclosure: KR has received fees from Abbott, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim and Orion Pharma. FG has received research grants from the Novo Nordisk Foundation (grant no NNF20OC0060561) and reports fees from Abbott, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Pharmacosmos, Orion Pharma and Alnylam, and is on the Cardiac Failure Review editorial board; this did not influence peer review. TD has no conflicts of interest to declare.

Ethics: The study complies with the Declaration of Helsinki. The research protocol was approved by the local research ethics committee (3-3013-1365/1) and the Data Protection Agency (P-2020-1087).

Informed Consent: Individual patient consent was not required due to the retrospective nature of the study.

Data Availability: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.

Author Contributions: Conception and design: FG, KR, TD. Data extraction and data analysis: TD. All authors made a substantial contribution to interpreting the data and writing the manuscript. All authors reviewed and approved of the final manuscript before submission Received: 27 January 2022 Accepted: 27 February 2022 Citation: Cardiac Failure Review 2022;8:e18. DOI: https://doi.org/10.15420/cfr.2022.09 Correspondence: Finn Gustafsson, Department of Cardiology, Rigshospitalet 2142, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. E: finn.gustafsson@regionh.dk 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) has an estimated global prevalence of 1–2% and is a major cause of morbidity and mortality.1 Despite a growing armoury of evidence-based therapies, it is estimated that 5–10% of patients deteriorate into advanced HF, which has a poor prognosis if not treated with advanced therapies.2 Abnormal central haemodynamics are a hallmark of advanced HF and right heart catheterisation (RHC) is an important procedure for identifying advanced disease and guide the timing of advanced therapies, such as heart transplantation or left ventricular assist device (LVAD) implantation.3,4 A range of measured and derived haemodynamic variables is used to determine the degree of haemodynamic impairment. Recently, the aortic pulsatility index (API) – a haemodynamic variable derived from systemic pulse pressure divided by pulmonary capillary wedge pressure (PCWP) – has been proposed as a new marker of left heart performance with

evidence of prognostic predictive abilities superior to the established haemodynamic measurements in patients with acute decompensated HF.5 API was introduced only recently and the association between API and long-term prognosis in advanced HF has not been described. The primary aim of this study was to test if the index had long-term prognostic predictive value in advanced stable HF, secondary to test the association between API and central haemodynamic measurements.

Methods Patients and Study Design

A cohort of HF patients referred for right heart catheterisation (RHC) at the Department of Cardiology at Copenhagen University Hospital, Rigshospitalet from 1 January 2002 to 31 October 2020 was investigated.

Patients were referred for evaluation for advanced therapy, i.e. implantation of an LVAD, total artificial heart implantation or heart

© RADCLIFFE CARDIOLOGY 2022 www.CFRjournal.com

Aortic Pulsatility Index in Heart Failure transplantation, or as a part of assessment of advanced HF. All RHCs were performed in the catheterisation laboratory as non-urgent procedures.

Pulmonary artery pulsatility index (PAPi) was determined using the formula:

Patients were identified through the hospital’s cardiac catheterisation database, from which data were extracted and linked to the patients’ medical records and the hospital’s echocardiography database. Patients were included if they had a documented left ventricular ejection fraction (LVEF) <45%. Patients were not required to have symptoms of advanced HF at the time of referral. However, these patients were included as they had recently experienced advanced HF symptoms and/or their HF condition was considered severe to the extent that referral for evaluation for advanced therapies was justified.

PAPi =

All patients were considered to have an element of chronic HF, but some patients could be in the state of worsening HF with decompensation during the time of their haemodynamic evaluation. Unstable patients requiring intensive care, ventilation or temporary mechanical support were excluded from the analysis. In cases of repeated RHC during the time period, only data from the first catheterisation was used.

Patients treated with mechanical circulatory support or heart transplantation at the time of catheterisation were excluded from the study as were patients aged under 16 years and those with congenital heart defects. Patients were required to be on optimal medical therapy (as tolerated) before referral.

The study complies with the Declaration of Helsinki. The research protocol was approved by the local research ethics committee (3-3013-1365/1) and the data protection agency (P-2020-1087). Individual patient consent was not required because of the retrospective nature of the study.

Haemodynamic Evaluation

All RHCs were performed in the cardiac catheterisation laboratory by four experienced physicians. A Swan-Ganz catheter was used with zeroing and calibration of the pressure transducer performed before measurements. The catheter was inserted in the internal jugular or the femoral vein, and correct placement was evaluated by fluoroscopy and by visualisation of pressure curves on a monitor.

