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Interventional Cardiology Review Volume 13 • Issue 1 • Spring 2018

Volume 13 • Issue 1 • Spring 2018

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Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review Karel M Van Praet, Christof Stamm, Simon H Sündermann, Alexander Meyer, Axel Unbehaun, Matteo Montagner, Timo Z Nazari Shafti, Stephan Jacobs, Volkmar Falk and Jörg Kempfert

Transcatheter Treatment of Functional Tricuspid Regurgitation Using the Trialign Device Christian Besler, Christopher U Meduri and Philipp Lurz

Is Complete Revascularisation Mandated for all Patients with Multivessel Coronary Artery Disease? Carlo De Innocentiis, Marco Zimarino and Raffaele De Caterina

Understanding Neurologic Complications Following TAVR Mohammed Imran Ghare and Alexandra Lansky

ISSN: 1756-1477

Transthoracic crossclamping using a transthoracic (Chitwood) clamp

Baseline Appearance of 23 mm Magna BPV after Deployment of 26 mm Medtronic Evolut R THV

Transcatheter Treatment of Severe Tricuspid Regurgitation With the Trialign Device

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Volume 13 • Issue 1 • Spring 2018

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Editor-in-Chief Simon Kennon Interventional Cardiologist and TAVI Operator, Barts Heart Centre, St Bartholomew’s Hospital, London

Section Editor – Structural

Section Editor – Coronary

Darren Mylotte

Angela Hoye

Galway University Hospitals, Galway

Castle Hill Hospital, Hull

Fernando Alfonso

A Pieter Kappetein

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Sergio Baptista

Tim Kinnaird

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

Athens Euroclinic, Athens, Greece University Hospital of Wales, Cardiff

Ajay Kirtane Columbia University Medical Center and New York-Presbyterian Hospital, New York

Ferrarotto Hospital, Catania

Olivier Bertrand Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib

Lutz Buellesfeld

Didier Locca

San Raffaele Hospital, Milan

University Hospital, Bern

Jonathan Byrne King’s College Hospital, London

Antonio Colombo San Raffaele Hospital, Milan

Royal Brompton & Harefield NHS Foundation Trust, London Centre Hospitalier Universitaire Vaudois, Lausanne CardioVascular Center, Frankfurt

Sapienza University of Rome, Rome

Andrew SP Sharp Royal Devon and Exeter Hospital and University of Exeter, Exeter

Elliot Smith London Chest Hospital, Barts Health NHS Trust, London Rigshospitalet - Copenhagen University Hospital, Copenhagen

Thomas Modine

Gregg Stone Columbia University Medical Center and New York-Presbyterian Hospital, New York

Corrado Tamburino Ferrarotto & Policlinico Hospital and University of Catania, Catania

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Nicolas Van Mieghem

Keith Oldroyd

Renu Virmani

Golden Jubilee National Hospital, Glasgow

Sameer Gafoor

Gennaro Sardella

Mount Sinai Hospital, New York

Marko Noc

Eric Eeckhout

Beth Israel Deaconess Medical Center, Boston

Lars Søndergaard

Columbia University Medical Center and New York-Presbyterian Hospital, New York

Carlo Di Mario

Jeffrey Popma

Roxana Mehran

Jeffrey Moses

Imperial College NHS Trust, London

Guy’s & St Thomas’ Hospital and King’s College London, London

Lausanne University Hospital, Lausanne

CHRU de Lille, Lille

Justin Davies

Divaka Perera

Crochan J O’Sullivan

Erasmus University Medical Center, Rotterdam CVPath Institute, Maryland

Mark Westwood

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

University Hospitals Bristol, Bristol

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

Juan Granada CRF Skirball Research Center, New York

Managing Editor Genevieve Walton • Production Helena Clements • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Chief Executive David Ramsey • Commercial Director David Bradbury •

Editorial Contact Genevieve Walton gen.walton@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image 3d illustration human body heart. © PIC4U | stock.adobe.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS. © 2018 All rights reserved

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ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 Frequency: Tri-annual Current issue: Spring 2018

Aims and Scope • Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. • Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Interventional Cardiology 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 • Interventional Cardiology Review is a bi-annual journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Interventional Cardiology Review is available in full online at www.ICRjournal.com

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.ICRjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Genevieve Walton gen.walton@radcliffecardiology.com

Reprints All articles included in Interventional Cardiology Review are available as reprints. Please contact the Publishing Director, Leiah Norcott leiah.norcott@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

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

Interventional Cardiology Review is distributed bi-annually through controlled circulation to senior healthcare professionals in the field in Europe.

Peer Review

All manuscripts published in Interventional Cardiology Review are available free-to-view at www.ICRjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review. n

• On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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CIRSE 2018 featuring

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Contents

Foreword

Simon Kennon Editor-in-Chief, ICR

Structural

Transcatheter Treatment of Functional Tricuspid Regurgitation Using the Trialign Device Christian Besler, Christopher U Meduri and Philipp Lurz

Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review

Bioprosthetic Valve Fracture During Valve-in-valve TAVR: Bench to Bedside

Understanding Neurologic Complications Following TAVR

Oral Anticoagulant Therapy for Early Post-TAVI Thrombosis

Assessing the Risk of Leaflet Motion Abnormality Following Transcatheter Aortic Valve Implantation

Karel M Van Praet, Christof Stamm, Simon H Sündermann, Alexander Meyer, Axel Unbehaun, Matteo Montagner, Timo Z Nazari Shafti, Stephan Jacobs, Volkmar Falk and Jörg Kempfert

John T Saxon, Keith B Allen, David J Cohen and Adnan K Chhatriwalla

Mohammed Imran Ghare and Alexandra Lansky

Neil Ruparelia

Luca Testa and Azeem Latib

Coronary

Challenges in Patients with Diabetes: Improving Clinical Outcomes After Percutaneous Coronary Intervention Through EVOlving Stent Technology Robert A Byrne, Shmuel Banai, Roisin Colleran and Antonio Colombo

Is Complete Revascularisation Mandated for all Patients with Multivessel Coronary Artery Disease? Carlo De Innocentiis, Marco Zimarino and Raffaele De Caterina

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Foreword

Simon Kennon is an Interventional Cardiologist and TAVI Operator at the Barts Heart Centre, St Bartholomew’s Hospital, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

2017 and all that.

he 2017 ESC/EACTS Guidelines for the management of valvular heart disease1 and in particular the recommendations with regard to choice of intervention mode for the treatment of aortic stenosis, may effect more change in cardiology treatment algorithms than most original research published in 2017, marking as they do, a significant shift towards transcatheter aortic valve implantation (TAVI) for intermediate risk patients. It will no doubt take time for this message to be disseminated throughout the cardiology community, however, the paper usefully documents in table form the factors which favour TAVI and those which favour conventional aortic valve replacement surgery. I am hopeful this will help individuals and heart teams develop a more nuanced and patient-centred approach to the management of aortic stenosis. Along similar lines, this issue of Interventional Cardiology Review presents papers that provide updates on specific complications of TAVI and the treatment of specific patient groups. Namely, stroke and cerebral embolism; valve thrombosis; and valve in valve interventions. Mohammed Imran Ghare and Alexandra Lansky provide an excellent review and analysis of the data relating to neurological complications of TAVI. Luca Testa & Azeem Latib, and Neil Ruparelia, respectively, review the diagnosis and treatment of TAVI valve thrombosis. Surgical bioprostheses often have surprisingly small inner diameters with the risk of patient prosthesis mismatch following valve in valve procedures; Adnan Chhatriwalla and colleagues review the novel practice of fracturing surgical aortic valve bioprostheses during such procedures in order to optimise valve areas. With mitral and tricuspid interventions progress in 2017 has been solid but unspectacular and notable for the low number and relatively high complexity of procedures being undertaken. The Mitralign / Trialign device is one of the leaders in this field and Philipp Lurz and colleagues usefully review its value in the treatment of functional tricuspid regurgitation. Of course, all transcatheter devices are an alternative to surgery and it is important that cardiologists know both the benefits as well as the limitations of the latter. To this end Jorg Kempfert and his team provide a state of the art review of minimally invasive surgical mitral valve repair. As far as coronary artery intervention is concerned, 2017 will for many be remembered as the year of ORBITA.2 Unlike valvular heart disease, medical treatment is an important part of the management of coronary artery disease, but it is important that the result of ORBITA be viewed objectively: they do not invalidate percutaneous coronary intervention (PCI) as a treatment of stable angina but rather provide a useful reminder of its limitations. At the other end of the spectrum, when compared to coronary artery bypass surgery, incomplete revascularisation has conventionally been regarded as one of the key limitations of PCI; Marco Zimarino and his team critically review the literature relating to this. Finally, I am pleased to announce that Interventional Cardiology Review is returning to a triannual publication in 2018 with two further issues in May and September. n 1. 2.

Baumgartner H, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease, Euro Heart J 2017;38:2739–86. Al-Lamee R, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet, 2017 Nov 1. pii: S0140-6736(17)32714-9. doi: 10.1016/S0140-6736(17)32714-9. [Epub ahead of print]

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Structural

Transcatheter Treatment of Functional Tricuspid Regurgitation Using the Trialign Device Christian Besler, 1 Christopher U Meduri 2 and Philipp Lurz 1 1. Department of Cardiology, University of Leipzig - Heart Center, Leipzig, Germany; 2. Marcus Heart Valve Center, Piedmont Heart Institute, Atlanta, Georgia, USA

Abstract Functional tricuspid regurgitation (TR) represents an important unmet need in clinical cardiology given its prevalence, adverse prognostic impact and symptom burden associated with progressive right heart failure. Several transcatheter techniques are currently in early clinical testing to provide alternative treatment options for patients deemed unsuitable for tricuspid valve surgery. Amongst them, the TrialignTM device (Mitralign, Inc.) represents a novel percutaneous tricuspid valve annuloplasty technique, which aims to reduce tricuspid annular dilatation in functional TR by delivering and cinching two pledgeted sutures to the posterior portion of the tricuspid annulus via transjugular access. Early clinical data suggest the Trialign technique is safe and feasible, and associated with an improvement in quality-of-life measures. However, further studies are needed to confirm these data in larger cohorts of patients with longer follow up. In addition, future trials need to address the question whether TR reduction with the Trialign and other devices leads to an improvement in the patient`s functional status and prognosis, over and above medical treatment alone.

Keywords Tricuspid valve, tricuspid regurgitation, transcatheter therapy, right ventricle, Trialign, Mitralign Disclosure: The authors have no conflict of interest to declare. Received: 21 July 2017 Accepted: 2 October 2017 Citation: Interventional Cardiology Review 2018;13(1):8–13. DOI: 10.15420/icr. 2017:21:1 Correspondence: Philipp Lurz, Department of Internal Medicine/Cardiology, University of Leipzig - Heart Center, Strümpellstraße 39, 04289 Leipzig, Germany. E: Philipp.Lurz@gmx.de

Accumulating evidence suggests that tricuspid regurgitation (TR) is independently associated with reduced long-term survival in the community and patients with ischaemic or dilated cardiomyopathy.1 Patients with moderate-to-severe TR suffer symptoms of progressive right heart failure, which are often difficult to treat with diuretic therapy. Prevalence estimates based on data from the Framingham Heart Study suggest that TR affects approximately 1.6 million patients in the US; however, only 0.5 % of patients are currently estimated to undergo tricuspid valve repair or replacement, suggesting a large unmet need in treatment options for TR.2 In developed countries, functional or secondary TR is the most frequent aetiology of tricuspid valve disease (accounting for approximately 80 % of all TR cases).3 Functional TR is caused by tricuspid annular dilatation and leaflet tethering in the setting of right ventricular remodelling due to pressure or volume overload. In clinical practice, alterations of right ventricular geometry and function are most commonly due to pulmonary hypertension and left-sided heart disease. Relevant mitral valve disease is observed in more than 30 % of cases of functional TR.4 Particularly in older patients, functional TR is often associated with AF.5 In addition, transvenous placement of pacemaker and implantable cardioverter defibrillator leads may have adverse effects on tricuspid valve function.6

Challenges in the Treatment of Patients with Functional Tricuspid Regurgitation Due to the common association with left-sided heart valve disease or cardiomyopathy, functional TR was merely considered as a bystander for a long time and management focused primarily on correction of the left-sided pathology.1 However, more recent data indicate that TR does not resolve following correction of left-sided heart valve disease.7

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Instead, moderate preoperative TR represents a significant risk factor for severe TR on follow up after mitral valve surgery, and the presence of tricuspid annular dilatation at the time of mitral valve surgery is associated with adverse right ventricular remodelling and increasing TR severity on echocardiographic follow up.8,9 Nevertheless, functional TR still remains undertreated and patients are referred for intervention late in the natural history of the disease when tricuspid annular or right ventricular dilatation is advanced and right ventricular function is impaired. This entails that many patients with severe TR are deemed at very high or prohibitive surgical risk. On the other hand, current guidelines emphasize the fact that data from clinical studies addressing the question as to when and how TR should be corrected are limited. Both the 2012 version of the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guideline, and the 2014 version of the American Heart Association/American College of Cardiology guideline for the management of patients with valvular heart disease provide a class I (level of evidence C) recommendation for tricuspid valve surgery in patients with severe TR undergoing left-sided valve intervention.10,11 Moreover, the guidelines provide a class I (level of evidence C) recommendation for surgery in symptomatic patients with severe isolated TR. A class IIa (level of evidence C) recommendation is given to patients with moderate primary TR and patients with mild or moderate secondary TR with dilated annulus (≥40 mm or >21 mm/m²) undergoing left-sided valve surgery.10,11 The latter recommendation justifying tricuspid valve surgery in patients with moderate or even mild TR appreciates the increased risk of progressive TR and right heart failure once tricuspid annular dilatation has occurred. In such instances, concomitant tricuspid valve repair can be performed without increased perioperative complication rates.12 In contrast,

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Mitralign for the Tricuspid Valve isolated reoperative tricuspid valve repair/replacement carries an excessively high operative risk.3 Compatible with this recommendation, a recent meta-analysis of fifteen studies including 2,840 patients suggested a reduction in cardiac-related mortality and improved echocardiographic outcomes for TR after a mean weighted follow up of 6 years in patients with concomitant tricuspid valve repair during leftsided valve surgery as compared with patients without concomitant tricuspid valve repair.13 In recent years a growing number of elderly patients with left-sided heart valve disease are treated by transcatheter valve technologies, and accumulating evidence suggests residual TR remains a predictor of adverse outcome in these patients. In patients with mitral regurgitation undergoing MitraClip® (Abbott Vascular) implantation, increasing TR severity correlates with higher one-year mortality and bleeding rates.14,15 Severity of TR in association with aortic stenosis is frequently progressive despite transcatheter aortic valve implantation.16 In addition, persistence of moderate or greater TR 6 months after transcatheter aortic valve implantation, but not preoperative TR severity, is associated with lower survival after adjustment for clinical variables and echocardiographic parameters of right ventricular function.16,17 Given the incidence and prognostic relevance of TR on the one hand and the challenges in providing treatment options on the other, there is increasing interest in the development of transcatheter approaches for treating TR.

Changes of Tricuspid Annular Geometry in Patients with Functional Tricuspid Regurgitation The tricuspid annulus is a complex and dynamic 3D structure that differs from the more symmetric saddle-shaped anatomy of the mitral annulus and is altered in the presence of different loading conditions of the right heart chambers.18 In addition, the tricuspid annular area changes significantly during the respiratory and cardiac cycle with an almost one-third increase during atrial systole and again in late systole/early diastole.19 Under physiological conditions the tricuspid annulus is elliptic or ‘egg’-shaped when imaged in a short-axis view (see Figure 1). Importantly, 3D-echocardiographic data suggest a normal tricuspid annulus is non-planar, exerting two high points (stretched towards the right atrium) anteroseptal adjacent to the aortic valve and posterolateral, as well as two low points (stretched towards the right ventricular apex) anterolateral and posteroseptal.20 The septal tricuspid leaflet arises directly from the tricuspid annulus above the interventricular septum and this medial portion of the tricuspid annulus is relatively fixed due to its position between the fibrous trigones, analogous to the intertrigonal portion of the mitral annulus.4 Therefore, the tricuspid annulus primarily dilates along the free wall, i.e. at the anterior and posterior leaflet attachments.7 In contrast to normal tricuspid annular geometry where the septolateral distance is larger than the anteroposterior distance, the tricuspid annulus becomes more circular and planar when functional dilatation occurs (see Figure 1). The displacement of the low and high points of the tricuspid annulus likely alters the papillary muscle-to-leaflet and annulus relationship, thereby contributing to leaflet tethering in functional TR.

Technical Difficulties in the Development of Transcatheter Therapies for Functional Tricuspid Regurgitation Several devices are currently in preclinical and early-clinical evaluation for transcatheter treatment of functional TR.21 However, the number of patients treated is still low and long-term haemodynamic and clinical benefits are unknown. As compared to interventional therapies

INTERVENTIONAL CARDIOLOGY REVIEW

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Figure 1: Changes of Tricuspid Annular Geometry in Functional Tricuspid Regurgitation Physiological conditions

Functional TR

Aortic valve

A Tricuspid valve

S S P

A A P P

Low points High points Tricuspid annulus

Under physiological conditions, the tricuspid annulus is non-planar and elliptical-shaped with two ‘high’ points located anteroseptal and posterolateral, and two ‘low’ points located anterolateral and posteroseptal (left side). In the setting of functional tricuspid regurgitation, annular dilatation predominantly occurs at the anterior and posterior leaflet attachments resulting in an increase of the septolateral diameter, and a more circular and planar shape of the tricuspid annulus. A = anterior; P = posterior; S = septal; TR = tricuspid regurgitation.

Figure 2: Anatomical Challenges in the Development of Transcatheter Techniques Targeting Functional Tricuspid Regurgitation Catheter navigation in the enlarged right atrium Severe dilatation and noncircular shape of the annulus Thin / nonuniform tissue of the annulus and leaflets Proximity of RCA to the annulus Angle of catheter approach (SVC, IVC) Noncompacted RV chamber with papillary muscles and moderator band Thin RV free wall Given the complex morphology of the right heart chambers and the close proximity of important anatomical structures (such as the atrioventricular node or right coronary artery), implementation of transcatheter approaches for functional tricuspid regurgitation is considered more challenging than transcatheter techniques for left-sided valvular disease. IVC = inferior vena cava; RCA = right coronary artery; RV = Right ventricle; SVC = Superior vena cava.

targeted to the aortic or mitral valve, transcatheter treatment of TR has to face a number of additional anatomical challenges, as summarised in Figure 2. In particular, device steering via femoral access is hampered due to the sharp angle between the inferior vena cava and the tricuspid valve annular plane. Catheter navigation in the enlarged right heart chambers can be challenging. Application of annular-based devices has to account for the thin and non-uniform tissue of the tricuspid annulus and leaflets as well as the course of the right coronary artery. Existing transcatheter therapies for functional TR can be divided into four groups according to their mode of action. The first group

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Structural Figure 3: Pre-procedural Assessment of the Tricuspid Valve by Echocardiography A

A: Transoesophageal 3D echocardiography providing a ‘surgical view’ of the tricuspid valve in a patient with functional TR; the image illustrates a substantial central coaptation defect of the tricuspid valve leaflets due to dilatation of the tricuspid annulus. B: Imaging of the posterior portion of the tricuspid annulus by transthoracic X-plane echocardiography; the tricuspid valve is visualised in a modified parasternal short-axis view and the depth of the landing zone (arrow) for the Trialign device is measured on biplane imaging.

comprises percutaneous tricuspid valve annuloplasty devices. Among these are the TrialignTM system (Mitralign, Inc.), which will be described in detail below, as well as the Cardioband device (Edwards Lifesciences) and the TriCinchTM system (4Tech Inc), which reduces the septolateral tricuspid annular diameter by implanting a corkscrew anchor in the anteroposterior tricuspid annulus and applying tension on the annulus via a Dacron band fixed to a self-expanding nitinol stent in the inferior vena cava.22–24 The second transcatheter technique currently used to treat functional TR is tricuspid edge-to-edge repair using the MitraClip system with a modified steering technique.25 The third group comprises techniques for heterotopic caval valve implantation, where either two dedicated self-expandable bioprosthetic valves (TricValve [P&F Products & Features Vertriebs GmbH, in cooperation with Braile Biomedica]) or balloon-expandable valves used to treat aortic stenosis (29 mm Edwards SAPIEN XT or SAPIEN 3 [Edwards Lifesciences Corp]) are placed in the inferior and superior vena cava.26,27 The use of balloon-expandable valves requires prior implantation of a selfexpandable stent in the inferior (and occasionally superior) vena cava to prepare a landing zone, given the large diameter of the vena cava and the hepatic vein confluence. Another device currently in clinical testing (FORMA Repair System, Edwards Lifesciences) aims to reduce malcoaptation of the tricuspid leaflets by placing a spacer through the central coaptation line, which reduces the regurgitant orifice area.28

Percutaneous Valve Annuloplasty: From Mitralign to Trialign The Trialign device is a transjugular suture-based tricuspid valve annuloplasty system that reduces tricuspid annular diameter through tissue plication.29 The underlying transcatheter annuloplasty technique, which is known as the Mitralign device, was originally designed for the treatment of functional mitral regurgitation and first successfully applied in 2013.29 For mitral regurgitation, two pairs of sutured pledget implants are placed in the mitral annulus in the medial (P1) and lateral (P3) scallop regions via transfemoral access through the aorta across the aortic valve. Plication is achieved by advancing a dedicated plication lock device over the two sutures attached to each pair of pledgets and, finally, a stainless steel lock is placed to maintain plication of the mitral annulus.29 In 2016, Nickenig et al. reported the results of a safety, feasibility and efficacy study testing the Mitralign system in 71 patients with functional mitral regurgitation and high surgical risk.30 The device was successfully implanted in 50 of 71 patients (70.4 %) with no intraprocedural deaths or necessity for acute conversion to open heart surgery. Cardiac

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tamponade requiring pericardiocentesis occurred in 4 patients, likely related to catheter manipulation within the ventricle. During 6 months of follow up, non-urgent mitral valve surgery was performed in one patient (2.4 %) and non-urgent percutaneous mitral valve repair in seven patients (17.1 %). Although beneficial effects on left ventricular volumes, mitral valve annular geometry and leaflet coaptation were observed after 6 months of follow up, mitral regurgitation itself improved only in 50 % of treated patients. The percentage of patients presenting with New York Heart Association (NYHA) functional class ≥III was reduced by 56 % and the 6-min walking distance significantly increased during follow up by 56 metres.30 Further data on the performance of the Mitralign device in patients with functional mitral regurgitation are not yet available. In 2015, Schofer et al. reported the first successful case of a direct percutaneous tricuspid valve annuloplasty in a patient with functional TR and prohibitive surgical risk using the Mitralign device with a modified delivery approach, a technique that is nowadays better known as the Trialign system.31 From a mechanistic point of view, this approach resembles a suture bicuspidization technique originally described by Kay et al.32 The Kay procedure aims to reduce TR by obliterating the annular segment corresponding to the posterior leaflet through placement of pledget-supported mattress sutures in the annulus. As a result, the tricuspid annular circumference is reduced and the tricuspid valve is converted into a smaller but competent mitral-like valve.32 Retrospective data suggest TR in patients treated by bicuspidization annuloplasty was zero to mild in 75 % at 3 years postoperatively, compared to 69 % in those undergoing ring annuloplasty.33 In a large retrospective series of 2,277 patients treated by various surgical techniques to eliminate TR, 81 % of patients treated by suture bicuspidization had zero or mild TR after 5 years of follow up, which compared well with other surgical techniques.34

Pre-procedural Assessment A comprehensive clinical, laboratory, echocardiographic and invasive evaluation is needed to assess whether a patient is suited for percutaneous tricuspid valve annuloplasty with the Trialign system. All patients treated so far were either enrolled in safety and performance studies or compassionate use cases. According to current study protocols, patients aged ≥18 and ≤80 years with moderate-to-severe chronic functional TR are considered symptomatic despite guidelinedirected medical therapy (i.e. NYHA class II, III or ambulatory IV) are considered. A heart team decision is needed to rule out the need for left-sided valve surgery and to decide whether tricuspid annuloplasty would be suited for the patient. Transthoracic and transoesophageal 2D/3D echocardiography is central to the evaluation of percutaneous tricuspid valve annuloplasty with the Trialign system, including deep oesophageal and transgastric imaging of the tricuspid valve (see Figure 3A). Current eligibility criteria for the Trialign procedure include a left ventricular ejection fraction ≥30 %, tricuspid annular plane systolic excursion (TAPSE) ≥13 mm and systolic pulmonary artery pressure (sPAP) ≤60 mmHg. Furthermore, emphasis needs to be paid on the tricuspid valve annular diameter (≥40 mm [or 21 mm/m2] and ≤55 mm [or 29 mm/m2]), tricuspid effective regurgitant orifice area (EROA; ≤1.2 cm2) and sufficient posterior annular dimension for device implantation. The latter is best visualised on transthoracic X-plane imaging of the tricuspid valve in a parasternal short-axis view (see Figure 3B).

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Mitralign for the Tricuspid Valve Procedural Details on the Trialign System During the Trialign procedure a pair of polyester pledgets are delivered across the tricuspid annulus in proximity to the anteroposterior and septo-posterior commissure, cinched by a polyester suture to obliterate the posterior tricuspid leaflet, and locked on the atrial side (see Figure 4A).31,35

Figure 4: Percutaneous Tricuspid Valve Annuloplasty Using the Trialign System A

Access Percutaneous tricuspid valve annuloplasty with the Trialign system requires two 14 F sheaths placed in the ventral and lateral portion of the right internal jugular vein with a distance of approximately 2 cm to avoid bleeding complications. In addition, a guide catheter needs to be placed in the right coronary artery via femoral access because of the close proximity of the right coronary artery to the posterior portion of the tricuspid annulus.

Crossing Wire Delivery As a first step, a dedicated deflectable tricuspid guide catheter (see Figure 4A) is advanced into the right ventricle via jugular access.31,35 The tricuspid guide catheter is designed to direct all subsequent procedural devices across the tricuspid valve orifice and towards the tricuspid annulus by advancement/retraction, deflection and rotation. Next, a tricuspid wire delivery catheter is advanced to access the ventricular side of the tricuspid annulus at the target location for pledget delivery. With the help of transoesophageal 2D/3D echocardiography and fluoroscopy, the tricuspid wire delivery catheter is directed to the septo-posterior location. Then, a crossing wire is advanced through the lumen of the tricuspid wire delivery catheter. The crossing wire is used to cross the annulus from the ventricular to atrial side, thereby providing a path for pledget delivery through the tricuspid annulus. It is connected to a radiofrequency energy source and radiofrequency energy is employed at the distal tip while moving the crossing wire through the tricuspid annular tissue (see Figure 4B). Afterwards, the position of the crossing wire along the tricuspid annulus and the annular depth is confirmed by echocardiography.

Snaring Once the crossing wire is properly placed at the septo-posterior portion of the tricuspid annulus the distal tip of the crossing wire is trapped in the right atrium by an endovascular snare system and retracted through the jugular access site.

Pledget Delivery Following snaring of the crossing wire, a tricuspid pledget deliver catheter is positioned in the right atrium and the deflected tricuspid guide catheter is positioned under the tricuspid annulus in the right ventricle. Next, the pledget delivery catheter is advanced through the tricuspid annulus into the tricuspid wire delivery catheter. The pledget delivery catheter seats the distal portion of the pledget on the ventricle side of the tricuspid annulus. Afterwards, the pledget delivery catheter is retracted back through the annulus to the atrial side and deploys the proximal portion of the pledget.31,35

Second Pledget Delivery The second pledget is positioned next to the anteroposterior commissure of the tricuspid annulus following the same technique as described for the septo-posterior location. A distance of 25â&#x20AC;&#x201C;28 mm between the pledget in the anteroposterior and septo-posterior location is recommended (see Figure 4C). Of note, to provide complete coverage of the posterior portion of the tricuspid annulus from the

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A: Tricuspid guide and wire delivery catheter of the Trialign system. B: Crossing wire delivery through the tricuspid annulus in proximity to the anteroposterior commissure. C: Visualisation of pledget placement by fluoroscopy and transoesophageal 3D echocardiography; note, the pledgeted sutures are not yet cinched and sutures can be visualised on 3D echocardiography. D: Implantation of two pairs of pledgets to provide complete coverage of the posterior portion of the tricuspid annulus from the anteroposterior to the septo-posterior commissure. Reproduced with permission of Mitralign, Inc.

