ICR 10.1 by Radcliffe Cardiology

Interventional Cardiology Review Volume 10 • Issue 1 • Spring 2015

Volume 10 • Issue 1 • Spring 2015

www.ICRjournal.com

The Role of Percutaneous Haemodynamic Support in High-risk Percutaneous Coronary Intervention and Cardiogenic Shock Dagmar M Ouweneel, Bimmer E Claessen, Krischan D Sjauw and José PS Henriques

Intravascular Ultrasound vs. Optical Coherence Tomography For Coronary Artery Imaging - Apples And Oranges? Krishnaraj S Rathod, Stephen M Hamshere, Daniel A Jones, and Anthony Mathur

Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation Roberto Spina, Chris Anthony, David WM Muller and David Roy

Percutaneous Closure of Patent Foramen Ovale – Data from Randomized Clinical Trials and Meta-Analyses Stefan Stortecky and Stephan Windecker

ISSN: 1756-1477

Intravascular ultrasound

Optical coherence tomography image of normal coronary arteries

Intra-procedural fluoroscopy and the animation of valve implantation process

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Volume 10 • Issue 1 • Spring 2015

www.ICRjournal.com

Editor-in-Chief Simon Kennon Interventional Cardiologist and Head of the Transcatheter Aortic Valve Implantation Programme at the London Chest Hospital, Barts Health NHS Trust, London

Section Editor – Structural

Section Editor – Coronary Tim Kinnaird

Darren Mylotte

University Hospital of Wales, Cardiff

Galway University Hospitals, Galway

Fernando Alfonso

Eric Eeckhout

Marko Noc

Cardiac Department,Hospital Universitario de La Princesa, Madrid

Centre Hospitalier Universitaire Vaudois, Lausanne

Andrew Archbold

Juan Granada

Jeffrey Popma

London Chest Hospital, Barts Health NHS Trust, London

CRF Skirball Research Center, New York

Beth Israel Deaconess Medical Center, Boston

Olivier Bertrand

A Pieter Kappetein

London Chest Hospital, Barts Health NHS Trust, London

Quebec Heart-Lung Insitute, Laval University, Quebec

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Elliot Smith

Lars Søndergaard

Lutz Buellesfeld

Demosthenes Katritsis

University Hospital, Bern

Athens Euroclinic, Athens, Greece

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Jonathan Byrne

Ajay Kirtane

Gregg Stone

King’s College Hospital, London

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

Antonio Colombo

Didier Locca

Nicolas Van Mieghem

San Raffaele Hospital, Milan

Lausanne University Hospital, Lausanne

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Imperial College NHS Trust, London

Roxana Mehran

Renu Virmani

Mount Sinai Hospital, New York

CVPath Institute, Maryland

Carlo Di Mario

Jeffrey Moses

Mark Westwood

Royal Brompton & Harefield NHS Foundation Trust, London

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

London Chest Hospital, Barts Health NHS Trust, London

Justin Davies

Design & Production Tatiana Losinska • Publication Manager Michael Schmool Publishing Director Liam O’Neill • Managing Director David Ramsey Managing Editor editor@radcliffecardiogy.com •

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

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Radcliﬀe Cardiology

Lifelong Learning for Cardiovascular Professionals

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, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2015 All rights reserved

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Established: June 2006 Frequency: Tri-annual Current issue: Spring 2015

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 update 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 tri-annual journal comprising review articles, editorials, and case reports. • The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Interventional Cardiology Review is replicated in full online at www.ICRjournal.com

Editorial Expertise Interventional Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities from 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.

Peer Review • 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, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, 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 either 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. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Managing Editor formalise the working title and scope of the article. Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.ICRjournal.com.

Reprints All articles included in Interventional Cardiology Review are available as reprints. Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Distribution and Readership Interventional Cardiology Review is distributed tri-annually through controlled circulation to senior professionals in the field in Europe.

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.

Online 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 and European Cardiology Review. n

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This one-day event features reviews of unmet clinical needs by renowned physicians experts, presentations by selected and most innovative companies, keynote lectures, moderated discussions and structured networking opportunities.

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Contents

Foreword 6 Simon Kennon, Editor-in-Chief, ICR Coronary Diagnosis & Imaging

Intravascular Ultrasound Versus Optical Coherence Tomography for Coronary Artery Imaging – Apples and Oranges?

Krishnaraj S Rathod, Stephen M Hamshere, Daniel A Jones and Anthony Mathur

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Michael Tsang and Sanjit Jolly

Cardiogenic Shock

The Role of Percutaneous Haemodynamic Support in High-risk Percutaneous Coronary Intervention and Cardiogenic Shock

Dagmar M Ouweneel, Bimmer E Claessen, Krischan D Sjauw and José PS Henriques

Percutaneous Coronary Intervention in Patients Who Have an Indication for Oral Anticoagulation – an Evidence-based Approach to Antithrombotic Therapy

Patent Foramen Ovale

Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention

EW Holroyd, AHS Mustafa, CW Khoo, R Butler, DG Fraser, J Nolan and MA Mamas

Contemporary Antiplatelet Strategies in the Treatment of STEMI using Primary Percutaneous Coronary Intervention

Sri Raveen Kandan and Thomas W Johnson

Primary Angioplasty and High Risk PCI

Structural

Sean Gallagher and R Andrew Archbold

Interventional Strategies in Thrombus Management for ST Elevation Myocardial Infarction

Adjunctive Pharmacotherapy

Preventive Percutaneous Coronary Intervention in ST-elevation Myocardial Infarction – The Primacy of Randomised Trials David S Wald and Jonathan P Bestwick

Percutaneous Closure of Patent Foramen Ovale – Data from Randomized Clinical Trials and Meta-Analyses

Stefan Stortecky and Stephan Windecker

Transcatheter Aortic Valve Implantation

Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation

Roberto Spina, Chris Anthony, David WM Muller and David Roy

The Current Situation and the Future of Emergent Cardiac Surgery in TAVI

Holger Eggebrecht and Axel Schmermund

T ricuspid Valve Repair

Indications for Surgery for Tricuspid Regurgitation

Yan Topilsky

INTERVENTIONAL CARDIOLOGY REVIEW

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Foreword

Simon Kennon is an Interventional Cardiologist and Head of the Transcatheter Aortic Valve Implantation Programme at the London Chest Hospital, Barts Health NHS Trust, 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.

he key aim of this journal is to provide up to date and detailed review of data relating to problems commonly encountered by cardiologists. This issue of Interventional Cardiology Review deals with a wide spectrum of such problems.

There are four articles that relate to our concerns about thrombus and bleeding in the context of coronary intervention. The effect of bleeding on outcomes following coronary intervention is reviewed by Holroyd et al. Coronary intervention in patients who require oral anticoagulation is reviewed by Gallagher et al. There are two papers in this group that relate to this issue in the context of primary angioplasty: Kandan et al review antiplatelet agents in this setting while Tsang et al review the pharmacological and mechanical management of thrombus in STEMI. Wald et al also provide a paper on primary angioplasty, explaining the importance of randomized trials to assess different treatment strategies. A paper by Ouweneel et al reviews haemodynamic support not only in primary angioplasty but in all high risk coronary interventions. Finally, a paper in the coronary section by Rathod et al compares the attributes and applications of the two available methods for the imaging of coronary arteries - intravascular ultrasound and optical coherence tomography. The structural section includes two papers on TAVI, one on patent foramen ovale and a final paper on the surgical treatment of tricuspid regurgitation. Eggebrecht et al review emergency cardiac surgery in TAVI and this is of particular interest at a time when we are anticipating one year outcomes following TAVI in intermediate risk patients. Spina et al review the growing field of TAVI as a treatment strategy for aortic regurgitation. The value of percutaneous closure of PFOs have been questioned by several papers over the last few years and Stortecky et al provide a detailed review that keeps us up to date with randomized trials in this field. Tricuspid regurgitation is a valve lesion encountered, in varying degrees of severity, on a daily basis by interventional cardiologists. Topilsky provides an excellent review of indications for surgical treatment. n

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Coronary Diagnosis & Imaging

Intravascular Ultrasound Versus Optical Coherence Tomography for Coronary Artery Imaging – Apples and Oranges? Krishnaraj S Rathod, 1,2,3 Stephen M Hamshere, 1,3 Daniel A Jones 1,2,3 and Anthony Mathur 1,2,3 1. Department of Cardiology, Barts Health NHS Trust; 2. Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University; 3. NIHR Cardiovascular Biomedical Research Unit, London Chest Hospital, London, UK

Abstract Intravascular imaging has advanced our understanding of coronary artery disease and facilitated decision-making in percutaneous coronary intervention (PCI). In particular, intravascular ultrasound (IVUS) has contributed significantly to modern PCI techniques. The recent introduction of optical coherence tomography (OCT) has further expanded this field due to its higher resolution and rapid image acquisition as compared with IVUS. Furthermore, OCT allows detailed planning of interventional strategies and optimisation before stent deployment, particularly with complex lesions. However, to date it is unclear whether OCT is superior to IVUS as an intracoronary imaging modality with limited data supporting OCT use in routine clinical practice. This review aims to compare these two intracoronary imaging techniques and the recent evidence for their use in this ever-changing field within interventional cardiology.

Keywords Intravascular ultrasound (IVUS), optical coherence tomography (OCT), intracoronary imaging Disclosure: The authors have no conflicts of interest to declare. Received: 15 September 2014 Accepted: 9 November 2014 Citation: Interventional Cardiology Review, 2015;10(1):8–15 Correspondence: Professor Anthony Mathur, Department of Cardiology, London Chest Hospital, Bonner Road, Bethnal Green, London E2 9JX, UK. E: a.mathur@qmul.ac.uk

Coronary angiography has been the gold standard technique for evaluating coronary arterial disease for the past 50 years. Increasingly, however, realisation of the limitations of coronary angiography, mainly the inability to supply information regarding the coronary wall, has prompted the design and development of adjunctive technologies to better evaluate not just luminal disease but also the burden and character of atherosclerotic plaque within the vessel. The development of intracoronary imaging modalities, namely intravascular ultrasound (IVUS) and optical coherence tomography (OCT), has progressed quickly and these technologies now have established roles in the diagnosis and treatment of coronary artery disease. In general, intracoronary devices that can assess the coronary endothelium use either acoustic or optical signals that are received by a coronary catheter (IVUS uses ultrasound, OCT uses near-infrared light). This review addresses these two widely used intracoronary imaging techniques, looking at their clinical applications, recent evidence for their use and describes new developments in the field.

Intravascular Ultrasound In the last 25 years IVUS has been established as the most commonly used intracoronary imaging device. An IVUS system consists of a flexible monorail catheter with an ultrasound transducer at its tip that emits ultrasound waves in the 10–40 MHz range and an electronics console to reconstruct the image (see Figure 1).1 After reflection from tissue, part of the ultrasound energy returns to the transducer and is converted into the image.

The mechanical transducer uses a single crystal on a rotational device, which visualises the entire vessel in cross-section providing better image quality (compared with phased array technology) of 100–150 μm.2 The main disadvantage of mechanical transducers is the central drive shaft that decreases flexibility and prevents the concurrent use of a central guidewire.3 However, newer rotational IVUS catheters have developed a monorail system that allows for the presence of a central guidewire. Phased array catheters use multiple transducer elements, which are mounted along the circumference of the catheter tip. Each element sends and receives ultrasounds from a sector and multiple sectors are gathered to produce a cross-sectional image of the artery. However, they are disadvantaged by a technically complex set-up, requiring detailed programming;3 but some of the newer catheters are easier to set up. Intracoronary imaging of coronary vessels by IVUS is performed using standard coronary interventional techniques and equipment (guiding catheter and 0.014 inch angioplasty guidewire) for catheter delivery along the guidewire beyond the target lesion/area of interest. Intravenous heparin and glyceryl trinitrate (nitroglycerin) are routinely administered before imaging. The IVUS catheter is then drawn back across the target lesion by either an automated pullback device (usually at a rate of 0.5–1.0 mm/s for any length) or by manual operator pull back. Importantly, as ultrasound waves pass through water and blood without major rebound signal, no coronary preparation is needed during image acquisition.

Safety of Intravascular Ultrasound There are two types of IVUS transducers for clinical use: the mechanical rotating transducer and the electronically switched phased array system.