The following haemodynamic variables were collected: PCWP; mean pulmonary artery pressure (MPAP); central venous pressure (CVP); cardiac output (CO) using the thermodilution technique; systolic blood pressure (SBP); diastolic blood pressure (DBP); and heart rate. Blood pressure was measured noninvasively using a semi-automated cuff method.

Derived variables were calculated as follows: API was determined using the formula:

API =

SBP − DBP PCWP

Cardiac index was determined as CO divided by the body surface area.

Body surface area was determined using the DuBois method.

Mean arterial pressure (MAP) was estimated using the formula:

MAP =

(2 × DBP) + SBP 3

Stroke volume index (SVi) was calculated using the formula: SVi=

(CO/heartrate) BSA

pulmonary artery systolic - diastolic pressure CVP

Statistical Analysis

API and N-terminal proB-type natriuretic peptide (NT-proBNP) were nonnormally distributed and were therefore log-transformed for analysis. API and NT-proBNP were reported as medians with interquartile range (IQR).

We reported all other continuous variables as mean ± standard deviation (SD) and categorical variables as numbers and/or percentages. Univariable and multivariable linear regression models were constructed including relevant haemodynamic measurements and important clinical variables.

Variables that presented with a p value of <0.05 in univariable regression models were included in the multivariable regression model.

The follow-up date was set at 31 October 2020. Events were defined as: death (all cause); implantation of a durable LVAD; total artificial heart implantation; or undergoing heart transplantation. Implantation of an LVAD was carried out as a bridge to transplantation or as destination therapy.

Cox proportional hazards models were used to determine API’s ability to predict: the combined endpoint of all-cause mortality, implantation of a durable LVAD, total artificial heart implantation or heart transplantation; or all-cause mortality while censoring patient data at the time of implantation of LVAD, total artificial heart implantation or heart transplantation. Patients were divided into tertiles according to API for the construction of Kaplan-Meier curves. Receiver operator characteristic (ROC) curves for 6 months (Supplementary Material Figures 1A and 1B) and 1-year follow-up time were constructed and area under the curve (AUC) was determined.

Two-sided p-values were used, and p<0.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 25, IBM).

Results Clinical Characteristics

API was calculated for 453 patients with advanced HF undergoing haemodynamic evaluation. Clinical features are summarised in Table 1.

Median API was 1.9 (1.2–3.3) and mean follow-up was 9.1 years. The total cohort was characterised by low LVEF (19% ± 9%), a majority of men (76%), a relatively young age (51 ± 13 years) and an above average BMI of 26 ± 6 kg/m². Thirty-one per cent had ischaemic HF aetiology. Only nine patients had severe mitral regurgitation (2%) and four had moderate-to-severe mitral regurgitation (1%).

Patients were divided into two groups according to low (<1.9) or high (≥1.9) API, where 226 patients had low API and 227 had high API. Comparing the two groups, we found that patients with low API were more often men (84% compared to 68% in the group with high API) and in a higher NYHA class (with 65% of patients with low API classified as NYHA III/IV versus 52% of patients with high API; p=0.009).

Patients with low API showed clinical signs of congestion more frequently that patients with high API, with 63% of patients with low API having at least one clinical sign of congestion compared to 38% of patients with high API. Patients with low API had higher median NT-proBNP levels (3,400 versus 1,311 ng/l; p<0.001) and lower LVEF (16% versus 22%; p<0.001).

CARDIAC FAILURE REVIEW www.CFRjournal.com

Aortic Pulsatility Index in Heart Failure Table 1: Patient Characteristics Total (n)

n=453

Low API (<1.9); n=226

High API (≥1.9); n=227 p-value

453

51 ± 13

51 ± 13

52 ± 12

0.289*

Sex (male)

453

344 (75.9%)

189 (83.6%)

155 (68.3%)

<0.001†

BMI (kg/m )

448

26.3 ± 5.8

26.1 ± 5.1

26.5 ± 6.5

0.485*

Risk factors: • Smoking§

428

302 (70.5%)

152 (71.4%)

150 (69.8%)

0.718†

138 (30.5%)

73 (32.3%)

65 (28.6%)

0.397†

200 (44.2%) 16 (3.5%) 13 (2.9%) 7 (1.5%)

98 (43.4%) 3 (1.3%) 6 (2.7%) 4 (1.8%)