Figure 5: Transcatheter Treatment of Severe Tricuspid Regurgitation With the Trialign Device A

Representative echocardiographic images visualising the severity of functional tricuspid regurgitation in a 77-year-old woman before (A) and after (B) percutaneous tricuspid valve annuloplasty with the Trialign device.

anteroposterior to the septo-posterior commissure, investigators have tried to implant two pairs of pledgets (see Figure 4D). Whether the twopair strategy is superior to implantation of a single pair of pledgets has not yet been tested.

Plication, Lock and Cut A dedicated plication lock delivery catheter is advanced over both pledget sutures to the atrial side of the tricuspid annulus. By advancing the plication lock delivery catheter towards the annulus, the portion of the tricuspid annulus and posterior tricuspid leaflet in-between the two pledgets is plicated. To secure plication the pledget delivery catheter deploys a lock onto the sutures. Finally, a suture cutter catheter is tracked over the locked sutures to the lock implant. The catheter tip encloses a blade that cuts both sutures right above the lock and allows removal of the proximal portion of the sutures. Representative echocardiographic images of a patient treated with a single pair of pledgets are shown in Figure 5.

Early Clinical Data on Safety and Performance Percutaneous tricuspid valve annuloplasty with the Trialign system is in early clinical evaluation, and data on the safety, feasibility and

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Structural clinical benefit are still limited. The first-in-human report of a direct transcatheter tricuspid valve annuloplasty using the Trialign system was published in 2015 by Schofer et al.31 An 89-year-old woman with recurrent right heart decompensation and massive TR (effective EROA 1.35 cm², tricuspid annular area of 14.1 cm2) underwent implantation of a single pair of pledgets, resulting in a 57 % reduction in tricuspid annular area and a 53 % reduction in effective EROA. Of note, right atrial pressure was reduced from 22 to 9 mmHg, and echocardiography revealed a profound increase in left ventricular stroke volume from 42 to 72 ml following the procedure.31 After publication of the first successful case of transcatheter treatment of functional TR with the Trialign device, another report emphasized the possibility of early failure due to pledget dehiscence.36 Recently, Hahn et al. reported the results of the Early Feasibility of the Mitralign Percutaneous Tricuspid Valve Annuloplasty System Also Known as Trialign (SCOUT) trial (NCT02574650), constituting the first report of an early feasibility trial for a transcatheter tricuspid valve device.35 The SCOUT trial is prospective, single-arm, multicentre, early feasibility study of the Trialign device and recruited 15 symptomatic patients (i.e. NYHA functional class ≥II) with moderate or greater functional TR. Detailed echocardiographic and quality-of-life measurements (i.e. NYHA functional class, Minnesota Living with Heart Failure Questionnaire and 6-min walk test) were performed at baseline and 30 days. Of note, all patients underwent successful device implantation with no serious complications. In one patient, coronary angiography after pledget delivery and lock showed tenting of the distal right coronary artery in the region of the plication with significant narrowing, ST-segment elevations on ECG and a fractional flow reserve of 0.57, requiring stent implantation. On follow up after 30 days, three patients had echocardiographic evidence of a single pledget detachment from the annulus.35 Significant reductions in tricuspid annular diameter and EROA were observed in the remaining patients. Left ventricular

odés-Cabau J, Taramasso M, O’Gara PT. Diagnosis and R treatment of tricuspid valve disease: current and future perspectives. Lancet 2016;388:2431–42. DOI: 10.1016/S01406736(16)00740-6; PMID: 27048553 2. Stuge O, Liddicoat J. Emerging opportunities for cardiac surgeons within structural heart disease. J Thorac Cardiovasc Surg 2006;132:1258–61. DOI: 10.1016/j.jtcvs.2006.08.049; PMID: 17140937 3. Taramasso M, Vanermen H, Maisano F, et al. The growing clinical importance of secondary tricuspid regurgitation. J Am Coll Cardiol 2012;59:703–10. DOI: 10.1016/j.jacc.2011.09.069; PMID: 22340261 4. Rogers JH, Bolling SF. The tricuspid valve: current perspective and evolving management of tricuspid regurgitation. Circulation 2009;119:2718–25. DOI: 10.1161/ CIRCULATIONAHA.108.842773; PMID: 19470900 5. Najib MQ, Vinales KL, Vittala SS, et al. Predictors for the development of severe tricuspid regurgitation with anatomically normal valve in patients with atrial fibrillation. Echocardiography 2012;29:140–6. DOI: 10.1111/j.15408175.2011.01565.x; PMID: 22067002 6. Chang JD, Manning WJ, Ebrille E, et al. Tricuspid valve dysfunction following pacemaker or cardioverter-defibrillator implantation. J Am Coll Cardiol 2017;69:2331–41. DOI: 10.1016/ j.jacc.2017.02.055; PMID: 28473139 7. Hahn RT. State-of-the-art review of echocardiographic imaging in the evaluation and treatment of functional tricuspid regurgitation. Circ Cardiovasc Imaging 2016;9;e005332. DOI: 10.1161/CIRCIMAGING.116.005332; PMID: 27974407 8. Takano H, Hiramatsu M, Kida H, et al. Severe tricuspid regurgitation after mitral valve surgery: the risk factors and results of the aggressive application of prophylactic tricuspid valve repair. Surg Today 2017;47:445–56. DOI: 10.1007/s00595016-1395-4; PMID: 27502597 9. Van de Veire NR, Braun J, Delgado V, et al. Tricuspid annuloplasty prevents right ventricular dilatation and progression of tricuspid regurgitation in patients with tricuspid annular dilatation undergoing mitral valve repair. J Thorac Cardiovasc Surg 2011;141:1431–9. DOI: 10.1016/ j.jtcvs.2010.05.050; PMID: 20832082 10. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular

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ejection fraction and right ventricular function (as measured by TAPSE) remained unchanged on echocardiography 30 days after the procedure. Despite a reduction of TR in the as-treated population (i.e. patients without pledget detachment) no significant difference in estimated sPAP was observed on echocardiography.35 Interestingly, left ventricular outflow tract stroke volume as measured by Doppler echocardiography increased following TR treatment with the Trialign device. Finally, reduction of TR in the intention-to-treat cohort translated into improvements in NYHA functional class, Minnesota Living with Heart Failure Questionnaire score and 6-min walking distance.35 The ongoing Safety and Performance of the Trialign Percutaneous Tricuspid Valve Annuloplasty System (SCOUT-II) study is a prospective, single‐arm, multicentre study in Europe and the US recruiting patients with moderate-to-severe TR in whom left‐sided valve surgery is not planned. SCOUT-II further investigates safety and performance of the Trialign system with follow up planned up to 2 years and is a European CE-Mark study.

Conclusion Moderate-to-severe TR is a common problem in clinical cardiology and is associated with significant morbidity and reduced long-term survival. Several transcatheter techniques are currently in preclinical and early clinical evaluation as a novel treatment option for patients with symptomatic functional TR and high surgical risk. The Trialign device is a novel percutaneous tricuspid valve annuloplasty technique targeting the pathophysiologic hallmark of functional TR, i.e. dilatation of the tricuspid annulus along its posterior portion. By delivering and cinching two pledgeted sutures the posterior portion of the tricuspid annulus and the posterior tricuspid leaflet is plicated. The SCOUT trial has confirmed the safety and feasibility of the device. However, clinical data are still limited, and further studies are needed to confirm these data in larger cohorts of patients and to investigate whether applying the Trialign device leads to clinical benefit in patients with functional TR. n

heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2438–88. DOI: 10.1016/j.jacc.2014.02.537; PMID: 24603192 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96. DOI: 10.1093/eurheartj/ehs109; PMID: 22922415 Pfannmüller B, Davierwala P, Hirnle G, et al. Concomitant tricuspid valve repair in patients with minimally invasive mitral valve surgery. Ann Cardiothorac Surg 2013;2:758–64. DOI: 10.3978/j.issn.2225-319X.2013.10.01; PMID: 24349978 Pagnesi M, Montalto C, Mangieri A, et al. Tricuspid annuloplasty versus a conservative approach in patients with functional tricuspid regurgitation undergoing left-sided heart valve surgery: a study-level meta-analysis. Int J Cardiol 2017;240:138–44. DOI: 10.1016/j.ijcard.2017.05.014; PMID: 28499671 Kalbacher D, Schäfer U, von Bardeleben RS, et al. Impact of tricuspid valve regurgitation in surgical high-risk patients undergoing MitraClip implantation: results from the TRAMI registry. EuroIntervention 2017;12:e1809–16. DOI: 10.4244/EIJD-16-00850; PMID: 28089952 Ohno Y, Attizzani GF, Capodanno D, et al. Association of tricuspid regurgitation with clinical and echocardiographic outcomes after percutaneous mitral valve repair with the MitraClip System: 30-day and 12-month follow-up from the GRASP Registry. Eur Heart J Cardiovasc Imaging 2014;15:1246–55. DOI: 10.1093/ehjci/jeu114; PMID: 24939944 Schwartz LA, Rozenbaum Z, Ghantous E, et al. Impact of right ventricular dysfunction and tricuspid regurgitation on outcomes in patients undergoing transcatheter aortic valve replacement. J Am Soc Echocardiogr 2017;30:36–46. DOI: 10.1016/j.echo.2016.08.016; PMID: 27742242 Barbanti M, Binder RK, Dvir D, et al. Prevalence and impact of preoperative moderate/severe tricuspid regurgitation on patients undergoing transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2015;85:677–84. DOI: 10.1002/ ccd.25512; PMID: 24740834 Ton-Nu TT, Levine RA, Handschumacher MD, et al. Geometric determinants of functional tricuspid regurgitation: insights from 3-dimensional echocardiography. Circulation

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2006;114:143–9. DOI: 10.1161/CIRCULATIONAHA.106.611889; PMID: 16818811 Knio ZO, Montealegre-Gallegos M, Yeh L, et al. Tricuspid annulus: a spatial and temporal analysis. Ann Card Anaesth 2016;19:599–605. DOI: 10.4103/0971-9784.191569; PMID: 27716689 Fukuda S, Saracino G, Matsumura Y, et al. Three-dimensional geometry of the tricuspid annulus in healthy subjects and in patients with functional tricuspid regurgitation: a realtime, 3-dimensional echocardiographic study. Circulation 2006;114:I492–8. DOI: 10.1161/CIRCULATIONAHA.105.000257; PMID: 16820625 Rodés-Cabau J, Hahn RT, Latib A, et al. Transcatheter therapies for treating tricuspid regurgitation. J Am Coll Cardiol 2016;67:1829–45. DOI: 10.1016/j.jacc.2016.01.063; PMID: 27081024 Hahn RT, Meduri CU, Davidson CJ, et al. Early feasibility study of a transcatheter tricuspid valve annuloplasty: SCOUT trial 30-day results. J Am Coll Cardiol 2017;69:1795–1806. DOI: 10.1016/j.jacc.2017.01.054; PMID: 28385308 Stephan von Bardeleben R, Tamm A, Emrich T, et al. Percutaneous transvenous direct annuloplasty of a human tricuspid valve using the Valtech Cardioband. Eur Heart J 2017;38:690. DOI: 10.1093/eurheartj/ehw399; PMID: 28363225 Rosser BA, Taramasso M, Maisano F. Transcatheter interventions for tricuspid regurgitation: TriCinch (4Tech). EuroIntervention 2016;12:Y110–2. DOI: 10.4244/EIJV12SYA30; PMID: 27640020 Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricuspid regurgitation with the edge-toedge MitraClip technique. Circulation 2017;135:1802–14. DOI: 10.1161/CIRCULATIONAHA.116.024848; PMID: 28336788 Lauten A, Doenst T, Hamadanchi A, et al. Percutaneous bicaval valve implantation for transcatheter treatment of tricuspid regurgitation: clinical observations and 12-month follow-up. Circ Cardiovasc Interv 2014;7:268–72. DOI: 10.1161/ CIRCINTERVENTIONS.113.001033; PMID: 24737337 Laule M, Stangl V, Sanad W, et al. Percutaneous transfemoral management of severe secondary tricuspid regurgitation with Edwards Sapien XT bioprosthesis: first-in-man experience. J Am Coll Cardiol 2013;61:1929–31. DOI: 10.1016/j.jacc.2013. 01.070; PMID: 23500268

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Mitralign for the Tricuspid Valve

28. C ampelo-Parada F, Perlman G, Philippon F, et al. First-inman experience of a novel transcatheter repair system for treating severe tricuspid regurgitation. J Am Coll Cardiol 2015;66:2475–83. DOI: 10.1016/j.jacc.2015.09.068; PMID: 26653620 29. Siminiak T, Dankowski R, Baszko A, et al. Percutaneous direct mitral annuloplasty using the Mitralign Bident system: description of the method and a case report. Kardiol Pol 2013;71:1287–92. DOI: 10.5603/KP.2013.0325; PMID: 24399585 30. Nickenig G, Schueler R, Dager A, et al. Treatment of chronic functional mitral valve regurgitation with a percutaneous annuloplasty system. J Am Coll Cardiol 2016;67:2927–36. DOI: 10.1016/j.jacc.2016.03.591; PMID: 27339489

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31. S chofer J, Bijuklic K, Tiburtius C, et al. First-in-human transcatheter tricuspid valve repair in a patient with severely regurgitant tricuspid valve. J Am Coll Cardiol 2015;65:1190–5. DOI: 10.1016/j.jacc.2015.01.025; PMID: 25748096 32. Kay JH, Maselli-Campagna G, Tsuji KK. Surgical treatment of tricuspid insufficiency. Ann Surg 1965;162:53–8. DOI: 10.1097/00000658-196507000-00009; PMID: 14313519 33. Ghanta RK, Chen R, Narayanasamy N, et al. Suture bicuspidization of the tricuspid valve versus ring annuloplasty for repair of functional tricuspid regurgitation: midterm results of 237 consecutive patients. J Thorac Cardiovasc Surg 2007;133:117–26. DOI: 10.1016/j.jtcvs.2006.08.068; PMID: 17198795

34. N avia JL, Nowicki ER, Blackstone EH, et al. Surgical management of secondary tricuspid valve regurgitation: annulus, commissure, or leaflet procedure? J Thorac Cardiovasc Surg 2010;139:1473–82. DOI: 10.1016/j.jtcvs.2010.02.046; PMID: 20394950 35. Hahn RT, Meduri CU, Davidson CJ, et al. Early feasibility study of a transcatheter tricuspid valve annuloplasty: SCOUT trial 30-day results. J Am Coll Cardiol 2017;69:1795–1806. DOI: 10.1016/j.jacc.2017.01.054; PMID: 28385308 36. Lurz P, Besler C, Kiefer P, et al. Early experience of the Trialign system for catheter-based treatment of severe tricuspid regurgitation. Eur Heart J 2016;37:3543. DOI: 10.1093/eurheartj/ ehw253; PMID: 27354054

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Structural

Minimally Invasive Surgical Mitral Valve Repair: State of the Art Review Karel M Van Praet, 1 Christof Stamm, 1 Simon H Sündermann, 1,2 Alexander Meyer, 1,2,3 Axel Unbehaun, 1 Matteo Montagner, 1 Timo Z Nazari Shafti, 1,2,3 Stephan Jacobs, 1 Volkmar Falk 1,2,3,4 and Jörg Kempfert 1 1. German Heart Center Berlin, Germany; 2. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Germany; 3. Berlin Institute of Health (BIH), Germany; 4. Charité – Universitätsmedizin Berlin, Germany

Abstract Minimally invasive surgical mitral valve repair (MVRepair) has become routine for the treatment of mitral valve regurgitation, and indications have been expanded to include reoperations. Current European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines for the management of valvular heart disease recommended standards in terms of mitral valve disease differentiation, timing of intervention and surgical techniques to improve patient care. Numerous minimally invasive techniques to lessen the invasiveness have been described, such as the minimal-access J-sternotomy (ministernotomy), the parasternal incision, the port-access technique and the right minithoracotomy. Despite the development of catheter-based techniques, surgical repair remains the gold standard today for nearly all patients with degenerative valvular diseases and the majority of patients with other types of valvular diseases. Techniques include resection of the prolapsed segment, neo-chordae implantation and ring annuloplasty. In this review, the current indications for mitral valve surgery are summarised and state-of-the-art MVRepair techniques are highlighted.

Keywords Minimally Invasive Surgery (MIS), Minimally Invasive Mitral Valve Surgery, Minimally Invasive Mitral Valve Repair, Mitral Valve Surgery, Mitral Valve Repair, Endoscopic Mitral Valve Surgery, EndoAortic Crossclamping, Minithoracotomy, Periareolar Approach, 2017 ESC/EACTS Guidelines for the management of valvular heart disease, European Society of Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS) Disclosure: The authors have no conflicts of interest to declare. Received: 14 October 2017 Accepted: 18 December 2017 Citation: Interventional Cardiology Review 2018;13(1):14–9. DOI: 10.15420/icr.2017:30:1 Correspondence: Karel M Van Praet, Resident at the Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin (Deutsches Herzzentrum Berlin), Augustenburger Platz 1, 13353 Berlin, Germany (Deutschland). E: vanpraet@dhzb.de

Reconstructive valve surgery encompasses a comprehensive system of valve analysis and related techniques based on three basic principles as described by Alain Carpentier and colleagues: restoring or preserving the full mobility of the leaflets, creating a large surface of leaflet coaptation and remodelling the annulus to provide an optimal and stable orifice area.1 Mitral valve regurgitation (MR) is one of the most common heart valve diseases represented in cardiac surgery.2 The most common entities are primary and secondary MR due to degenerative changes and ischaemia.3 Today, mitral valve repair (MVRepair) is the gold standard for the treatment of significant MR with results of high patient satisfaction, short hospital stay, low perioperative morbidity and mortality rates and excellent long-term outcomes.4 The enhancements of minimally invasive surgical techniques has led to a decrease in surgical trauma and accelerated postoperative recovery, resulting in increased acceptance of these operating techniques.4,5 Despite these satisfying results, there is ongoing discussion about the ideal timing for the intervention in asymptomatic patients.6 Some groups prefer a watchful waiting strategy; others promote an early intervention, which is recommended in the recently updated 2017 European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines for the management of valvular heart disease.7

History of the Minimally Invasive Surgical Access for Mitral Valve Repair Less invasive approaches to cardiac surgical procedures have been developed in an effort to decrease rates of patient morbidity and

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enhance postoperative recovery in comparison with conventional methods.8 The different approaches that have been used for minimally invasive MV surgery are parasternal incision, minimal-access J-sternotomy (ministernotomy) and right minithoracotomy.8–14 Cosgrove and Navia initially used a 10 cm right parasternal incision to expose both the aortic valve and MV.8,12 This technique included resection of the third and fourth costal cartilages.8 Although safe and effective operations were performed using the parasternal incision, significant disadvantages included occasional chest-wall instability, sacrifice of the right internal thoracic artery, occasional difficulty with aortic valve exposure and difficult conversion to median sternotomy.8 The ministernotomy approach, as described by Svensson,15 has been used for aortic valve and MV procedures.8,11,16,15 This incision provides good exposure of the MV, allows central cannulation, and when necessary, can easily be enlarged to full sternotomy without the need for a second skin incision.8 Furthermore, Loulmet and colleagues found that patients who underwent ministernotomy suffered less pain than those who were treated with a thoracotomy.8,11 However, this strongly depends on the length of incision and degree of spreading of the ribs.8 Casselman and colleagues demonstrated that 93.5 % of patients who received a right minithoracotomy approach reported minimal to almost no procedure-related pain.17 The surgeons only used a soft-tissue

Minimally Invasive Surgical Mitral Valve Repair retractor, and, therefore, avoided any tension on the ribs. This approach offers excellent visualisation of the MV and gives a direct line of view of the left atriotomy and the MV, as the image is perpendicular to the visual plane.8,18,19 Furthermore, the right minithoracotomy approach carries a cosmetic advantage over midline incisions, particularly in women.8,20 Subsequently, robotic MV surgery was fashioned on the already welldeveloped platform of minimally invasive surgical (MIS) MVRepair and added features such as true 3D high-magnification visualisation with a dual camera scope, multidirectional endoaortic cardiac instrument articulation, motion scaling, tremor filtration, and to a degree, a potentially even smaller incision, approaching a totally endoscopic procedure.22 Operative, cardiopulmonary bypass (CPB), and cross-clamp times tend to be longer than nonrobotic minimally invasive approaches.21,22 Excellent results from Dr Chitwood’s large East Carolina University series of 200 robotic MVRepairs have been reported.22–24

Indications for Minimally Invasive Surgical Mitral Valve Repair MR is the second-most frequent indication for valve surgery in Europe.7,25 It is essential to distinguish primary from secondary MR, particularly regarding surgical and transcatheter interventional management.7,26

Primary Mitral Valve Regurgitation and Indications for Intervention In primary MR, one or several components of the MV apparatus are directly affected. The most frequent aetiology is degenerative (prolapse, flail leaflet).7 Endocarditis is one of the causes of primary MR, which is specifically discussed in ESC guidelines.7,27 According to the 2017 ESC/EACTS guidelines for the management for valvular heart disease, indications for surgery in severe chronic primary MR are shown in Table 1 and Figure 1.

Secondary Mitral Valve Regurgitation and Indications for Intervention In secondary MR (previously also referred to as ‘functional MR’), the valve leaflets and chordae are structurally normal and MR results from an imbalance between closing and tethering forces on the valve secondary to alterations in left ventricular geometry.7,28 It is most commonly seen in dilated or ischaemic cardiomyopathies. Annular dilatation in patients with chronic atrial fibrillation and left articular enlargement can also be an underlying mechanism.7 The presence of chronic secondary MR is associated with impaired prognosis.29 However, in contrast to primary MR, there is currently no evidence that a reduction of secondary MR improves survival. According to the 2017 ESC/EACTS guidelines for the management for valvular heart disease, the limited data regarding secondary MR had led to a lower level of evidence for treatment recommendations (see Table 2) and highlight the importance of decision making by the heart team (as heart failure and electrophysiology specialists should be involved).7

Operative Techniques for Minimally Invasive Surgical Access for Mitral Valve Repair

Table 1: Indications for Interventions for Severe Primary Mitral Valve Regurgitation Recommendations

Class Level

Mitral valve repair should be the preferred technique when the results are expected to be durable.

Surgery is indicated in symptomatic patients with LVEF >30%.

Surgery is indicated in asymptomatic patients with LV dysfunction (LVESD >45 mm* and/or LVEF <60%).

Surgery should be considered in asymptomatic patients with preserved LV function (LVESD <45 mm and LVEF >60%) and atrial fibrillation secondary to mitral regurgitation or pulmonary hyper-tension (systolic pulmonary pressure at rest >50 mmHg**).

IIa

Mitral valve repair should be considered in symptomatic patients with severe LV dysfunction (LVEF <30% and/or LVESD >55 mm) refractory to medical therapy when likelihood of successful repair is high and comorbidity low.

IIa

Mitral valve replacement may be considered in symptomatic patients with severe LV dysfunction (LVEF <30% and/or LVESD >55 mm) refractory to medical therapy when likelihood of successful repair is low and comorbidity low.

IIb

Percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe primary mitral regurgitation who fulfil the echocardiographic criteria of eligibility and are judged inoperable or at high surgical risk by the Heart Team, avoiding futility.

IIb

Surgery should be considered in asymptomatic patients with preserved LVEF (>60%) and LVESD 40-44 mm* when a durable repair is likely, surgical risk is low, the repair is performed in heart valve centres, and at least one of the following findings is present: - flail leaflet or, - presence of significant LA dilatation (volume index >60 mL/m2 BSA) insinus rhythm.

Source: courtesy of Professor Volkmar Falk; adapted from Baumgartner, et al., 2017. BSA = body surface area; LA = left atrial; LV = left ventricular; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; SPAP = systolic pulmonary artery pressure. *Cut-offs refer to average-size adults and may require adaptation in patients with unusually small or large stature. **If an elevated SPAP is the only indication for surgery, the value should be confirmed by invasive measurement.

of the valve.30 Three principal goals of MVRepair were introduced by Carpentier: stabilisation of the annulus with the retention of an adequately sized mitral orifice, restoration of physiological leaflet motion and recreation of a sufficient line of coaptation.1,6 The first technique to reach this was the ‘French correction’, introduced in 1983.6,31

Degenerative Mitral Valve Regurgitation

For the purpose of widespread surgical applicability and equipment availability, this section focuses on the right lateral minithoracotomy nonrobotic, transthoracic cross-clamping and endoaortic cross-clamping techniques.

At the German Heart Center Berlin, almost all patients with degenerative MR undergo ring annuloplasty using a semi-rigid ring (CarpentierEdwards Physio II Annuloplasty Ring, Edwards Lifesciences) and neochordae using the loop technique.32 Ring annuloplasty is necessary to achieve a durable repair.21,33

Repair Techniques

Ischaemic Mitral Valve Regurgitation

The surgical technique for repairing the MV can be selected according to the aetiology of the failing valve, and the abnormal segments

Ischaemic MR repair includes annuloplasty with a closed, and often, undersized ring.

INTERVENTIONAL CARDIOLOGY REVIEW

Structural Figure 1: Management of Severe Chronic Primary Mitral Valve Regurgitation Management of severe chronic primary mitral regurgitation

Symptoms

LVEF ≤60 % or LVESD ≥45 mm

New onset of AF or SPAP >50 mmHg No

Yes

Follow-up

Yes

Part of the complexity of MV neochordal replacement with expanded polytetrafluoroethylene (ePTFE) sutures is determining the correct replacement chordal length and knotting the ePTFE suture without sliding the knot. von Oppell and Mohr described this technique of measuring the required chordal length and making a ‘premeasured’ Gore-Tex chordal loop that abolishes problems of inadvertently altering chordal length during fixation.32

Refractory to medical therapy

Yes

High likelihood of durable repair, low surgical risk, and presence of risk factorsa No

Rheumatic valve repair techniques include commissural fusion release, detachment of papillary muscle fusion, resection of prolapsing segments and ring annuloplasty.

LVEF >30 %

Yes

MR repair techniques include excision of all infected and inflamed tissue, and repair of the missing tissue with fresh pericardial patch or primary suturing. Some patients need implantation of artificial chordae and most undergo ring annuloplasty.

Rheumatic Mitral Valve Disease Yes

Mitral Valve Endocarditis

Yes

Medical therapy Durable valve repair is likely and low comorbidity No

Yes

Extended HF treatment/percutaneous edge-to-edge repair

Surgery (repair whenever possible) Source: Courtesy of Professor Volkmar Falk; adapted from Baumgartner, et al., 2017. AF = atrial fibrillation; BSA = body surface area; CRT = cardiac resynchronisation therapy; HF = heart failure; LA = left atrial; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; SPAP = systolic pulmonary arterial pressure. aWhen there is a high likelihood of durable valve repair at a low risk, valve repair should be considered (IIa C) in patients with LVESD ≥40 mm and one of the following is present: flail leaflet or LA volume ≥60 ml/m2 BSA at sinus rhythm. bExtended HF management includes the following: CRT, ventricular assist devices, cardiac restraint devices and heart transplantation.

Table 2: Indications for Mitral Valve Intervention in Chronic Secondary Mitral Regurgitation

Setup in the Operating Room for Minimally Invasive Surgical Access for Mitral Valve Repair Through a Right Lateral Minithoracotomy The right lateral minithoracotomy in combination with adjunctive videoscopy and peripheral CPB has become the preferred approach at the German Heart Center Berlin. Images from the operative setups are shown in Figures 2 and 3.

Patient Positioning and Anaesthetics The patient is intubated with a double lumen endotracheal tube and positioned supine with a small pillow under the right scapula to elevate the right hemithorax. If endoaortic balloon occlusion cross-clamping is planned, placement of bilateral radial arterial catheters will provide immediate warning of cephalad displacement of the endoballoon and subsequent innominate arterial obstruction.