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There is good evidence for the safety of IVUS use.4 Major complication rates (such as coronary artery dissection) are reported as <0.5 %.3

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Intravascular Ultrasound Versus Optical Coherence Tomography for Coronary Artery Imaging

Minor complication rates vary from 1 to 3 % and are mainly due to coronary artery spasm, which is generally transient and responsive to intracoronary administration of nitrate.

Figure 1: Schematic of an Intravascular Ultrasound System

Uses of Intravascular Ultrasound Characterisation of Atherosclerosis IVUS can be used to measure plaque extent, morphology and distribution,5–7 and importantly provides information about plaque composition. This is because denser material such as calcium reflect more ultrasound waves, which results in a higher intensity image. Additionally, calcium does not allow any ultrasound waves to penetrate to deeper tissue, hence producing an acoustic shadow. On the other hand, lipid-laden lesions appear hypoechoic and fibromuscular lesions generate low-intensity or ‘soft’ echoes.3 Lipid-laden or fibromuscular lesions may exhibit a prominent echogenic fibrous cap, although most fibrous caps are too thin to be resolved by IVUS. IVUS therefore allows important decisions to be made with regard to intervention – for example, if calcium is identified, then rotational atherectomy could be considered.3 Apart from the greyscale image used for plaque interpretation, extensive research investigating ways of improving the assessment of plaque composition by IVUS has been performed. The Kawasaki group at the Gifu University Graduate School of Medicine in Japan has published studies using integrated backscatter signals from the radiofrequency signal of ultrasound, and based on the backscatter IVUS image, they have used colour to code different components of plaque.8,9 Another established technique developed by Volcano Corporation® (Rancho Cordova, CA, US) uses radiofrequency signals to determine plaque composition.10 In this technique, the distortion of radiofrequency signal by the plaque is passed through an algorithm, which is then colour-coded and superimposed on the grey image – a technique commercialised as ‘Virtual Histology intravascular ultrasound’ (VH-IVUS).10 Recent imaging technology now allows the reconstruction of VH-IVUS images in a longitudinal view, enabling a more comprehensive analysis of the total length of the plaque, its spatial orientation and its relation to the rest of the coronary artery. The potential of this imaging modality for analysing plaque vulnerability was demonstrated in a recent study where VH-IVUS backscatter data from ex vivo left anterior descending coronary arteries were recorded and compared with histological interpretation of the same sites.11 The overall predictive accuracies for VH-IVUS were 93.5 % for fibrotic tissue, 94.1 % for fibro-fatty tissue, 95.8 % for necrotic core and 96.7 % for dense calcium.11 Further data were provided by the Carotid Artery Plaque Virtual Histology Evaluation (CAPITAL) study,12 where a strong correlation between VH-IVUS plaque characterisation and characterisation following direct histological examination of the plaque (following endarterectomy) was demonstrated with a predictive accuracy of 99.4 % for thin-cap fibroatheroma (TCFA), which is thought to be the precursor lesion of plaque rupture, and 96.1 % for calcified TCFA.12

Transmit beamformer

Monitor

IVUS Catheter System Processor

Computer

Pulser AM

Switch

RM Receive beamformer

Multi-channel analogue front end

The intravascular ultrasound (IVUS) catheter contains an acoustic mirror (AM) that is rotated by a motor (RM) to emit outbound acoustic wave signals. A piezoelectric transducer (PT) converts the inbound acoustic waves into electrical signals. To create the electrical signal that is inputted to the IVUS catheter a transmit beamformer generates electrical pulses that are timed and scaled to the coronary vessel. The electrical signals pass through a high-voltage pulser to excite the IVUS catheter. After the PT element receives the incoming acoustic waves and converts them to electric signals they pass to the analogue front-end to amplify and filter the signal, which is then passed to the receive beamformer that reconstructs the data and converts it to images within the main computer system.

In addition, IVUS has been useful in demonstrating diffuse disease in angiographically, ‘normal’ arteries, which may have as much as one-third of their cross-sectional area filled with diffuse plaque.14,15

Does Intravascular Ultrasound Use Improve Outcomes? Identifying Vulnerable Plaque The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial, used angiography, three-vessel greyscale and radiofrequency IVUS to evaluate the natural history of atherosclerosis in a prospective group of 697 patients with acute coronary syndromes who underwent percutaneous coronary intervention (PCI) and subsequent optimal medical therapy. During a median follow-up of 3.4 years, culprit lesions at the time of initial study were felt to be related to major adverse cardiac events (MACE) in 12.9 % of patients, with non-culprit lesions responsible in 11.6 %. After multivariate analysis, non-culprit lesions associated with recurrent events were more likely to have three characteristics: a minimal luminal area of <4 mm2; a plaque burden of >70 %; or classified as TCFA. Furthermore, those lesions that were responsible for future MACE were observed to be mild when assessed by angiography (mean diameter of stenosis 32 ± 21 %), but using IVUS, these lesions had a plaque burden of 67 ± 10 %. At the time of follow-up, these lesions had progressed angiographically to a mean angiographic diameter stenosis of 65 ± 16 %.16 It is important to note, however, that while IVUS has been observed to be a validated tool to predict lesions responsible for future MACE, it is not able to image well through calcium, nor is it accurate in identifying thrombus.17

Assessment After Percutaneous Coronary Intervention

Vessel Dimensions

In a randomised trial studying drug-eluting stent (DES) deployments with or without IVUS guidance in 210 patients, IVUS use led to more frequent post-dilations, higher balloon inflation pressures and the use of larger balloon sizes. However, despite this there was no significant difference in MACE rates (11 versus 12 %; p = not significant) at 18-month follow-up.18 A further retrospective study found no significant differences in the rates of restenosis with and without optimal stent expansion guided by IVUS in 250 patients undergoing PCI with DES.19

Although angiography allows measurement of luminal diameters in two-dimensional views, IVUS produces a tomographic view, which provides higher resolution as well as precise vessel and plaque dimensions. 13 Therefore, the true minimal and maximal luminal diameter can be measured with IVUS. Furthermore, the cross-sectional area measurement of the lumen as well as the vessel can be obtained.13

Although currently insufficient evidence exists to support a reduction in the rates of restenosis with IVUS use there is some evidence supporting IVUS guidance to reduce rates of stent thrombosis. In one study of 884 patients with DES implantation, IVUS-guidance was associated with less direct stenting, more post-dilation, greater cutting balloon and rotational atherectomy use. At 30 days and

INTERVENTIONAL CARDIOLOGY REVIEW

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Coronary Diagnosis & Imaging Figure 2: Schematic of Optical Coherence Tomography Imaging System

Monitor

SW Laser source

50/50 splitter unit

Computer

RW RM

The pulse of light from the laser source is split equally between the tissue wave (TW) and the reference wave (RW). The RW reflects off the reference window (RW) to calculate distance of pullback. The returning TW signal from the tissue is combined with the returning RW signal from the reference mirror (RM) and this is converted to images within the main computer system.

Figure 3: Intracoronary Imaging of a Normal Coronary Artery A

when adequate coronary preparation has occurred. As the light source is easily absorbed by blood there is a need for coronary preparation prior to image acquisition. The use of pure contrast through a manifold to prepare the coronary artery with total blood removal is generally recommended with most left coronary systems requiring 10–14 mls and right coronary arteries 8–10 mls. The OCT system consists of an OCT imaging catheter (ImageWite TM, St Jude TM, St Paul, Minnesota, US) and an OCT system console, which contains the optical imaging engine and computer signal acquisition (M2/M3 CV OCT Imaging System, LightLab Imaging, Inc, Westford, Massachusetts, US).

Image Acquisition Limitations of Optical Coherence Tomography Due to the need for complete coronary preparation, if any blood pooling remains, a high signal will remain within the image distorting the final image. In addition, as the guidewire does not run through the entire length of the OCT catheter, all images will have a silhouette of the guidewire with reduction of image quality in these areas (see Figure 3).

Safety of Optical Coherence Tomography The relatively low energy used in OCT (5.0–8.0 mW) does not cause functional or structural damage to the coronary tissue. The main safety concern with OCT is the use of a contrast bolus in coronary A: Intravascular ultrasound image; B: Optical coherence tomography image of normal coronary arteries. Red circle indicates position occupied by imaging catheter and + shows the ‘drop-out’ signal produced by the guidewire.

12 months, lower rates of definite stent thrombosis were seen in the IVUS group (0.5 versus 1.4 %; p=0.046 and 0.7 versus 2.0 %; p=0.014, respectively).20

preparation – however, studies have shown that no patients suffered contrast-induced nephropathy, but there is a relatively small risk of coronary spasm and electrocardiogram (ECG) changes during contrast administration.22

Assessment of Coronary Lesions with Optical Coherence Tomography Plaque Characterisation

Optical Coherence Tomography – a New Era of Intracoronary Imaging OCT was first developed by two Japanese researchers at the Yamagata University (Japan) and subsequently at the Massachusetts Institute of Technology in the US in 1991. In vitro OCT was initially performed in the retina but adopted in the coronary artery later in the same year.1,21 Instead of ultrasound (like IVUS), OCT uses near-infrared light, which is absorbed by water, lipids and erythrocytes (see Figure 2). The high-resolution of OCT has allowed use of this technology for both clinical and research purposes.21 OCT has widely been used in the assessment of coronary anatomy over the last decade, and has a wide range of clinical applications including coronary plaque anatomy, post-PCI stent position and malapposition. Within research, OCT has been able to improve the evaluation of stent endothelisation post-implantation. Although initial OCT systems consisted of time-domain optical coherence tomography (TD-OCT) technology, this has been surpassed by frequency-domain optical coherence tomography (FD-OCT) technology. Current OCT catheters are 3.2 Fr flexible short monorail systems with an optical emitting transducer that emits a near-infrared wavelength of about 1,300 nm. Unlike the IVUS catheter, the OCT catheter transducer lies 20 mm behind the distal marker. The transducer contains optical fibres with a micro-lens transducer that is placed beyond the target lesion along a standard guidewire. The OCT catheter does not move during image acquisition, instead the transducer moves back inside the central part of the catheter. The catheters have an automated pullback system at a rate of 25 mm per second with an image range of 50–70 mm

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Since there is greater spatial resolution with OCT compared with IVUS (see Figure 3), OCT can provide more detail regarding the microstructure of the vessel wall and specifically OCT has been shown to identify TCFA, a feature not possible by IVUS. Studies have shown a high degree of correlation between OCT imaging and fibrous cap thickness on histologic evaluation.1,17,23 In addition, OCT can identify TCFA by measuring the thickness of the fibrous cap and the arc of the lipid-rich plaque.24–26 Lipid pools are less sharply delineated than calcification and show lower signal intensity. Lipids also exhibit more heterogeneous backscattering than fibrous plaques.27,28 OCT has been shown to be helpful in determining prognosis by identifying vulnerable plaques. A prospective study of the characteristics of non-culprit lesions in 53 patients with coronary artery disease undergoing PCI showed that TCFA (as assessed by OCT) and the presence of micro-channels had a significant correlation with plaque progression (defined as >0.4 mm increase in minimal luminal diameter) at a seven-month follow-up.29

Thrombus Thrombus is well visualised by OCT with the technique able to distinguish between different thrombus phenotypes. 25,26,30 OCT images for white thrombi (composed of platelets and leucocytes) produce a signal-rich mass whereas red thrombi (containing mainly erythrocytes) produce high backscattering protrusions with strong signal attenuation.31 If there is a large red thrombus, then this may interrupt the visualisation of the characteristics of an underlying plaque due to signal attenuation. It is possible to misinterpret

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Intravascular Ultrasound Versus Optical Coherence Tomography for Coronary Artery Imaging

mural thrombi as lipid-rich fibroatheroma, due to similar OCT single attenuation patterns produced by these two plaque components. Therefore, thorough examination of the structures and surface are required to differentiate between these two pathologies.