102 (44.9%) 13 (5.7%) 7 (3.1%) 3 (1.3%)

0.736† 0.011† 0.785† 0.699†

8 (1.8%) 24 (5.3%) 39 (8.6%) 8 (1.8%)

5 (2.2%) 14 (6.2%) 18 (8.0%) 5 (2.2%)

3 (1.3%) 10 (4.4%) 21 (9.3%) 3 (1.3%)

0.472† 0.395† 0.625 0.472†

Age 2

Heart failure aetiology: • Ischaemic • Non-ischaemic Dilated cardiomyopathy (not further specified) Hypertension Valvular heart disease Tachycardia induced Peri- or postpartum Cardiomyopathy Toxin induced Other • Unknown/not reported Comorbidities: • AF • Chronic obstructive pulmonary disease • Diabetes||

449 450 451

162 (36.1%) 31 (6.9%) 82 (18.2%)

90 (40.4%) 10 (4.4%) 50 (22.2%)

72 (31.9%) 21 (9.3%) 32 (14.2%)

0.061† 0.041† 0.026†

NYHA functional class III or IV

424

247 (58.3%)

135 (64.6%)

112 (52.1%)

0.009†

Clinical signs: • Jugular vein distention • S3 gallops • Pulmonary rales • Ascites • Hepatomegaly • Peripheral oedema

320 334 406 155 258 394

86 (26.9%) 65 (19.5%) 72 (17.5%) 46 (29.7%) 47 (18.2%) 105 (26.6%)

60 (35.5%) 49 (30.1%) 46 (22.4%) 34 (37.4%) 36 (25.9%) 74 (37.4%)

26 (17.2%) 16 (9.4%) 26 (12.9%) 12 (18.8%) 11 (9.2%) 31 (15.8%)

<0.001† <0.001† 0.012† 0.013† 0.001† <0.001†

Laboratory analysis: • eGFR (ml/min/1.73 m2) • NT-proBNP (ng/l)

377 126

72 ± 26 2,593 (1,040–5,150)

72 ± 26 3,400 (2,072–6,360)

72 ± 26 1,311 (499–3,104)

0.912* <0.001||

Echocardiography: • Left ventricular ejection fraction (%) • TAPSE (cm)

453 273

19 ± 9 1.7 ± 0.5

16 ± 7 1.5 ± 0.5

22 ± 9 1.8 ± 0.6

<0.001* <0.001*

Medications: • ACE inhibitors, ARB or ARNI • β-blockers • Aldosterone receptor antagonists • Loop diuretics • SGLT2 inhibitors • Inotropy

447 447 435 445 98 451

361 (80.8%) 300 (67.1%) 256 (58.9%) 399 (89.7%) 3 (3.1%) 30 (6.7%)

169 (76.5%) 141 (63.8%) 121 (57.1%) 201 (91.4%) 2 (3.9%) 24 (10.7%)

192 (85.0%) 159 (70.4%) 135 (60.5%) 198 (88.0%) 1 (2.1%) 6 (2.7%)

0.023† 0.140† 0.463† 0.244† 0.607† 0.001†

10 (2.2%) 69 (15.3%) 13 (2.9%) 60 (13.3%)

3 (1.3%) 38 (16.9%) 7 (3.1%) 30 (13.3%)

7 (3.1%) 31 (13.7%) 6 (2.6%) 30 (13.2%)

0.206† 0.339† 0.766† 0.971†

78 ± 19 104 ± 18 66 ± 12 78 ± 12 4.8 ± 1.6 2.4 ± 0.7 19.7 ± 7.9 28.6 ± 10.3 10.5 ± 5.6 34.8 ± 13.4 2.6 ± 1.8 1.9 (1.2–3.3)

87 ± 20 98 ± 15 66 ± 11 77 ± 12 4.4 ± 1.4 2.2 ± 0.6 25.7 ± 4.8 34.7 ± 7.9 13.4 ± 5.3 27.1 ± 7.8 2.1 ± 1.3 1.2 (1.0–1.5)

69 ± 14 111 ± 18 65 ± 12 80 ± 13 5.3 ± 1.7 2.7 ± 0.7 13.8 ± 5.7 22.5 ± 8.7 7.6 ± 4.3 42.7 ± 14.3 3.1 ± 2.0 3.3 (2.4–4.8)

<0.001* <0.001* 0.109* 0.007* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001‡