Recommendations

Class Level

Incisional Approach

Surgery is indicated in patients with severe secondary mitral regurgitationundergoing CABG and LVEF >30%.

Surgery should be considered in symptomatic patients with severe secondary mitral regurgitation, LVEF <30% but with an option for revascularization, and evidence of myocardial viability.

IIa

When revascularization is not indicated, surgery may be considered in patients with severe secondary mitral regurgitation and LVEF >30%, who remain symptomatic despite optimal medical management (including CRT if indicated) and have a low surgical risk.

IIb

In patients with severe secondary mitral regurgitation and LVEF <30% who remain symptomatic despite optimal medical management (including CRT if indicated) and who have no option for revascularization, the Heart Team may consider percutaneous edge-to-edge procedure or valve surgery after careful evaluation for ventricular assist device or heart transplant according to individual patient characteristics.

IIb

A small 4 cm right lateral minithoracotomy, inframammary in men and in the submammary crease in women, is used to enter the thorax through the fourth intercostal space (ICS). A more lateral incision provides a more en face view of the MV, albeit at the expense of distance. A more medial approach provides closer access to all structures. A small thoracic and soft tissue retractor is used to spread the ribs. Alternative access as a variation of the standard right lateral minithoracotomy is the permutative periareolar ‘nipple-cut’ to surgically approach the intrathoracic organs and perform the MVRepair. This minimally invasive periareolar approach for surgical MVRepair in male patients entails a 3 cm small convex incision that straddles the right areolar border (Figure 2). Therefore, we use a soft-tissue retractor without additional rib spreading. Patient scar assessment scale scores suggest that this periareolar approach delivers patient-satisfying results regarding cosmetic and sensory function outcomes. The endoscopic periareolar approach is safe, efficient and cosmetically appealing, and compared with the conventional minithoracotomy for MIS MVRepair, the periareolar approach proves to be feasible and allows for surgery through an elegant incision without traumatic rib spreading. This technique is reproducible and even allows for complex MVRepair, additional tricuspid valve (TV) procedures and cryo-ablation (results of this study were presented during an oral presentation at ISMICS 2017 in Rome and EACTS 2017 in Vienna).

Source: courtesy of Professor Volkmar Falk; adapted from Baumgartner, et al., 2017. CABG = coronary artery bypass grafting; CRT = cardiac resynchronisation therapy; LVEF = left ventricular ejection fraction.

INTERVENTIONAL CARDIOLOGY REVIEW

Minimally Invasive Surgical Mitral Valve Repair Intrathoracic Exposure The right hemidiaphragm is retracted caudal and to the right with a suture placed in the tendonous dome and brought out by a suture hook through a stab incision in the right sixth or seventh space. The pericardium is opened 3–4 cm anterior and parallel to the phrenic nerve from the distal ascending aorta to the diaphragm.

Figure 2: The Minimally Invasive Periareolar ‘Nipple-cut’ Approach for Surgical Mitral Valve Repair

Cannulation and CPB The patient is connected to CPB by cannulation of the femoral artery and vein (single venous cannula for isolated MV procedures) through a 2 cm oblique incision in the groin. Transoesophageal echocardiography (TEE) is mandatory to confirm the optimum location of the tip of the venous cannula in the right atrium (Figure 3). Body temperature is maintained at around 34°C and vacuum-assisted venous drainage is used throughout the procedure. In general, a 14, 16 or 18 FR arterial cannula is sufficient depending on patient size and arterial diameter. Introduction of the cannula should be carried out with TEE confirmation of the endoaortic luminal position of the wire to minimise the risk of localised vessel dissection or injury. A 22 FR long venous cannula is sufficient and can be positioned at the inferior vena cava (IVC)/right articular junction by TEE guidance.

The minimally invasive periareolar nipple-cut approach for surgical mitral valve repair in male patients entails a 3cm small convex incision that straddles the right areolar border. A. Just before incision, the right periareolar border gets delined. B. Incised skin C. Aesthetically appealing postoperative result after the procedure is performed.

Aortic Clamping (see Figure 4) Transthoracic Cross-clamping The transthoracic Chitwood clamp can be inserted via a 5 mm port through the third ICS at the right midaxillary line and positioned near the ascending aorta. Two litres of antegrade cardioplegia is delivered directly into the aortic root through a long needle and repeated after 90–120 minutes, if necessary.

Figure 3: Complete Setup for Fully Endoscopic Highdefinition 3D Minimally Invasive Mitral Valve Surgery

Endoartic Cross-clamping Using an aortic endoclamp placed through a side limb of the femoral arterial CPB cannula, aortic cross-clamping, antegrade cardioplegia administration and aortic root venting can be accomplished. The endoclamp is a multi-lumen catheter with an inflatable balloon at its distal end, which provides endo-aortic clamping. A central lumen can provide antegrade cardioplegia delivery or alternatively aortic root venting. A second tip lumen allows monitoring of aortic root pressure.

Video-assisted Endoscopic Monitoring Once the thorax has been entered, a high-definition standard (0° for direct vision minimally invasive MV surgery or 30° for fully-endoscopic high-definition 3D MIS MV surgery [see Figure 3]) thoracoscope can be placed into the chest via a 10 mm port through the second or third interspace at the right anterior axillary line. The thoracoscope not only provides an additional view from which to perform subsequent work, but also brightly illuminates the entire chest. Throughout the procedure, the surgical field is flooded with carbon dioxide through the camera port.

neochordae to Alfieri’s edge-to-edge repair. Ischaemic MR is corrected using an undersized annuloplasty ring.

MV Exposure and Surgical Mitral Valve Repair

De-airing and Closure

The MV is accessed through a paraseptal incision and a left atrial retractor is used to expose the MV. MVRepair for degenerative MV disease is most commonly performed using the Gore-Tex neochordae using the loop technique.32 Assessment of the optimal length and precise fixation of neochordae to the papillary muscles and the free edge of the mitral leaflets are the fundamental aspects of this technique. A semi-rigid annuloplasty ring is implanted to support the repair. MV competency is restored in patients with Barlow’s disease, using a myriad of different techniques from leaflet resection to

After completing the mitral procedure, the right superior pulmonary vein vent should be placed across the competent MV to a depth such that venting holes are in both the ventricle and the atrium. The left atrium is then de-aired by filling it with saline during closure. A direct closure of a patient foramen ovale (PFO)/atrial septal defect (ASD) can be easily performed through the left atrial approach; however, patch closure of the ASD, TV repair or TV replacement have to be accessed through the right atrium after establishing total CPB by clamping the superior and inferior vena cavae. TV repair or TV replacement can also be performed after

INTERVENTIONAL CARDIOLOGY REVIEW

High-definition 3D minimally invasive mitral valve surgery as performed by Jörg Kempfert, MD and his team at the German Heart Center, Berlin. A. The minimally invasive periareolar approach for surgical mitral valve repair in male patients entails a 3 cm small convex incision that straddles the right areolar border. A soft-tissue retractor without additional rib spreading is used. B. A 3D screen is used. C. The surgeon operating on the mitral valve fully endoscopically with 3D glasses. Complete peripheral cardiopulmonary bypass with endoaortic cross-clamping using the endoaortic balloon is being performed. D. Ring annuloplasty.

Structural Figure 4: Schematic Drawings of Aortic Cross-clamping Techniques

Left: Endoaotic cross-clamping using an endoaortic balloon. Right: Transthoracic cross-clamping using a transthoracic (Chitwood) clamp.

releasing the aortic clamp. Epicardial pacing wires should be placed while the heart is still decompressed on CPB. Following this, separation from CPB, decannulation, TEE examination of adequacy of mitral repair, and reversal of anticoagulation are all conducted as in a standard operation.

Results Results of Minimally Invasive Surgical Mitral Valve Repair in Patients with Severe Primary Mitral Valve Regurgitation Institutions such as the German Heart Center Berlin, the Heart Center Leipzig, Germany and the OLV Clinic Aalst, Belgium contribute immensely to the development, progress and quality of minimally invasive MV surgery. Therefore, these high-volume programmes have high and durable repair rates with minimal mortality. Casselman and collaegues described the results of 187 patients who had undergone MIS MVRepair in a 4-year study.17 The operative technique was successfully performed in all but two patients. Therefore, success rate was almost 100 % and it proved immediate technical feasibility of the minimally invasive procedure. Freedom from MV reoperation was 99.5 % ± 0.5 % at 30 days, 97.1 % ± 1.4 % at 1 year and 93.3 % ± 2.6 % at 4 years. Seeburger and colleagues described the results of 1,339 patients who had undergone MIS MVRepair in an 8-year study.4,35 Success rate was almost 100 %. The 5-year Kaplan–Meier estimation for freedom from MV reoperation was 96.3 %. The 30-day mortality rate was 2.4 % and the 5-year survival rate was 82.6 %. Davierwala and colleagues described the results of 3,438 patients who had undergone minimally invasive MV surgery during 1999–2010, of which 2,829 were MVRepairs.21 For MVRepair, the survival rates were 87.0 ± 0.7 % and 74.2 ± 1.4 % at 5 and 10 years, respectively. The rates of freedom from reoperation were 96.6 ± 0.4 % and 92.9 ± 0.9 % at 5 and 10 years, respectively.

Results of Minimally Invasive Surgical Mitral Valve Repair in Patients with Chronic Secondary Mitral Valve Regurgitation Sündermann and colleagues reported that the outcome of patients undergoing MVRepair for secondary MR is dependent to the underlying cause of cardiomyopathy and the concomitant procedure.6 Gummert

and colleagues described a 30-day mortality rate of 6.1 % and a 5-year survival rate of 66 % in patients with dilated and ischaemic cardiomyopathy.36 TV repair and atrial fibrillation ablation and atrial size reduction were the only accepted concomitant procedure.6,36 Bax and colleagues reported their results for 51 patients undergoing coronary revascularisation and parallel restrictive MVRepair in ischaemic cardiomyopathy.37 Their early mortality rate was 5.6 % and the 2-year survival was 84 %. One patient had to undergo reoperation for recurrent MR. The 2-year echocardiographic follow-up showed no or mild MR in all patients as well as a decrease in left ventricular end systolic and end diastolic dimensions. Additionally, differences in outcome in regards of the use of a complete or a partial annuloplasty ring have been observed by Kwon and colleagues.38 In a retrospective study of 479 patients who had undergone MVRepair due to secondary MR, they found a greater freedom from recurrent MR in the 209 patients in whom a complete ring was used compared with 270 patients treated with a partial ring. A difference in survival rates during the follow-up could not be detected.

Perspective According to guidelines, surgical repair should be performed whenever feasible and early intervention is warranted when durability is predicted.39 However, careful patient selection (and operator experience) plays a key role in achieving ideal initial and sustained outcomes. Therefore, as postulated by Maisano and colleagues,39 endovascular transcatheter therapy for MR (e.g. the MitraClip procedure) currently should be limited to patients who otherwise would not be eligible for surgery. In patients with lowrisk degenerative MR, surgical repair will remain the standard of care for many years, with transcatheter MV repair (TMVRep) and transcatheter MV implantation (TMVI) playing a role in high-risk or inoperable patients who are not amenable for MIS MVRepair or eventually for TMVRep.39 In patients with chronic secondary MR, the role of surgery is less well established in patients who are not candidates for coronary artery bypass graft, and most patients are treated medically. TMVRep may be a safe, palliative approach for such patients, and several large-scale randomised ongoing trials investigate the effectiveness of the MitraClip in this scenario. In the future, careful patient selection will play a fundamental role in identifying specific patients most likely to benefit from MV surgery versus TMVI versus TMVRep.39

Conclusions The right anterolateral minithoracotomy in the fourth intercostal space is currently the most commonly applied approach. For these procedures, videoscopic assistance and the use of telemanipulative robots (e.g. da Vinci system) are adjunctive techniques for further decreasing trauma of the surgical access. In experienced hands, the minimally invasive approach has shown excellent results with regard to operative complications and the durability of surgical MVRepair. Furthermore, today MVRepair is the gold standard for treatment of significant MR with results of high patient satisfaction, short hospital stay, low perioperative morbidity and mortality rates and excellent long-term outcomes.

Acknowledgements The authors would like to thank Professor Volkmar Falk for sharing Figure 1 and Tables 1 and 2 with us. We also would like to thank our graphic team at the German Heart Center Berlin (Helge Haselbach and Christian Meier) for drawing the schematic figures and taking the professional photographs of the operative setups. n

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Minimally Invasive Surgical Mitral Valve Repair 1.

9. 10.

11.

12.

13.

14.

15.

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Surg 1997;64:1501–3. DOI: 10.1016/S0003-4975(97)00927-2; PMID: 9386741. 16. G illinov AM, Cosgrove DM. Minimally invasive mitral valve surgery: mini-sternotomy with extended transseptal approach. Semin Thorac Cardiovasc Surg 1999;11:206–11. PMID: 10451251. 17. Casselman FP, Van Slycke S, Dom H, et al. Endoscopic mitral valve repair: feasible, reproducible and durable. J Thorac Cardiovasc Surg 2003;125:273–82. DOI: 10.1067/mtc.2003.19; PMID: 12579095. 18. Onnasch JF, Schneider F, Falk V, et al. Five years of less invasive mitral valve surgery: from experimental to routine approach. Heart Surg Forum 2002;5:132–5. PMID: 12125665. 19. Onnasch JF, Schneider F, Falk V, et al. Minimally invasive approach for redo mitral valve surgery: a true benefit for the patient. J Card Surg 2002;17:14–9. PMID: 12027121. 20. Reichenspurner H, Boehm DH, Gulbins H, et al. Threedimensional video and robot-assisted port-access mitral valve operation. Ann Thorac Surg 2000;69:1176–81. PMID: 10800815. 21. Davierwala PM, Seeburger J, Pfannmueller B, et al. Minimally invasive mitral valve surgery : “The Leipzig experience”. Ann Cardiothorac Surg 2013;2:744–50. DOI: 10.3978/j.issn.2225319X.2013.10.14; PMID: 24349976. 22. Woo YJ, Seeburger J, Mohr FW. Minimally Invasive Valve Surgery. Semin Thorac Cardiovasc Surg 2007;19:289–98. DOI: 10.1053/j.semtcvs.2007.10.005; PMID: 18395627. 23. Woo YJ, Rodriguez E, Atluri P, Chitwood WR. Minimally Invasive, robotic, and off-pump mitral valve surgery. Semin Thorac Cardiovasc Surg 2006;18:139–47. DOI: 10.1053/j. semtcvs.2006.07.004; PMID: 17157235. 24. Rodriguez E, Kypson AP, Moten SC, et al. Robotic mitral surgery at East Carolina University: a 6 year experience. Int J Med Robot 2006;2:211–5. DOI: 10.1002/rcs.80; PMID: 17520634. 25. Lung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231–43. PMID: 12831818. 26. De Bonis M, Al-attar N, Antunes M, et al. Surgical and interventional management of mitral valve regurgitation : a position statement from the European Society of Cardiology Working Groups on Cardiovascular Surgery and Valvular Heart Disease. Eur Heart J 2016;37:133–9. DOI: 10.1093/eurheartj/ ehv322; PMID: 26152116. 27. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015;36:3075–128. DOI: 10.1093/eurheartj/ehv319; PMID: 26320109.

28. L evine RA, Schwammenthal E. Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying concepts. Circulation 2005;112:745–58. DOI: 10.1161/ CIRCULATIONAHA.104.486720; PMID: 16061756. 29. Grigioni F, Enriquez-sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759–64. PMID: 11282907 30. Spiegelstein D, Ghosh P, Sternik L, et al. Current strategies of mitral valve repair. Isr Med Assoc J 2007;9:303–9. PMID: 17491227. 31. Schubert SA, Mehaffey JH, Charles EJ, Kron IL. Mitral Valve Repair: The French Correction Versus the American Correction. Surg Clin North Am 2017;97:867–88. DOI: 10.1016/j. suc.2017.03.009; PMID: 28728720. 32. von Oppell UO, Mohr FW. Chordal replacement for both minimally invasive and conventional mitral valve surgery using premeasured Gore-Tex loops. Ann Thorac Surg 2000;70:2166–8. PMID: 11156150. 33. Gillinov AM, Tantiwongkosri K, Blackstone EH, et al. Is prosthetic anuloplasty necessary for durable mitral valve repair? Ann Thorac Surg 2009;88:76–82. DOI: 10.1016/j. athoracsur.2009.03.089; PMID: 19559197. 34. Saunders PC, Grossi EA, Sharony R, et al. Minimally invasive technology for mitral valve surgery via left thoracotomy: experience with forty cases. J Thorac Cardiovasc Surg 2004;127:1026–31. DOI: 10.1016/j.jtcvs.2003.08.053; PMID: 15052199. 35. Seeburger J, Borger MA, Falk V, et al. Minimal invasive mitral valve repair for mitral regurgitation: results of 1339 consecutive patients. Eur J Cardiothorac Surg 2008;34:760–5. DOI: 10.1016/j.ejcts.2008.05.015; PMID: 18586512. 36. Gummert JF, Rahmel A, Bucerius J, et al. Mitral valve repair in patients with end stage cardiomyopathy: who benefits? Eur J Cardiothorac Surg 2003;23:1017–22. PMID: 12829081. 37. Bax JJ, Braun J, Somer ST, et al. Restrictive annuloplasty and coronary revascularization in ischemic mitral regurgitation results in reverse left ventricular remodelling. Circulation 2004;110:II-103–8. DOI: 10.1161/01.CIR.0000138196.06772.4e; PMID: 15364847. 38. Kwon MH, Lee LS, Cevasco M, et al. Recurrence of mitral regurgitation after partial versus complete mitral valve ring annuloplasty for functional mitral regurgitation. J Thorac Cardiovasc Surg 2013;146:616–22. DOI: 10.1016/j. jtcvs.2012.07.049; PMID: 22921822. 39. Maisano F, Alfieri O, Banai S, et al. The future of transcatheter mitral valve interventions: competitive or complementary role of repair vs. replacement? Eur Heart J 2015;36:1651–9. DOI: 10.1093/eurheartj/ehv123; PMID: 25870204.

Structural

Bioprosthetic Valve Fracture During Valve-in-valve TAVR: Bench to Bedside John T Saxon, 1,2 Keith B Allen, 1,2 David J Cohen 1,2 and Adnan K Chhatriwalla 1,2 1. Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA; 2. University of Missouri – Kansas City, Kansas City, MO, USA

Abstract Valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) has been established as a safe and effective means of treating failed surgical bioprosthetic valves (BPVs) in patients at high risk for complications related to reoperation. Patients who undergo VIV TAVR are at risk of patient–prosthesis mismatch, as the transcatheter heart valve (THV) is implanted within the ring of the existing BPV, limiting full expansion and reducing the maximum achievable effective orifice area of the THV. Importantly, patient–prosthesis mismatch and high residual transvalvular gradients are associated with reduced survival following VIV TAVR. Bioprosthetic valve fracture (BVF) is as a novel technique to address this problem. During BPV, a non-compliant valvuloplasty balloon is positioned within the BPV frame, and a highpressure balloon inflation is performed to fracture the surgical sewing ring of the BPV. This allows for further expansion of the BPV as well as the implanted THV, thus increasing the maximum effective orifice area that can be achieved after VIV TAVR. This review focuses on the current evidence base for BVF to facilitate VIV TAVR, including initial bench testing, procedural technique, clinical experience and future directions.

Keywords Transcatheter aortic valve replacement, valve-in-valve TAVR, bioprosthetic valve fracture, patient–prosthesis mismatch, aortic stenosis Disclosure: Dr. Chhatriwalla receives research and clinical trial support from, acts as a proctor of, and is on the speakers bureau of Medtronic, Edwards Lifesciences and St. Jude Medical. Dr. Cohen receives research and clinical trial support from Medtronic, St. Jude Medical, and Edwards Lifesciences. Dr. Allen receives research support from Abbott Medical and Edwards Lifesciences, and is on the speakers bureau of Edwards Lifesciences and Medtronic. Dr. Saxon has no disclosures. Received: 10 October 2017 Accepted: 4 December 2017 Citation: Interventional Cardiology Review 2018;13(1):20–6. DOI: 10.15420/icr.2017:29:1 Correspondence: Adnan Chhatriwalla, MD, Saint Luke’s Mid America Heart Institute, 4330 Wornall Road, Suite 2000, Kansas City, MO 64111, USA. E: achhatriwalla@saint-lukes.org

Surgical aortic valve replacement (SAVR) has long been the standard of care for aortic valve replacement. More recently, transcatheter aortic valve replacement (TAVR) has been established as a safe, effective and less invasive method of valve replacement in patients with severe aortic stenosis who are at intermediate or high risk for complications related to SAVR.1–4 For patients who present with surgical bioprosthetic valve (BPV) degeneration, reoperation may be associated with increased risks.5,6 Valve-in-valve (VIV) TAVR has emerged as a safe and effective therapy for such patients.7,8 The US Food and Drug Administration has approved VIV TAVR with both self-expanding and balloon-expandable prostheses for patients with failed BPVs who are at high risk for complications related to reoperation. Although VIV TAVR is a promising alternative to repeat SAVR, patient– prosthesis mismatch (PPM) is a concern. Broadly, PPM is defined as any situation in which the effective orifice area (EOA) of a prosthetic valve is smaller than the orifice of the patients’ native aortic valve; severe aortic PPM is defined as an indexed EOA ≤0.65 cm2/m2.9 Patients who undergo VIV TAVR are particularly at risk for PPM because the TAVR prosthesis is implanted within the frame of the previous BPV, thereby reducing the maximum EOA that can be achieved with the new valve. Importantly, severe PPM and small labelled BPV size (≤21 mm) have been associated with higher mortality following VIV TAVR.10–12 In the VIVID Registry, which is the largest series of VIV TAVR published to date, the incidence of severe PPM following VIV TAVR was 31.8 %.7 Furthermore, patients in the same series with a small labelled surgical valve size (≤21 mm) had a reduced survival at 1 year (74.8 %) compared with patients with an intermediate (21–25 mm) sized BPV

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(81.8 %) or a large (≥25 mm) BPV (93.3 %), suggesting that PPM has a negative impact on survival following VIV TAVR. Several strategies have been developed to avoid PPM following VIV TAVR. Use of a transcatheter heart valve (THV) with supra-annular leaflet positioning (e.g. CoreValve Evolut, Medtronic, Minneapolis, MN, USA) may result in a larger EOA due to the supra-annular position of the prosthetic leaflets, and a higher THV implant depth may improve inflow dynamics and augment the effective EOA.13–17 Recently, several publications have reported on the concept of fracturing the surgical BPV ring with a high-pressure balloon inflation in order to dilate the BPV and permit further expansion of the THV,18–20 improving haemodynamic results in such patients.21–24 This review summarises our current knowledge of BPV fracture (BVF) to facilitate VIV TAVR, including information obtained from bench testing, procedural techniques, early clinical experience and future directions.

Bench Testing To date, there have been two published series regarding the tolerance of commercially available BPVs to high-pressure balloon inflation using non-compliant valvuloplasty balloons. Results of BVF in Trifecta (St Jude, Minneapolis, MN, USA), Mitroflow (Sorin, Milan, Italy), Magna Ease (Edwards Lifesciences, Irvine, CA, USA), Mosaic (Medtronic), Magna (Edwards Lifesciences), Hancock II (Medtronic) and Biocor Epic (St Jude) valves using Atlas Gold (Bard, Tempe, AZ, USA) and True Balloons (Bard) have been reported.21,24 The procedural technique for BVF bench testing is displayed in Figure 1. Non-compliant balloons were positioned within small BPVs (i.e. labelled

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Bioprosthetic Valve Fracture During VIV TAVR valve size 19 or 21 mm). Valvuloplasty balloons were sized 1 mm larger than the labelled surgical valve size. A high-pressure stopcock was used to separately attach a syringe and an indeflator to the balloon. With the stopcock open to the syringe, an initial hand inflation was performed to rapidly inflate the balloon, then the stopcock was opened to the indeflator, and the pressure was gradually increased in the balloon system until the BPV ring fractured. Fracture of the BPV ring was typically associated with a sudden decrease in inflation pressure, visible release of the balloon waist, and/or an audible “click”. BVF was considered unsuccessful if the balloon ruptured without evidence of valve fracture. The fracture threshold was reported as the lowest inflation pressure necessary to cause BPV ring fracture. Following BVF, the fractured valves were inspected for protruding elements or other potentially harmful results related to BPV disruption.21,24 The findings of systematic bench testing are summarised in Table 1. BPVs that could be consistently fractured in both series were Magna, Magna Ease, Mitroflow, Mosaic and Biocor Epic. Upon dissection of the sewing cuff, the fractured elements were directly visualised to confirm complete separation of the ring element (Figure 2).21,24 Hancock II valves could not be fractured in either series. BVF of 19 mm Trifecta valves was also unsuccessful in both series.21 A partial fracture of the 21 mm Trifecta valve (separation of the lower of two parallel rings of the frame) was noted by both groups. However, this partial fracture only occurred at very high inflation pressure (26 atm) or after the use of serial balloon inflations with increasing balloon diameter. Neither authors recommended BVF in Trifecta valves. The minimum inflation pressures necessary to fracture similar valves were slightly different in the two series (Table 1). In general terms, BPVs with an alloyed metal ribbon ring (Magna and Magna Ease) demonstrated a higher fracture threshold (18–24 atm) than BPVs with a polymer ring (Biocor Epic, Mosaic, Mitroflow; 8–12 atm). Different techniques were used to measure inflation pressure at the moment of fracture in the two series, thus the small differences in observed fracture thresholds were not unexpected. In practical terms, precise knowledge of the fracture threshold may not be necessary. Rather, when a clinical case of BVF is planned, the most critical information is the knowledge that a particular type of valve can be fractured, and the approximate inflation pressure that will result in fracture. Therefore, the largely concordant findings between the two series serves as an excellent guide for operators when planning a BVF procedure.

Indications At present, the indications to perform BVF to facilitate VIV TAVR are not fully defined. The majority of patients, in particular those with large surgical valves, are likely to achieve an adequate haemodynamic result with VIV TAVR, and patients without PPM following VIV TAVR have an excellent survival to 1 year.7,8 Therefore, patients who stand to benefit the most from BVF are those who are predisposed to PPM and high residual transvalvular gradients following VIV TAVR, including those with small BPVs (labelled valve size ≤21 mm) and/or stenosis as the mechanism of BPV failure.7,8 Whether patients with large BPVs (>21 mm labelled valve size) or intermediate transvalvular gradients (10–20 mmHg) after VIV TAVR stand to benefit from BVF is not known.