Figure 4: Optical Coherence Tomographic Pictures of Restenotic Tissue Following Drug-eluting Stent Implantation A

Vessel Sizing OCT allows clear delineation between the lumen and vessel wall, although due to shallow penetration there may be a limit in the detail of the whole vessel structure visualised as compared with IVUS imaging.32 OCT also provides accurate measurement of reference lumen diameters with studies showing that for proximal culprit lesions, TD-OCT measurements were almost identical to those measured with IVUS.33

Optimising Percutaneous Coronary Intervention OCT allows detailed evaluation of strut apposition to the vessel wall and stent expansion after stent deployment. As the infrared light cannot penetrate into the metal struts of the stent, the luminal surface shows a strong reflection with shadowing behind the struts and consequently improves the visibility of individual stent struts. After stent deployment, OCT allows visualisation of stent edge dissection, tissue protrusion and incomplete stent apposition that may not be detected by either IVUS or angiography alone.33,34 OCT has also been used as one of the primary imaging modalities for follow-up evaluation of several bioabsorbable vascular scaffolds (BVS), which are being studied in clinical trials. A recently published study35 evaluated 100 lesions from 73 patients comparing BVS with an equal number of matched lesions treated with second-generation DES. OCT of these lesions showed a significantly higher rate of tissue prolapse and higher rates of incomplete strut apposition at the proximal edge in the BVS group. However, there was no difference in the overall rates of incomplete strut apposition. Therefore using OCT, this study demonstrated that BVS had similar post-procedure area stenosis and minimal lumen area as second-generation DES. Another study, the ABSORB study,36 investigated 30 patients with a single de novo coronary artery lesion treated with BVS, who were followed up for two years clinically and with multiple imaging methods including OCT. At two years after implantation, 34.5 % of strut locations had no discernible features detected by OCT, suggesting a significant reduction in restenosis as well as reducing the risk of late thrombosis. Stent area measured by OCT could potentially be an alternative endpoint of PCI. This is because OCT has helped to predict no reflow26 post-PCI, based on the presence of TCFA. The clinical significance of these OCT findings and whether they warrant further intervention remains unclear; with a small natural history study showing that these findings resolved without significant restenosis or thrombus formation at six-month follow-up.37 To date, no studies have been completed investigating the role of OCT in optimising PCI for non-ST-segment elevation acute coronary syndromes (NSTEACS). The Does Optical Coherence Tomography Optimise Results of Stenting (DOCTORS) study will randomise 250 patients to have OCT-guided angioplasty or angioplasty alone. In addition to the safety of OCT in angioplasty for NSTEACS, the study will also investigate whether OCT yields useful additional information beyond that obtained by angiography alone and whether this information changes interventional strategy.38 Finally, a recent study investigated the use of OCT to guide the management of patients with ACS and large thrombus burden.39 The study involved 852 patients with ACS. Of these patients, 101 had large thrombus burden and underwent thrombectomy to restore Thrombolysis

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A: 10 % luminal loss (* and blue arrow); B: 87 % luminal loss (* and blue arrow).

In Myocardial Infarction (TIMI) 3 flow. These patients subsequently had OCT on days 0–2 (acute), days 3–6 (early) and days 7–30 (late). The study found that the delayed group had reduced thrombus burden, resulting in 38 % of patients not requiring stent implantation. This suggests that OCT identified culprit lesion morphology not discerned by angiography alone and therefore OCT facilitated PCI decision-making.

Assessment of Neointimal Coverage with Optical Coherence Tomography Strut coverage is an important surrogate risk factor of stent thrombosis. According to IVUS examinations, most DES appear uncovered by neointima; however, the limited resolution of IVUS makes it difficult to calculate the thickness or even extent of neointimal coverage. Using OCT, strut coverage is clearly seen and both the coverage of individual struts and the thickness of neointimal coverage can be assessed accurately.40 In one study, at six-months follow-up, 89 % of sirolimus-eluting stents (SES) lesions were covered by thin neointima, and 64 % of the stent struts were covered with neointima that had a thickness of less than 100 μm (which would be undetectable by IVUS).40 Even though the introduction of DES has led to reduced rates of restenosis, this complication following PCI still occurs and our understanding of its pathophysiology is still poor. OCT has helped advance our understanding, with studies demonstrating that stent restenosis is not homogenous. Furthermore, OCT imaging allows separation of restenotic tissue into homogenous, layered and heterogeneous groups. This was demonstrated in a study where paclitaxel-eluting stent restenosis could be easily classified into these three groups using OCT.41 Figure 4 demonstrates the sensitivity of OCT in characterising the extent of restenosis after DES implantation. OCT has been increasingly used as an endpoint in clinical trials of newer generation DES, e.g. the Limus Eluted from A Durable versus Erodable Stent coating (LEADERS) randomised trial comparing a biolimus-eluting stent (BES) with SES. Here, 56 consecutive patients underwent OCT during angiographic follow-up at nine months. At an average follow-up of nine months, strut coverage was more complete in patients allocated to BES compared with those with SES.42 However, whether uncovered stent struts visualised by OCT directly relate to late stent thrombosis after PCI remains largely unclear.

Optical Coherence Tomography Observations of Very Late Stent Thrombosis After Drug-eluting Stent Implant It is believed that very late stent thrombosis may be due to delayed arterial healing as well as incomplete endothelialisation following stent

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Coronary Diagnosis & Imaging Figure 5: Malapposition Demonstrated by Intravascular Ultrasound and Optical Coherence Tomography Imaging A

IVUS

A: Intravascular ultrasound; B: Optical coherence tomography. Both images show that there is malapposition (* and red arrow).

Table 1: Technical Characteristics of Intravascular Ultrasound and Frequency-domain Optical Coherence Tomography IVUS

FD-OCT

Technology

Near-infrared

Ultrasound

Axial resolution, um

100–150

12–15

Axial resolution, um

100–150

12–15

Lateral resolution, um

150–300

Frame rate, fps

100

Pullback speed. Mm/s

0.5–2.0

10–15

Scan diameter, mm

8–10

Tissue penetration

4–8

1–2

Balloon occlusion

Unnecessary

Image through blood field

Yes

Blood removal with contrast

Yes

Catheter size

3.5 Fr

3.2 Fr

Guidewire required

Yes

Wavelength

1.3 um

10–40 MHz

FD = frequency-domain; fps = frames per second; IVUS = intravascular ultrasound; OCT = optical coherence tomography. Source: modified from Terashima M, et al., 2012.21

implantation.43 OCT has been used to observe very late stent thrombosis 29 months after SES implantation. Here OCT showed multiple inter-strut ulcer-like appearances and late strut malappositions.44 These changes could represent OCT signs of very late stent thrombosis. Although these observations are important to understand differences in stent design, further studies are required to determine the clinical significance of these findings, and in particular, whether information obtained using OCT can be predictive in identifying patients at risk of stent thrombosis or restenosis. Large-scale, prospective studies are needed to address clinical questions such as the relationship between clinical outcome and DES deployment, vascular healing, the time course of endothelial stent coverage, as well as the threshold for stent coverage and late-stent thrombosis.

Comparison of the Two Techniques IVUS provides useful information regarding vessel size, plaque morphology/area and can be used to guide the selection of interventional strategies; however, it is limited by image resolution. This is where OCT has demonstrated superiority with improved image resolution and contrast, and is therefore more attractive for the assessment of coronary arteries in further detail. The resolution of OCT (10–20 μm) is 10-fold higher than that of IVUS (100–150 μm); however, as a consequence, the penetration depth is lower (OCT: 1–2 mm compared with IVUS: 4–8 mm).25 Therefore, there is a limit

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Table 2: Comparison of Characterisation of Pathology Using Intravascular Ultrasound and Optical Coherence Tomography OCT

VH-IVUS

Necrotic core

Thin-cap fibroatheroma

+++

Thrombus

+++

Calcium

+++

Stent apposition/expansion

+++

Dissection

+++

Ostial lesion evaluation

IVUS = intravascular ultrasound; OCT = optical coherence tomography; VH-IVUS = virtual histology intravascular ultrasound; +++ = excellent capability; ++ = good capability; + = poor capability; - = impossible; N/A = not applicable. Source: modified from Sanidas E, Dangas G, 2013.48

in the ability of IVUS to detect intimal tears, thrombus and stent malapposition (see Figure 5) whereas OCT has been demonstrated to visualise intimal hyperplasia, intraluminal thrombi, stent edge dissection and mural thrombus after PCI.22,45,46 Specific differences between OCT and IVUS are shown in Table 1. With respect to plaque characterisation, OCT allows greater in-depth visualisation of detailed coronary struts including characteristics of coronary plaque (i.e. lipid-rich, fibrous and calcified plaques).25,26 However, in several applications, the shallower penetration of OCT may be a drawback. Whole vessel structures, including the external elastic lamina, cannot be visualised consistently by OCT, especially through lesions with a high amount of lipid-rich plaque burden. The relative merits of all the described intracoronary imaging modalities are shown in Table 2. From a practical perspective one of the biggest differences between IVUS and OCT remains the need to replace the coronary blood pool with contrast during acquisition of OCT images. This involves the simultaneous injection of contrast to obtain the high definition images possible with OCT.47 The clinical value of the higher resolution images in guiding decision-making is still under evaluation.38

Studies Comparing Intravascular Ultrasound versus Optical Coherence Tomography A recent prospective multicentre study (OCT Compared with IVUS in a Coronary Lesion Assessment [OPUS-CLASS] study) investigated the reliability of FD-OCT for coronary measurements compared with quantitative coronary angiography (QCA) and IVUS. Within a 100 patient cohort, both FD-OCT and IVUS exhibited good interobserver reproducibility, but the variability between measurements was approximately twice as high for the IVUS measurements as compared with the FD-OCT (0.32 versus 0.16 mm2).49 In addition, IVUS overestimated the lumen area and was less reproducible than FD-OCT (8.03 ± 0.58 mm2 versus 7.45 ± 0.17 mm2; p<0.001).49 FD-OCT therefore provided accurate and reproducible quantitative measurements of coronary dimensions in the clinical setting. However, a recent randomised controlled trial comparing FD-OCT against IVUS for PCI optimisation reported that there was inferior stent expansion, both focal (65 versus 80 %, p=0.002) and diffuse (84 versus 99 %, p=0.003), when FD-OCT was used for guidance. PCI guided by FD-OCT also showed a significant increase in residual stent-edge plaque burden (51 versus 42 %, p<0.001). However, there were no significant differences in stent apposition.50 Therefore, this study found that IVUS

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Intravascular Ultrasound Versus Optical Coherence Tomography for Coronary Artery Imaging

Table 3: Comparing the Clinical Evidence of Intravascular Ultrasound and Optical Coherence Tomography Intravascular Ultrasound

Frequency Domain Optical Coherence Tomography

Characterisation of

Studies have demonstrated improved visualisation of

OCT is able to identify TCFA (which is thought to be the precursor

atherosclerosis

plaque by using backscatter IVUS to colour code plaque

lesion of plaque rupture), a feature not possible by IVUS. Studies

components.8,9

have shown a high degree of correlation between OCT imaging and fibrous cap thickness on histologic evaluation.1,14,20

One study examined 130 segments of fresh peripheral arteries using ultrasound imaging and compared the findings with corresponding histopathological sections. Atherosclerotic plaque was readily visualised but could not always be differentiated from the underlying media.13 In 54 atherosclerotic sites imagined by IVUS compared with formalin-fixed and fresh histological sections of the coronary arteries, ultrasound accurately predicted histological plaque composition in 96 % of cases. Anatomic features of the coronary arteries that were easily discernible were the lumen–plaque and media–adventitia interfaces.6

Vessel dimensions

VH-IVUS has improved visualisation of fibrotic tissue,

The characteristics of non-culprit lesions in 53 patients with

fibro-fatty tissue and dense calcium.11 The CAPITAL

coronary artery disease undergoing PCI, has been assessed.

study11 showed strong correlation between VH-IVUS

The study showed that TCFA and the presence of microchannels

plaque characterisation and characterisation following

had a significant correlation with plaque progression (defined as

true histological examination of the plaque following

>0.4 mm increase in minimal luminal diameter) at a seven-month

carotid artery endarterectomy.

follow-up.29

True minimal and maximal luminal diameter can be

OCT can also provide accurate measurement of reference lumen

measured. The cross-sectional area measurement of

diameters. Especially with proximal culprit lesions, TD-OCT

the lumen as well as the vessel can be obtained.13

measurements have been demonstrated to be almost identical to those measured with IVUS.33

Identifying vulnerable plaque

PROSPECT trial studied 697 patients with acute coronary syndromes using IVUS to identify lesions that were responsible for future MACE in 67 % of cases. However, IVUS was not useful in identifying thrombus or calcium.17