Devices: • Pacemaker • ICD • CRT-P • CRT-D Resting haemodynamic parameters: • Heart rate (BPM) • Systolic blood pressure (mmHg) • Diastolic blood pressure (mmHg) • MAP (mmHg) • Cardiac output (l/min) • Cardiac index (l/m/m2) • PCWP (mmHg) • MPAP (mmHg) • CVP (mmHg) • SVi (ml/m2) • PAPi • API (IQR)

451

94 453 453 453 450 445 453 449 448 94 445 453

n=patients with obtained information in the category. Values are given as numbers and valid % (n [%]), mean with SD or as median or interquartile range (IQR). *Student’s t-test; †χ2 analysis; ‡Mann–Whitney U test; §current or former; ||non-insulin or insulin-dependent diabetes. ACE = angiotensin-converting enzyme; API = aortic pulsatility index; ARB = angiotensin II receptor blockers; ARNI = angiotensin receptor neprilysin inhibitor; CVP = central venous pressure; eGFR = estimated glomerular filtration rate; MAP = mean arterial pressure; MPAP = mean pulmonary artery pressure; NT-proBNP = N-terminal proB-type natriuretic peptide; NYHA = New York Heart Association; PAPi = pulmonary artery pulsatility index; PCWP = pulmonary capillary wedge pressure; SGLT-2 = sodium– glucose cotransporter 2; TAPSE = tricuspid annular plane systolic excursion; SVi = stroke volume index.

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Aortic Pulsatility Index in Heart Failure Table 2: Regression Models – Association Between Log(API) and Haemodynamic and Clinical Variables Variable

Univariable Model

Multivariable Model 1

Unstandardised β Coefficient (95% CI)

p-value

CVP

−0.028 [−0.032, −0.024]

Cardiac index Heart rate

Unstandardised β Coefficient (95% CI)

Multivariable Model 2 p-value

Unstandardised β Coefficient (95% CI)

p-value

<0.001

−0.016 [−0.028, −0.004]

0.010

0.130 [0.095–0.165]

<0.001

−0.048 [−0.187, 0.091]

0.488

−0.007 [−0.010, −0.004]

<0.001

−0.005 [−0.009, −0.002]

0.006

Log(NT-proBNP) −0.285 [−0.370, −0.199]

<0.001

0.004 [−0.143, 0.151]

0.952

eGFR

0.000 [−0.001, 0.001]

0.877

NYHA III/IV

−0.193 [−0.167, −0.058]

<0.001

−0.112 [−0.288 to −0.043]

0.010

Sex

−0.110 [−0.172, −0.048]

0.001

−0.116 [−0.177, −0.053]

<0.001

−0.166 [0.308–0.025]

0.023

Age

0.001 [−0.001, 0.003]

0.289

0.002 [−0.001, 0.004]

0.149

LVEF

0.014 [0.012–0.017]

<0.001

0.014 [0.007–0.020]

<0.001

BMI

0.002 [−0.003, 0.006]

0.448

The overall multivariable model 2 was significant with a p-value <0.001. Adjusted R2 for the model was 0.673. API = aortic pulsatility index; CVP = central venous pressure; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction; MAP = mean arterial pressure; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association.

Table 3: Cox Models HR (95% CI)

p-value

Models for Combined Endpoint Univariable model Log(API)

with low API were significantly more haemodynamically deranged for almost all measured parameters.

Compared with patients with high API, patients with low API had a higher heart rate (87 ± 20 BPM versus 69 ± 14 BPM; p<0.001), lower SBP (98 ± 15 mmHg versus 111 ± 18 mmHg; p<0.001) and lower MAP (77 ± 12 mmHg versus 80 ± 13 mmHg; p=0.007). Their CO (4.4 ± 1.4 l/min versus 5.3 ± 1.7 l/min; p<0.001), cardiac index (2.2 ± 0.6 l/min/m2 versus 2.7 ± 0.7 l/min/m2; p<0.001) and SVi (27.1 ± 7.8 versus 42.7 ± 14.3; p<0.001) were reduced. PCWP (25.7 ± 4.8 mmHg versus 13.8 ± 5.7 mmHg; p<0.001), MPAP (34.7 ± 7.9 mmHg versus 22.5 ± 8.7 mmHg; p<0.001) and CVP (13.4 ± 5.3 mmHg versus 7.6 ± 4.3 mmHg; p<0.001) were elevated. Patients with low API had significantly lower PAPi (2.1 ± 1.3 versus 3.1 ± 2.0; p<0.001) than those with high API.