Clinical Application Translating the ex vivo BVF technique to a clinical setting is intuitive (Figure 2). During a case of VIV TAVR, a non-compliant valvuloplasty balloon, such as those used in bench testing, is positioned across the BPV

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Figure 1: Technique of High-pressure Balloon Inflation to Perform Bioprosthetic Valve Fracture

(1) A high pressure stopcock connects the valvuloplasty balloon to a syringe of dilute contrast and an indeflator. (2) The syringe is used to inflate the balloon manually. (3) The stopcock is turned so that the syringe is off and the indeflator is on. (4) The indeflator is dialed to the desired pressure, until the bioprosthetic valve fractures or the balloon ruptures.

ring (Figure 3a) over a stiff wire. At that point, the procedural technique is the same as depicted in Figure 1b,c. During rapid ventricular pacing, an initial hand inflation is used to fill the balloon with dilute contrast, then a coronary indeflator is used to increase the inflation pressure to the threshold for valve fracture. BPV fracture is accompanied by the same auditory, visual and haptic feedback as is observed during bench testing: a sudden drop in inflation pressure, a visible release of the balloon waist (Figure 3b,c) and/or an audible “click”. The valvuloplasty balloon is then deflated and removed. Figure 3d depicts the final result from the same clinical case, with a dramatic increase in expansion of both the TAVR prosthesis and BPV ring. Of note, given the prolonged nature of the pacing run that is often required, we prefer to perform all BVF procedures under general anesthesia to minimise any temporary neurologic sequelae. An example of the haemodynamic result of a clinical case of BVF with VIV TAVR is depicted in Figure 3. A 76-year-old man with a history of combined coronary artery bypass grafting (CABG) and SAVR, with a 23 mm Mosaic BPV 10 years prior, presented with symptoms of class III diastolic heart failure and severe BPV stenosis, with a mean transvalvular gradient of 49 mmHg, a peak Doppler velocity of 4.7 m/s and dimensionless index of 0.25. The Society of Thoracic Surgeons (STS) predicted risk of mortality was 8.2 %, and after a Heart Team evaluation, VIV TAVR was recommended. Baseline invasive haemodynamics (Figure 3a) demonstrated a mean gradient of 36 mmHg with a calculated valve EOA of 0.7 cm2. After deployment of a 26 mm CoreValve Evolut R self-expanding TAVR prosthesis, the mean gradient was reduced to 25 mmHg, with a corresponding EOA of 1.2 cm2 (Figure 3b). BVF was then performed with a 24 mm True Balloon, and the bioprosthetic ring fractured at 10 atm. Final haemodynamics demonstrated a mean gradient of 3 mmHg and an EOA of 1.7 cm2 (Figure 3c). At 1 month follow up, the patient was doing well, with New York Heart Association class 1 functional status. An echocardiogram at that time demonstrated a mean transvalvular gradient of 8 mmHg, with a peak Doppler velocity of 2.0 m/s and a dimensionless index of 0.68.

Clinical Experience The procedural and haemodynamic results of patients who have been treated with VIV TAVR and BVF in two published case series are displayed in Table 2.22,23 A total of 30 patients with a mean age of 79.0 years were treated with VIV TAVR for failed BPVs. The majority of cases were performed to treat BPV stenosis, with a mean time from SAVR implant to VIV TAVR of 10.4 years. Fifteen patients were treated with TAVR prior to BVF, and

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Structural Table 1: Combined Results of Bioprosthetic Valve Fracture Bench Testing Manufacturer/

Valve

Bard TRU Balloon

Bard Atlas Gold** Appearance

Brand

Size

Fracture/Pressure

St. Jude Trifecta

St Jude Biocor Epic

19 mm

21 mm

YES/ 8 atm

NOT TESTED

19 mm

YES/ 10 atm

21 mm

YES/ 10 atm

YES/ 8 atm

21 mm

NOT TESTED

19 mm

YES/ 12 atm

NOT TESTED

21 mm

YES/ 12 atm

YES/ 10 atm

19 mm

YES/ 18 atm

YES/ 19 atm

21 mm

YES/ 18 atm

YES/ 21 atm

19 mm

YES/ 24 atm

NOT TESTED

21 mm

YES/ 24 atm

After Fracture

Medtronic Mosaic

Medtronic Hancock II

Sorin Mitroflow

Edwards MagnaEase

Edwards Magna

Balloons sized 1 mm larger than valve size. The Medtronic Mosaic and Sorin Mitroflow have no metal ring. Therefore, their appearance after fracture remains unchanged. Source: Johansen, et al., 2017; Allen, et al., 2017; **these date obtained from Johansen et al., 2017.

15 patients were treated with BVF followed by TAVR implant. There were no reports of perioperative death, coronary artery obstruction, annular rupture, aortic root injury, paravalvular leak or pericardial effusion. Two patients suffered small periprocedural strokes that were confirmed with MRI, and both patients later recovered full neurological function.22,23 Ten cases were performed with backup haemodynamic support with extracorporeal membrane oxygenation (ECMO), and 100 % long-term survival was noted in one case series (n=10), with a mean follow up of 438 days.23 The procedural results reported in these two case series highlight the haemodynamic benefit of BVF (Table 2). For the combined cohort, the mean gradient was reduced from 41 mmHg pre-procedure to 11 mmHg after BVF and VIV TAVR, which corresponds to an improvement in EOA from 0.75 to 1.7 cm2. In one series, most of the patients (15/20) were treated with BVF after VIV TAVR was performed. For this subset of patients, the mean pre-procedural gradient was reduced from 41.9 to 20.5 mmHg after VIV TAVR, and the mean gradient was further reduced from 20.5 to 6.7 mmHg following BVF. This corresponds to mean EOAs

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of 0.6, 1.0 and 1.7 cm2, respectively. The benefit of BVF to improve the procedural results of VIV TAVR is evident: with VIV TAVR alone, these patients would have been left with a suboptimal EOA of 1.0 cm2 and a final mean gradient of 20.5 mmHg.

Complications Although the haemodynamic benefit of BVF is clear, the incremental risk posed by BVF in addition to VIV TAVR is not fully known. In the two clinical series published to date (total n=30), complications were few. Two patients suffered a small periprocedural stroke, with complete resolution of neurological deficits. One patient suffered complete atrioventricular block requiring a permanent pacemaker.22,23 However, stroke and heart block are potential complications of TAVR even in the absence of BVF. Despite the relatively low complication rate in the published series and unpublished clinical experience, there are some theoretical risks specific to the BVF procedure that must be considered. Although there were no incidents of aortic root disruption, paravalvular leak, aortic insufficiency or coronary occlusion in the published case series, it is important to acknowledge that the clinical experience with

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Bioprosthetic Valve Fracture During VIV TAVR BVF is still early. There is still much to learn about the specific clinical and anatomic features that predispose patients to complications.

Figure 2: Fractured 21 mm Mitroflow Bioprosthetic Valve

Coronary Artery Obstruction As is true of VIV TAVR, one of the major concerns with BVF is the potential for coronary artery obstruction. A recent registry of VIV TAVR reported an incidence of coronary artery obstruction of 3.5 % with VIV TAVR,25 which appears to be decreasing as experience with VIV TAVR grows.26 There are several risk factors for coronary obstruction during VIV TAVR: narrow coronary sinuses, low coronary artery ostia, bulky bioprosthetic leaflets, reimplanted coronary arteries and type of BPV, i.e. those with leaflets mounted external to the stent frame (Mitroflow, Trifecta).26 Whereas the typical concern with native valve TAVR is coronary ostial height in relation to the native aortic annulus, during VIV TAVR the most important factor is the anticipated distance between the coronary ostia and the final position of the BPV leaflets.26 This relationship can be assessed during pre-procedural coronary angiography as well as by computed tomography, wherein a “virtual THV” can be superimposed on the CT images to determine the relationship between the BPV leaflets and the coronary arteries.26 A virtual THV to coronary distance of less than 3 mm is considered to place a patient at high risk for coronary occlusion.26 With BVF, the architecture of the BPV is altered such that the final position of the BPV leaflets is less certain. In bench testing, measurement of the BPV following BVF demonstrated a maximum gain in BPV diameter of 3–4 mm. Further expansion of the BPV is restricted by the Dacron sewing cuff, which remains intact after valve fracture.21 The additional space in the coronary sinuses necessary to accommodate BVF is not fully understood. Extrapolating from the recommended safety margins of VIV TAVR, it is reasonable to estimate that a BPV to coronary distance of less than 5 mm could be considered to place a patient at high risk for coronary occlusion when BVF is performed. To date, there are no published cases of coronary occlusion attributable to BVF. If there is pre-procedural concern for coronary occlusion, standard precautions are recommended, including wire protection of the coronary artery as deemed appropriate by the operators.

THV selection Careful selection of the THV is an important part of the evaluation prior to BVF. Both self-expanding and balloon-expandable THVs are currently approved for use in VIV TAVR in the US. There are some data to suggest that self-expanding THVs result in superior procedural haemodynamics and increased EOA when used for VIV TAVR, compared with balloonexpandable valves,14,17 largely due to the supra-annular position of the prosthetic leaflets on the self-expanding frame. However, BVF can be successfully performed in the setting of VIV with both self-expanding and balloon-expandable THVs. There is some concern that the highpressure balloon inflation used to perform BVF may cause structural damage to the self-expanding valve frame or leaflets, resulting in severe acute valvular regurgitation. This can largely be avoided by using a balloon smaller than the constrained segment of the selfexpanding THV, and by positioning the BVF balloon such that the balloon shoulder is lower (i.e. more ventricular) than where the leaflets are anchored to the frame.21 However, care must be employed to ensure the valvuloplasty balloon and delivery wire are well-positioned in the ventricle as well. In terms of TAVR prosthesis selection, BVF adds an extra element of pre-procedural consideration. Appropriate THV selection for VIV

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The Dacron sewing cuff has been partially removed to display the single separation of the polymer ring. x indicates the surgical ring which has been fractured.

TAVR is guided by the true inner diameter of the BPV, rather than the labelled surgical valve size, as there can be considerable difference in these measurements between different valve models.27 BVF results in structural expansion of the BPV, changing the true inner diameter of the BPV considerably. Based on measurements made during bench testing, it appears that the maximum gain in diameter that can be achieved with BVF is between 3 and 4 mm.21 Thus, there are some situations in which a larger TAVR prosthesis may be appropriate for a BVF procedure than would be selected for a stand-alone VIV TAVR. For example, in a patient with a 21 mm Mitroflow, which has an inner diameter of 17 mm, BVF might result in expansion of the inner diameter to 20–21 mm. In this situation, it is not known whether a partially constrained 23 mm transcatheter valve would result in better haemodynamics than a fully expanded 20 mm transcatheter valve. In vitro testing has suggested that a larger prosthesis, even if expanded to a less than nominal diameter, may result in a more favourable transvalvular gradient.17 However, this concept has not been rigorously tested in clinical practice, and the interaction between TAVR prosthesis expansion and optimal haemodynamics after BVF is not fully understood.

Selection of Valvuloplasty Balloon Both Atlas Gold and True Dilatation balloons are consistently able to fracture small surgical valves, both in bench testing (Table 1) and clinical experience.21–24 In bench testing and the majority of clinical cases, balloons sized 1 mm larger than the labelled valve size were utilised. However, during some clinical cases, smaller balloons (i.e. sized 1 mm larger than the true inner diameter of the BPV) were used successfully. It stands to reason that balloons need only be sized larger than the internal diameter of the BPV to fracture the valve, especially if a THV is already implanted in the BPV. Whether smaller balloons consistently fracture BPVs remains to be seen. Furthermore, it is not known if larger BPVs (i.e. >21 mm) will fracture consistently with valvuloplasty balloons sized 1 mm larger than the labelled BPV size, as the force exerted by larger balloons in larger prostheses may be somewhat different than in small valves, and this has not been systematically tested clinically or on the bench.

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Structural Figure 3: A: Baseline Appearance of 23 mm Magna BPV after Deployment of 26 mm Medtronic Evolut R THV. B: Initial Balloon Inflation During BVF. C: Appearance of BPV and Balloon after BPV Ring Fracture. Note the Visible Release of the Balloon Waist and Expansion of BPV Compared to (B). D: Final Appearance after VIV TAVR and BVF

BVF = bioprosthetic valve fracture; BVP = bioprosthetic valve fracture; TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve; VIV = valve-in-valve.

Timing of BVF Whether BVF is optimally performed before or after implantation of the TAVR prosthesis is not known. There are theoretical advantages to both strategies. If BVF is performed first followed by TAVR implantation, this may allow for confirmation that the BPV can be fractured prior to TAVR implantation, which in theory may allow for selection of a larger TAVR prosthesis. However, bench testing and clinical experience have demonstrated consistent success in fracturing most BPVs, thus it does not appear to be necessary to ensure BVF is successful prior to THV implantation. Some operators have preferred to perform BVF prior to VIV TAVR to avoid the theoretical concern of subclinical damage to the prosthetic leaflets during high-pressure balloon inflation, which might impact long-term THV durability. Performing BVF before VIV TAVR has the potential benefit of sparing the THV the high-pressure balloon inflation. However, it should also be noted that balloon-expandable THV leaflets are subjected to pressure at the time of crimping, and at the time of implantation regardless of whether BVF is performed. Furthermore, as noted above, in self-expanding THV valves, BVF should be performed by placing the balloon shoulder below the level of the supra-annular valve leaflets to avoid any possibility of leaflet injury. At this time there are no robust long-term data regarding THV durability after BVF. The 100 % long-term survival in one case series (n=10) is a promising sign that patients do well after BVF. However, haemodynamic and quality of life data are not available in this cohort. It is also not known whether there are any differences between procedural outcomes of BVF performed before or after VIV TAVR. However, some data suggest that there may be some disadvantage to performing BVF first, especially when a balloon-expandable THV is used. In bench testing, if a balloon-expandable THV was implanted nominally within a fractured BPV using standard inflation, the compliant delivery balloon was not sufficient to fully expand the TAVR prosthesis, and a notable constraint remained after the TAVR valve was implanted.21 A final, high-pressure balloon inflation was necessary to fully expand the balloon-expandable TAVR prosthesis. Interestingly, when self-expanding TAVR valves were implanted within fractured BPVs, there appeared to be sufficient radial strength to re-expand the fractured BPV and achieve nominal deployment diameter, without a final high-pressure balloon inflation.21 Haemodynamic data may also support the strategy to perform VIV TAVR prior to BVF. In the currently published series (n=30), the final

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haemodynamics when VIV TAVR was performed first, followed by BVF, appear to be superior to the results when BVF was performed first (Table 2). Although patients treated with BVF first (n=15) had a similar pre-procedural gradient and EOA to those who underwent TAVR first (n=15), the final mean gradient and EOA in the BVF-first group were less favourable compared with the haemodynamics in the TAVR-first group (14 mmHg and 1.4 cm2 vs 7 mmHg and 1.7 cm2, respectively). However, this comparison might be confounded by differences in the valves that were fractured or the THV selected for VIV TAVR. In the BVF-first group, 13 of 15 patients (87 %) were treated with a balloonexpandable THV, with a nominal pressure implantation, and no highpressure balloon inflation following the THV. These data suggest that a final high-pressure inflation following BVF with a balloon-expandable THV may be necessary to optimise THV expansion and procedural results. It is important to interpret these findings with caution, as the total number of patients in each group is small and the results are subject to confounding.

Longer-term Outcomes There are some available data regarding haemodynamic durability at 1 month following BVF. In a series of 18 patients who underwent BVF prior to VIV TAVR, the baseline mean transvalvular gradient and EOA were 42.8±17.0 mmHg and 0.8±0.3 cm2, respectively, which improved to 8.1±3.6 mmHg and 1.96±0.58 cm2, respectively, after VIV TAVR and BVF. At 1 month, mean gradient and EOA by echocardiography were 12.7±5.0 mmHg and 1.64±0.3 cm2, respectively, which were not statistically different to the final procedural haemodynamic measurements. Long-term follow-up of these patients is ongoing. In contrast to concerns that BVF may result in impaired TAVR durability, it is also possible that BVF actually improves durability, considering that a high residual gradient after VIV TAVR is associated with worse outcomes. Poor expansion of prosthetic leaflets has been associated with early BPV failure, as leaflet folding results in stress and strain points on the leaflets, which leads to leaflet calcification and fibrosis, and can accelerate BPV degeneration.28 In theory, by optimising THV expansion and reducing the transvalvular gradient, BVF might decrease leaflet stress and degeneration and improve long-term THV durability. If this is indeed the case, then all patients undergoing VIV TAVR might benefit from BVF, irrespective of the size of their BPV or the residual gradient following THV implantation. Ultimately, comparisons of longterm outcomes between patients who undergo BVF before or after VIV TAVR first will be important to understand the optimal BVF strategy.

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Bioprosthetic Valve Fracture During VIV TAVR Figure 4: A: Baseline Haemodynamics Prior to VIV TAVR. The Mean Gradient was Measured at 39 mmHg and the Mean EOA was Calculated at 0.7 cm 2. B: Post-VIV TAVR. The Mean Gradient was Measured at 25 mmHg and the EOA was Calculated at 1.2 cm 2. C: Post-BVF. The Final Mean Gradient was Measured at 3 mmHg and the EOA was Calculated at 1.7 cm 2 A

Table 2: Combined Clinical Cases of BVF and VIV TAVR

Combined

BVF first

TAVR first

Number of patients

Mean age (years)

79.0

82.2

75.7

Age of BPV (years)

10.4

10.9

9.9

Mean BPV true inner diameter

17.4

16.6

18.1

Haemodynamic support (ECMO)

Self-expanding TAVR

Balloon-expandable TAVR

Baseline mean gradient

Baseline EOA

0.75

0.7

0.8

200

180

F 160

160

140

Post-TAVR mean gradient

120

Post-TAVR EOA

1.0

100

Final mean gradient

Final EOA

1.7

1.3

2.0

Sorin Mitroflow

Edwards Magna

Edwards Perimount

Medtronic Mosaic

St Jude Biocor Epic

mmHg

60 40 20

0 8:36:41 AM

8:36:49 AM

BVP = bioprosthetic valve; BVF = bioprosthetic valve fracture; ECMO = extracorporeal membrane oxygenation; EOA = effective orifice area; NA = not available; TAVR = transcatheter aortic valve replacement. Source: Chhatriwalla, et al., 2017; Nielsen-Kudsk, et al., 2017.

200

Haemodynamic Support

180

F 160

160

140

Due to concern that BVF may result in aortic root injury or coronary artery obstruction, some operators have preferred to perform BVF only in the setting of full haemodynamic backup with ECMO (Table 2). To date, no published reports of aortic root injury or haemodynamic collapse attributable to BVF exist. As clinical experience with BVF has accumulated, it appears that full haemodynamic backup is not routinely necessary. We do not recommend routine use of ECMO during these cases, especially as ECMO requires additional further large-bore vascular access, further exposing the patient to potential vascular complications. However, in certain situations ECMO may be beneficial, such as a patient with very high risk for coronary occlusion with VIV TAVR and BVF.

F mmHg

120 100

100

0 8:53:51 AM

8:53:53 AM

Future Directions C 200

180

F 160

160

140

120

100

F mmHg

200

9:08:15 AM

9:08:17 AM

BVF = bioprosthetic valve fracture; EOA = effective orifice area; TAVR = transcatheter aortic valve replacement; VIV = valve-in-valve. Source: Chhatriwalla, et al., 2017.22

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The initial bench testing and clinical experience with BVF and VIV TAVR establishes a firm foundation for this procedure in patients with failed aortic BPVs. However, there are many unanswered questions relating to this novel technique. Whether BVF has an impact on the survival of patients who are at risk of PPM following VIV TAVR remains to be seen. Further data are needed as to the quality of life benefit that is gained from VIV TAVR with BVF compared with VIV TAVR alone. The feasibility of BVF in patients with larger BPVs (>21 mm labelled BPV size) has not been well studied, and whether this will improve the procedural results or outcomes for these patients is equally unknown. The safety margins for performing BVF in patients at risk of coronary obstruction and aortic root injury are not fully understood and warrant further study. Finally, it remains to be seen whether BVF can be performed safely and successfully, and with benefit, in conjunction with VIV procedures in the mitral, pulmonary or tricuspid positions. As our experience grows, the indications for and technique of BVF will undoubtedly continue to be refined. n

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Structural 1.

dams DH, Popma JJ, Reardon MJ. Transcatheter aorticA valve replacement with a self-expanding prosthesis. N Engl J Med 2014;371:967–8. DOI: 10.1056/NEJMc1408396; PMID: 25184874 2. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/ NEJMoa1008232; PMID: 20961243 3. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 4. Leon MB, Smith CR. Transcatheter aortic-valve replacement. N Engl J Med 2016;375:700–1. PMID: 27532839 5. Balsam LB, Grossi EA, Greenhouse DG, et al. Reoperative valve surgery in the elderly: predictors of risk and long-term survival. Ann Thorac Surg 2010;90:1195–200. DOI: 10.1016/ j.athoracsur.2010.04.057; PMID: 20868814 6. Kaneko T, Loberman D, Gosev I, et al. Reoperative aortic valve replacement in the octogenarians-minimally invasive technique in the era of transcatheter valve replacement. J Thorac Cardiovasc Surg 2014;147:155–62. DOI: 10.1016/ j.jtcvs.2013.08.076; PMID: 24183906 7. Dvir D, Webb JG, Bleiziffer S, et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA 2014;312:162–70. DOI: 10.1001/jama.2014.7246; PMID: 25005653 8. Webb JG, Mack MJ, White JM, et al. Transcatheter aortic valve implantation within degenerated aortic surgical bioprostheses: PARTNER 2 valve-in-valve registry. J Am Coll Cardiol 2017;69:2253–62. DOI: 10.1016/j.jacc.2017.02.057; PMID: 28473128 9. Rahimtoola SH. The problem of valve prosthesis-patient mismatch. Circulation 1978;58:20–4. DOI: 10.1161/01. CIR.58.1.20; PMID: 348341 10. Blais C, Dumesnil JG, Baillot R, et al. Impact of valve prosthesis-patient mismatch on short-term mortality after aortic valve replacement. Circulation 2003;108:983–8. DOI: 10.1161/01.CIR.0000085167.67105.32; PMID: 12912812 11. Koene BM, Soliman Hamad MA, Bouma W, et al. Impact of prosthesis-patient mismatch on early and late mortality after

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12.

13.

14.

15.

16.

17.

18.

19.

20.

aortic valve replacement. J Cardiothorac Surg 2013;8:96. DOI: 10.1186/1749-8090-8-96; PMID: 23594366 Dayan V, Vignolo G, Soca G, et al. Predictors and outcomes of prosthesis-patient mismatch after aortic valve replacement. JACC Cardiovasc Imaging 2016;9:924–33. DOI: 10.1016/j.jcmg. 2015.10.026; PMID: 27236530 Azadani AN, Jaussaud N, Matthews PB, et al. Transcatheter aortic valves inadequately relieve stenosis in small degenerated bioprostheses. Interact Cardiovasc Thorac Surg 2010;11:70–7. DOI: 10.1510/icvts.2009.225144; PMID: 20395249 Simonato M, Azadani AN, Webb J, et al. In vitro evaluation of implantation depth in valve-in-valve using different transcatheter heart valves. EuroIntervention 2016;12:909–17. DOI: 10.4244/EIJV12I7A149; PMID: 27639744 Simonato M, Webb J, Kornowski R, et al. Transcatheter replacement of failed bioprosthetic valves: large multicenter assessment of the effect of implantation depth on hemodynamics after aortic valve-in-valve. Circ Cardiovasc Interv 2016;9:e003651. DOI: 10.1161/ CIRCINTERVENTIONS.115.003651; PMID: 27301396 Zenses AS, Mitchell J, Evin M, et al. In vitro study of valve-in-valve performance with the CoreValve selfexpandable prosthesis implanted in different positions and sizes within the Trifecta surgical heart valve. Comput Methods Biomech Biomed Engin 2015;18(Suppl 1):2086–7. DOI: 10.1080/10255842.2015.1069634; PMID: 26260517 Azadani AN, Reardon M, Simonato M, et al. Effect of transcatheter aortic valve size and position on valve-invalve hemodynamics: an in vitro study. J Thorac Cardiovasc Surg 2017;153:1303–15. Nielsen-Kudsk JE, Christiansen EH, Terkelsen CJ, et al. Fracturing the ring of small mitroflow bioprostheses by highpressure balloon predilatation in transcatheter aortic valvein-valve implantation. Circ Cardiovasc Interv 2015;8:e002667. DOI: 10.1161/CIRCINTERVENTIONS.115.002667; PMID: 26208503 Brown SC, Cools B, Gewillig M. Cracking a tricuspid perimount bioprosthesis to optimize a second transcatheter sapien valve-in-valve placement. Catheter Cardiovasc Interv 2016;88: 456–9. DOI: 10.1002/ccd.26507; PMID: 27015096 Tanase D, Grohmann J, Schubert S, et al. Cracking the ring of Edwards Perimount bioprosthesis with ultrahigh pressure

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balloons prior to transcatheter valve in valve implantation. Int J Cardiol 2014;176:1048–9. DOI: 10.1016/j.ijcard.2014.07.175; PMID: 25156860 Allen KB, Chhatriwalla AK, Cohen DJ, et al. Bioprosthetic valve fracture to facilitate transcatheter valve-in-valve implantation. Ann Thorac Surg 2017;104:1501–8. DOI: 10.1016/ j.athoracsur.2017.04.007; PMID: 28669505 Chhatriwalla AK, Allen KB, Saxon JT, et al. Bioprosthetic valve fracture improves the hemodynamic results of valve-in-valve transcatheter aortic valve replacement. Circ Cardiovasc Interv 2017;10:e005216. DOI: 10.1161/ CIRCINTERVENTIONS.117.005216; PMID: 28698291 Nielsen-Kudsk JE, Andersen A, et al. High-pressure balloon fracturing of small dysfunctional Mitroflow bioprostheses facilitates transcatheter aortic valve-in-valve implantation. EuroIntervention 2017;13:e1020–5. DOI: 10.4244/EIJ-D-17-00244; PMID: 28691908 Johansen P, Engholt H, Tang M, et al. Fracturing mechanics before valve-in-valve therapy of small aortic bioprosthetic heart valves. EuroIntervention 2017;13:e1026–31. DOI: 10.4244/ EIJ-D-17-00245; PMID: 28691909 Dvir D, Webb J, Brecker S, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: results from the global valve-in-valve registry. Circulation 2012;126:2335–44. DOI: 10.1161/ CIRCULATIONAHA.112.104505; PMID: 23052028 Dvir D, Leipsic J, Blanke P, et al. Coronary obstruction in transcatheter aortic valve-in-valve implantation: preprocedural evaluation, device selection, protection, and treatment. Circ Cardiovasc Interv 2015;8:e002079. DOI: 10.1161/CIRCINTERVENTIONS.114.002079; PMID: 25593122 Bapat VN, Attia R, Thomas M. Effect of valve design on the stent internal diameter of a bioprosthetic valve: a concept of true internal diameter and its implications for the valvein-valve procedure. JACC Cardiovasc Interv 2014;7:115–7. DOI: 10.1016/j.jcin.2013.10.012; PMID: 24440016 Abbasi M, Azadani AN. Leaflet stress and strain distributions following incomplete transcatheter aortic valve expansion. J Biomech 2015;48:3663–71. DOI: 10.1016/ j.jbiomech.2015.08.012; PMID: 26338100

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Structural

Understanding Neurologic Complications Following TAVR Mohammed Imran Ghare and Alexandra Lansky Yale School of Medicine, Section of Cardiovascular Medicine

Abstract Transcatheter aortic valve replacement is a groundbreaking treatment modality for severe, symptomatic aortic stenosis. Despite the rapid progression in indications to include intermediate-risk patients, the risk of peri-procedural stroke remains, with a higher incidence rate than previously reported. Accurate assessment of peri-procedural stroke rates requires selection of careful and meaningful trial endpoints during evaluation of neuroprotective devices. In this article, we review recommendations and stroke definitions from academic research consortiums along with device trial results.

Keywords Cardioembolic protection, neuroprotection, transcatheter aortic valve replacement, transcatheter aortic valve implantation, peri-procedural stroke Disclosure: Mohammed Imran Ghare is funded by an NIH (2T35HL007649-31) grant to Yale University. Received: 13 July 2017 Accepted: 23 August 2017 Citation: Interventional Cardiology Review 2018;13(1):27–32. DOI: 10.15420/icr.2017:25:1 Correspondence: Alexandra Lansky, 135 College Street, Suite 101, New Haven, CT 06510, USA. E: alexandra.lansky@yale.edu

Transcatheter aortic valve replacement (TAVR) is an innovative treatment modality for patients with severe symptomatic aortic stenosis (AS). After gaining initial market approval in Europe in 2007 and 4 years later in the US, TAVR continues to make large strides. An estimated 340,000 TAVR procedures have been completed in Europe in the immediate 5 years after approval and a further 10,000 procedures in the US were completed in the 2 years following approval in 2011.1 Global TAVR procedure volumes are expected to reach 300,000 annually, ushered in by the broadening of indications from everemerging data. Placement of Aortic Transcatheter Valve (PARTNER) I A and B were pivotal, initial trials, that established TAVR as an effective treatment for patients who were not surgical candidates.2–4 More recently, indications have continued to expand with the PARTNER II and Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trial results demonstrating TAVR as a non-inferior alternative to surgery in patients at intermediate risk, leading to US approval in this expanded population.5,6 TAVR is not without its complications; cerebrovascular accidents are one of the most important and clinically significant adverse events. Neuroprotection devices aimed at thwarting lesions, though promising, have yet to gain widespread clinical use. Establishing TAVR as the preferred treatment modality for severe symptomatic AS necessitates a more thorough understanding of iatrogenic stroke risk and measures to mitigate such complications.