Assessment after PCI

In a study investigating DES deployment, IVUS use led

Neointima coverage: One study, at six-month follow-up showed

to more frequent post-dilations, higher balloon inflation

that 89 % of the SES lesions were covered by thin neointima, and

pressures and larger balloon sizes. However, despite

that 64 % of the stent struts were covered with neointima that

this there was no significant difference in MACE rates

had a thickness of <100 μm (which would be undetectable by

(11 versus 12 %; p=NS) at 18-month follow-up.18

IVUS).40

884 patients with DES implantation IVUS-guidance was

Restenosis: One study showed that OCT imaging can separate

associated with less direct stenting, more post-dilation and

restenotic tissue into homogenous, layered and heterogeneous

greater cutting balloon and rotational atherectomy use.20

groups.41 In the LEADERS trial, 56 consecutive patients underwent OCT during angiographic follow-up at nine months after BES implantation. At an average follow-up of nine months, strut coverage was more complete in patients allocated to BES when compared to those with SES.42

Thrombosis

Another study used OCT to observe very late stent thrombosis 29 months after SES implantation. Here OCT showed multiple inter-strut ulcer-like appearance and late strut malapposition.44

BES = biolimus-eluting stent; CAPITAL = Carotid Artery Plaque Virtual Histology Evaluation study; DES = drug-eluting stent; FD = frequency-domain; IVUS = intravascular ultrasound; LEADERS = Limus Eluted from A Durable versus Erodable Stent coating; MACE = major adverse cardiac events; NS = not significant; OCT = optical coherence tomography; PCI = percutaneous coronary intervention; PROSPECT = Providing Regional Observations to Study Predictors of Events in the Coronary Tree study; SES = sirolimus-eluting stent; TCFA = thin-cap fibroatheroma; VH-IVUS = virtual histology intravascular ultrasound.

had a significant advantage over OCT in terms of the reduction of residual stent-edge plaque burden and visibility of vessel border, which is in contrast to the results of the OPUS-CLASS study.49 Table 3 is a summary of current clinical evidence for IVUS and OCT use.

coronary lesions (Class IIa, Level of Evidence B recommendation). These guidelines also recommend the use of IVUS to evaluate the aetiology of stent restenosis and stent thrombosis (Class IIa, Level of Evidence C). The routine use of IVUS for evaluation of lesions when PCI is not planned was given a Class III recommendation.51

Current Clinical Practice Guidelines The 2011 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) guidelines for PCI recommends the use of IVUS for the evaluation of angiographically indeterminate left main lesions and angiographically indeterminate (50–70 % stenosis) non-left main

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The 2010 European guidelines (European Society of Cardiology [ESC]) for Myocardial Revascularisation give a Class IIb, Level of Evidence C recommendation for the use of IVUS during unprotected left main PCI only.52 The lack of recommendation for other lesions or vessels appears to be related to limited data showing that IVUS reliably

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Coronary Diagnosis & Imaging reduces MACE. However, the 2011 ACCF/AHA/SCAI guidelines do provide a Class IIa, Level of Evidence B recommendation for the use of IVUS for evaluation of donor coronary artery disease or allograft vasculopathy in post-cardiac transplantation patients.51 Currently neither the American (2011 ACCF/AHA/SCAI guidelines) nor European (ESC) guidelines provide recommendations for the routine use of OCT in clinical practice.51,52 However, more recent guidelines published in February 2014 by The National Institute for Health and Care Excellence (NICE)53 suggest that the evidence on the safety of OCT to guide PCI showed no major concerns. Due to the current available evidence on efficacy being limited in quantity and quality, it is recommended by NICE that this procedure should only be used with special arrangements for clinical governance, consent and audit or research.53

Future Clinical Research and Application of intra-coronary Imaging OCT despite its extensive use in research studies has not yet been established in clinical practice and therefore currently should be seen as complementary to rather than replacing IVUS. However, it is expected that with the development of FD-OCT, the procedure will become both quicker and easier. As mentioned above, one major disadvantage of OCT is its limitation in the penetration depth (i.e. of approximately 2 mm). Therefore, although current OCT systems can demonstrate thin fibrous caps and thin neointimal coverage on DES, it is unable to quantify total plaque volume. Hence, development of new devices in conjunction with OCT might be helpful for both patient evaluation and clinical trials. In addition, the need for optimal clearance of blood from the vessel lumen often requires extra doses of contrast to generate interpretable images. There are an increasing number of OCT studies being reported, which will hopefully further clarify the role of OCT in the near future. The FFR or OCT Guidance to RevasculariZe Intermediate Coronary Stenosis Using Angioplasty (FORZA) study will aim to compare the clinical and the economic impact of fractional flow reserve (FFR) versus OCT guidance in the percutaneous management of patients with angiographically intermediate coronary lesions.54 The DOCTORS study will evaluate the impact of changes in procedural strategy resulting from the use of OCT after angioplasty and stent implantation of a lesion responsible for NSTEACS.55

1. Mintz GS, Nissen SE, Anderson WD, et al., American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents, J Am Coll Cardiol, 2001;37:1478–92. 2. Johnson PM, Patel J, Yeung M, Kaul P, Intra-coronary imaging modalities, Curr Treat Options Cardiovasc Med, 2014;16:304. 3. Nissen SE, Yock P, Intravascular ultrasound: novel pathophysiological insights and current clinical applications, Circulation, 2001;103:604–16. 4. Batkoff BW, Linker DT, Safety of intracoronary ultrasound: data from a Multicenter European Registry, Cathet Cardiovasc Diagn, 1996;38:238–41. 5. Gussenhoven EJ, Essed CE, Lancée CT, et al., Arterial wall characteristics determined by intravascular ultrasound imaging: an in vitro study, J Am Coll Cardiol, 1989;14:947–52. 6. Potkin BN, Bartorelli AL, Gessert JM, et al., Coronary artery imaging with intravascular high-frequency ultrasound, Circulation, 1990;81:1575–85. 7. Fitzgerald PJ, St Goar FG, Connolly AJ, et al., Intravascular ultrasound imaging of coronary arteries. Is three layers the norm?, Circulation, 1992;86:154–8. 8. Kawasaki M, Sano K, Okubo M, et al., Volumetric quantitative analysis of tissue characteristics of coronary plaques after

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Finally, there has been little use of OCT in patients presenting with ST-elevation myocardial infarction (STEMI). Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty (OCTAVIA), is a recent study, which enrolled 140 STEMI patients who underwent primary PCI with an everolimus-eluting stent, and which demonstrated that at nine months, OCT showed that more than 90 % of patients had fully covered stent struts.56 Although this was a small study, it is likely that because of the superiority of OCT technology over IVUS, there will probably be many more studies that will use OCT to investigate plaque characterisation during primary PCI. In addition to the rapid progress with OCT, future developments in IVUS are also expected with significant research ongoing in developing combinations of imaging modalities. Combining near-infrared spectroscopy (NIRS) technology with IVUS allows better characterisation of lipid-rich plaque within a coronary artery.57 There are a number of ways by which NIRS-IVUS can help the optimisation of PCI and even play an important role in the prevention of spontaneous coronary events. Studies have suggested that NIRS has identified large, often circumferential lipid-rich plaques at the culprit site in most patients experiencing a STEMI.58 These data are now being translated into two large-scale prospective studies that will investigate the use of NIRS in the prediction of cardiac events beyond the success achieved with plaque burden in the PROSPECT Study.16,59

Conclusions The development of OCT has markedly improved intracoronary image resolution compared with IVUS. OCT is superior to IVUS in a number of aspects, particularly distinguishing thrombus formation, coronary dissection and incomplete stent apposition following implantation. OCT also assists the characterisation of neointimal coverage after stent implantation and thrombus formation, thereby allowing early comparison of new technologies using intermediate endpoints. Both techniques are clearly useful in diagnosing, planning and evaluating the results of coronary intervention. Whether this provides a significant improvement to clinical decision-making is still debatable and intracoronary imaging therefore exists as a useful adjunct to clinical practice. The role in assessment of new technologies is more certain and the superiority of the images obtained using OCT is therefore more important. Whether OCT will replace IVUS as the clinical tool of choice for intracoronary imaging remains undetermined and will be guided by the results of ongoing clinical trials. n

statin therapy using three-dimensional integrated backscatter intravascular ultrasound, J Am Coll Cardiol, 2005;45:1946–53. 9. Kawasaki M, Takatsu H, Noda T, et al., In vivo quantitative tissue characterization of human coronary arterial plaques by use of integrated backscatter intravascular ultrasound and comparison with angioscopic findings, Circulation, 2002;105:2487–92. 10. Nair A, Kuban BD, Tuzcu EM, et al., Coronary plaque classification with intravascular ultrasound radiofrequency data analysis, Circulation, 2002;106:2200–6. 11. Nair A, Margolis MP, Kuban BD, Vince DG, Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation, EuroIntervention, 2007;3:113–20. 12. Diethrich EB, Pauliina Margolis M, Reid DB, et al., Virtual histology intravascular ultrasound assessment of carotid artery disease: the Carotid Artery Plaque Virtual Histology Evaluation (CAPITAL) study, J Endovasc Ther, 2007;14:676–86. 13. Nishimura RA, Edwards WD, Warnes CA, et al., Intravascular ultrasound imaging: in vitro validation and pathologic correlation, J Am Coll Cardiol, 1990;16:145–54. 14. Mintz GS, Painter JA, Pichard AD, et al., Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlation, J Am Coll Cardiol, 1995;25:1479–85.

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ultrasound, J Invasive Cardiol, 2010;22:541–5. 34. Bouma BE, Tearney GJ, Yabushita H, et al., Evaluation of intracoronary stenting by intravascular optical coherence tomography, Heart, 2003;89:317–20. 35. Mattesini A, Secco GG, Dall’Ara G, et al., ABSORB biodegradable stents versus second-generation metal stents: a comparison study of 100 complex lesions treated under OCT guidance, JACC Cardiovasc Interv, 2014;7:741–50. 36. Serruys PW, Ormiston JA, Onuma Y, et al., A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods, Lancet , 2009;373:897–910. 37. Kume T, Okura H, Miyamoto Y, et al., Natural history of stent edge dissection, tissue protrusion and incomplete stent apposition detectable only on optical coherence tomography after stent implantation – preliminary observation, Circ J, 2012;76:698–703. 38. Meneveau N, Ecarnot F, Souteyrand G, et al., Does optical coherence tomography optimize results of stenting? Rationale and study design, Am Heart J, 2014;168:175–81.e1–2. 39. Souteyrand G, Amabile N, Combaret N, et al., Invasive management without stents in selected acute coronary syndrome patients with a large thrombus burden: a prospective study of optical coherence tomography guided treatment decisions, EuroIntervention, 2014 [Epub ahead of print]. 40. Matsumoto D, Shite J, Shinke T, et al., Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography, Eur Heart J, 2007;28:961–7. 41. Gonzalo N, Serruys PW, Okamura T, et al., Optical coherence tomography patterns of stent restenosis, Am Heart J, 2009;158:284–93. 42. Barlis P, Regar E, Serruys PW, et al., An optical coherence tomography study of a biodegradable vs. durable polymercoated limus-eluting stent: a LEADERS trial sub-study, Eur Heart J, 2010;31:165–76. 43. Finn AV, Nakazawa G, Joner M, et al., Vascular responses to drug eluting stents: importance of delayed healing, Arterioscler Thromb Vasc Biol, 2007;27:1500–10. 44. Sawada T, Shite J, Shinke T, et al., Very late thrombosis of sirolimus-eluting stent due to late malapposition: serial observations with optical coherence tomography, J Cardiol, 2008;52:290–5. 45. Suter MJ, Nadkarni SK, Weisz G, et al., Intravascular optical imaging technology for investigating the coronary artery, JACC Cardiovasc imaging, 2011;4:1022–39. 46. Yun SH, Tearney GJ, Vakoc BJ, et al., Comprehensive volumetric optical microscopy in vivo, Nat Med, 2006;12:1429–33. 47. Kataiwa H, Tanaka A, Kitabata H, et al., Safety and usefulness of non-occlusion image acquisition technique