0.33 (0.22-0.49)

<0.001

Log(API) corrected for age, male sex, NYHA class III or IV and eGFR

0.33 (0.20-0.56)

<0.001

Log(API) corrected for age, male sex, NYHA class III or IV, eGFR and log(NTproBNP)

0.61 (0.22-1.73)

0.354

0.56 (0.35-0.90)

0.015

Supplementary Material Table 1 shows patient characteristics stratified according to NYHA class.

Log(API) corrected for age, male sex, NYHA class III or IV and eGFR

0.49 (0.26-0.95)

0.034

Log(API) corrected for age, male sex, NYHA class III or IV, eGFR and log(NTproBNP)

2.49 (0.53-11.9)

0.251

Association Between API and Haemodynamic and Clinical Variables

Multivariable model

Models for All-cause Mortality Univariable model Log(API) Multivariable model

API = aortic pulsatility index; eGFR = estimated glomerular filtration rate; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association.

Tricuspid annular plane systolic excursion was significantly lower in patients with low API than in those with high API (1.5 versus 1.8; p<0.001).

The eGFR was generally mildly decreased with no differences in renal function between groups.

There were no significant differences between groups in standard of care HF medication except that patients with low API were less often prescribed angiotensin-converting enzyme-inhibitors, angiotensin II receptor blockers or angiotensin receptor neprilysin inhibitors (ARNIs) than patients with high API (77 versus 85%; p=0.023). There were no differences between groups regarding prescriptions of ARNI (six patients in each group).

Patients with low API received inotropic support more often (defined as patients receiving infusion of inotropic medications – dobutamine, dopamine, milrinone or norepinephrine – at the time of the haemodynamic evaluation) than patients with high API (11 versus 3%; p=0.001). Patients

Log(API) was significantly associated with CVP (p<0.001), cardiac index (p<0.001), heart rate (p<0.001), log(NT-proBNP) (p<0.001), NYHA III/IV (p<0.001), male sex (p=0.001) and LVEF (p<0.001) in univariable linear regression analysis. Age, eGFR and BMI were not associated with log(API).

In an intermediate multivariable model including only age and sex, male sex was strongly associated with log(API) (p<0.001).

In multivariable analysis including all significant variables from the univariable analysis, CVP (p=0.01), heart rate (p=0.006), NYHA III/IV (p=0.010), male sex (p=0.023) and LVEF (p<0.001) were found to be significantly associated with log(API). Cardiac index and log(NT - proBNP) lost their statistical significance in the multivariable model (Table 2).

API and Outcome

Log(API) predicted freedom from the combined endpoint of death, LVAD implantation, total artificial heart implantation or heart transplantation (HR 0.33; 95% CI [0.22–0.49]; p<0.001) and freedom from all-cause mortality (HR 0.56; 95% CI [0.35–0.90]; p=0.015; Table 3).

When adjusting for age, sex, NYHA class and eGFR in multivariable Cox analysis, log(API) remained independently associated with freedom

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Aortic Pulsatility Index in Heart Failure

A Kaplan-Meier curve demonstrated there were significant differences (log rank p-value <0.001) between patients grouped in tertiles according to API for the combined endpoint (Figure 1A). Median time to the combined endpoint was 1.5 years for the lowest tertile and 8.1 years for the highest.

There were no statistically significant differences between subgroups for all-cause mortality (log rank p=0.079; Figure 1B).

ROC curves showed an AUC of 0.694 (95% CI [0.642–0.747]; p<0.001) for the combined endpoint at 1-year follow-up and an AUC of 0.617 (95% CI [0.543–0.692; p=0.005) for all-cause mortality at 1-year follow-up (Figure 2). Furthermore, additional ROC curves for the combined endpoint and all-cause mortality at 6 months’ follow-up showed an AUC of 0.706 (95% CI [0.651–0.760]; p<0.001) for the combined endpoint and an AUC of 0.618 (95% CI [0.553–0.703]; p=0.012) for all-cause mortality (Supplementary Material Figures 1A and 1B).

Discussion

This study aimed to evaluate the novel haemodynamic variable API and its ability to predict long-term prognosis in advanced HF. To our knowledge, it is the largest study to analyse the prognostic impact of API and the only study with long-term follow-up.