Stroke Definitions In the context of valve replacement clinical trials, three large research consortiums define stroke and provide guidelines for endpoint selection that are presented in Table 1: The Valve Academic Research Consortium (VARC)-2, American Heart Association/American Stroke Association (AHA/ASA), and more recently the Neurologic Academic Research Consortium (NeuroARC). Definitions for stroke and transient ischaemic attack (TIA) have matured with neuroimaging techniques and increased availability of MRI, focusing on tissue-based criteria instead of symptoms.7,8 The most recent publication from the AHA/ASA

ICR_Lansky_FINAL.indd 27

addressing stroke definitions placed an emphasis on CNS infarctions, which is defined in Table 1.8 Accordingly, neuroimaging is sufficient for identification of CNS infarction and stroke. In contrast, VARC-2 defines both disabling and non-disabling strokes primarily based on a clinical evaluation and scoring tool, the modified Rankin Scale (mRS) (Table 1).9 Comparatively, the AHA/ASA definition distinguishes sole CNS infarct from clinical stroke while VARC-2 does not define silent infarcts nor is there a distinction between sole CNS infarct from clinical stroke. The approach outlined by NeuroARC defines the full spectrum of cerebrovascular injury combining well-established symptom-based criteria with more sensitive tissue-based findings.10 A more comprehensive set of definitions should spur data acquisition allowing a distinction to be made between clinically meaningful and incidental findings. Accordingly, NeuroARC classifications fall into three major types: “overt (acutely symptomatic) CNS injury (Type 1), covert (acutely asymptomatic) CNS injury (Type 2), and neurological dysfunction (acutely symptomatic) without CNS injury (Type 3)”. The three major types can be further broken down into subtypes; however, for the purposes of our discussion, we present the most frequently encountered definitions in Table 1.

Peri-procedural Stroke Rates The rate of combined stroke or transient ischaemic attack in early trials (PARTNER A) comparing TAVR to surgical aortic valve replacement (SAVR), was reported to be 5.5 % versus 2.4 % at 30 days (p=0.04) and 8.3 % versus 4.3 % (p=0.04) at one year, respectively.11 In PARTNER B, TAVR was compared to medical management for patients who were not suitable SAVR candidates: stroke was observed more frequently amongst TAVR patients at 1 year, 7.8 % versus 3.9 % (p=0.18).4 Importantly, there was no independent adjudication of stroke in the PARTNER I trials. Therefore, the observed difference in stroke rates and timings between surgery and TAVR must be considered hypothesis generating only. All other randomized trials point towards higher risk of stroke in SAVR compared to TAVR. For example, comparisons of

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Structural Table 1: Selected Stoke Definitions Valve Academic Research Consortium-29

American Heart Association/American Stroke Association

NeuroARC10

Disabling stroke: An mRS score of 2 or more Definition of CNS infarction: CNS infarction is brain, at 90 days and an increase in at least one mRS spinal cord, or retinal cell death attributable to ischaemia, category from an individual’s pre-stroke baseline. based on Non-disabling stroke: An mRS score of <2 at 1. Pathological, imaging, or other objective evidence of 90 days or one that does not result in an increase cerebral, spinal cord, or retinal focal ischaemic injury in at least one mRS category from an individual’s in a defined vascular distribution; or pre-stroke baseline. 2. Clinical evidence of cerebral, spinal cord, or retinal Stroke: duration of a focal or global neurological focal ischaemic injury based on symptoms persisting deficit ≥24 h; or 24 h if available neuroimaging ≥24 h or until death, and other aetiologies excluded. documents a new haemorrhage or infarct; or the neurological deficit results in death. (Note: CNS infarction includes hemorrhagic infarctions, types I and II; see “Haemorrhagic Infarction”.) Definition of ischaemic stroke: An episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. (Note: Evidence of CNS infarction is as defined previously.) Definition of silent CNS infarction: Imaging or neuropathological evidence of CNS infarction, without a history of acute neurological dysfunction attributable to the lesion.

Type 1.a Ischaemic stroke: Sudden onset of neurological signs or symptoms fitting a focal or multifocal vascular territory within the brain, spinal cord, or retina, that:

Note: When CNS infarction location does not match the transient symptoms, the event would be classified as covert CNS infarction (Type 2a) and a TIA (Type 3a), but not as an ischaemic stroke.

Type 2.a Covert CNS infarction: Brain, spinal cord, or retinal cell death attributable to focal or multifocal ischaemia, on the basis of neuroimaging or pathological evidence of CNS infarction, without a history of acute neurological symptoms consistent with the lesion location.

Type 3.a TIA: Transient focal neurological signs or symptoms (lasting <24 h) presumed to be due to focal brain, spinal cord, or retinal ischaemia, but without evidence of acute infarction by neuroimaging or pathology (or in the absence of imaging).

1. Persist for ≥24 h or until death, with pathology or neuroimaging evidence that demonstrates either: a. CNS infarction in the corresponding vascular territory (with or without hemorrhage); or b. Absence of other apparent causes (including hemorrhage), even if no evidence of acute ischaemia in the corresponding vascular territory is detected; or 2. Symptoms lasting <24 h, with pathology or neuroimaging confirmation of CNS infarction in the corresponding vascular territory.

CNS = central nervous system; mRS = modified ranking scale; TIA = transient ischaemic attack.

Table 2: Current Neuroprotection Devices Under Investigation Device

Manufacturer

Type

Access

Position

Coverage area

Delivery

Pore Size

(µm)

Embrella

100

Edwards Lifesciences

Deflector

Radial/brachial

Aorta

Innominate LCC+/− LSA

Trials PROTAVI-C,

Triguard Keystone Heart Ltd Deflector Femoral Aorta Innominate LCC and LSA 9F 140

DEFLECT I/II/III, REFLECT

Claret Montage Claret Medical Inc. Filter Radial/brachial Innominate Innominate LCC 6F 140 and LCC

CLEAN-TAVI, SENTINEL, MISTRAL

Embol-X

Tao-EmbolX

Edwards Lifesciences

Filter

Direct aortic

LCC = left common carotid; LSA = left subclavian artery. Source: Freeman, et al., 2014.

Aorta

Medtronic’s CoreValveTM to surgery observed all stroke less frequently in TAVR patients than in the surgical group at 2 years, 10.9 % versus 16.6 % (p=0.05).12 In a prospective, non-randomized, single-arm clinical study of CoreValve in patients at extreme surgical risk, combined stroke rates at 30 days and 1 year were reported to be 4.0 % and 7.0 %, respectively. More recently, SURTAVI results from an intermediate risk cohort found 4.5 % of patients in the SAVR group had a disabling

ICR_Lansky_FINAL.indd 28

Innominate LCC and LSA

24F

120

stroke compared to the 2.6 % in TAVR group at 24 months.5 Thus, even among intermediate risk patients, stroke is a serious concern. The Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) registry captured 26,414 TAVR procedures as of December 2014. VARC defined, clinically adjudicated stroke rates were approximately 2 % in the STS/ACC TVT registry.13 Though the risk of stroke continues to decrease with advancements in

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Understanding Neurologic Complications Following TAVR

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4.6 4

Rate (%)

2.6

2.6 2

1.6

Adapted from Lansky, 2017.29

Figure 2: Stroke Rate Variation Among Several Studies: Mild, Moderate, and Severe Strokes Mild, Moderate and Severe Stroke

Peri-procedural Stroke Timing

27 25

Rate (%)

17 15

) au s H 5)

La ns

sig

(N eu

eu ro TA VR

III ky ns La 3)

sé es M

(T AV R)

TR AL ) IS (M m gh e ie M Va n

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Increased risk for stroke following TAVR can be categorized into three distinct phases. The early phase, defined as the immediate 24 hours following a procedure, is most likely a direct result of the procedure and accounts for up 50 % of all cerebrovascular injury.20–23 Still, following TAVR, patients are at an increased risk during the delayed phase between days 2 and 30. Finally, stroke can occur up to 1 year following TAVR during the late phase. Late phase strokes may be attributed to patient comorbidities such as asymptomatic carotid stenosis or atrial fibrillation amongst other patient-related risk factors.9 In the PARTNER IA trial, within the randomized SAVR cohort, 62.5 % of the major strokes occurred within the first 2 days, 25 % between 5 and 30 days, and only 1 occurred after 30 days.24 In patients undergoing TAVR, a more significant proportion of early strokes occurred >24h after the procedure.25,26 Of the 11 post-procedure strokes in inoperable PARTNER patients, 27 % were within 24 hours, 55 % between 1 and 5 days, and 18 % after 1 week.4 Similarly, amongst a multicentre Canadian study, only 25 % of 30-day strokes were seen within 24h post-procedure.27 These statistics represent only clinically overt strokes and do not reflect covert strokes. Neuro-TAVI was a prospective study assessing neurologic complications in 44 patients. Of the 77.3 % of patients receiving diffusion-weighted MRI (DW-MRI) imaging, 94 % had a CNS lesion identified between post-procedure days 2 and 6. Pre-procedure MRI imaging was not performed and it was assumed that all lesions were new. At 30 days, 43 % of patients had NIH Stroke Scale (NIHSS) or Montreal Cognitive Assessment (MoCA) worsening.28 NeuroARC classifies neurological event timing into two categories: peri-procedural occurring up to 30 days post-intervention and late occurring any time after 30 days post-procedure. Accurate

5.9

5.8

Stroke rates alone do not provide a complete assessment of periprocedural brain injury. Surrogate markers for clinical outcomes aid in device appraisal as CNS infarction can be acutely clinically silent and hence not meet criteria for stroke. Routine neuroimaging studies in patients undergoing TAVR procedures report that acutely silent ischaemic cerebral infarction caused by showers of cerebral emboli during valve instrumentation and placement is frequent. Volumetric analysis of infarcted brain tissue in these imaging studies ranged from 1.5 cm3 to 4.3 cm3, translating into a shocking estimation of 1 billion synapses and 2 million neurons.17 The implications linking acutely spontaneous silent CNS embolization to subsequent neurologic and cognitive impairment are immense, yet a gap in knowledge must be filled with respect to long-term neurologic and cognitive consequences of procedure-related iatrogenic cerebral embolization.18,19

Severe Stroke

Pa rtn er rtn 2 er (2 01 S3 2) Pa H rtn R (2 er 0 15 S3 ) IR S3 (2 0 CE 15 AD ) VA IR (2 N 01 CE CH 5) CV O (2 IC 0 E 15 SX CH ) R O ( 20 IC 14 E CV ) G oo (2 01 le y G 4) CV oo le (2 y 0 Lo 15 US tu ) Pi s( v 20 ot RE 15 al PR CV ) IS E ( 20 II Lo 14 tu ) s( 20 14 )

The stroke incidence reported in these randomized approval TAVI trials represents only a small proportion of the totality of symptomatic stroke as they report major and disabling strokes. Indeed, stroke rates in aortic valve replacement studies vary based on stroke definition. Severe strokes rates, including major and disabling strokes, ranged from 1.6 % to 5.9 % (see Figure 1). Recent studies that include mild, moderate and severe symptomatic strokes, have reported total stroke rates ranging from 9 % up to 28 % with systematic evaluation by neurologists and neuroimaging in both SAVR and TAVR (see Figure 2).14–16 Variability in stroke incident rates is a factor of both differences in definitions and ascertainment method.

Figure 1: Stroke Rate Variation Among Several Studies: Severe Strokes

valve technology, operator experience and patient selection, it remains a persistent and irrefutable reality.

Adapted from Lansky, 2017.29

and meaningful stroke rates following valve implantation cannot rely solely on clinical symptoms, yet the clinical consequences of surrogate markers for infarct such as DW-MRI remain poorly defined. The distinct phases in which stroke occurs post-procedurally play a significant role in determining optimal timepoints for identifying CNS lesions in TAVR and neuroprotection trials.

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Structural Clinical Insight: Patient and Physician Perceptions A peri-procedural stroke has calamitous clinical consequences for the patient. Peri-procedural stroke results in a five-fold increase in mortality.24,30 Furthermore, 40 % of survivors become permanently dependent, while a further 80 % experience social isolation and significant financial strain.31,32 It is therefore predictable that, when queried, a cohort of 785 patients viewed stroke as being 50 % to 250 % worse than death. Conversely, cardiologists viewed a patient’s death as being a worse outcome compared to stroke.33 Unfortunately, a disconnect exists between patient and physician perception that cannot be brushed aside.

Significance of Covert Stroke Systematic studies in elderly patient populations without symptomatic cerebrovascular disease, notably the Framingham Study, Rotterdam Study, and Cardiovascular Health study, consistently identified MRI evidence of infarct. 34–36 The Leukoaraiosis and Disability (LADIS) study, in elderly patients with minor neurocognitive symptoms and minor neurocognitive disability, identified MRI evidence of infarct to an ever greater extent.37 These significant findings cannot be written off as benign effects of ageing as there is evidence that covert MRI findings associated with subtle brain dysfunction are more prevalent than covert stroke.38,39 Correlating the wide array of neurologic findings with radiologic evidence in TAVR trials is an arduous task that can only benefit from accelerated, standardized data collection.

Stroke Mechanisms in the Context of TAVR Early phase strokes are most likely related to procedural factors. Catheter manipulation within the aorta along with valve, catheter, and wire manipulation across the aortic valve are the most likely causes of procedural embolization.40–42 The transfemoral approach remains the preferred method for access, yet the STS/ACC TVT registry revealed that in 2013 the transapical approach, for a brief period, was used in more than 40 % of patients.13 A single-centre, prospective study comparing transapical to transfemoral access in 1000 patients found VARC-2-defined stroke rates to be comparable between the two approaches.43 Though access does not seem to play a part in stroke rates, in a study investigating use of a dual filter embolic protection device (SentinelTM), embolic debris was captured from 99 % of patients undergoing TAVR. Histological examination of the debris was significant for fibrin, amorphous calcium and connective tissue consistent with derivation from aortic valve leaflets or the aortic wall.44 In relation to TAVR, ischaemic stroke must be contrasted from global hypoxaemic injury. Ischaemic stroke always occurs in specific vascular territories, either arterial or venous, while global hypoxemic-ischaemic injury results in diffuse neuronal injury irrespective of vascular territory.45 Mortality rates for severe global hypoxic-ischaemic injury reach 80 % compared to <13 % with ischaemic stroke.46,47 Neuroprotection devices cannot be expected to impact global hypoxaemic-ischaemic injury and can only be beneficial for focal or multifocal ischaemic injury.

Selecting Neurologic Endpoints in Cardiovascular Trials As stroke continues to be a serious peri-procedural complication of TAVR, it is important to collect accurate and meaningful data for device assessment. The most complete approach favours combining clinically validated screening tools, such as the NIHSS and MoCA, with sensitive imaging methods, such as DW-MRI.

ICR_Lansky_FINAL.indd 30

Radiologic Guided Endpoints in Cardiovascular Trials Ischaemic CNS tissue changes can be identified by DW-MRI within minutes to days.48,49 A Cochrane review comparing CT and MRI to the clinical diagnosis as a reference found DW-MRI to be significantly more sensitive than CT imaging.50 MRI is thus the preferred imaging modality for detection of CNS ischemia (see Figure 3). Accurate quantification of brain ischaemia further contributes to the utility of DW-MRI. Lesion volumes are maximal 5–7 days following injury, and can change 1–3 weeks after injury.51,52 NeuroARC recommends routine MRI imaging at 2–7 days following a procedure and non-routine MRI imaging if neurologic symptoms or delirium develop. Routine MRI endpoints should include Total Lesion Volume (TLV) (mm3).10 In a study comparing 32 TAVR patients to a historical cohort of 21 patients undergoing SAVR, 84 % of the TAVR patients had new DW-MRI lesions versus 48 % in the SAVR cohort. Both at the time of imaging and 3-month follow-up, there were no detectable cognitive defects when assessed by Mini Mental Status Exam (MMSE) or NIHSS.44 In a prospective study of 44 TAVR patients, DW-MRI lesions were detected in 94 % of patients, but neurologic impairment detected by NIHSS worsening occurred in only 22.6 % of patients at discharge and 14.8 % of patients at 30 days.28 As DW-MRI imaging is one of the most sensitive radiographic imaging modalities, there may be a poor correlation between DW-MRI endpoints and clinical symptoms in early trial phases. The goal of acquiring routine radiographic evidence is to make correlative assessments at later stages of trials, weeks and years after valve implantation.

Clinical Evaluations as Endpoints in Cardiovascular Trials The tools available for clinical assessments of neurologic and functional impairment along with cognitive ability are numerous. In the acute setting of a stroke, the NIHSS, first described by Brott et al. in 1989, is a well-established and highly validated tool for assessing the severity and prognosis of a stroke.53–56 The NIHSS can be used in trials to routinely screen patients following cardiovascular procedures. Long-term stroke outcomes are assessed with the modified Rankin Scale (mRS) at 90 days to classify adverse events as disabling or non-disabling.57,58 Pre-procedural assessments of stroke, disability, delirium, cognition and quality of life should also be made and can be supplemented by baseline MRI imaging. Following a procedure, stroke, disability, cognition and quality of life should be assessed after 30–90 days and 1 year. A battery of tests is available to assess cognition.10 The Montreal Cognitive Assessment (MoCA) is commonly used as a screening, royalty-free clinical tool to detect frank cognitive changes.59 Interobserver variability in some tests is a real concern; however, most tests use standardized forms or calculators that reduce variability. With more routine acquisition and reporting, MoCA scores across multiple timepoints can be used to draw long-term correlations between DW-MRI acquired TLV and cognition.

Neuroprotective Devices Currently, four embolic protection devices exist that have been previously described; two of which are deflectors and two of which are filters. These devices vary by access, valve access, position, coverage area, sheath size, and pore size (µm) but all ultimately attempt to prevent embolic debris during valve implantation from reaching cerebral circulation.60 A meta-analysis of five randomized clinical trials including 625 patients, combining CLEAN-TAVI, DEFLECT III, EMBOL-X, MISTRAL-C, and SENTINEL studies, and using death or stroke as a composite endpoint, found that neuroprotective devices reduced absolute risk

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Understanding Neurologic Complications Following TAVR by 4 % for a NNT of approximately 22.61 It is difficult to assess the significance of this meta-analysis as there is extensive heterogeneity in the studies due to various valves, neuroprotective devices, MRI scanners (3T versus 1.5T), patient risk and operator experience.

Figure 3: Diffusion Weighted Magnetic Resonance Images at Baseline and Following Cerebral Embolism

Sentinel TM (Claret Medical) MISTRAL-C was a hypothesis generating study randomizing TAVR patients to receive the Sentinel Cerebral Protection System (CPS). In this small trial with 32 patients in the device arm and 33 in the control arm, neurocognition was protected in the device arm when assessed by MMSE and MoCA at 5±1 days and there was also a decrease in number and volume of new MRI lesions.62 MoCA and MMSE testing at such an early time is not reflective of long-term consequences. Following MISTRAL-C, the Claret MontageTM Dual Filter System was studied in CLEAN-TAVI where the device was found to reduce the volume and size of new brain lesions on MRI 2 days post-TAVR; however, the stroke rate was similar between the intervention and control groups.14 In the SENTINEL trial, one of the most recent and largest studies to date, Kapadia et al. shed valuable light on the status of cardioembolic protection. In a 1:1:1 ratio, patients were randomized to an imaging control arm, imaging device arm, and a safety arm. DW-MRI did not detect a significant reduction in median total new lesion volume at 2–7 days after TAVR. Importantly, neurologic and neurocognitive function at 30 and 90 days were not significantly different either between the device and control group, although debris was found within filters in 99 % of patients.63 On the basis of the totality of data, the Claret device recently gained FDA approval in the US.

Embrella (Edwards Lifesciences) PROTAVI-C was a pilot study for the Embrella deflector in which RodésCabau et al. enrolled 54 patients, 12 of whom were controls and 42 receiving the device. Though DW-MRI detected lesions in both groups at 7 days after TAVR, the lesion volume was lower in the group receiving the device. Notably, there were statistically significant mild improvements in MoCA scores at 30 days in the device arm, but the control group also experienced MoCA improvement, albeit statistically insignificant. MMSE scores remained relatively unchanged for both groups from baseline and 30 days post-procedure.64 In a restrospective analysis of Embrella in which 15 patients received the device compared to a historical cohort of 37 patients who did not receive the device, Samim et al. found higher rates of ischaemic lesions in DW-MRI (9.0 versus 5.0, p=0.044) with Embrella, and this device is no longer under clinical evaluation.65

Embol-X (Edwards Lifesciences) The Embol-X device was developed for use in open-heart surgery and requires direct access to the aorta. Modification of the device allowed it to be successfully used in three initial case reports for technical success and safety.66,67 Mack et al. recently presented results of a study investigating Embol-X, an embolic protection cannula positioned in the ascending aorta, and CardioGard, an intra-aortic filtration device, in SAVR patients. The trial was stopped early due to an interim analysis for futility. Though the devices captured debris in most patients, freedom from clinical or radiographic CNS infarction, the primary endpoint, was not observed.68

TriGuard TM (Keystone Heart Ltd) DEFLECT I was a prospective, multicentre study aimed to evaluate safety and performance, in which 37 patients were enrolled.

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ICR_Lansky_FINAL.indd 31

A: Baseline; B: Following Cerebral Embolism. Arrows indicate areas of restricted diffusion. Adapted from Meller, et al., 2014.69

Post-procedure DW-MRI demonstrated that the presence of new cerebral ischaemic lesions was similar to historical controls (82 % versus 76 %, p=NS). It was further found that per-patient total lesion volume was 34 % lower when compared to the historical control (TLV 0.2 versus 0.3 cm3). Patients with complete cerebral vessel coverage experienced 89 % lower TLV compared to incomplete cerebral vessel coverage. With a MoCA score of 26 as the threshold for impairment, impaired patients had higher total median lesion volumes (163.18 cm3) compared to unimpaired patients (130.05 cm3).15 DEFLECT III was a multicentre, prospective, randomized study of TriGuard HDH Embolic Deflection Device in 85 patients randomized to TAVR with TriGuard or TAVR alone. Per-treatment population analysis revealed that TriGuard use was associated with greater freedom from new ischaemic brain lesions (26.9 % versus 11.15 %) and fewer neurologic deficits assessed by NIHSS (3.1 % versus 15.4 %). In terms of neurocognition, TriGuard use resulted in improved MoCA scores at discharge and 30 days along with better performance on a delayed memory tasks (p=0.028) at discharge.15 Long-term neurocognitive performance data, with a follow-up >1 year, is not available for any studies. The REFLECT US IDE trial is currently ongoing.

Conclusion TAVR continues to evolve with the expansion of indications in intermediate risk patients. With the imminent inclusion of low-risk patients, cerebral infarction during TAVR may play a larger role in patients who presumably have more to lose. Despite the gravity and widespread prevalence of cerebral embolization during TAVR, there is a lack of clinical data to fully understand the long-term consequences of covert CNS infarction. Cerebral embolization during TAVR is a certainty, yet the uncertainties lay in demonstrating the clinical benefits of cerebral embolic protection and determining the optimal study design for evaluating devices aimed at mitigating risk. These methodological limitations and gaps in evidence linking acutely silent CNS infarction with longer-term neurologic and cognitive effects have led to delays in adopting cerebral protection. While short- and long-term clinical evidence continues to evolve and in the absence of a safety hazard, demonstrating a reduction in the extent of CNS infarction (irrespective of symptoms) should be sufficient burden of proof for cerebral embolic protection. n

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Structural 1.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

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Structural

Oral Anticoagulant Therapy for Early Post-TAVI Thrombosis Neil Ruparelia Oxford Heart Centre, John Radcliffe Hospital, Oxford

Abstract While transcatheter aortic valve implantation (TAVI) is now the accepted treatment option of choice for patients presenting with severe symptomatic aortic stenosis who are deemed to be inoperable or of high surgical risk, there have been concerns regarding the risk of early valve failure and durability. One potential limitation is the occurrence of early post-TAVI thrombosis. Whilst the incidence of obstructive transcatheter heart valve (THV) thrombosis is <1 %, with technological advances in imaging, it is increasingly apparent that the overall true incidence is likely to be much higher with between 7–40 % of patients observed to have appearances strongly suggestive of asymptomatic subclinical THV thrombosis. This short review discusses the diagnosis of early THV thrombosis and the role of anticoagulation therapy for the management of these patients.

Keywords Transcatheter aortic valve implantation, TAVI, thrombosis, leaflet thickening, anticoagulation, antiplatelet Disclosure: The author has no conflicts of interest to declare. Received: 29 May 2017 Accepted: 31 August 2017 Citation: Interventional Cardiology Review 2018;13(1):33–6. DOI: 10.15420/icr.2017:14:1. Correspondence: Dr Neil Ruparelia, Department of Cardiology, Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Oxford, OX3 8LP, United Kingdom, Phone: +44 1865 220325, Fax: +44 1865 740409. E: neil.ruparelia@gmail.com

Transcatheter aortic valve implantation (TAVI) is now the accepted treatment option of choice for patients presenting with severe symptomatic aortic stenosis who are deemed to be inoperable or of high surgical risk.1,2 Short- and intermediate-term outcomes have been promising3–5 and with increasing institutional and operator experience combined with technological advancements there has been interest in the applicability of TAVI in the management of intermediate-risk6,7 and even low-risk8 patients. However, as with surgical bioprosthetic valves, there have been concerns with regard to the risk of early valve failure and durability.9,10 One potential limitation is the occurrence of early post-TAVI thrombosis.11 Following surgical valve replacement, the occurrence of thrombosis is associated with increased mortality and morbidity12,13 and in contemporary imaging studies has been reported to occur in up to 5 % of patients.14 TAVI thrombosis is thought to be more common than this14,15 and has been postulated to be an important contributing factor toward early valve degeneration with the development of poorly-mobile thickened valve leaflets and even possibly pannus formation.16 In the setting of transcatheter heart valves (THV) the mechanisms, frequency and optimal management strategy of thrombosis is currently poorly understood and based upon a small number of case reports and retrospective studies.15,17–20 Whilst the incidence of obstructive THV thrombosis is <1 %,20 the overall incidence is likely to be much higher with advances in imaging technology identifying up to 40 % of patients21,22 (the majority of whom are asymptomatic) following TAVI with valve appearances strongly suggestive of thrombosis. The role of anticoagulation in the treatment of patients presenting with obstructive symptomatic THV thrombosis is well defined. However, optimal post-TAVI antithrombotic regimens and the management

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and the rationale of intervention for patients with asymptomatic non-obstructive pathology are currently uncertain. The diagnosis of early TAVI thrombosis and the role of anticoagulation therapy for the management of these patients are discussed in this review.

Possible Causes of Early TAVI Thrombosis Factors contributing to the occurrence of early TAVI thrombosis are likely to be multifactorial. Patients with chronic renal failure, not being treated with an oral anticoagulant agent and with low left ventricular ejection fraction appear to be at higher risk of thrombosis. 14,21 Furthermore there may also be mechanical, valve-related features that may increase the likelihood for the development of early thrombosis, with possible causes including moderate–severe regional underexpansion (≤90˚) or an intra-annular valve position.23

Diagnosis Prosthetic valve thrombosis is traditionally defined as any thrombus not caused by infection and that is attached to or near a surgical valve resulting in some degree of blood flow obstruction, interference with valve function, or is sufficiently large to warrant treatment24,25 and as such refers to symptomatic patients. Patients presenting with obstructive THV thrombosis commonly exhibit signs and symptoms of congestive cardiac failure. Historically, transthoracic echocardiography (TTE) has been the imaging modality most commonly used to evaluate prosthetic valve function and the presence of thrombus in this setting (Figure 1) and is invaluable in the assessment of transvalvular gradients, calculation of the effective orifice valve area and the presence of large thrombi.13 The confirmation of the presence of small thrombi is more challenging and in these instances, transoesophageal echocardiography – by virtue of its greater spatial resolution – may be useful in confirming a diagnosis. Most recently, technological advances in contrast-enhanced multi-detector computed tomography

Access at: www.ICRjournal.com

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Structural Figure 1: Example of Early Transcatheter Aortic Valve Thrombosis

Computed tomography demonstrating hypoattenuation indicating thrombus formation (arrows, A, B). Confirmed upon transthoracic echocardiography (arrow, C) and transoesophageal echocardiography (arrow, D). Transvalvular gradient also noted to be elevated at 4 metres/second (E) that resolved one month after initiation of anticoagulation therapy to 2.3 metres/second (F).