for optical coherence tomography, Circ J, 2008;72:1536–7. 48. Sanidas E, Dangas G, Evolution of intravascular assessment of coronary anatomy and physiology: from ultrasound imaging to optical and flow assessment, Eur J Clin Invest, 2013;43:996–1008. 49. Kubo T, Akasaka T, Shite J, et al., OCT compared with IVUS in a coronary lesion assessment: the OPUS-CLASS study, JACC Cardiovasc Imaging, 2013;6:1095–104. 50. Habara M, Nasu K, Terashima M, et al., Impact of frequency-domain optical coherence tomography guidance for optimal coronary stent implantation in comparison with intravascular ultrasound guidance, Circ Cardiovasc Interv, 2012;5:193–201. 51. Levine GN, Bates ER, Blankenship JC, et al., 2011 ACCF/AHA/ SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions, J Am Coll Cardiol, 2011;58:e44–122. 52. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI), Wijns W, Kolh P, Danchin N, et al., Guidelines on myocardial revascularization, Eur Heart J , 2010;31:2501–55. 53. Optical coherence tomography to guide percutaneous coronary intervention. NICE interventional procedures guidance [IPG481], 2014. Available at: www.nice.org.uk/ Guidance/IPG481 (Accessed 1 July 2014). 54. Clinicaltrials.gov, FFR or OCT Guidance to RevasculariZe Intermediate Coronary Stenosis Using Angioplasty (FORZA), 2013. Available at: www.clinicaltrials.gov/ct2/show/ NCT01824030 (Accessed 1 July 2014). 55. Clinicaltrials.gov, Does Optical Coherence Tomography Optimise Results of Stenting (DOCTORS), 2013. Available at: www.clinicaltrials.gov/ct2/show/NCT01743274 (Accessed 1 July 2014). 56. Medscape: STEMI in Women: Same Plaques, Same Stent Outcomes: OCTAVIA, Medscape, 2014. Available at: www. medscape.com/viewarticle/825391 (Accessed 1 July 2014). 57. Goldstein JA, Dixon SR, Stone GW, NIRS-IVUS Imaging Identifies Lesions at High Risk of Peri-Procedural Myocardial Infarction, J Invasive Cardiol, 2013;25:14A–6A. 58. Madder RD, Steinberg DH, Anderson RD, Multimodality direct coronary imaging with combined near-infrared spectroscopy and intravascular ultrasound: initial US experience, Catheter Cardiovasc Interv, 2013;81:551–7. 59. Madder RD, Stone GW, Erlinge D, Muller JE, The Search for Vulnerable Plaque — The Pace Quickens, J Invasive Cardiol, 2013;25:20A–4A.

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Coronary Adjunctive Pharmacotherapy

Percutaneous Coronary Intervention in Patients Who Have an Indication for Oral Anticoagulation – an Evidence-based Approach to Antithrombotic Therapy Sean Gallagher 1,2 and R Andrew Archbold 1,2 1. Department of Cardiology, Barts Health NHS Trust; 2. NIHR Cardiovascular Biomedical Research Unit, London Chest Hospital, London, UK

Abstract Dual antiplatelet therapy (DAPT) is required following percutaneous coronary intervention (PCI) to prevent stent thrombosis. The optimal antithrombotic therapy following PCI for patients with an indication for long-term oral anticoagulation (OAC) is uncertain. DAPT and OAC, a combination known as ‘triple therapy’, reduces cardiovascular event rates but is associated with a substantial risk of bleeding. Recent data suggest that the duration of DAPT (and thereby triple therapy in those who also require OAC) can be limited to 1–3 months following newgeneration drug-eluting stent deployment, and that aspirin may be omitted from triple therapy, without increasing the rate of ischaemic cardiovascular events. The increasing use of non-vitamin K antagonist oral anticoagulants and new antiplatelet agents (prasugrel and ticagrelor) has further complicated antithrombotic prescribing. This article aims to provide a summary of the evidence regarding antithrombotic therapy after PCI in patients who have an indication for OAC and to provide a framework to aid clinical decision-making in this area.

Keywords Antithrombotic therapy, triple therapy, dual antiplatelet therapy, stent thrombosis, percutaneous coronary intervention Disclosure: The authors have no conflicts of interest to declare. Received: 16 December 2014 Accepted: 29 January 2015 Citation: Interventional Cardiology Review, 2015;10(1):16–21 Correspondence: R Andrew Archbold, Department of Cardiology, London Chest Hospital, Bonner Road, London, E2 9JX, UK. E: andrew.archbold2@bartshealth.nhs.uk

Patients who undergo coronary artery stenting require dual antiplatelet therapy (DAPT) in order to reduce their risk of stent thrombosis. Long-term oral anticoagulation (OAC) is indicated for the primary and secondary prevention of thrombotic events in patients with atrial fibrillation (AF), mechanical heart valves, intra-cardiac thrombus, venous thromboembolic disease and some hypercoagulable states. Those patients who undergo percutaneous coronary intervention (PCI) and who have an indication for long-term OAC present a clinical dilemma in relation to their antithrombotic therapy – should they be treated with DAPT and OAC (‘triple therapy’), a regimen which is effective at the prevention of thrombotic events but which is associated with an increased risk of bleeding;1–4 should OAC be deferred in order to reduce the risk of bleeding but at the increased risk of systemic arterial or venous thrombotic events;5 or should the duration of DAPT be curtailed in order to reduce the risk of bleeding but with the potential increased risk of stent thrombosis? The advent of non-vitamin K antagonist oral anticoagulants (NOACs) and the increasing use of prasugrel and ticagrelor in patients who undergo PCI following an acute coronary syndrome (ACS) has further complicated clinical decision-making. This article aims to provide a summary of the evidence regarding antithrombotic therapy following PCI for patients who have an indication for OAC with a focus on recent randomised trials, which have influenced clinical practice in this area.

an approximate rate of 0.1–0.4 % per year.6 Stent thrombosis is associated with a mortality rate of up to 45 %.7 Platelet activation consequent to atheromatous plaque disruption during coronary angioplasty and stent deployment is one of the main mechanisms underlying stent thrombosis. Delayed stent strut epithelialisation and reactions to polymer are important mechanisms in cases of late drug-eluting stent (DES) thrombosis. Dual antiplatelet therapy is central to the prevention of stent thrombosis. Historical randomised trials showed a lower rate of stent thrombosis and of bleeding complications in patients who were treated with aspirin and ticlopidine than in patients who received aspirin and OAC.8–11 Ticlopidine use was associated with the common occurrence of side effects and blood dyscrasias, so aspirin and clopidogrel emerged as the standard post-PCI prophylaxis against stent thrombosis once trial data suggested equivalent efficacy for these two DAPT regimens.12 DAPT is required for four weeks after the deployment of a bare metal stent (BMS). Concerns regarding the incidence of late stent thrombosis in patients who were treated using first generation DES have largely dissipated with modifications in stent design and polymer technology.13 Nevertheless, it is usual for DAPT to be taken for at least 6–12 months after second or third generation DES use. Premature discontinuation of DAPT is the most consistent predictor of stent thrombosis.7

Antiplatelet Therapy to Prevent Coronary Artery Stent Thrombosis

Vitamin K Antagonists

Stent thrombosis is an infrequent but serious complication following PCI. Stent thrombosis within one month of PCI occurs with a frequency of 0.2–0.8 %, while stent thrombosis more than one month after PCI occurs at

Archbold_FINAL.indd 16

Oral Anticoagulation for Stroke Prevention in Patients with Atrial Fibrillation AF is the most common indication for long-term OAC. AF affects up to 2 % of the general population and as many as 15 % of octogenarians.14–16 Blood stasis within the non-contractile left atrium predisposes these subjects to thromboembolic cerebral infarction,

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Antithrombotic Therapy After PCI in Patients Who Require OAC

with an average annual stroke rate of about 5 % in non-valvular AF.17 OAC with a vitamin K antagonist (VKA) such as warfarin is highly effective at reducing the risk of stroke in patients with AF. In a meta-analysis of 29 studies, which included 28,044 patients, for example, VKA therapy was associated with a 67 % relative reduction in the rate of ischaemic stroke.18 Warfarin is substantially more effective than aspirin, which reduced the risk of stroke in patients with AF by 22 % in placebo-controlled trials.18,19 Warfarin is also considerably more effective than DAPT at preventing stroke in patients with AF. Atrial Fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W) was stopped early when a clear significant result was demonstrated between patients who were randomly allocated to VKA therapy compared with aspirin and clopidogrel, with an annual rate of stroke, systemic embolus, myocardial infarction (MI) or vascular death of 3.9 % in the VKA group compared with 5.6 % in the DAPT group.5 ACTIVE-A subsequently showed that aspirin and clopidogrel was superior to aspirin alone for stroke prevention in patients with AF with a relative risk reduction of 28 %.20 Discontinuation of OAC in patients with AF, even temporarily, is associated with an increased stroke risk.5

Non-vitamin K Antagonist Oral Anticoagulants NOACs such as the direct thrombin inhibitor, dabigatran and the factor Xa inhibitors, rivaroxaban and apixaban, have recently emerged as alternatives to warfarin for stroke prevention in patients with AF. When compared with a VKA in randomised trials, dabigatran 150 mg twice daily reduced the risk of stroke,20 dabigatran 110 mg twice daily reduced the rate of major bleeding,20 apixaban reduced the rate of mortality, stroke and major bleeding,21 and all three agents were associated with a lower rate of intracerebral haemorrhage.21–23 Furthermore, their use has practical advantages, which include fixed dosing, no need for blood test monitoring and fewer drug interactions when compared with warfarin. These data form the evidence base for current clinical practice regarding stroke prevention in patients with AF. The balance between benefit and risk from OAC should be assessed through formal stratification of stroke risk using the CHA2DS2-VASc score (see Table 1) and the bleeding risk using the HAS-BLED score.24,25 Stroke risk is very low in men with a CHA2DS2-VASC score of 0 and in women with a CHA2DS2VASc score of 1. A HAS-BLED score ≥3 is associated with an elevated risk of bleeding in patients taking OAC. Nevertheless, most patients with AF should be treated with OAC to lower their risk of stroke.24 Aspirin monotherapy is not recommended for the prevention of stroke in patients with AF.26 DAPT should only be considered for this purpose in patients who refuse to take OAC or in whom there is a clear contraindication to OAC and the bleeding risk is low.24

Antithrombotic Therapy Following Percutaneous Coronary Intervention for Patients with an Indication for Oral Anticoagulation Nearly 10 % of patients who undergo PCI have an indication for longterm OAC.27 Coronary artery disease which requires PCI is present in more than 20 % of patients with AF.28 There are currently no definitive randomised trial data to guide decision-making regarding antithrombotic regimens following PCI for these patients. The inferior efficacy of OAC compared with DAPT for the prevention of stent thrombosis and the converse situation in relation to stroke prevention in patients with AF has led to the assumption that all three antithrombotic agents are required in order to achieve an acceptably low rate of adverse cardiac and cerebral events after PCI in patients who have AF.

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Table 1: CHA2DS2-VASc Score and Annual Stroke Rates CHA2DS2-VASC Score 0

Adjusted Annual Stroke Rate 0%

1.3 %

2.2 %

3.2 %

4.0 %

6.7 %

9.8 %

9.6 %

6.7 %

15.2 %

Modified from the European Society of Cardiology guidelines for the management of atrial fibrillation.24

Triple Antithrombotic Therapy – Rates of Vascular Events and Bleeding The combination of all three antithrombotic agents after PCI might be expected to minimise the risk of both stroke and stent thrombosis but it would also be expected to increase bleeding rates. Data from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE) registry showed that approximately one-third of patients with ACS who were established on OAC at hospital admission had their OAC discontinued when DAPT was started following PCI.29 It seems likely that this practice related to concerns regarding the risk of bleeding with triple therapy. In the absence of randomised trials in this area, information regarding clinical outcomes for patients who have received triple therapy come from observational studies. A recent meta-analysis of nine studies, which included 1,996 patients requiring OAC who underwent PCI, compared clinical outcomes in those who received triple therapy with those who received DAPT.30 In this analysis, triple therapy was associated with a lower rate of cardiac death, MI, stent thrombosis or target lesion revascularisation (odds ratio [OR] 0.60; 95 % confidence interval [CI] 0.42–0.86; p=0.005) and all-cause mortality (OR 0.59; 95 % CI 0.39–0.90; p=0.01) compared with DAPT. Major bleeding in the first six months after PCI, however, was significantly more common (4.1 versus 1.9 %; p=0.04) in patients who received triple therapy than DAPT (OR 2.12; 95 % CI 1.05–4.29). In registries of patients who received triple therapy after PCI, the rate of major bleeding or need for blood transfusion ranged from approximately 5 % early after PCI to more than 10 % at 12 months.1–4 In a nationwide Danish registry of 11,480 patients with AF who were admitted for MI or PCI between 2001 and 2009, bleeding requiring hospital admission was significantly more frequent (14.2 events per 100 person-years) in patients who received triple therapy than in patients who received DAPT or OAC plus either aspirin or clopidogrel (9.7 versus 7.0 versus 6.9 events per 100 person-years, respectively).31 Furthermore, the bleeding risk was front-loaded with a hospital admission rate higher than 20 % in the first 90 days after PCI in patients who received triple therapy. In the post hoc analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, the rate of major bleeding after PCI for acute MI during the index hospital admission was 17.1 % in patients treated with triple therapy compared with 6.5 % in patients who received DAPT (p<0.0001).32 Major bleeding or the need for blood transfusion after PCI is associated with increased mortality.33 Minor bleeding complicates clinical management and may

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Coronary Adjunctive Pharmacotherapy lead to discontinuation of OAC or DAPT with consequent loss of their protective effect against thrombotic vascular events.5,7 It is desirable to limit the duration of triple therapy as much as possible, particularly in patients who are at high risk of bleeding. In patients who require OAC, this can only be achieved by curtailing the period of DAPT.