We demonstrated that log(API) was strongly associated with right-sided filling pressures in univariable and multivariable models. Furthermore, we demonstrated that log(API) was a significant predictor of freedom from the combined endpoint and all-cause mortality in univariable Cox models and an independent factor when adjusting for multiple known variables associated with a worse outcome in HF. Pulmonary artery pulsatility index (PAPi), a derived haemodynamic parameter calculated as pulmonary artery pulse pressure divided by central venous pressure, has recently been established in clinical settings as a marker of right ventricular function with prognostic implications.6 API could be understood as a marker in line with PAPi but linked to the systemic rather than the pulmonary circulation. API is derived from PCWP (i.e. an estimate of preload of the left ventricle [LV]) and pulse pressure, which is a function of stroke volume and LV afterload, and thus API could be an integrated measure for LV function taking into consideration the loading conditions. In this study, we found an increased event rate as API

A 100 Freedom from the combined endpoint (%)

There was no statistically significant interaction effect of NYHA class (NYHA I–II versus NYHA III–IV) on log(API)’s ability to predict freedom from the combined endpoint (p=0.789) and all-cause mortality (p=0.805) in univariable Cox models. There was a statistically significant interaction effect of aetiology (ischaemic versus non-ischaemic) on the ability of log(API) ability to predict freedom from the combined endpoint (p=0.030) but not all-cause mortality (p=0.185). When patients were divided according to aetiology in two separate Cox models, log(API) remained a significant predictor of freedom from the combined endpoint for both ischaemic (HR 0.09; CI [0.03–0.26; p<0.001) and non-ischaemic (HR 0.51; CI [0.27–0.96; p=0.036) patients (Supplementary Material Table 2).

Figure 1: Kaplan-Meier Curves

90 80 70 60 50 40 30 20 10 0

Log rank p<0.001 0

1

2

3

4

5

6

7

8

9

10

Time (years) B

100 90

Freedom from the death (%)

from the combined endpoint (HR 0.33; 95% CI [0.20–0.56]; p<0.001) and all-cause mortality (HR 0.49; 95% CI [0.26–0.96]; p=0.034).

However, the associations did not reach statistical significance when further adjusting for log(NT-proBNP) for either the combined endpoint (HR 0.61; CI [0.22–1.73]; p=0.354) or all-cause mortality (HR 2.49; CI [0.53–11.8; p=0.251). It had no significant effect on the results of any of the Cox models if data from patients on inotropy were excluded from the analysis.

80 70 60 50 40 30 20 10 0

Log-rank p<0.079 0

1

2

3

4

5

6

7

8

9

10

Time (years) Lowest tertile of API

Intermediate tertile of API

Highest tertile of API

A: Kaplan-Meier curve for the combined endpoint (implantation of a durable left ventricular assist device, total artificial heart or transplantation). B: Kaplan-Meier curve for all-cause mortality.

decreased. This is in line with published literature, where low pulse pressure and high left ventricular filling pressures are known individual predictors of a worse prognosis in advanced HF. 7,8 There is a growing list of derived haemodynamic variables with prognostic implications. One such is cardiac power output (CPO). CPO is calculated as mean arterial pressure multiplied by CO and divided by 451; it integrates flow and pressure and could be viewed as the hydraulic pumping ability of the heart. It has been shown that resting CPO serves as a powerful prognostic factor in a broad spectrum of patients with acute cardiac disease as well as in ambulatory patients with advanced HF.9,10 In contrast to CPO, API does not take CO directly into account. However, since there is greater uncertainty on CO measurements, this could be an advantage of API, possibly making it a more accurate estimate. Future studies should explore this further.

A recent study by Belkin et al. examined data from the ESCAPE trial and showed that API was a better predictor of clinical outcome than traditional haemodynamic variables at 6 months’ follow-up in a cohort of 189 patients with acute decompensated HF.5 In another study, Belkin et al. examined a cohort of 244 patients with acute, chronic and worsening HF who were all treated with milrinone and found that low

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Aortic Pulsatility Index in Heart Failure Figure 2: Sensitivity and Specificity of Arterial Pulsatility Index A

ROC curve

ROC curve

B

0.8

0.8

0.6

0.6

Sensitivity

1.0

Sensitivity

1.0

0.4

0.4

0.2

0.2

0

0

0.2

0.4

0.6

0.8

1.0

0

0

Specificity

0.2

0.4

0.6

0.8

1.0

Specificity

A: Combined endpoint at 1-year follow-up. B: All-cause mortality at 1-year follow-up.