(MDCT) have enabled it to become an invaluable adjunctive imaging modality with the presence of features including hypoattenuated leaflet thickening and ≥50 % reduction of leaflet motion26 further supporting the diagnosis of THV thrombosis (Figure 1). A second group of patients who were previously poorly defined and are now increasingly being recognised, are those who present with abnormalities in valve appearance, leaflet movement or an increase in transvalvular gradients but without symptoms. Whilst no abnormality may be appreciable on TTE (with a ‘normal’ functioning valve), features supporting the diagnosis of THV thrombosis can be detected with the aid of MDCT.18,22,26 The natural history of this condition is currently unclear and CT sub-studies have been included as part of the recently launched randomised controlled trials investigating efficacy of TAVI versus surgical aortic valve replacement in low risk patients. The Placement Of Aortic Trascatheter Valves 3 (PARTNER 3) trial will include a 400-patient sub-study in an attempt to provide clarity on leaflet mobility and thrombosis among patients treated with the SAPIEN 3 (Edwards LifeSciences) and similarly the Medtronic low-risk study investigating the Evolut R device will also include a 400-patient CT substudy to further investigate this clinical entity.

ICR_Ruparelia_FINAL.indd 34

Clinical Data Data from a randomised trial and two registries have been analysed: the Portico Re-Sheathable Transcatheter Aortic Valve System US IDE (PORTICO IDE) trial, and the Assessment Of Transcatheter And Surgical Aortic Bioprosthetic Valve Thrombosis And Its Treatment With Anticoagulation (RESOLVE) and Subclinical Aortic Valve Bioprosthesis Thrombosis Assessed By 4D CT (SAVORY) registries.22 No patient receiving therapeutic anticoagulation with warfarin (for other indications e.g. AF), compared with dual antiplatelet therapy, was noted to have reduced leaflet motion (trial: 0 % versus 50 %, p=0.01; pooled registries: 0 % versus 29 %, p=0.04) during follow-up.22 Furthermore, in patients found to have reduced leaflet motion, normal leaflet motion was restored in all 11 patients that subsequently received oral anticoagulation with warfarin, but in only 1 out of 10 patients not receiving anticoagulation (p<0.01).22 In a more recent study, the risk of THV thrombosis was 10.7 % in patients who did not receive warfarin versus 1.8 % in patients who received anticoagulation. Furthermore, subsequent treatment with warfarin resulted in normalisation of valve function in 85 % of patients.21 The efficacy of systemic anticoagulation with warfarin for the management of THV thrombosis is further supported by a number of case reports in the setting of both obstructive15,27,28 and non-obstructive 29 valve thrombosis. Novel anticoagulants (NOAC) may also have a role in the management of these patients.19 Consequently, systemic anticoagulation is the cornerstone of treatment for patients presenting THV thrombosis early after TAVI. There is therefore considerable interest in understanding the optimal anti-platelet and anti-coagulant strategy following TAVI to reduce the risk of thrombosis. However, in view of the generally high-risk elderly population that are commonly treated with TAVI, the risk of bleeding has to be balanced against any theoretical benefit. Whilst predominantly designed for patients with coronary disease, current bleeding risk scores (e.g. Can Rapid Risk Stratification Of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation Of The ACC/AHA Guideline [CRUSADE]30 and Acute Coronary Treatment and Intervention Outcomes Network [ACTION]31) are often used in this population to determine bleeding risk prior to deciding upon a definitive strategy. The current guidelines for the administration of anti-platelet and antithrombotic agents following TAVI are summarised in Table 1.

Management The management of patients presenting with early TAVI thrombosis varies between patients who are symptomatic and those who have subclinical thrombosis. This is further discussed in the subsequent sections and a flow chart illustrating a potential management approach is summarised in Figure 2.

Symptomatic THV Thrombosis In patients presenting with obstructive (i.e. symptomatic) TAVI thrombosis, systemic anticoagulation should be initiated immediately with heparin. In patients in extremis (e.g. haemodynamic compromise), surgical intervention – including thrombectomy or valve replacement – should be considered. 32 However, the majority of patients who have been treated with TAVI are likely to be deemed inoperable or of prohibitive risk for this approach because of concomitant comorbidities. In these instances, fibrinolysis should be considered 32,33 followed by systemic anticoagulation with heparin and then warfarin.

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Oral Anticoagulation for TAVI Thrombosis Table 1: Current Recommendations for Anti-Platelet and Anti-thrombotic Therapy Following TAVI

ACC/AHA Guidelines

ESC/EACTS Guidelines

ACC Expert Consensus

Immediately Following TAVI • Aspirin 75–100 mg/day + • Low-dose aspirin + thienopyridine • Aspirin 75–100 mg/day + clopidogrel clopidogrel 75 mg/day for 75 mg/day for 3–6 months 6 months (IIb) • VKA to achieve an INR of 2.5 • For patients with AF: VKA + aspirin • Consider VKA (INR 2.0–2.5) if at for at least 3 months in patients or thienopyridine (accounting risk of AF or VTE for 3 months at low risk of bleeding (IIb) of bleeding risk) Long-term

• Lifelong aspirin 75–100 mg/day (IIb)

• Aspirin or thienopyridine alone

• Lifelong aspirin 75–100 mg/day

ACC = American College of Cardiology; AF = atrial fibrillation; AHA = American Heart Association; EACTS = European Association for Cardio-Thoracic Surgery; ESC = European Society of Cardiology; INR = international normalised ratio; TAVI = transcatheter aortic valve implantation; VKA = Vitamin K antagonist; VTE = venous thromboembolism.

Table 2: Current On-going Studies Investigating Anti-Coagulant/Anti-Platelet Strategies Following TAVI Study Name

Patient Groups

Primary Endpoint

Planned Recruitment (n)

Completion Date

ATLANTIS35

Apixaban versus DAPT or VKA

Death, MI, stroke, embolism, prosthesis thrombus, major bleeding

1,509

2019

GALILEO36

Rivaroxaban + aspirin versus DAPT

Death, MI, stroke, embolism, prosthesis thrombus, major bleeding

1,520

2018

GALILEO (sub-study: evaluation by 4DCT)36

Rivaroxaban + aspirin versus DAPT

Leaflet thickening and motion

300

2018

POPULAR TAVI37

Aspirin versus DAPT versus OAC versus OAC + clopidogrel

Bleeding

1,000

2017

AUREA38

DAPT versus OAC for 3 months following TAVI

Cerebral thromboembolism by cardiac magnetic resonance imaging

124

2018

4DCT = four-dimensional, volume-rendered computed tomography; ATLANTIS = Anti-thrombotic Strategy After Trans-aortic Valve Implantation For Aortic Stenosis; AUREA = Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI; DAPT = dual antiplatelet therapy; GALILEO = Global Study Comparing A Rivaroxaban-Based Antithrombotic Strategy To An Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement To Optimize Clinical Outcomes; MI = myocardial infarction; OAC = oral anticoagulation; POPULAR TAVI = Antiplatelet Therapy For Patients Undergoing TAVI; VKA = vitamin K antagonist.

In symptomatic patients who are haemodynamically stable, the anticoagulant agent of choice is currently warfarin. However, there have been reports of efficacy with direct oral anticoagulants.14,19 It is currently unclear as to the optimal length of treatment, with recurrence of THV thrombus noted following discontinuation of warfarin.22 Ideally, life-long therapy should be instigated but the final decision should be made on a patient-by-patient basis after balancing the benefits against the risks of bleeding in this high-risk patient cohort. If the decision is made to stop anticoagulation therapy, this should only be recommended when valve function has normalised and patients should be treated with long-term anti-platelet therapy with frequent clinical and echocardiographic surveillance with reports of recurrence with cessation of anticoagulant therapy.29

Figure 2: An Approach To The Management of Patients Presenting With Valve Thrombosis Early After Transcatheter Aortic Valve Implantation

Suspected TAVI thrombosis?

CT/TTE/TOE to confirm diagnosis

Yes

Symptomatic

Asymptomatic

Haemodynamic Compromise?

Bleeding Risk

Asymptomatic THV Thrombosis In patients presenting with asymptomatic or non-obstructive THV thrombosis (normal transvalvular gradients), the optimal management is uncertain. With advancements in MDCT, it is increasingly clear that this is a relatively common finding and, whilst it does appear to improve with systemic anticoagulation, there are reports of spontaneous resolution over time. Furthermore, and most importantly, the clinical sequelae are poorly characterised, with currently available data suggesting no difference in mortality or stroke but more transient ischaemic attacks in patients noted to have asymptomatic valve thickening.14 This is particularly important in view of the fact that initiation of anticoagulation therapy in this elderly co-morbid population is associated with a relatively high risk of bleeding complications. On the basis of the currently available data, routine anticoagulation following TAVI in this high-risk group cannot be currently recommended and is the subject of on-going study (Table 2).

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No High

Surgical Risk

Systemic anticoagulation

High

Low VKA (3–6 months)

Interval Imaging

Low Fibrinolysis

Surgical Intervention

Resolution No Lifelong VKA

Yes Lifelong aspirin

CT = computed tomography; TAVI = transcatheter aortic valve implantation; TOE = transoesophageal echocardiogram; TTE = transthoracic echocardiogram; VKA = vitamin K antagonist.

Unresolved Issues On the basis of current observations, there are a number of unanswered questions with regard to the management of patients presenting with THV thrombosis early after TAVI:

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Structural • T he optimal duration of anticoagulation therapy for the treatment of THV thrombosis. • Whether all patients should be ‘screened’ with MDCT for subclinical THV thrombosis and, if so, at what time-point. • The benefit of routine post-TAVI anticoagulation to prevent the occurrence of valve thickening or reduced leaflet motion. • The clinical relevance of non-obstructive asymptomatic valve thickening/reduced leaflet motion with regard to clinical outcomes and valve durability. On the basis of the currently available data, routine systemic anticoagulation or screening MDCT to determine the presence/absence of valve thickening following TAVI is not recommended. However, a number of studies are on-going to investigate these issues further

ahanian A, Alfieri O, Andreott F, et al. Joint Task Force on V the Management of Valvular Heart Disease of the European Society of Cardiology, European Association for Cardio Thoracic Surgery. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96. DOI:10.1093/eurheartj/ehs109; PMID: 22922415. 2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: A Report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol 2017;70:252–89. DOI: 10.1016/j.jacc.2017.03.011; PMID: 28315732. 3. Deeb GM, Reardon MJ, Chetcuti S, et al, CoreValve USCI. 3-year outcomes in high-risk patients who underwent surgical or transcatheter aortic valve replacement. J Am Coll Cardiol 2016;67:2565–74. DOI: 10.1016/j.jacc.2016.03.506; PMID: 27050187. 4. Kapadia SR, Leon MB, Makkar RR, et al. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2485–91. DOI: 10.1016/S0140-6736(15)60290-2; PMID: 25788231. 5. Mack MJ, Leon MB, Smith CR, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477–84. DOI: 10.1016/S0140-6736(15)60308-7; PMID: 25788234. 6. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324. 7. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or Transcatheter Aortic-Valve Replacement in IntermediateRisk Patients. N Engl J Med 2017;376:1321–31. DOI: 10.1056/ NEJMoa1700456; PMID: 28304219. 8. Thyregod HG, Steinbruchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196. 9. Arsalan M, Walther T. Durability of prostheses for transcatheter aortic valve implantation. Nat Rev Cardiol. 2016;13:360–7. DOI: 10.1038/nrcardio.2016.43; PMID: 27053461. 10. Mylotte D, Andalib A, Theriault-Lauzier P, et al. Transcatheter heart valve failure: a systematic review. Eur heart J 2015;36:1306–27. DOI: 10.1093/eurheartj/ehu388; PMID: 25265974. 11. Schirmer SH, Mahfoud F, Fries P, Scheller B. Thrombosis of TAVI prosthesis-cause for concern or innocent bystander? A comment and review of currently available data. Clinical Res Cardiol 2017;106:79–84. DOI: 10.1007/s00392-016-1061-2; PMID: 27995320. 12. Egbe AC, Connolly HM, Schaff HV. Bioprosthetic valve thrombosis: What we know and what we need to know. J Thorac Cardiovasc Surg 2016;152:975–8. DOI: 10.1016/ j.jtcversus2016.04.049; PMID: 27234023.

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(Table 2), the results of which are eagerly awaited to determine optimal peri- and post-procedural anti-platelet and anticoagulant strategies.

Conclusion Anticoagulation therapy forms the cornerstone of management for the treatment of early post-TAVI thrombosis. To date, warfarin has been the most commonly used agent and is associated with rapid improvement in the appearance and haemodynamics of TAVI valves in symptomatic patients. In patients presenting with obstructive symptomatic THV thrombosis, warfarin should ideally be continued for life. The clinical significance and the optimal management of patients presenting with asymptomatic non-obstructive valve thickening and/ or reduced valve motion is currently uncertain and is the subject of a number of on-going large-scale clinical trials. n

13. R oudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart 2007;93:137–42. DOI: 10.1136/hrt.2005.071183; PMID: 17170355. 14. Chakravarty T, Sondergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389:2383–92. DOI: 10.1016/S0140-6736(17)30757-2; PMID: 28330690. 15. Latib A, Messika-Zeitoun D, Maisano F, et al. Reversible Edwards Sapien XT dysfunction due to prosthesis thrombosis presenting as early structural deterioration. J Am Coll Cardiol 2013;61:787–9. DOI: 10.1016/j.jacc.2012.10.016; PMID: 23219300. 16. Egbe AC, Pislaru SV, Pellikka PA, et al. Bioprosthetic valve thrombosis versus structural failure: Clinical and echocardiographic predictors. J Am Coll Cardiol 2015;66:2285–94. DOI: 10.1016/j.jacc.2015.09.022; PMID: 26610876. 17. Cordoba-Soriano JG, Puri R, Amat-Santos I, et al. Valve thrombosis following transcatheter aortic valve implantation: a systematic review. Rev Esp Cardiol 2015;68:198–204. DOI: 10.1016/j.rec.2014.10.003; PMID: 25667117. 18. Leetmaa T, Hansson NC, Leipsic J, et al. Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv 2015;8:e001596. DOI: 10.1161/ CIRCINTERVENTIONS.114.001596; PMID: 25873726. 19. Ruparelia N, Panoulas VF, Frame A, et al. Successful treatment of very early thrombosis of SAPIEN 3 valve with direct oral anticoagulant therapy. J Heart Valve Dis 2016;25:211–3. PMID: 27989069. 20. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8:e001779. DOI: 10.1161/ CIRCINTERVENTIONS.114.001779; PMID: 25873727. 21. Hansson NC, Grove EL, Andersen HR, et al. transcatheter aortic valve thrombosis: incidence, predisposing factors, and clinical implications. J Am Coll Cardiol 2016 Nov 08;68(19):205969. DOI: 10.1016/j.jacc.2016.08.010; PMID: 27580689. 22. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24. DOI: 10.1056/NEJMoa1509233; PMID: 26436963. 23. Fuchs A, de Backer O, Brooks M, et al. Subclinical leaflet thickening and stent frame geometry in self-expanding transcatheter heart valves. EuroIntervention 2017 pii: EIJ-D-1700373. DOI: 10.4244/EIJ-D-17-00373; PMID: 28741579; epub ahead of press. 24. Akins CW, Miller DC, Turina MI, et al. Guidelines for reporting mortality and morbidity after cardiac valve interventions. Annals Thorac Surg 2008;85:1490–5. DOI: 10.1016/ j.athoracsur.2007.12.082; PMID: 18355567. 25. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60:1438–54. DOI: 10.1016/j.jacc.2012.09.001; PMID: 23036636. 26. Jilaihawi H, Asch FM, Manasse E, et al. Systematic CT methodology for the evaluation of subclinical leaflet thrombosis. JACC Cardiovasc Imaging 2017;10:461–70. DOI: 10.1016/j.jcmg.2017.02.005; PMID: 28385256.

27. T repels T, Martens S, Doss M, et al. Images in cardiovascular medicine. Thrombotic restenosis after minimally invasive implantation of aortic valve stent. Circulation 2009;120:e23–4. DOI: 10.1161/CIRCULATIONAHA.109.864892; PMID: 19635975. 28. Lancellotti P, Radermecker MA, Weisz SH, Legrand V. Subacute transcatheter CoreValve thrombotic obstruction. Circ Cardiovasc Interv 2013;6:e32-3. DOI: 10.1161/ CIRCINTERVENTIONS.113.000213; PMID: 23780297. 29. Ruile P, Jander N, Blanke P, et al. Course of early subclinical leaflet thrombosis after transcatheter aortic valve implantation with or without oral anticoagulation. Clin Res Cardiol 2017;106:85–95. DOI: 10.1007/s00392-016-1052-3; PMID: 27853942. 30. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation 2009;119:1873–82. DOI: 10.1161/ CIRCULATIONAHA.108.828541; PMID: 19332461. 31. Mathews R, Peterson ED, Chen AY, et al. In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®-GWTGTM. Am J Cardiol 2011;107:1136–43. DOI: 10.1016/j.amjcard.2010.12.009; PMID: 21324428. 32. Roudaut R, Lafitte S, Roudaut MF, et al. Management of prosthetic heart valve obstruction: fibrinolysis versus surgery. Early results and long-term follow-up in a single-centre study of 263 cases. Arch Cardiovas Dis 2009;102:269–77. DOI: 10.1016/j.acvd.2009.01.007; PMID: 19427604. 33. Biteker M, Altun I, Basaran O, et al. Treatment of prosthetic valve thrombosis: Current evidence and future directions. J Clin Med Res 2015;7:932–6. DOI: 10.14740/jocmr2392w; PMID: 26566406. 34. Otto CM, Kumbhani DJ, Alexander KP, et al. 2017 ACC expert consensus decision pathway for transcatheter aortic valve replacement in the management of adults with aortic stenosis: A report of the American College of Cardiology task force on clinical expert consensus documents. J Am Coll Cardiol 2017;69:1313–46. DOI: 10.1016/j.jacc.2016.12.006; PMID: 28063810. 35. Anti-thrombotic strategy after trans-aortic valve implantation for aortic stenosis (ATLANTIS) NCT02664649. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02664649 (accessed 26 September 2017). 36. Windecker S, Tijssen J, Giustino G, et al. Trial design: Rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: Rationale and design of the GALILEO study. Am Heart J 2017;184:81–7. DOI: 10.1016/j.ahj.2016.10.017; PMID: 27892890. 37. Nijenhuis VJ, Bennaghmouch N, Hassell M, et al. Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation. Am Heart J 2016;173:77–85. DOI: 10.1016/j.ahj.2015.11.008; PMID: 26920599. 38. Dual antiplatelet therapy versus oral anticoagulation for a short time to prevent cerebral embolism after TAVI (AUREA) NCT01642134. 2017. Available at: https://clinicaltrials.gov/ct2/ show/NCT01642134?term=NCT01642134&rank=1 (accessed 26 September 2017).

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Assessing the Risk of Leaflet Motion Abnormality Following Transcatheter Aortic Valve Implantation Luca Testa 1 and Azeem Latib 2 1. Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese; 2. San Raffaele Scientific Institute, Milan, Italy

Abstract Leaflet motion abnormalities are a relatively new entity in the field of transcatheter aortic valve implantation and are associated with a range of different conditions, the extreme being prosthetic valve dysfunction with high gradients or central regurgitation and possibly early thrombotic degeneration. Another extreme condition is the incidental finding of leaflet thickening, but with normal transvalvular gradients. Transthoracic echocardiography is a useful screening tool for the detection of symptomatic thrombosis, but it has limited use in the detection of subclinical thrombosis and/or motion abnormalities alone. We, hereby, discuss the evidence for the potential screening process and subsequent management of those conditions associated with the leaflet motion abnormalities.

Keywords Leaflet motion, TAVI, transcatheter aortic valve implantation Disclosure: Both authors have no conflict of interest to disclose. Acknowledgement: We would like to thank Mrs Giulia and Ms Martina for their irreplaceable help. Received: 7 July 2017 Accepted: 12 August 2017 Citation: Interventional Cardiology Review 2018;13(1):37–9. DOI: 10.15420/icr.2017:24:2 Correspondence: Luca Testa, Department of Cardiology, San Donato Hospital, Piazza E. Malan 2, San Donato Milanese, 20098 Milano, Italy. E: luctes@gmail.com

Leaflet motion abnormalities (LMAs) are a relatively new entity in the field of transcatheter aortic valves (TAVs).1–4 They can be associated with the thrombosis of the bioprosthesis (TAVT), often leading to dramatic clinical scenarios1 or, on the other hand, they can result in a hypoattenuated leaflet thickening (HALT) and/or reduced leaflet motion (RELM), both usually associated with gradients within the normal range.2–4 We hereby discuss the potential screening process and subsequent management of LMAs and their possible associated clinical transcatheter aortic valves conditions, with a specific focus on the role of the imaging modalities.

Incidence of Transcatheter Aortic Valve Implantation With Thrombosis of the Bioprosthesis Most of the cases of TAVT reported in the literature presented with recurrence of symptoms at follow-up, non-ST-elevation myocardial infarction, embolic events (such as stroke) or cardiac arrest.5–9 Possible treatments for TAVT include anticoagulation, TAV implantation (TAVI)in-TAVI and surgical aortic valve replacement (SAVR).5,6,8,10 In recently published registries, the cumulative incidence of symptomatic TAVT ranged from 0.61 to 2.8 %.1,10 Almost all patients in the registries presented with worsening shortness of breath, and elevated transaortic gradients were detected in the majority of the patients (24 of 26 [92.3 %]). TAVT presented as thickened leaflets or thrombotic apposition of leaflets in 76.9 % and thrombotic mass on the leaflets in 23.1 %. Anticoagulation was successful in 23 of 26 patients (88.4 %), the remaining patients have been treated with transcatheter valve-in-valve procedure or surgical aortic valve replacement.

(VR) imaging.2 RELM was noted in 39 of 187 (20.9 %) patients and in multiple transcatheter valve types, including the Portico™ valve (St. Jude Medical); SAPIEN, SAPIEN XT and SAPIEN 3 (Edwards Lifesciences); CoreValve™ (Medtronic) and the Lotus™ Valve System (Boston Scientific). Pache et al. performed contrast computed tomography (CT) in 156 patients undergoing TAVI with the SAPIEN 3 valve at a median of 5 days post TAVI; HALT was noted in 16 (10.3 %) patients.3 Leetmaa et al. performed CT in 140 patients with SAPIEN XT valves within 3 months post implantation.4 TAVT (defined as HALT) was present in five patients (4 %), four of these patients being asymptomatic with no echocardiographic evidence of significantly elevated gradients.

Echocardiography Transthoracic echocardiography (TTE) plays a crucial role to exclude regurgitation and/or stenosis, but it provides inadequate details to assess the possible presence of HALT/RELM. Of note, the presence of HALT/RELM, is usually associated with ‘normal’ gradients. It is thus conceivable that after calculating normal gradients (which are usually higher than the native valve) even an expert echocardiographer may not carefully look for HALT/RELM. The latter issue may imply that the real incidence of this phenomenon is far from being precisely depicted. In some occasions, the transoesophageal echocardiogram (TEE) may be helpful to detect the RELM, before or after the CT scan findings; however, it is impractical to advocate the use of TEE in all cases, especially when the TTE shows normal gradients and no suspicious findings.

Computed Tomography The prevalence of HALT/RELM has been reported in three studies.7 Makkar et al. reported findings from 55 patients using 3D volume-rendered

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All acquisition protocols enabling the formal assessment of leaflet motion and thickening employs contrast CT with retrospective gating.

Access at: www.ICRjournal.com

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Structural Figure 1: Examples of HALT in Contemporary Transcatheter Aortic Bioprostheses Evolut R

Lotus

Portico

Symetis

Systole

Diastole

HALT

Sapien

be established before prospective studies and clinical practice are carried out.

HALT = hypoattenuated leaflet thickening.

The acquisition is usually performed in the craniocaudal direction from the aortic arch to the diaphragm and images reconstructed at 0.6 mm slices with 0.3 mm overlap and iterative reconstruction for evaluation at 10 % intervals within the 0–90 % RR range. To minimise radiation exposure a dose-modulation approach can be used, thus the reducing dose in the 55–100 % RR range (diastole). CT images are usually reconstructed in the systolic phase using 3mensio Valves™ version 7.0 or 7.1 (3mensio Medical Imaging BV), and Vitrea® Software Version 6.7.2 (Vital Images, Inc.). The valve leaflets can be assessed using both 2D (axial cross-section assessment) and 3D-VR imaging. The VR images can be generated using centreline reconstructions and the hockey puck feature in 3mensio or using front-cut plane or 5 mm thick slab VR functions in Vitrea. In Vitrea, the medium de-noising filter was employed. Of note, while leaflets with normal motion are difficult to visualise on 4D VR-CT, leaflets with reduced motion can be clearly seen in 3D or 4D images. Hypo-attenuating lesions can be studied on maximal intensity projection (MIP) 2D CT and correlated to reduced leaflet motion on 3mensio software with the use of the marker feature and on Vitrea software using the VR auto-alignment with MIP feature. Theoretically, the CT-scan acquisition and reconstruction can be deemed as the gold-standard imaging tool to visualise the leaflets; however, it provides no haemodynamic information. Thus, the CT scan is actually complementary to the TTE/TEE, although in all the published series on this topic, the CT scan has been used to confirm the diagnosis.

Echocardiography Versus Computed Tomography A discrepancy must be acknowledged between CT and echocardiographic findings. Despite a 10–15 % prevalence of subclinical thrombosis with CT, elevated gradients (a mean gradient of >20 mm Hg) with echocardiography are infrequent.1–6 This observation implies that CT detects early subclinical thrombosis, whereas echocardiography detects the late consequences of thrombosis – i.e. valvular stenosis. This also indicates that not all thromboses result in valve degeneration, i.e. early thrombosis might resolve spontaneously.11 Dynamic 4D CT imaging has consistently been used for detection of subclinical thrombosis, although consensus of definitions and quantification of leaflet thrombosis with CT is lacking and should

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Moreover, the CT timing after TAVI to detect meaningful leaflet thrombosis is unknown. It has been postulated that the timing of imaging might affect the proportions of leaflet thrombosis with different valve types (see Figure 1);8 however, there is no evidence to support a risk linked to a specific type of bioprosthesis.

Impact of HALT/RELM on Clinical Events and the Role of Anticoagulation Leetmaa et al. did not observe any cases of HALT (TAV thrombosis) in patients on anticoagulation.4 Makkar et al. reported similar findings in patients on anticoagulants compared with patients on antiplatelet therapy,2 and initiation of anticoagulation following detection of HALT/ RELM resulted in resolution of the imaging findings and of the LMA in all patients.2–4 Of note, with respect to the presence of leaflet thrombosis and possible subsequent clinical events, a discrepancy is noted between the 10–15 % prevalence of CT thrombosis and the proportion of 3–4 % of patients with stroke in large clinical trials. Moreover, Chakravarty et al. reported that, in addition to subclinical leaflet thrombosis being less common in patients receiving warfarin or non-vitamin K antagonist oral anticoagulants than in those receiving antiplatelet agents, the thrombosis resolved in all 36 patients who were given anticoagulants, but persisted in 20 of 22 (91 %) patients not receiving anticoagulants.7 The fact that HALT/RELM is seldom observed in patients on anticoagulants and often resolves with initiation of anticoagulation suggests that this finding is related to TAVT. Thus, it may be reasonable to perform a CT scan in selected clinical situations (dysfunctional TAVI, worsening heart failure, stroke/transient ischaemic attack, myocardial infarction or other clinical situations suggesting embolic phenomena) and patients on anticoagulants with symptomatic TAV thrombosis (HALT/RELM). On the other hand, given the risks of chronic anticoagulation, questions remain: • Should all patients be offered such therapy? • Should patients be selected according to imaging findings? • What is the optimal duration of treatment? • With new oral anticoagulants being considered to be preferable over vitamin K antagonists, how and when should we re-assess the efficacy of the treatment? Moreover, predictors of subclinical TAV thrombosis (including the propensity of individual valve types) are unknown.