Limiting the Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention BMS use affords the opportunity to limit the duration of triple therapy to one month after PCI in patients who require OAC. However, there are well-founded reasons why DES use might be preferable to BMS use in some patients who require OAC. The use of DES more than halves the requirement for repeat revascularisation compared with BMS use. Minimising the requirement for repeat invasive procedures is particularly desirable in patients who are taking OAC. Those patients who are at high risk of restenosis are likely to benefit most from DES use. Several randomised controlled trials have now been published, which compared clinical outcomes in patients who received limited duration or standard duration DAPT after PCI using DES. In the REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation (RESET) trial, 2,117 patients who underwent PCI using the Endeavor® zotarolimus eluting stent (ZES) (Medtronic Inc, Minneapolis, Minnesota, US) were randomly assigned to receive either three months or 12 months DAPT after the procedure.34 The primary endpoint of cardiovascular death, MI, stent thrombosis, target vessel revascularisation (TVR) or bleeding at one-year occurred in 4.7 % patients in each group (p<0.0001 for non-inferiority of three months compared with 12 months DAPT). The rates of death, MI or stent thrombosis were 0.8 versus 1.3 % (p=0.48) and of stent thrombosis were 0.2 versus 0.3 % (p=0.65), respectively, in patients who received three months compared with 12 months DAPT. There were no cases of stent thrombosis after three months in the limited duration DAPT group. The Optimized duration of Clopidogrel Therapy Following Treatment with the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial was of similar design, involving the random allocation of more than 3,000 patients undergoing PCI with ZES to receive either three months or 12 months DAPT.35 At one-year the rate of the primary endpoint (a composite of all-cause mortality, MI, stroke and major bleeding) was 6.0 % in the three-month DAPT group compared with 5.8 % in the 12-month DAPT group (p=0.002 for non-inferiority of three months versus 12 months DAPT). One-year rates of major adverse cardiac events were similar between groups (8.3 versus 7.4 %, respectively; hazard ratio [HR] 1.12; 95 % CI 0.87–1.45). Nor were there significant differences between groups in the rates of the primary net clinical benefit endpoint, major adverse cardiac events or stent thrombosis that occurred between three and 12 months. The Resolute ZES (Medtronic Inc, Minneapolis, Minnesota, US) has CE Mark approval for only one month of DAPT following deployment. This was granted after analysis of a cohort of 4,896 patients who received this stent showed that the rate of stent thrombosis was very low (0.11 %) among the 903 patients whose DAPT was interrupted more than one month (and less than 12 months) following PCI.36 This rate was no higher than the 0.84 % rate of stent thrombosis observed among the 3,827 patients whose DAPT was uninterrupted, and it was significantly lower than the rate of 3.61 % in the 166 patients whose DAPT was interrupted within one month of stent deployment (p<0.001). In this cohort, DAPT was interrupted for >14 days in 874

Archbold_FINAL.indd 18

patients. All six cases of stent thrombosis occurred in the 122 patients whose DAPT was interrupted within the first month of therapy while there were no cases of stent thrombosis among the 752 patients whose DAPT was interrupted between one and 12 months after PCI. The rate of cardiac death or target vessel MI was 6.84 % among patients whose DAPT was interrupted for >14 days within one month of PCI, 1.41 % when DAPT was interrupted for >14 days between one and 12 months after PCI and 4.08 % in the 4,071 patients whose DAPT was not interrupted for >14 days.

Is Dual Antiplatelet Therapy Necessary After Percutaneous Coronary Intervention in Patients Taking Oral Anticoagulation? The question of whether or not DAPT (and thereby triple antithrombotic therapy in patients who require OAC) is needed at all following PCI was investigated in the What is the Optimal antiplatElet therapy in patients with oral anticoagulation and coronary StenTing (WOEST) trial.37 In this trial, 573 patients who were receiving OAC with a VKA and who underwent PCI were randomly assigned to clopidogrel and OAC or to triple therapy. The primary endpoint of any bleeding event within one year of PCI occurred significantly less frequently in patients in the clopidogrel and OAC group compared with the triple therapy group (19.4 versus 44.4 %; HR 0.36 [95 % CI 0.26–0.50]; p<0.0001). The secondary endpoint, a composite of death, MI, stent thrombosis, stroke or TVR, was also significantly reduced in patients taking clopidogrel and OAC compared with triple therapy (11.1 versus 17.6 %; HR 0.60 [95 % CI 0.38–0.94]; p=0.025). The omission of aspirin therefore led to a greater than 50 % reduction in bleeding without a detectable increase in adverse cardiovascular events. These results suggest that triple therapy may be unnecessary following PCI for patients who are treated with OAC. Before applying the findings of the WOEST trial to routine clinical practice, several observations should be made about its methodology and results. The trial medication was administered in open label fashion, which might have introduced bias into the results. Most of the bleeding episodes were ‘minor’ or ‘moderate’ in severity depending upon the bleeding event classification used. There were relatively low rates of radial artery access and proton pump inhibitor use, which might have mitigated against lower bleeding rates. Importantly, the WOEST trial was not adequately powered to demonstrate non-inferiority for the composite secondary endpoint of cardiovascular events. On the other hand, the bleeding events committee were blinded to treatment allocation; the difference in bleeding events between groups was accounted for by lower rates in the clopidogrel and OAC group of overt haemorrhage causing a drop in haemoglobin concentration of 3–5 g/dL or a drop in haemoglobin concentration of >4 g/dL without overt haemorrhage (Thrombolysis In Myocardial Infarction [TIMI] minor bleeding) and by a lower rate of blood transfusions (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] study moderate bleeding), events well worth avoiding; and there was no trend towards higher rates of stent thrombosis in patients who received clopidogrel and OAC compared with triple therapy, with rates of any stent thrombosis of 1.4 versus 3.2 %, definite stent thrombosis 0.4 versus 1.1 %, probable stent thrombosis 0 versus 0.7 % and possible stent thrombosis 1.1 versus 1.4 %, respectively. Indeed, the significantly lower rate of cardiovascular events in the clopidogrel and OAC group makes it unlikely that a clinically meaningful excess of cardiovascular events arises from omitting aspirin after PCI in patients who are taking

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Antithrombotic Therapy After PCI in Patients Who Require OAC

Table 2: Recommendations from the European Society of Cardiology for Antithrombotic Therapy After Percutaneous Coronary Intervention in Patients with an Indication for Oral Anticoagulation Recommendations In patients with a firm indication for OAC (e.g. AF with CHA2DS2-Vasc score >2, venous thromboembolism,

Class and Level of Evidence IC

LV thrombus or mechanical valve prosthesis), OAC is recommended in addition to antiplatelet therapy. New-generation DES are preferred over BMS among patients requiring OAC if bleeding risk is low (HAS-BLED <2).

IIa C

In patients with SCAD and AF with CHA2DS2-Vasc score >2 at low bleeding risk (HAS-BLED <2), initial triple therapy

IIa C

of (N)OAC and aspirin* and clopidogrel** should be considered for a duration of at least one month after BMS or new-generation DES followed by dual therapy with (N)OAC and aspirin or clopidogrel continued up to 12 months. DAPT should be considered as alternative to initial triple therapy for patients with SCAD and AF with a CHA2DS2-VASc score <1.

IIa C

In patients with ACS and AF at low bleeding risk (HAS-BLED <2), initial triple therapy of (N)OAC and aspirin and clopidogrel

IIa C

should be considered for a duration of six months irrespective of stent type followed by (N)OAC and aspirin or clopidogrel continued up to 12 months. In patients requiring OAC at high bleeding risk (HAS-BLED >3), triple therapy of (N)OAC and aspirin and clopidogrel should

IIa C

be considered for a duration of one month followed by (N)OAC and aspirin or clopidogrel irrespective of clinical setting (SCAD or ACS) and stent type (BMS or new-generation DES). Dual therapy of (N)OAC and clopidogrel may be considered as an alternative to initial triple therapy in selected patients.

IIb B

The use of ticagrelor and prasugrel as part of initial triple therapy is not recommended.

III C

revascularisation.47

Modified from the European Society of Cardiology guidelines on myocardial *All doses of aspirin 75–100 mg per day. **All doses of clopidogrel 75 mg per day. ACS = acute coronary syndrome; AF = atrial fibrillation; BMS = bare metal stent; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; LV = left ventricular; (N)OAC = (non-vitamin K) antagonist oral anticoagulation; SCAD = stable coronary artery disease.

clopidogrel and OAC. Furthermore, these findings are consistent with an analysis of 12,165 patients with AF hospitalised for MI or PCI in the Danish registry referred to earlier in which one-year rates

with DAPT after ACS. In this study, the combination of DAPT with rivaroxaban 20 mg daily, its usual dose for stroke prevention in AF, rates of TIMI major and TIMI minor bleeding within six months were

of cardiovascular events and all-cause mortality were compared in patients who received different antithrombotic regimens.38 Rates of MI or cardiovascular death, stroke and all-cause mortality were similar in patients who were treated with the combination of clopidogrel and OAC with a VKA compared with triple therapy. By contrast, the ischaemic stroke rate was significantly higher in patients who were treated with DAPT (aspirin and clopidogrel) and all-cause mortality was significantly higher in patients who were treated with DAPT or with aspirin and OAC. Taken together, these data suggest that clopidogrel and OAC is at least as effective and as safe as triple therapy.

low at 1.8 and 0.9 %, respectively, but the rate of bleeding requiring medical attention at 180 days was 14.3 %.40 In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RELY) study, which defined the relative efficacy and safety of dabigatran 110 mg twice daily, dabigatran 150 mg twice daily and warfarin for stroke prevention in AF, 38 % of the 18,113 patients also received antiplatelet therapy during the study period. The rate of bleeding was significantly higher in patients who took OAC plus one antiplatelet agent than in patients who took OAC only and was highest in patients who took OAC and DAPT irrespective of the OAC used. However, the rate of bleeding was lowest for patients who took dabigatran 110 mg twice daily, whether they were taking OAC only, OAC plus one antiplatelet agent or OAC plus DAPT.41 NOAC-based triple therapy has not yet been compared with warfarin-based triple therapy in a randomised trial. Further research is needed to define whether or not NOAC or warfarin is the preferred OAC for patients who require OAC following PCI.