API was strongly associated with needs for advanced therapies or with death at 30-day follow-up.11 Our study demonstrated that API was an independent predictor of clinical outcomes in multivariable Cox proportional hazards models, though not when adjusting for log(NT-proBNP), which is also known to be a strong prognostic predictive factor in advanced HF.12 We speculate that this could be owing to lack of power, since NT-proBNP was reported for only one in four patients, leaving the sample size for analysis moderate. Further studies are required to determine if API provides prognostic information beyond that of NT-proBNP. In contrast to Belkin et al., we only found acceptable AUC values for the combined endpoint and additionally poor discrimination abilities of API in ROC curves for all-cause mortality. It is important to note that where Belkin’s studies investigated mostly acute, decompensated HF patients, our cohort was mainly elective, stable patients. Furthermore, we investigated long-term prognosis (years) compared to much shorter (days to months) in Belkin’s two studies, and this could be a possible explanation for why our results differ. This is supported by the fact that when constructing ROC curves for 6 months follow-up time (as used by Belkin et al. analysing the ESCAPE trial), our AUC for the combined outcome (0.706) was similar to Belkin’s (0.708).

In the current study, low API was associated with generally sicker patients, as they had more frequent signs of congestion, more deranged haemodynamics and a greater need for inotropy. Our findings suggest that calculation of API could be useful for risk stratification in patients with advanced HF. Calculation of API in patients undergoing RHC is simple and may add to the characterisation of the LV and, in turn, provide prognostic information in patients with advanced HF. API has recently been introduced and the

impact of API in HF should be confirmed in other studies, thresholds clearly defined and added value determined before clinical recommendations for use can be made.

Limitations

Several limitations in this study must be acknowledged. Because of its retrospective nature, conclusions on cause-effect relationships cannot be made. The study included a selected HF patient population with an indication for RHC referred for evaluation at a single specialised centre, which introduces the risk of selection bias. The population investigated were much younger than HF patients on average, which may limit the ability to extrapolate our results to the general HF population.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors were recommended for HF patients with reduced ejection fraction in 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure.13 Since SGLT-2 inhibitors may reduce PCWP and only three patients in our cohort were taking SGLT-2 inhibitors, our data may not represent patients on updated guideline-recommended HF medication.14 Future studies should include patients treated with this drug class.

Systolic and diastolic blood pressure were measured noninvasively by semiautomatic blood pressure cuff and we cannot exclude the possibility off less consistent measurements than those that would have been obtained from an intra-arterial catheter.

Conclusion

The novel haemodynamic measurement API predicted freedom from the combined endpoint and all-cause mortality even when correcting for known variables associated with a worse outcome in HF. Further studies should explore the prognostic value of API in advanced, stable HF.

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Aortic Pulsatility Index in Heart Failure

Clinical Perspective

• Calculation of the aortic pulsatility index is simple and may add to the characterisation of the left ventricle.

• The aortic pulsatility index is independently associated with freedom from advanced therapies or death in long-term follow-up.

• The aortic pulsatility index could be useful in risk stratification in patients with advanced heart failure.

1.

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Aalders M, Kok W. Comparison of hemodynamic factors predicting prognosis in heart failure: a systematic review. J Clin Med 2019;8:1757. https://doi.org/10.3390/jcm8101757; PMID: 31652650.

Mendoza DD, Cooper HA, Panza JA. Cardiac power output predicts mortality across a broad spectrum of patients with acute cardiac disease. Am Heart J 2007;153:366–70. https:// doi.org/10.1016/j.ahj.2006.11.014; PMID: 17307413.

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advanced heart failure. Am J Cardiol 2017;120:973–9. https:// doi.org/10.1016/j.amjcard.2017.06.028; PMID: 28739034.

Belkin MN, Kalantari S, Kanelidis AJ, et al. Aortic pulsatility index: a novel hemodynamic variable for evaluation of decompensated heart failure. J Card Fail 2021;27:1045–52. https://doi.org/10.1016/j.cardfail.2021.05.010; PMID: 34048919.

MacGowan GA, Neely D, Peaston R, et al. Evaluation of NT-proBNP to predict outcomes in advanced heart failure.

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Omar M, Jensen J, Frederiksen PH, et al. Effect of empagliflozin on hemodynamics in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 2020;76:2740–51. https://doi.org/10.1016/j.jacc.2020.10.005; PMID: 33272368.