Conclusion Before robust evidence that the imaging finding of HALT/RELM alone is clinically relevant becomes available, the management of patients with TAVI should not change. Both the European Society of Cardiology and American College of Cardiology/American Heart Association guidelines provide a Class IIb recommendation for dual antiplatelet therapy, but do not recommend routine anticoagulation.12,13 It is also wise to embrace the US Food and Drug Administration perspective that, based on findings to date regarding reduced leaflet motion, stated that the overall benefit–risk balance for use of TAVI remains favourable when they are used for their approved indications.9 n

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Post-TAVI Leaflet Motion Abnormality Following

Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8:pii: e001779. DOI: 10.1161/ CIRCINTERVENTIONS.114.001779; PMID: 25873727. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24. DOI: 10.1056/NEJMoa1509233; PMID: 26436963. Pache G, Schoechlin S, Blanke P, et al. Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2016;37:2263–71. DOI: 10.1093/ eurheartj/ehv526; PMID: 26446193. Leetmaa T, Hansson NC, Leipsic J, et al. Early aortic transcatheter heart valve thrombosis: diagnostic value of contrast-enhanced multidetector computed tomography. Circ Cardiovasc Interv 2015;8:pii: e001596. DOI: 10.1161/ CIRCINTERVENTIONS.114.001596; PMID: 25873726. Trepels T, Martens S, Doss M, et al. Images in cardiovascular medicine. Thrombotic restenosis after minimally invasive implantation of aortic valve stent. Circulation 2009;120:e23–4.

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DOI: 10.1161/CIRCULATIONAHA.109.864892; PMID: 19635975. Lancellotti P, Radermecker MA, Weisz SH, Legrand V. Subacute transcatheter CoreValve thrombotic obstruction. Circ Cardiovasc Interv 2013;6:e32–3. DOI: 10.1161/ CIRCINTERVENTIONS.113.000213; PMID: 23780297. 7. Chakravarty T, Søndergaard L, Friedman J, et al; on behalf of the RESOLVE and SAVORY Investigators. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389,2383–92. DOI: 10.1016/S0140-6736(17)30757-2; PMID: 28330690. 8. Bax JJ, Stone GW. Bioprosthetic surgical and transcatheter heart valve thrombosis. Lancet 2017;389:2352–4. DOI: 10.1016/S0140-6736(17)30764-X; PMID: 28330691. 9. Laschinger JC, Wu C, Ibrahim NG, Shuren JE. Reduced leaflet motion in bioprosthetic aortic valves–the FDA perspective. N Engl J Med 2015;373:1996–8. DOI: 10.1056/NEJMp1512264; PMID: 26437127. 10. Jose J, Sulimov DS, El-Mawardy M, et al. Clinical bioprosthetic heart valve thrombosis after transcatheter aortic valve

replacement: incidence, characteristics, and treatment outcomes. JACC Cardiovasc Interv 2017;10:686–97. DOI: 10.1016/j.jcin.2017.01.045; PMID: 28385406. 11. Sondergaard L. Subclinical leaflet thrombosis in bioprosthetic aortic valves. JACC Cardiovasc Interv 2017; 10:204–20. DOI: 10.1016/j.jcin.2016.10.042; PMID: 28104218. 12. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ ACC focused update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. DOI: 10.1161/ CIR.0000000000000503; PMID: 28298458 13. The Task force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; doi:10.1093/eurheartj/ehx391; epub ahead of press.

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Coronary

Challenges in Patients with Diabetes: Improving Clinical Outcomes After Percutaneous Coronary Intervention Through EVOlving Stent Technology Robert A Byrne, 1 Shmuel Banai, 2 Roisin Colleran 1 and Antonio Colombo 3 1. German Heart Centre Munich, Technical University of Munich, Munich, Germany; 2. Tel Aviv Medical Center, Israel; 3. San Raffaele Hospital, Milan, Italy

Abstract Patients with diabetes have poorer outcomes after percutaneous coronary intervention than patients without diabetes. The Cre8™ EVO drug-eluting stent (DES) has design features that aim to improve clinical outcomes in patients with diabetes. These include Abluminal Reservoir Technology – a proprietary polymer-free drug-release system consisting of reservoirs on the abluminal surface of the stent that control drug release and direct the drug exclusively towards the vessel wall – and the Amphilimus™ drug formulation, which enables enhanced drug–tissue permeation utilising fatty acid transport pathways. The latter is particularly advantageous in patients with diabetes, whose cell metabolism favours increased cellular uptake of fatty acid. Furthermore, evidence suggests that mTOR inhibitors (-limus drugs) utilised in conventional DES are less effective in diabetic cells. The new stent architecture provides high device deliverability and conformability, facilitating clinical use in complex disease patterns and high-risk lesion morphologies. Clinical evidence for the efficacy and safety of the Cre8™ DES in patients with diabetes has been demonstrated in a number of clinical trials and observational registries. These data are reviewed herein, along with an overview of on-going randomised trials.

Keywords Coronary artery disease, diabetes, drug-eluting stent, percutaneous coronary intervention Disclosure: Dr Byrne has received research grants from Boston Scientific and Heartflow, and lecture fees from B. Braun Melsungen, Biotronik and Boston Scientific. Dr Colleran has received a research grant from the Irish Board for Training in Cardiovascular Medicine, sponsored by MSD. Dr Banai and Dr Colombo have no conflicts of interest to declare. Acknowledgement: The authors are grateful to the technical editing support provided by Katrina Mountfort of Medical Media Communications (Scientific) Ltd, which was funded by Alvimedica Received: 3 October 2017 Accepted: 19 October 2017 Citation: Interventional Cardiology Review 2018;13(1):40–4. DOI: 10.15420/icr.2017:27:1 Correspondence: Robert A. Byrne, Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany; E: byrne@dhm.mhn.de

Newer generation polymeric metallic drug-eluting stents (DES) have shown improved efficacy and safety compared with bare-metal stents and first-generation DES, improving patient outcomes after percutaneous coronary intervention (PCI) and facilitating the treatment of more complex coronary disease.1 However, clinical outcomes in certain lesion and patient subsets remain suboptimal. Procedural and/or technological refinements may improve success rates in such scenarios. Patients with diabetes represent one such complex subgroup as they continue to have worse outcomes following PCI compared with patients without diabetes.2 The latest DES technological enhancements may have an important impact in improving the outcomes of these patients. The Cre8™ EVO (Alvimedica) represents novel DES technology that features laser-cut reservoirs on the abluminal surface of the stent that support the controlled polymer-free elution of Amphilimus™. In the current review, we discuss coronary revascularisation in patients with diabetes, with a focus on the latest efficacy and safety data from studies evaluating the Amphilimus™ polymer-free DES and its latest iteration, the Cre8™ EVO stent, in patients with diabetes.

Clinical Efficacy of DES in Patients with Diabetes Diabetes has become a global health emergency. At present, an estimated 415 million adults have diabetes worldwide.3 By 2040, this is projected to rise to 642 million.3 In addition, it is estimated that

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there are 192.8 million people worldwide with undiagnosed diabetes.3 More than 25 % of patients referred for coronary revascularisation procedures have diabetes. Such patients have a higher risk of complications compared with patients without diabetes, and their long-term prognosis is worse in terms of restenosis, stent thrombosis, myocardial infarction (MI) and death.4–8 Clinical outcomes in diabetic patients treated with DES versus bare-metal stents, as well as the comparative performance of several DES, have been assessed in randomised trials and large observational registries.9 The 300-patient randomised Comparison of Everolimus-eluting Stent versus Sirolimuseluting Stent Implantation for de novo Coronary Artery Disease in Patients with Diabetes Mellitus (ESSENCE-DIABETES) trial succeeded in showing non-inferiority of everolimus-eluting stents (EESs) compared to first-generation sirolimus-eluting stents with respect to angiographic late lumen loss (LLL) at 8 months with no significant difference in clinical outcomes at 1 year, although the trial was not powered to show a statistical difference with respect to the latter.10 A pooled analysis of 6,780 patients treated with second-generation EES versus first generation paclitaxel-eluting stents enrolled in the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) II, SPIRIT III and SPIRIT IV and the SecondGeneration Everolimus-Eluting and Paclitaxel-Eluting Stents in RealLife Practice (COMPARE) randomised trials showed that despite improved safety and efficacy of EES in non-diabetic patients at 2

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Improving Outcomes in Diabetes with EVOlving Stent Technology

Revascularisation in Diabetic Patients with Multivessel Coronary Artery Disease European guidelines for clinical practice recommend coronary artery bypass graft (CABG) surgery in preference to PCI in diabetic patients with multivessel disease, with PCI considered a treatment alternative in patients with a low SYNTAX score (≤22).17 However, randomised trials comparing PCI with CABG in patients with diabetes are somewhat outdated. The largest trial to compare PCI with CABG for the treatment of multivessel coronary artery disease in diabetic patients was the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial, which found CABG to be superior to PCI with respect to the primary endpoint, the combined incidence of death, non-fatal MI or stroke. This was driven by a reduction in both non-fatal MI and death in the CABG group, albeit with an almost two-fold higher incidence of stroke.18 However, the trial is limited by the use of first-generation DES in 94 % of patients in the PCI group. Moreover, of 33,000 patients screened, only 1,900 (5.7 %) were enrolled, only 2.5 % of enrolled patients had a left ventricular ejection fraction <40 %, and only 35.5 % had a SYNTAX score ≤22 – all factors limiting the external validity of results. Other randomised trials comparing PCI and CABG were underpowered with respect to their primary outcome measures. Both the Coronary Artery Revascularization in Diabetes (CARDia) study19 and the Veterans Affairs Coronary Artery Revascularization in Diabetes Study (VA CARDS) were terminated early due to slow enrolment.20 The CARDia trial enrolled 510 of the 600 patients planned and failed to show non-inferiority of PCI versus CABG with respect to the combined incidence of death, MI or stroke. VA-CARDS randomised only 207 (3 %) of 6,678 patients screened, representing only one-quarter of the planned sample size. Both trials were also limited by the use of first-generation DES as well as bare-metal stents in the CARDia study. Finally, a subgroup analysis of patients with diabetes enrolled in the Synergy between PCI with TAXUS and CABG (SYNTAX) study (n=452)21 found no significant difference in the combined incidence of all-cause death, MI or stroke between the two groups, although the trial was not designed to show such a difference in subgroups. Despite the fact that patients with diabetes fared worse than patients without diabetes in the SYNTAX trial, the presence of diabetes was not found to be independently associated with increased risk of major adverse cardiac events in multivariable analysis. It is clear that only one randomised study comparing PCI and CABG in patients with diabetes was adequately powered to show a difference between treatment groups with respect to its primary endpoint, and that all trials are limited by the use of predominantly first-generation DES. Irrespective of the revascularisation strategy, patients with diabetes are at a higher risk of progression of de novo native coronary artery disease compared with patients without diabetes. Furthermore,

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Figure 1: Effect of Leptin at the Vascular Level Pathological status (Hyperleptinaemia)

Angiogenesis VEGF Monobutyrin

Leptin Adipocyte

– endothelial cell proliferation ↑ – VSMC proliferation ↑ – GM-CSF/G-CSF ↑ – proliferation hematopoietic progenitors

RESTENOSIS

Immune system

PERMANENT INFLAMMATORY STATUS

– Activation of monocytes – T-cell activation

Atherogenesis TNF-α IL-6 LPL Acute phase reactants

PLAQUE PROGRESSION

– platelet aggregation ↑ – VSMC proliferation ↑ – ROS production ↑ – MCP-1 upregulation – IL-6, TNF-α ↑

PRO-THROMBOTIC STATUS

GM-CSF = granulocyte–macrophage colony-stimulating factor; G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPL = lipoprotein lipase; MCP-1 = monocyte chemoattractant protein-1; ROS = reactive oxygen species; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor; VSMC = vascular smooth muscle cell. Adapted from Werner et al., 2004.26

Figure 2: The Cre8™ EVO New Stent Architecture (EvenArt). Shortened pitch

Reservoirs + Amphilimus™ + New Stent Arcllitecture Total tissue drug concentration Drug eluted from a single strut

versus Polymer + drug

Vessel Wall

Drug concentration

years, there was no difference between the devices with respect to outcomes in diabetic patients (n=1,869).11 Furthermore, different second-generation DES devices – utilising permanent or bioresorbable polymers – have not demonstrated differential efficacy in patients with diabetes.12,13 In scanning electron microscopy studies, cracks and inhomogeneous distribution of coating have been observed on all DES types assessed.14,15 Such occurrences can promote platelet aggregation, stent thrombosis and, in individuals with diabetes, trigger an inflammatory response within the vessel wall, potentially accelerating progression of atherosclerosis and risk of restenosis.16

Cre8™EVO

Typical competitor Blood Flow

while angiographic patency of the internal mammary artery has been demonstrated to be >90 % at follow-up of ≥10 years, venous bypass grafts tend to degenerate much earlier and existing randomised data do not address the comparative efficacy of PCI versus CABG beyond 5 years. An unmet need remains for a contemporary comparison of CABG surgery versus PCI in patients with diabetes using a newergeneration DES – preferably a DES specifically designed to treat patients with diabetes – and highly potent antiplatelet therapies with superior antithrombotic efficacy over clopidogrel with prospective long-term follow-up.22

Design Features of the Cre8™ Stent The mammalian targets of rapamycin (mTOR) inhibitors (-limus drugs) are less active in people with diabetes compared to those without the condition. One reason for this is the direct resistance of vascular smooth muscle cells to mTOR inhibition in people with diabetes.23,24 The mTOR receptor is involved in the restenotic response cascade caused by vascular injury through the degradation of p27kip1 – a cyclin-dependent kinase inhibitor. Dysregulation of mTOR and p27kip1, coupled with an increase in the activity of the extracellular signal response kinase 1/2, has been found to promote intimal hyperplasia in the setting of diabetes mellitus.23 Dose–response curves have shown that a 10-fold higher concentration of mTOR inhibitor is required in a diabetic cell to achieve a similar level of inhibition to a non-diabetic cell.24

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Coronary Figure 3: NEXT Study: 5-year Outcomes. Overall population

Diabetic population 32 p=0.0645

32 28

% of patients

24 20

-33 % 14.5

13.1

p=0.0187 8.8

p=1.000

2.7

4 0

p=0.2359

-39 %

2.1

5.5

Cardiac death

-45 %

-66 % p=0.0132

14.7

p=0.4359

TLR

20.6

11.4

9.1

2.9

0.7

TV MI

p=0.3466

12 8.8

13/148 21/145 4/148 3/145 1/148 8/145 13/148 19/145 Hierarchical TLF

26.5

p=0.1278

4/44 9/34

0/148 1/145

0/44 5/34

Hierarchical TLF

Cardiac death

TV MI

Cre8™ (18 pts)

Cre8™ (44 pts)

TAXUS Liberté (145 pts)

TAXUS Liberté (34 pts)

5/44

7/34

TLR

TLF = target lesion failure; TLR = target lesion revascularisation; TV MI = target vessel myocardial infarction. Adapted from Romaguera 201725.

Another factor contributing to the relative lack of efficacy of mTOR inhibitors in patients with diabetes is the impact of hormones. Being overweight is a strong risk factor for diabetes and cardiovascular disease; >90 % of patients with type 2 diabetes are overweight or obese.26 Human obesity is associated with elevated levels of leptin, a hormone secreted by adipocytes and perivascular tissue, particularly in overweight patients. Leptin has a number of specific vascular effects: first, it promotes angiogenesis, which contributes to restenosis; second, it activates the immune system, resulting in a permanent inflammatory status; and third, it accelerates atherogenesis, promoting plaque progression, see Figure 1.27,28 A nine-fold increase in the dose of sirolimus has been shown to be required to inhibit leptin-induced intimal hyperplasia.29 Therefore, in order to improve PCI efficacy in patients with diabetes, the concentration of drug level attained in diabetic cells needs to be increased. Other features of the Cre8™ DES may optimise clinical efficacy in patients with diabetes. First, the Amphilimus™ formulation is a proprietary technology in which sirolimus and a fatty acid are combined and eluted together to achieve enhanced drug bioavailability, more homogeneous drug distribution and greater drug stability.30 Sirolimus is a highly potent immunosuppressant drug with anti-proliferative and anti-microbial activities as well as anti-inflammatory properties. The Amphilimus™ formulation of Cre8™ makes use of the key role of fatty acids in cellular metabolism in patients with diabetes. While in the nondiabetic cell, fatty acid metabolism is responsible for 70 % of adenosine triphosphate generation (the remainder being produced by glucose oxidation), in the diabetic cell fatty acid oxidation is responsible for 100 % of adenosine triphosphate production due to membrane protein overexpression, which results in the higher binding and translocation of fatty acids.31 Another key feature of the Cre8™ DES is abluminal reservoir technology: a proprietary polymer-free drug-release system consisting of reservoirs on the stent’s abluminal surface which direct drug release exclusively towards the vessel wall. This has proven the only polymerfree technology capable of providing the same sustained elution kinetics as the most effective polymeric DES, allowing peak drugtissue concentration during the first days after implantation, 50 % drug

ICR Byrne_FINAL.indd 42

elution within approximately 18 days, 65–70 % elution within 30 days and complete drug elution within 90 days.32 Unlike polymers, which determine the speed of release of substances according to their size, abluminal reservoirs allow a mix of substances to be simultaneously eluted for maximised synergetic effect; the kinetic release being determined by the reservoir shape.30 Refinement of the Cre8™ stent architecture aims to further improve homogeneity of drug distribution within the vessel wall, particularly in the case of the complex coronary anatomies and pathologies typically encountered in patients with diabetes. The new stent architecture (EvenArt) features a shortened pitch with reduced crown width and a different link number and pattern compared with the previous design, the combination of which results in an enhanced elution profile, see Figure 2. The reservoirs are closer together, ensuring more homogeneous drug deliverability.33 The new design also results in greater conformability,33 which is particularly important in individuals with diabetes, who tend to present with smaller vessels, a higher incidence of multivessel disease, more lesions in proximal locations (including the left main coronary artery), impaired circulation and increased coronary artery calcification.34 Additional features of the stent include thin struts (70/80 μm) consisting of cobalt–chromium; a Bio Inducer Surface (consisting of pure carbon); no stent shortening upon expansion; and two platinum markers at the stent ends. Delivery system features include a balanced and hydrophilic coated shaft, short balloon tapers (or shoulders) – which aid device deliverability and minimise trauma to the adjacent vessel, while reducing the risk of stent displacement on the balloon during dilatation – and a balloon-rated burst pressure of 18 atm across the entire product range, which includes diameters from 2.25 mm to 4.5 mm and nominal lengths of 9–46 mm.33

Clinical Evidence for use of the Cre8™ stent in Patients with Diabetes Randomised Studies The first clinical study to demonstrate the clinical efficacy of the Cre8™ DES was the International Randomized Comparison Between DES Limus Carbostent and TAXUS Drug-eluting Stents in the Treatment of De Novo Coronary Lesions (NEXT) trial, which allocated patients with ischaemic myocardial symptoms related to de novo lesions in

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The Randomized Comparison of Reservoir-based Polymer-free Amphilimus™-eluting Stents versus Everolimus-eluting Stents in Patients with Diabetes Mellitus (RESERVOIR) clinical trial enrolled 112 patients with diabetes on glucose-lowering therapy with a single de novo lesion in a maximum of two coronary arteries.37 Participants were randomised to treatment with the Cre8™ stent (n=56) or a XIENCE™ (Abbott) EES (n=56). The primary endpoint was mean neointimal hyperplasia volume obstruction as measured by optical coherence tomography after 9 months, and was numerically lower in the Cre8™ group compared with the XIENCE group (11.97 ± 5.94 % versus 16.11 ± 18.18 %; p=0.0003 for noninferiority; p=0.22 for superiority). Prespecified subgroup analyses showed a consistent treatment effect in favour of the Cre8™ arm across all subgroups. Importantly, this difference was statistically significant in the subgroup with suboptimal metabolic control (Hb1Ac greater than the median value; p=0.02). In terms of secondary endpoints, angiographic LLL in the Cre8™ group was 0.14 ± 0.24 compared with 0.24 ± 0.57 in the XIENCE group, with a striking difference in standard deviations that highlights the consistent performance of the Cre8™ DES. There was also a trend towards a larger minimum lumen diameter in the Cre8™ versus the control group in-stent (2.38 ± 0.44 versus 2.19 ± 0.59; p=0.07) and in segment (2.09 ± 0.59 versus 1.84 ± 0.61; p=0.02). Notably, the degree of LLL observed in RESERVOIR was consistent with that already seen in the NEXT trial and the Prove Abluminal Reservoir Technology Clinical benefit in all comers patients (pARTicip8) observational study, see Figure 4. There were no differences between the Cre8™ or XIENCE groups with respect to any clinical endpoint, including cardiac death (1.8 % versus 0 %, respectively; p=1.0), myocardial infarction (0 % versus 1.8 %, respectively; p=1.0), definite or probable stent thrombosis (1.7 % versus 1.7 %, respectively; p=1.0) or repeat revascularisation (TLR 5.2 % versus 8.6 %, respectively; p=0.46). However, the study was underpowered to detect such differences between treatment groups.

Non-randomised Studies The pARTicip8 study recruited 1,186 patients with de novo lesions in native coronary arteries and symptoms of myocardial ischaemia at 30 European sites. The study aimed to evaluate the safety and efficacy of the Cre8™ stent in a broadly inclusive real-world population, with a specific focus on diabetic subgroups. The primary endpoint was a composite of cardiac death, target vessel MI and clinically-indicated TLR at 6-month follow-up. Of the patients enrolled, 308 (25.8 %) had

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Figure 4: In-stent Late Lumen Loss in Studies Evaluating the Cre8™ Drug-eluting Stent in Patients with Diabetes. 0.5 In-stent Late lumen loss (mm)

native coronary arteries (n=323) to treatment with the Cre8™ DES or a paclitaxel-eluting stent (TAXUS™ Liberté®, Boston Scientific).35 The primary endpoint was 6-month angiographic in-stent LLL. At 6 months, the Cre8™ group had reduced LLL by 60 % compared with the TAXUS group (p<0.0001). This finding was even more pronounced in the subgroup of patients with diabetes (n=82), where a 72 % reduction in LLL was observed (p<0.0001). At 5 years, patients in the Cre8™ group showed a trend towards a 39 % reduction in cumulative target lesion failure (TLF, the combined incidence of cardiac death, target vessel MI and all target lesion revascularisation [TLR]) compared with the TAXUS groups (8.8 % versus 14.5 %, respectively; p=0.13) and a reduction of 66 % in the diabetic subgroup with a trend toward statistical significance (9.1 % versus 26.5 %, respectively; p=0.06), see Figure 3.25 These trends were driven by a significant reduction in target vessel MI in the Cre8™ group in both the overall and diabetic populations. It is notable that among patients treated with the Cre8™ stent, the rate of TLF in the diabetic subgroup was similar to that of the overall study population.36

0.4 0.3 0.16 ± 0.13

0.2 0.12 ± 0.29

0.14 ± 0.24

0.1 0.0

PARTICIP8 NEXT (diabetic sub-group) (diabetic sub-group)

RESERVOIR

diabetes. At 1 year, the incidence of the primary endpoint was 2.8 % in the overall population and 4.7 % in the diabetic subgroup.36 In a propensity-score-matched analysis, patients from the Amphilimus™ iTalian mUlicenTre rEgistry (ASTUTE) database were matched with patients from the Italian Nobori Stent ProspectIve REgistry (INSPIRE-1) who were treated with biolimus-eluting stents during the same period. In the diabetic subgroup, a 62 % reduction in TLF (5 % versus 13 %; p<0.001) and a 57 % reduction in TLR (4 % versus 9 %; p=0.005) were observed in the Cre8™ versus the biolimus-eluting stents groups, see Figure 5. Stent type was found to be an independent predictor of TLF, with an odds ratio of 2.76 (95 % CI 1.36–5.56).38

Future Randomised Studies While the growing body of randomised and observational data supports the efficacy of the Cre8™ DES, studies to date have not been powered to demonstrate superiority over comparator DES. Against this background, a large randomised study – the Second-generation drUgelutinG stents in diAbetes: a Randomised Trial (SUGAR Trial) – is planned. The trial aims to randomise 1,164 “all-comer” patients undergoing PCI at 29 centres in Spain to treatment with the amphilimus-eluting stent or a zotarolimus-eluting stent in a 1:1 ratio. The primary endpoint, TLF – defined as the composite of cardiac death, target vessel MI and TLR – will be assessed at 12 months for non-inferiority and at 24 months for superiority. A second randomised trial, the Clinical benefit in “all comer” patients with DIABetes to prove Cre8™ EVO (Diab8) study,39 aims to recruit 3,040 all-comer patients with diabetes undergoing PCI at 54 international sites. Patients will be randomised in a 1:1 treatment allocation to the Cre8™ EVO stent or an EES. The primary endpoint is TLR at 12 months. There will be a sequential analysis for non-inferiority and then for superiority. Secondary endpoints include cardiac death and target vessel MI at 12 months and TLR (superiority) at 24 months. In summary, the Cre8™ DES has shown promising results in the treatment of patients with diabetes in both subgroup analyses of randomised trials and observational studies. The large-scale SUGAR Trial and Diab8 study aim to provide randomised evidence to support the efficacy and safety of the Cre8™ and Cre8™ EVO stents in patients with diabetes.

Summary and Concluding Remarks The rising prevalence of diabetes worldwide has made effective treatments for people with diabetes an urgent priority. However, current revascularisation strategies remain suboptimal in this subset of

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Coronary Figure 5: Italian Propensity-matched Analysis: Cre8™ versus Biolimus-eluting Stents.

Target lesion failure (%)

100

BD-BES Cre8™

50 30 25 20 15 10 5 0

100

TLF

-62 %

180

270

360

255 412

245 406

235 398

226 389

118 321

BD-BES Cre8™

P365≤ 0.001; HR (95 %CI) = 0.307 (0.174–0.5427) Mantel-Cox test 13 % 8% 2%

TLR

30 25 20 15 10 5 0

-57 % P365 = 0.005; HR (95 %CI) = 0.384 (0.197–0.749) Mantel-Cox test

4% 2% 180

255 412

246 406

234 398

9% 4% 270

360

227 388

175 312

BD-BES = biodegradable polymer biolimus-eluting stent; TLF = target lesion failure; TLR = target lesion revascularisation. Adapted from Godino et al, 2017.38

patients. Patients with diabetes have worse outcomes compared with the general patient population following revascularisation, and secondgeneration DES have failed to significantly impact on outcomes in such patients. The Cre8™ DES utilises abluminal reservoirs that slowly elute the Amphilimus™ formulation to overcome -limus resistance and the proliferative effect of hormones in diabetic cells, and thus increase cellular uptake of sirolimus. The new stent architecture of the Cre8™

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EVO stent – EvenArt – is designed to enhance the elution profile in challenging anatomies. Finally, a growing body of randomised and observational data suggests favourable comparative performance of the Cre8™ DES with other DES in patients with diabetes. The results of large-scale randomised trials specifically comparing the Cre8™ or Cre8™ EVO DES with current-generation DES in diabetic patients are eagerly awaited. n

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the Amphilimus eluting polymer-free DES. Oral presentation, EuroPCR, 2017. Obesity Society. Your Weight and Diabetes. 2015. Available at: http://www.obesity.org/content/weight-diabetes (accessed 6 November 2017). Werner N, Nickenig G. From fat fighter to risk factor – the zigzag trek of leptin. Arterioscler Thromb Vasc Biol 2004;24:7–9. DOI: 10.1161/01; PMID: 14707035. Schafer K, Halle M, Goeschen C, et al. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004;24:112–7. DOI: 10.1161/01. ATV.0000105904.02142.e7; PMID: 14615386. Shan J, Nguyen TB, Totary-Jain H, et al. Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors. Proc Natl Acad Sci U S A 2008;105:19006–11. DOI: 10.1073/pnas.0809743105; PMID: 19020099. CARRIé D. Advances with polymer-free amphilimus-eluting stents. Minerva Cardioangiol 2016;64:339–53. PMID: 26934663. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 2010;90:367–417. DOI: 10.1152/ physrev.00003.2009; PMID: 20086080. Moretti C, Lolli V, Perona G, et al. Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymerfree DES with Amphilimus™ formulation. EuroIntervention 2012;7:1087–94. DOI: 10.4244/EIJV7I9A173; PMID: 22130128. Alvimedica. DES – Cre8™. 2017. Available at: http://www. alvimedica.com/product/Cre8™/ (accessed 9 November 2017) Morgan KP, Kapur A, Beatt KJ. Anatomy of coronary disease in diabetic patients: an explanation for poorer outcomes after percutaneous coronary intervention and potential target for intervention. Heart 2004;90:732–8. DOI: 10.1136/ hrt.2003.021014; PMID: 15201238. Carrié D, Berland J, Verheye S, et al. A multicenter randomized trial comparing amphilimus- with paclitaxel-eluting stents in de novo native coronary artery lesions. J Am Coll Cardiol 2012;59:1371–6. DOI: 10.1016/j.jacc.2011.12.009; PMID: 22284328. Carrie D. Polymer-free Cre8™ DES: Design, Current Status and Future Directions. Presented at: TCT 2015 – Transcatherter Cardiovascular Therapeutics, San Francisco, CA, 11–15 October 2015. Romaguera R, Gomez-Hospital JA, Gomez-Lara J, et al. A Randomized Comparison of Reservoir-Based Polymer-Free Amphilimus™-Eluting Stents Versus Everolimus-Eluting Stents with Durable Polymer in Patients with Diabetes Mellitus: The RESERVOIR Clinical Trial. JACC Cardiovasc Interv 2016;9:42–50. DO: 10.1016/j.jcin.2015.09.020; PMID: 26762910. Godino C, Pivato CA, Chiarito M, et al. Polymer-free amphilimus-eluting stent versus biodegradable polymer biolimus-eluting stent in patients with and without diabetes mellitus. Int J Cardiol 2017;245:69–76. DOI: 10.1016/j. ijcard.2017.06.028; PMID: 28874301. Alvimedica. Cre8™ EVO Approval of CE Mark. 2017. Available at: http://www.alvimedica.com/Cre8™-evo-approval-ce-mark/ (accessed 6 November 2017)

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Coronary

Is Complete Revascularisation Mandated for all Patients with Multivessel Coronary Artery Disease? Carlo De Innocentiis, Marco Zimarino and Raffaele De Caterina Institute of Cardiology and Centre of Excellence on Ageing, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

Abstract In multivessel coronary artery disease (MVCAD), myocardial revascularisation can be achieved by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), with complete revascularisation on all diseased coronary segments or with incomplete revascularisation on selectively targeted lesions. Complete revascularisation confers a long-term prognostic benefit, but is associated with a higher rate of periprocedural events compared with incomplete revascularisation. In most patients with MVCAD, the main advantage of CABG over PCI is conferred by the achievement of more extensive revascularisation. According to current international guidelines, PCI is generally preferred in single-vessel disease, low-risk MVCAD or isolated left main disease; whereas CABG is usually recommended in patients with complex two-vessel disease, most patients with three-vessel disease and/or non-isolated left main disease. In patients with MVCAD, the choice on revascularisation modality should depend on a multifactorial evaluation, taking into account not only coronary anatomy, the ischaemic burden, myocardial function, age and the presence of comorbidities, but also the adequacy of myocardial revascularisation.

Keywords Coronary artery bypass grafting, multivessel coronary artery disease, percutaneous coronary intervention, myocardial revascularization Disclosure: The authors have no conflicts of interest to declare. Received: 6 July 2017 Accepted: 7 September 2017 Citation: Interventional Cardiology Review 2018;13(1):45–50. DOI: 10.15420/icr.2017:23:1 Correspondence: Marco Zimarino, Institute of Cardiology, “G. d’Annunzio” University of Chieti-Pescara, C/O Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy. E: m.zimarino@unich.it

Multivessel coronary artery disease (MVCAD) is defined by the presence of ≥50 % diameter stenosis of two or more epicardial coronary arteries. The presence of MVCAD indicates poorer prognosis and a significantly higher mortality than single-vessel disease. In MVCAD, revascularisation can be achieved by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).1,2 A comprehensive definition of the adequacy of myocardial revascularisation should take into account the size of the vessel, the angiographic and functional severity of the lesion, and the viability of the myocardial territory.3 Accordingly, anatomic and functional complete revascularisation (CR) are not always synonymous. Generally, the anatomic CR is defined by treatment of all ≥50 % stenosis in vessels of ≥1.5 mm diameter, whereas functional CR is defined by treatment of all lesions assessed as functionally relevant (with both invasive or non-invasive methods) in the presence of myocardial viability in the dependent territory, see Table 1.3 At present, only a few trials have been specifically designed to directly evaluate the adequacy of revascularisation. Current literature, mostly relying on meta-analyses of non-randomised observational studies,4,5 lists the adequacy of revascularisation among factors that should guide the choice of treatment strategy. In most patients with MVCAD, the main advantage of CABG over PCI seems to be conferred by the achievement of more extensive revascularisation. Most of the difference in terms of the benefit of CABG over PCI seems to derive from patients who undergo incomplete revascularisation (IR). As documented in a recent patient-level analysis, long-term mortality was similar between patients undergoing CR with either PCI or CABG, whereas it was significantly higher with IR after PCI than CABG.6

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Although much less invasive than traditional CABG, PCI yields lower rates of CR in patients with multiple coronary lesions.7 IR can occasionally be implemented in addition to CABG in order to reduce complications, mainly when minimally invasive or off-pump surgery is attempted.8 The advantages of CR have emerged from long-term follow-up studies showing a direct relationship between the number of coronary segments treated and the reduction in cardiovascular events. IR reduces potential periprocedural complications, especially in high-risk patients; however, this comes at the price of a noticeable risk of future adverse cardiovascular events.3

Complete vs Incomplete Revascularisation in ST-elevation Myocardial Infarction Available guidelines for myocardial revascularisation clearly state that the infarct-related artery (IRA) should be systematically treated during the initial intervention in patients presenting with ST-elevation MI (STEMI).1,2 Nevertheless, up to 50 % of these patients have MVCAD, with angiographic documentation of signiﬁcant stenosis affecting a non-IRA. The presence of MVCAD in this context identifies a subgroup of patients with more than double the risk of death at 30 days than individuals in whom the IRA is the only diseased vessel.9 The PCI strategies available in patients with STEMI and MVCAD include: IRA-only primary PCI with medical management of nonculprit lesions in the absence of spontaneous angina or myocardial ischaemia on stress testing; MVCAD PCI at the time of primary PCI

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Coronary Table 1: Revascularisation Strategies Revascularization Strategy

Definition

Complete anatomic Treatment of all coronary segments revascularisation >1.5 mm with a ≥50 % DS supplying viable ischemic myocardium Functionally-adequate revascularisation Lesion-specific

Treatment of all coronary segments >1.5 mm with a FFR <0.80

Myocardial specific Treatment of all coronary segments >1.5 mm with a ≥50 % DS supplying viable ischemic myocardium Incomplete revascularisation When it is not possible or suitable to treat all coronary segments with significant disease (either ≥50 % DS or FFR<0.80) supplying viable myocardium DS = diameter stenosis; FFR = fractional flow reserve. Adapted from Zimarino et al., 2013.3

(ad hoc procedure); and primary PCI of the IRA followed by staged PCI of non-IRAs later during the index hospitalisation or soon after hospital discharge.1,2,10 Previous clinical practice guidelines recommended against PCI of nonculprit artery stenoses at the time of primary PCI in haemodynamicallystable patients with STEMI; however, there is now growing evidence that a strategy of multivessel PCI – either at the time of primary PCI or as a planned, staged procedure – may be beneficial and safe in selected patients with STEMI.1,10 A network meta-analysis has suggested that multivessel staged PCI may be associated with a better outcome than multivessel primary PCI,11 but such data are still insufficient to inform a recommendation with regard to the optimal timing of non-culprit vessel PCI.12–14 In fact, a more recent meta-analysis showed that CR at the index procedure or as a staged procedure – whether during hospitalisation or after discharge – was associated with a reduction in the risk of adverse events, although the effect was mostly due to a reduction in the risk of urgent revascularisation. There was no difference between various strategies in the risk of all-cause mortality and spontaneous reinfarction at a median of 25 months.15 The best revascularisation strategy of the non-culprit lesions is not, therefore, well established.16 Apart from the potential overestimation of the severity of non-IRA due to heightened vascular tone,17 major concerns when attempting CR in a STEMI derive from: the prolongation of the primary PCI procedure, which will increase the volume of contrast medium used with its inherent risk of contrast-induced nephropathy;18 the risk of jeopardising viable myocardium during revascularisation of a non-IRA; and the higher risk of stent thrombosis by operating in the highly thrombogenic peri-infarction milieu. More extensive acute revascularisation in patients with STEMI may be safer in the current era due to advances in stent technology and antiplatelet therapy, mainly in higher risk subgroups.19 This might reduce the duration of hospitalisation, resource utilisation and costs. Available studies have excluded subjects with concurrent chronic total occlusion (CTO) lesions. This condition is a further independent predictor of both early and late survival.20 It is usually found in 10–15 % of patients with STEMI. The Percutaneous Intervention for Concurrent

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Chronic Total Occlusions in Patients With STEMI (EXPLORE) trial recently showed that additional CTO–PCI within 1 week after primary PCI for STEMI is feasible and safe, but does not infer a benefit in terms of left ventricular function or volumes.21 The main points of criticism of published studies are that no ischaemia testing nor guideline-based treatments (staged PCI) were performed in the control group, leaving potentially critical lesions untreated.12–14 This criticism can be partially overcome thanks to the MULTivessel Immediate Versus STAged RevaScularization in Acute Myocardial Infarction (MULTISTARS AMI) trial (NCT03135275), which is currently randomising individuals to immediate or staged CR. This study intends to include approximately 1,200 patients. It has a primary composite endpoint of all-cause death, non-fatal MI and unplanned ischaemiadriven coronary revascularisation. The on-going Complete vs Culpritonly Revascularization to Treat Multivessel Disease After Primary PCI for STEMI (COMPLETE) trial (NCT01740479) is randomising patients with STEMI to CR strategy with staged PCI of all suitable non-culprit lesions or culprit lesion-only revascularisation. The estimated enrolment is 3,900 individuals and the primary endpoint is the composite of cardiovascular death or new MI. The study should be completed in December 2018. Although the fractional flow reserve (FFR) is infrequently evaluated in non-IRA in the setting of primary PCI, it may be helpful to assess the haemodynamic signiﬁcance of potential target lesions. In this context, the Ffr-gUidance for compLete Non-cuLprit REVASCularization (FULL REVASC) study (NCT02862119) is currently randomising STEMI patients with MVCAD to a conservative strategy of IRA-only primary PCI or to FFR-guided ad hoc or staged revascularisation. This study will enrol an estimated 4,052 patients. The primary outcome is the combined endpoint of all-cause mortality and MI. It is anticipated that all of the data will be collected by October 2019. In summary, based on current evidence, patients with STEMI and MVCAD should receive CR if admitted with cardiogenic shock or with persistent ischaemia after treatment of the culprit lesion. In haemodynamically-stable patients, multivessel PCI is a valuable option, either at the time of primary PCI or as a planned staged procedure during the same hospitalisation.

Complete vs Incomplete Revascularisation in Non-ST-Elevation Acute Coronary Syndromes Non-ST-elevation acute coronary syndrome (NSTE-ACS) is the most frequent phenotype of acute coronary syndromes. Patients presenting with NSTE-ACS are a very heterogeneous group with a highly variable prognosis. In patients with NSTE-ACS, the optimal timing and treatment strategy in the presence of MVCAD is still unclear.1,22,23 In NSTE-ACS, the identification of the culprit lesion can be more problematic than in STEMI, as ECG is a poor predictor of IRA and ST-depression usually does not precisely localise in the myocardial territory with evolving ischaemia. Thus, the identification of the culprit lesion is usually achieved by a combination of factors including angiographic characteristics and information from an imaging technique. MVCAD is present in approximately 50 % of patients with NSTE-ACS. In such cases, the revascularisation strategy is more complex and the choice has to be made between multivessel PCI, culprit-lesion-

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Myocardial Revascularization in MVCAD only PCI occasionally followed by a staged PCI, CABG or a hybrid revascularisation.1 Immediate CR during the index procedure can be more safely performed in MVCAD than with STEMI. Multivessel stenting is potentially associated with greater contrast load and periprocedural myocardial infarction,24 as well as with a higher risk of both later restenosis and stent thrombosis.25 Multivessel PCI, in contrast, has been repeatedly associated with lower death and MI at mid-term follow up.26–28 A functional assessment of lesion severity and myocardial viability is likely to be crucial to limit intervention to coronary segments expected to provide myocardial benefit from revascularisation, thus maximising the benefit and reducing risks. The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial has shown that FFR “re-categorises” patients otherwise classified as MVCAD by angiography, and that the treatment of lesions with a FFR <0.80 reduces long-term adverse events in comparison to the allegedly unnecessary deployment of stents in all lesions judged as severe only on the basis of angiography.29 As for the assessment of an “acceptable” angiography-based IR, Genereaux et al. proposed the residual SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) score, documenting a significant increased risk of 1-year death or MI for a value >8.30 In order to define the optimal timing of CR, the Single-Staged Compared With Multi-Staged PCI in Multivessel NSTEMI Patients (SMILE) trial randomised patients to immediate CR or to culprit-only revascularisation, followed by revascularisation of the remaining lesions during the index hospitalisation. Lower rates of major adverse cardiovascular and cerebrovascular events in the ad hoc group were documented at a 1-year follow up.31 However, the difference was essentially driven by the higher rate of target vessel revascularisation in the multistage group. In some cases hybrid coronary revascularisation, combining minimallyinvasive CABG to the left anterior descending (LAD) coronary artery and PCI of non-LAD arteries might offer potential advantages beyond CABG or PCI alone.32 Guidelines are inconclusive about the most appropriate timing of treatment in patients presenting with NSTE-ACS and MVCAD at present.22,23 Concerning treatment strategy, in current guidelines CABG is recommended over PCI in patients with a baseline SYNTAX score >22, with left main or three-vessel coronary artery disease involving the proximal LAD. Ad hoc multivessel PCI, although extensively performed in low-risk patients (see Figure 1), is associated with increased risk of periprocedural damage and contrast-induced nephropathy. In patients with a SYNTAX score ≤22, a staged PCI aimed at treating all significant coronary segments supplying viable myocardium after an initial PCI directed only to the culprit lesion might be the strategy of choice as it reduces the procedural risk, dilutes the amount of contrast medium over time and allows the functional evaluation of “presumed non-culprit” lesion-related myocardial territories, as well as reducing patients’ symptoms.1,22,23

Complete vs Incomplete Revascularisation in Stable Coronary Artery Disease Stable coronary artery disease (SCAD) is generally characterised by episodes of reversible myocardial demand/supply mismatch related to ischaemia. Episodes are usually inducible by exercise, emotion or other stress but may also occur spontaneously. SCAD also includes

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Figure 1: An 87-year-old Patient with Previous Stroke Admitted for Non-ST-elevation Acute Coronary Syndrome LM

LAD

LAD LM

RCA

LCx LCx

LAD LAD LM

LCx

LM LCx

(A, B) Coronary angiography documented a left main bifurcation critical lesion (black arrows) and (C) severe lesions in mid right coronary artery (white arrow), which was distally occluded (*). (D, E) The risk of cardiac surgery was considered unacceptable so the patient underwent provisional drug-eluting stenting (E, dotted lines) on the left main with final kissing balloon, while the right coronary artery was left untreated. After the procedure, creatinine clearance remained within normal limits. LAD = left anterior descending; LCx = left circumflex; LM = left main; RCA = right coronary artery.

the stabilised, often asymptomatic, phases following an acute coronary syndrome.1,33,34 Guideline-directed optimal medical therapy (OMT) is recommended for all patients with SCAD because of the reduced risk of death and MI and the improvement of symptoms; however, 50 % of medicallytreated patients have persistent symptoms within 1 year.34 The principal goal of revascularisation here is the relief of ischaemia to improve quality of life and exercise capacity, to reduce the amount of antianginal drugs, and ultimately to improve prognosis over and above the beneficial effects of medical treatment. Most recent international guidelines recommend myocardial revascularisation for patients with SCAD in the presence of ﬂow-limiting lesions and limiting symptoms if individuals are unresponsive to medical treatment. There is substantial evidence supporting the association between the extent of myocardial ischaemia and the risk of cardiovascular events, as well as the direct relationship between the burden of ischaemia and the severity of prognosis.1,33,34 The most valuable source of data on an adequately-sized population of patients who have undergone either CABG or PCI is the randomised SYNTAX trial.35 This trial compared drug-eluting stent–PCI with CABG in patients with stable MVCAD.7 Patients were treated with the intention of achieving anatomic CR of all vessels ≥1.5 mm in diameter with stenosis ≥50 %. No functional evaluation was available. Individuals with less extensive MVCAD, as documented by a low (<22) SYNTAX score, had similar 1- and 3-year major adverse cardiac or cerebrovascular event rates after PCI and CABG. A higher 3-year risk of major adverse cardiac or cerebrovascular events has been documented after PCI compared to CABG for patients with intermediate (23–32) and high (>32) scores.36 Robust data now recommend functional evaluation of reversible myocardial ischaemia prior to elective revascularisation. It is now well documented that revascularisation of lesions that are not producing significant ischaemia confers a cost in terms of adverse outcomes.37 Here, OMT is a better alternative. Conversely, patients with moderate-to-severe

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Coronary Figure 2: A 67-year-old Patient with Diabetes Admitted for Recurrent Chest Pain and had a Positive Exercise Test

RCA

LAD

LCx

LAD

$ B

Echocardiogram showed a normal ventricular function with a mild-to-moderate mitral regurgitation. Coronary angiography showed: (A) critical stenosis (arrowhead) of the right coronary artery (RCA); and (B) severe lesions of both the mid left anterior descending (LAD) (arrows) and the left circumflex (LCx) (*) artery. The SYNTAX score was <22. The patient underwent fractional flow reserve assessment on non-culprit lesions. Fractional flow reserve on the LAD artery was 0.75 and on the left LCx was 0.93. (C, D) Percutaneous coronary intervention with a drug-eluting stent was performed on both RCA and LAD (dotted lines), while the LCx lesion was left untreated. The patient was discharged on dual antiplatelet and statin therapy. LAD = left anterior descending; LCx = left circumflex; RCA = right coronary artery.

symptoms and/or extensive ischaemia should be strongly considered for revascularisation therapy. Despite this recommendation, the majority of patients with SCAD undergoing elective PCI have no preceding documentation of myocardial ischaemia.38–40 In this setting, accurate non-invasive (multidetector CT, stress echocardiography, perfusion scintigraphy, stress-MRI and/or PET-CT) or invasive (FFR, intravascular ultrasound, optical coherence tomography scan) identification of the lesions deemed responsible for ischaemia might improve outcomes in patients undergoing revascularisation. The availability and extensive validation of the FFR now offer a surrogate for ischemia and thereby represent an alternative to noninvasive stress imaging (see Figure 2). In the FAME study, patients who had been listed for multivessel PCI were randomised to angiographically- or FFR-guided stenting (using a FFR cut-off value of 0.80).41 The FFR-guided strategy was found to be both cost-saving and cost-effective.42 The strategy was also associated with a significant reduction in the occurrence of the composite primary clinical endpoint of death, nonfatal MI and repeat revascularisation at 1 year (p=0.02), as well as a significant reduction in mortality plus MI at 2 years (p=0.02).43 A functional evaluation of lesion severity may now be obtained by non-invasive coronary imaging. The Determination of Fractional Flow Reserve by Anatomic Computed Tomographic AngiOgraphy (DeFACTO) trial documented that FFR can be non-invasively obtained with CT angiography and, together with CT itself, is associated with improved diagnostic accuracy and discrimination compared with CT alone for the diagnosis of haemodynamically-significant coronary artery disease.44 Finally, cardiac magnetic resonance is increasingly being utilised in ischaemic heart disease for both the detection of lesions producing ischaemia45 and the identification of myocardial viability.46

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The importance of functional evaluation has been well demonstrated by the results of the FAME 2 trial.47 About 900 SCAD patients with functionally-signiﬁcant stenosis (FFR ≤0.80) were randomly assigned to either OMT or OMT plus FFR-guided PCI, with predominant use of drug-eluting stents (>97 %). The study was stopped prematurely by the Data Safety Monitoring Board due to the signiﬁcantly lower incidence of a composite of death, MI and urgent revascularisation favouring FFR-guided PCI plus OMT (4.3 %) as compared with OMT alone (12.7 %, p<0.001), although the result was driven by the “soft” component of urgent revascularisation. The on-going International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial (NCT01471522) should finally answer the fundamental question of whether myocardial revascularisation in addition to OMT in patients with moderate to severe ischaemia is associated with survival benefit compared with OMT alone. Another point of criticism in achieving CR is the presence of CTO, which is frequently documented in patients with MVCAD (between 18 % and 52 % of cases).1,48 There is little consensus as to whether such lesions should be routinely treated by PCI.49,50 Potential benefits of successful PCI may include symptom relief, resolution of ischaemia and functional improvement. CTO–PCI has lower success rates than PCI of nonCTO lesions, with potentially serious complications; however, in high-volume centres with specific expertise, contemporary success rates of 80–90 % have been reported.51,52 In the setting of SCAD there is a clear lack of evidence, with randomised data derived from two unpublished trials. The optimal medical therapy with or without stenting for chronic coronary occlusion (Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients with Chronic Total Occlusion [DECISION-CTO], NCT01078051), although with some relevant limitations and despite a high technical success rate, failed to demonstrate a benefit with CTO–PCI on top of OMT. Recently released data from the Randomized Multicentre Trial to Evaluate the Utilization of Revascularization or Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusion (EuroCTO, NCT01760083) showed that CTO–PCI improved quality of life, as assessed by the standardised Seattle Angina Questionnaire, in patients undergoing CTO–PCI. This benefit was coupled with a low rate of periprocedural complications. Further studies are necessary to assess the impact of PCI–CTO on symptom improvement and prognosis, especially in selected populations such as patients with high ischaemic burden. Currently, the use of CTO–PCI to improve quality of life should be restricted to selected patients in high-volume centres with specific expertise. Current guidelines recommend CABG over PCI in patients with threevessel disease, non-isolated left main disease or with involvement of the proximal LAD artery plus one other major coronary artery. CABG has to be considered in patients when in-stent restenosis recurrence is located on the LAD, where several devices have evenly failed. 25 The benefit obtained with CABG seems to be larger with a systematic utilisation of the left internal mammary artery (IMA), an atherosclerosis-free conduit with patency rates >90 % at 10 years.53 Nevertheless, the Arterial Revascularization Trial (ART) recently failed to document any 5-year benefit for patients with MVCAD who received bilateral IMA as compared with single left IMA utilisation.54 The choice between revascularisation techniques should be based on several factors, including anatomical and clinical features.

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Myocardial Revascularization in MVCAD It requires a multidisciplinary approach to decision making by the heart team.

Conclusions The extent of myocardial revascularisation is a major determinant of survival among MVCAD patients. Based on available evidence, revascularisation with either CABG or PCI has similar benefits in terms of survival in patients with MVCAD, with a prognostic advantage for CABG in the presence of more extensive disease and in patients with diabetes. Both PCI and CABG should always aim at functional CR. Patients with diabetes and extensive coronary disease have a reduced

uthors/Task Force Members, Windecker S, Kolh P, A Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339. 2. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/ SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: an update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2016;133:1135–47. DOI: 10.1161/CIR.0000000000000336; PMID: 26490017. 3. Zimarino M, Curzen N, Cicchitti V, De Caterina R. The adequacy of myocardial revascularization in patients with multivessel coronary artery disease. Int J Cardiol 2013;168:1748–57. DOI: 10.1016/j.ijcard.2013.05.004; PMID: 23742927. 4. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol 2013;62:1421–31. DOI: 10.1016/j.jacc.2013.05.033; PMID: 23747787. 5. Zimarino M, Ricci F, Romanello M, et al. Complete myocardial revascularization confers a larger clinical benefit when performed with state-of-the-art techniques in high-risk patients with multivessel coronary artery disease: a metaanalysis of randomized and observational studies. Catheter Cardivasc Interv 2016;8:3–12. DOI: 10.1002/ccd.25923; PMID: 25846673. 6. Ahn JM, Park DW, Lee CW, et al. Comparison of stenting versus bypass surgery according to the completeness of revascularization in severe coronary artery disease: patientlevel pooled analysis of the SYNTAX, PRECOMBAT, and BEST Trials. JACC Cardiovasc Interv 2017;10:1415–24. DOI: 10.1016/ j.jcin.2017.04.037; PMID: 28728654. 7. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. DOI: 10.1016/ S0140-6736(13)60141-5; PMID: 23439102. 8. Zimarino M, Gallina S, Di Fulvio M, et al. Intraoperative ischemia and long-term events after minimally invasive coronary surgery. Ann Thorac Surg 2004;78:135–41. DOI: 10.1016/j.athoracsur.2003.12.030; PMID: 15223418. 9. Park DW, Clare RM, Schulte PJ, et al. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA 2014;312:2019–27. DOI: 10.1001/ jama.2014.15095; PMID: 25399277. 10. Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology (ESC), Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. DOI: 10.1093/eurheartj/ehs215; PMID: 2292241. 11. Vlaar PJ, Mahmoud KD, Holmes DR, et al. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: a pairwise and network meta-analysis. J Am Coll Cardiol 2011;58:692–703. DOI: 10.1016/j.jacc.2011.03.046; PMID: 21816304. 12. Wald DS, Morris JK, Wald NJ, et al. The PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013;369:1115–23. DOI: 10.1056/ NEJMoa1305520; PMID: 23991625.

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risk of death and MI when they have undergone CABG, which attains CR more frequently than PCI. PCI is better suited in patients presenting with acute coronary syndrome and a suitable anatomy, where CR can be achieved through staged procedures that allow risk containment and the evaluation of both myocardial viability and lesion relevance. The adequacy of myocardial revascularisation should be the priority when choosing between PCI and CABG in patients with MVCAD. A concerted multidisciplinary decision-making process should guide physicians, taking into account anatomy, left ventricular function, the extent of inducible ischaemia, myocardial viability, comorbidities and patients’ informed choices. n

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42. F earon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122:2545–50. DOI: 10.1161/ CIRCULATIONAHA.109.925396; PMID: 21126973. 43. Pijls NH, Fearon WF, Tonino PA, et al. Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56:177–84. DOI: 10.1016/j.jacc.2010.04.012; PMID: 20537493. 44. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308:1237–45. DOI: 10.1001/2012.jama.11274; PMID: 22922562. 45. Watkins S, McGeoch R, Lyne J, et al. Validation of magnetic resonance myocardial perfusion imaging with fractional flow reserve for the detection of significant coronary heart disease. Circulation 2009;120:2207–13. DOI: 10.1161/ CIRCULATIONAHA.109.872358; PMID: 19917885. 46. Kirschbaum SW, Springeling T, Boersma E, et al. Complete percutaneous revascularization for multivessel disease in patients with impaired left ventricular function: pre- and post-procedural evaluation by cardiac magnetic resonance imaging. JACC Cardiovasc Interv 2010;3:392–400. DOI: 10.1016/ j.jcin.2010.01.011; PMID: 20398866. 47. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. DOI: 10.1056/ NEJMoa1205361; PMID: 22924638.

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