Potential Future Antithrombotic Strategies with a Limited Evidence Base Non-vitamin K Antagonist Oral Anticoagulant-based Antithrombotic Therapy Dabigatran, apixaban and rivaroxaban were associated with significantly lower rates of intracranial haemorrhage than warfarin in randomised trials of stroke prevention in patients with AF,21–23 while dabigatran at a dose of 110 mg twice daily22 and apixaban also significantly reduced the rate of major bleeding compared with VKA.21 These data combined with the more predictable pharmacokinetic and pharmacodynamic profile of NOACs compared with VKAs raise the prospect of triple therapy or dual therapy (NOAC and clopidogrel) regimens, which carry a lower risk of bleeding than warfarin-containing regimens. Insights into the risk of bleeding with NOAC-based triple therapy come from studies, which have investigated the combination of a NOAC with DAPT to reduce ischaemic cardiac events in patients following ACS. In the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis In Myocardial Infarction (ATLAS ACS 2-TIMI 51) study, the addition of low dose rivaroxaban (either 2.5 mg or 5 mg twice daily) to DAPT reduced the composite endpoint of cardiac death, MI and stroke after ACS but increased the rate of major bleeding and of intracranial bleeding.39 The ATLAS ACS 2-TIMI 46 study was designed to assess the safety and efficacy of various doses of rivaroxaban in combination

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Archbold_FINAL.indd 19

Antithrombotic Combination Therapy Incorporating New Antiplatelet Agents About 20 % of patients who undergo PCI achieve inadequate inhibition of platelet function from clopidogrel therapy.42 These clopidogrel non-responders experience higher rates of cardiovascular events than clopidogrel responders. Prasugrel and ticagrelor are newer, more potent antiplatelet agents than clopidogrel, which are being used with increasing frequency after ACS. Prasugrel is a potent thienopyridine, which has less inter-individual variation in platelet inhibition than clopidogrel. In the Trial to Assess Improvements in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel - Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38), prasugrel and aspirin was superior to clopidogrel and aspirin in reducing adverse cardiac events (primarily MI and stent thrombosis) following an ACS.43 The increased efficacy of prasugrel came at the expense of significantly increased rates of major bleeding, including life-threatening bleeding. In the only published registry of patients taking triple therapy comprising aspirin, prasugrel

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Coronary Adjunctive Pharmacotherapy and warfarin (used in 21 patients), this regimen was associated with a more than fourfold increase in bleeding (28.6 versus 6.7 %; p<0.001) without any difference in efficacy when compared with aspirin, clopidogrel and warfarin (taken in 356 patients).44 Ticagrelor is a direct-acting, reversible inhibitor of the platelet P2Y12 receptor. Like prasugrel, it provides more consistent inhibition of platelet function than clopidogrel. In the Study of Platelet Inhibition and Patient Outcomes (PLATO), patients with ACS who were randomly allocated to receive the combination of ticagrelor and aspirin experienced lower rates of recurrent MI and of all-cause mortality than patients who were randomly allocated to receive clopidogrel and aspirin.45 There was no significant difference in rates of major bleeding between the ticagrelor and clopidogrel groups (11.6 versus 11.2 %, respectively; p=0.4). There are currently no data, which describe the efficacy and safety of ticagrelor-based triple therapy. In PLATO, for instance, the study medication was stopped if OAC was administered. However, a recently published small Swedish study described outcomes among 107 patients with ACS who were discharged taking a combination of ticagrelor and warfarin and compared them to a historical control group of 159 patients with a similar baseline bleeding risk who were discharged taking aspirin, clopidogrel and warfarin.46 Rates of major bleeding and of ischaemic events (a composite of stroke or TIA, arterial embolism and recurrent ACS) at three months were not significantly different (7.5 versus 7.0 % and 4.7 versus 3.2 %, respectively) in patients taking ticagrelor and warfarin compared with triple therapy. Further data are required before firm recommendations can be made regarding combinations of antithrombotic therapy, which include OAC and prasugrel or ticagrelor.

Current Guidelines The use of triple therapy in patients after PCI is determined by the strength of their indication for OAC. The 2014 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularisation recommend

1. Khurram Z, Chou E, Minutello R, et al., Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding, J Invasive Cardiol, 2006;18:162–4. 2. Manzano-Fernández S, Pastor FJ, Marín F, et al., Increased major bleeding complications related to triple antithrombotic therapy usage in patients with atrial fibrillation undergoing percutaneous coronary artery stenting, Chest, 2008;134:559–67. 3. Orford J, Fasseas P, Melby S, et al., Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation, Am Heart J, 2004;147:463–7. 4. Rogacka R, Chieffo A, Michev I, et al., Dual antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients taking chronic oral anticoagulation, JACC Cardiovasc Interv, 2008;1:56–61. 5. Connolly S, Pogue J, Hart R, et al., Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial, Lancet, 2006;367:1903–12. 6. Palmerini T, Kirtane AJ, Serruys PW, et al., Stent thrombosis with everolimus-eluting stents: meta-analysis of comparative randomized controlled trials, Circ Cardiovasc Interv, 2012;5:357–64. 7. Iakovou I, Schmidt T, Bonizzoni E, et al., Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, JAMA, 2005;293:2126–30. 8. Bertrand ME, Legrand V, Boland J, et al., Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study, Circulation, 1998;98:1597–603. 9. Leon MB, Baim DS, Popma JJ, et al., A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis

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that triple therapy should be used in patients with AF who have a CHA2DS2-VASc score >2, mechanical heart valves, intracardiac thrombus or recent or recurrent venous thromboembolism (see Table 2).47 They recommend that decisions regarding stent type (DES or BMS) and duration of triple therapy are made after formal assessment of the bleeding risk using the HAS-BLED score. Patients who are at low risk of bleeding (HAS-BLED score ≤2) should be treated using new-generation DES in preference to BMS, since these patients are likely to tolerate a longer period of triple therapy than other patients. By contrast, it is recommended that the duration of triple therapy should not exceed one month in patients who have a high bleeding risk (HAS-BLED score >3). In these patients, the choice of stent (DES or BMS) should be decided on an individual basis, and OAC and clopidogrel may be considered as an alternative to triple therapy.

Conclusion The optimal antithrombotic regimen following PCI in patients who require OAC is yet to be determined. The different balance in individual patients between their risk of arterial or venous thrombotic events, stent thrombosis and bleeding means that there is unlikely to be a single antithrombotic regimen of choice for all patients who have an indication for OAC after PCI. Current guidelines recommend triple therapy comprising aspirin, clopidogrel and either warfarin or a NOAC in the post-procedure period for all patients who have a clear indication for OAC in order to reduce their risk of stent thrombosis and thrombotic arterial or venous events. However, this regimen is associated with a high rate of bleeding complications. Recently published trials suggest that DAPT (and thereby triple therapy in patients who require OAC) can be limited safely to three months, and potentially to one month, following the deployment of new-generation DES without an excess risk of stent thrombosis. Furthermore, triple therapy may be unnecessary, the combination of OAC plus clopidogrel (without aspirin) providing similar protection against stroke and stent thrombosis but with a significant reduction in bleeding compared with triple therapy in one randomised trial. n

Study Investigators, N Engl J Med, 1998;339:1665–71. 10. Schühlen H, Hadamitzky M, Walter H, et al., Major benefit from antiplatelet therapy for patients at high risk for adverse cardiac events after coronary Palmaz-Schatz stent placement: analysis of a prospective risk stratification protocol in the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, Circulation, 1997;95:2015–21. 11. Urban P, Macaya C, Rupprecht HJ, et al., Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS), Circulation, 1998;98:2126–32. 12. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, Doubleblind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS), Circulation, 2000;102:624–9. 13. Tada T, Byrne RA, Simunovic I, et al., Risk of stent thrombosis among bare-metal stents, first-generation drugeluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients, JACC Cardiovasc Interv, 2013;6:1267–74. 14. Go AS, Hylek EM, Phillips KA, et al., Implications of stroke risk criteria on the anticoagulation decision in nonvalvular atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study, Circulation, 2000;102:11–3. 15. Heeringa J, van der Kuip DA, Hofman A, et al., Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study, Eur Heart J, 2006;27:949–53. 16. Stewart S, Hart C, Hole D, Mcmurray J, Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study, Heart, 2001;86:516–21. 17. Fuster V, Rydén LE, Cannom DS, et al., ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to

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Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society, Circulation, 2006;114:e257–354. Hart RG, Benavente O, McBride R, Pearce LA, Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis, Ann Intern Med, 1999;131:492–501. van Walraven C, Hart RG, Singer DE, et al., Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis, JAMA, 2002;288:2441–8. Connolly SJ, Pogue J, Hart RG, et al., Effect of clopidogrel added to aspirin in patients with atrial fibrillation, N Engl J Med, 2009;360:2066–78. Granger CB, Alexander JH, McMurray JJ, et al., Apixaban versus warfarin in patients with atrial fibrillation, N Engl J Med, 2011;365:981–92. Connolly SJ, Ezekowitz MD, Yusuf S, et al., Dabigatran versus warfarin in patients with atrial fibrillation, N Engl J Med, 2009;361:1139–51. Patel MR, Mahaffey KW, Garg J, et al., Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, N Engl J Med, 2011;365:883–91. Camm AJ, Kirchhof P, Lip GY, et al., Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC), Eur Heart J, 2010;31:2369–429. Pisters R, Lane DA, Nieuwlaat R, et al., A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey, Chest, 2010;138:1093–100. National Institute for Health and Care Excellence 2014. Atrial fibrillation: the management of atrial fibrillation. CG 180. Available at: www.nice.org.uk/guidance/cg180/evidence/ cg180-atrial-fibrillation-update-full-guideline3 (accessed 2 January 2015). Karjalainen PP, Porela P, Ylitalo A, et al., Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting, Eur Heart J, 2007;28:726–32. Lip GY, Huber K, Andreotti F, et al., Management of

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antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting, Thromb Haemost, 2010;103:13–28. Wang TY, Robinson LA, Ou FS, et al., Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry, Am Heart J, 2008;155:361–8. Zhao HJ, Zheng ZT, Wang ZH, et al., “Triple therapy” rather than “triple threat”: a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment, Chest, 2011;139:260–70. Lamberts M, Olesen JB, Ruwald MH, et al., Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study, Circulation, 2012;126:1185–93. Nikolsky E, Mehran R, Dangas GD, et al., Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial), Am J Cardiol, 2012;109:831–8. Doyle BJ, Rihal CS, Gastineau DA, Holmes DR Jr, Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice, J Am Coll Cardiol, 2009;53:2019–27.

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34. Kim BK, Hong MK, Shin DH, et al., A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation), J Am Coll Cardiol, 2012;60:1340–8. 35. Feres F, Costa RA, Abizaid A, et al., Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial, JAMA, 2013;310:2510–22. 36. Silber S, Kirtane AJ, Belardi JA, et al., Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation, Eur Heart J, 2014;35:1949–56. 37. Dewilde WJ, Oirbans T, Verheugt FW, et al., Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial, Lancet, 2013;381:1107–15. 38. Lamberts M, Gislason GH, Olesen JB, et al., Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention, J Am Coll Cardiol, 2013;62:981–9. 39. Mega JL, Braunwald E, Wiviott SD, et al., Rivaroxaban in patients with a recent acute coronary syndrome, N Engl J Med, 2012;366:9–19. 40. Mega JL, Braunwald E, Mohanavelu S, et al., Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial, Lancet, 2009;374:29–38.

41. Dans AL, Connolly SJ, Wallentin L, et al., Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, Circulation, 2013;127:634–40. 42. Snoep JD, Hovens MM, Eikenboom JC, et al., Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis, Am Heart J, 2007;154:221–31. 43. Wiviott SD, Braunwald E, Mccabe CH, et al., Prasugrel versus clopidogrel in patients with acute coronary syndromes, N Engl J Med, 2007;357:2001–15. 44. Sarafoff N, Martischnig A, Wealer J, et al., Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation, J Am Coll Cardiol, 2013;61:2060–6. 45. Wallentin L, Becker RC, Budaj A, et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med, 2009;361:1045–57. 46. Braun OÖ, Bico B, Chaudhry U, et al., Concomitant use of warfarin and ticagrelor as an alternative to triple antithrombotic therapy after an acute coronary syndrome, Thromb Res, 2015;135:26–30. 47. Windecker S, Kolh P, 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.

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LE ATION.

Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention Eric W Holroyd, 1 Ahmad HS Mustafa, 2 Chee W Khoo, 1 Rob Butler, 1 Douglas G Fraser, 2 Jim Nolan 1 and Mamas A Mamas 2,3 1. Department of Cardiology, University Hospital North Staffordshire, Stoke-on-Trent; 2. Manchester Heart Centre, Manchester Royal Infirmary, Central Manchester University Hospitals NHS Trust, Manchester; 3. The Farr Institute, University of Manchester, Manchester, UK

Abstract Advances in anti-thrombotic and anti-platelet therapies have improved outcomes in patients undergoing percutaneous coronary interventions (PCIs) through a reduction in ischaemic events, at the expense of peri-procedural bleeding complications. These may occur through either the access site through which the PCI was performed or through non-access-related sites. There are currently over 10 definitions of major bleeding events consisting of clinical events, changes in laboratory parameters and clinical outcomes, where different definitions will differentially influence the reported incidence of major bleeding events. Use of different major bleeding definitions has been shown to change the reported outcome of a number of therapeutic strategies in randomised controlled trials but as yet a universal bleeding definition has not gained widespread adoption in assessing the efficacy of such therapeutic interventions. Major bleeding complications are independently associated with adverse mortality and major adverse cardiovascular event (MACE) outcomes, irrespective of the definition of major bleeding used, with the worst outcomes associate with non-access-site related bleeds. We consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies, including access site choice, pharmacological considerations and formal bleeding risk assessment to minimise such bleeding events.

Keywords Percutaneous coronary intervention (PCI), haemorrhage, peri-procedural bleeding complications, mortality, adverse outcomes Disclosure: The authors have no conflicts of interest to declare. Received: 26 November 2014 Accepted: 29 January 2015 Citation: Interventional Cardiology Review, 2015;10(1):22–5 Correspondence: EW Holroyd, Consultant Cardiologist, University Hospital of North Staffordshire, City General Hospital, Stoke-on-Trent, UK. E: eric.holroyd@uhns.nhs.uk

Major bleeding or haemorrhage following a percutaneous coronary intervention (PCI) is not a benign event. There is now convincing evidence that it independently predicts increased mortality and adverse outcomes in patients.1,2 The adverse outcomes associated with a bleeding event are not just as a direct result of the haemorrhagic event, such as whether or not a patient survives their gastrointestinal (GI) or intracranial haemorrhage, but are seen in the subsequent progress of the patient up to at least one year after the event. Herein, we discuss the recent data on post-PCI bleeding and the difficulties in comparing different studies with different methodologies and definitions of major haemorrhage. We then consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies to minimise such bleeding events.

thrombolysis of STEMI and relied predominantly on laboratory measures, such as haemoglobin. Over time the TIMI definition has evolved to encompass more bleeding complications to reflect modern practice and require clinical, or radiographic, evidence of actual blood loss.8,9 However, the TIMI definition is still biased to identify acute and very severe bleeds and there can be uncertainty about when peak and trough haemoglobin level should be measured. Other criticisms include the nomenclature. A TIMI ‘minor’ bleed can have a haemoglobin drop of 3–5g/l, which is not minor and indeed could have life-threatening consequences. Recent consensus statements by the Bleeding Academic Research Consortium (BARC) have tried to standardise bleeding definitions, but the success of this endeavour will only be judged in time.15

Importance of Definition

The definition of peri-procedural major bleed used can eliminate the effect of a given therapeutic intervention and thereby influence the outcome of a study. The RIVAL trial,16 a landmark, multicentre trial comparing radial and femoral PCI, did not demonstrate a significant difference in non-coronary artery bypass grafting (CABG) related major bleeding, as defined by the study. RIVAL defined major bleeding as either: fatal, requiring transfusion of 2 or more units, causing hypotension requiring inotropes, requiring surgery, leading to disability, intracranial bleeding or a drop of >50 g/l of haemoglobin. However, using a broader definition of major bleeding, such as the

Major bleeding rates in modern PCI practice are highly variable in the published literature. They range from less than 1 % to nearly 10 % in PCI for ST-elevation myocardial infarction (STEMI). This is dependent on a number of procedural factors but also importantly on the definition of major haemorrhage the study uses.3–7 Definitions are based on a combination of laboratory and clinical factors to indicate severity (see Table 1).8–15 The Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria have been used for over 25 years. They were developed to classify major and minor haemorrhage following

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ACUITY definition,11 which includes bleeds causing large haemotomas or pseudoaneurysms requiring intervention, then radial access was associated with a significant reduction in major bleeding (odds ratio [OR] 0.43; p<0.00001) and thus the overall impact of the trial is different. It is therefore important to consider the definition of haemorrhage used in any trial related to PCI outcomes, particularly if comparison is being made between trials with different methodology. This may have a profound influence on a day-to-day practice for the clinical cardiologist and, indeed, may help influence a decision to switch from femoral to radial practice or use glycoprotein IIb/IIIa inhibitors (GPIs), based on the ‘headline’ message of a trial.

Table 1: Definitions of Major and Minor Haemorrhage Used to Classify the Severity of Bleeding following Percutaneous Coronary Intervention

TIMI8,9

GUSTO10

Different definitions of major bleeding will also have a differential impact on mortality and MACE outcomes, for example the REPLACE-2 (OR 6.69, 95 % confidence interval [CI] 2.26–19.81), STEEPLE (OR 6.59, 95 % CI 3.89–11.16) and BARC (OR 5.40, 95 % CI 1.74–16.74) had the worst prognostic impacts on mortality while HORIZONS-AMI (OR 1.51, 95 % CI 1.11–2.05) had the least impact in a recent meta-analysis.1

Clinically overt haemorrhage associated

does not meet

with a drop in haemoglobin of 5 g/dl

severe/moderate

Fatal bleeding (results in death <7 days)

criteria

Severe or life-threatening Resulting in substantial hemodynamic compromise requiring treatment Moderate Requiring blood transfusion but not resulting in haemodynamic compromise

ACUITY11

Intracranial or intraocular haemorrhage

HORIZONS12

Access site haemorrhage requiring intervention >5 cm haematoma Retroperitoneal Reduction in haemoglobin concentration of >4 g/dl without an overt source of

The risk of bleeding following PCI in a patient is increased if the patient is older, has a more acute presentation, has renal failure, heart failure or is haemodynamically compromised.21,22 These factors all predict a poorer outcome in themselves. Does bleeding postPCI independently predict poor outcome or is it a marker for other comorbidity? Previous studies, which did not account for the higher incidence of these comorbidities in patients who bled, could overestimate the impact of bleeding in the future. Indeed, following an analysis of the Global Registry of Acute Coronary Events (GRACE) data, which took account of the comorbidity, then eliminated the significance of the effect of bleeding, the authors concluded that the comorbidities associated with major bleeding accounted for the higher mortality observed.23 Our recent meta-analysis1 of 42 studies including over 500,000 patients, reported that studies that did not adjust for the incidence of confounding comorbidity in patients that bled demonstrated that major bleeding conferred a sixfold increased risk of death, which reduced to threefold once baseline covariates were adjusted for. It is therefore important to consider the confounding influence of comorbidities on the long-term impact of peri-procedural bleeding.

Minor Bleeding Mild bleeding that

Intracerebral haemorrhage

Impact of Major Bleeding Post-percutaneous Coronary Intervention Major bleeding events following a PCI are associated with adverse outcomes such as increased mortality and major adverse cardiovascular events (MACE). 17–19 Major bleeding complications account for 12.1 % of all in-hospital mortality after PCI in the National Cardiovascular Data Registry.20

Major Bleeding Any intracranial bleeding

bleeding Reduction in haemoglobin concentration of >3 g/dl with an overt source of bleeding Reoperation for bleeding Use of any blood product transfusion GRACE13,14

Requiring a transfusion of >2 units blood Resulting in a decrease in haematocrit of >10 % Intracerebral haemorrhage Resulting in stroke or death

BARC15

Type 0: No bleeding Type 1: Bleeding that is not actionable Type 2: Any actionable sign of haemorrhage not type 3, 4 or 5 but at least one of: (1) requiring non-surgical, medical intervention by a healthcare professional, (2) leading to hospitalisation or increased level of care, or (3) prompting evaluation Type 3a: Overt bleeding plus haemoglobin drop of 3 to <5 g/dl (provided haemoglobin drop is related to bleed) Any transfusion with overt bleeding Type 3b: Overt bleeding plus haemoglobin drop >5 g/dl (provided haemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control Bleeding requiring intravenous vasoactive agents

Mechanism of Effect

Type 3c: Intracranial haemorrhage

Why does bleeding have such a profound effect on outcome following PCI? Clearly in the acute setting, a GI or intracranial haemorrhage can cause fatal blood loss. Blood loss can occur from the access site, e.g. the femoral artery, or away from the access site, such as intra-cranially or in the contralateral retroperitoneal space. GI haemorrhage after PCI for acute myocardial infarction is associated independently with a prolonged hospital stay and greater mortality in-hospital and at 6-month mortality.24 Access-site-related bleeding, such as major femoral bleeding complications requiring transfusion, are also independently associated with increased 30-day mortality.25 When we compare non-access site, or systemic, bleeding with such

Subcategories confirmed by autopsy or

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imaging or lumbar puncture Intraocular bleed compromising vision Type 4: Coronary artery bypass graft -related bleeding Type 5: Fatal bleeding

access site bleeding, both are associated with increased 1-year mortality, although non-access site bleeding confers poorer prognosis and is associated with a twofold greater impact on 1-year mortality compared with access-site-related bleeding.26

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Coronary Adjunctive Pharmacotherapy Peri-procedural mortality directly due to the acute haemorrhage does not explain why the adverse outcomes are observed up to a year after the PCI. Bleeding complications may affect the long-term prognosis via several distinct mechanisms. The premature discontinuation of anti-platelet medications may increase the risk of stent thrombosis, itself an independent predictor of long-term outcome.27 Erythropoietin production is stimulated in an anaemic state following blood loss. This could contribute to a pro-thrombotic state beyond the acute phase through platelet activation and induction of plasminogen activator inhibitor-1 (PAI-1) and thus worsen prognosis.28–30 Treatment with erythropoietin in patients following STEMI has been shown to increase the composite end point of death, MI, stroke and stent thrombosis.31 Blood transfusions themselves have an adverse impact on mortality. This has been demonstrated independently of the bleeding and haematocrit 30 days after the event32,33 and with use of other blood products, such as plasma or platelets, which may be necessary following a major haemorrhage.34 For example, our recent meta-analysis of 2,258,711 patients undergoing PCI with 54,000 transfusion events demonstrated that blood transfusion was independently associated with an increase in mortality (OR 3.02, 95 % CI 2.16–4.21) and MACE (OR 3.15, 95 % CI 2.59–3.82) with similar observations recorded in studies that adjusted for baseline hematocrit, anaemia and bleeding.35 Potential mechanisms through which the long-term adverse outcome of transfusion may be

patient.39 Patients with the highest risk of bleeding, assessed in this way, gained most from a transradial route for their PCI, with a greater mortality benefit than those at a lower risk of bleeding. Paradoxically, perhaps, patients assessed as having a higher risk of bleeding were unfortunately less likely to receive a transradial PCI in this retrospective study.

mediated are thought to include, the prothrombotic effects of CD40 ligand released by platelets and inhibition of endogenous fibrinolytic systems.28,36 Furthermore, during storage, significant changes in the deformability of red blood cells, as well as changes in their shape, may predispose to ‘plugging’ of transfused cells at the microvascular level, leading to tissue ischaemia. Therefore, the adverse outcomes associated with a bleeding event are likely to relate to the site of the bleed and the acute haemorrhagic event itself, as well as the therapeutic interventions undertaken following the bleeding event, such as discontinuation of anti-platelet therapy, reversal of anticoagulants and receipt of blood transfusions.

P2Y12 agents (prasugrel and ticagrelor). The newer P2Y12 agents also improve outcomes following the percutaneous treatment of acute coronary syndrome (ACS) compared with clopidogrel, at the expense of increased bleeding risk.44,45 Fondaparinux given instead of enoxaparin to ACS patients reduces major bleeding and improves long-term mortality.46

Bleeding Avoidance Strategies Peri-procedural major bleeding complications independently predict higher mortality and poorer outcomes. The importance of avoiding such complications is increasingly apparent and strategies to achieve this need to be a fundamental part interventional practice. The radial artery should be the preferred access route for PCI to avoid access site-related bleeding events although there may be circumstances, where this may not be possible or femoral devices, such as intra-aortic balloon pumps, may be required. There is evidence that the change in practice from femoral to radial access has influenced outcome. Analysis of the UK national PCI database, comparing primary PCI outcome for STEMI, demonstrated significantly fewer access-site related bleeding complications via the radial approach, which was independently associated with a 30 % reduction in 30-day mortality whose magnitude was similar to that observed following a move from thrombolysis to primary PCI in the management of STEMI.37 Similarly, a meta-analysis of randomised controlled trials of STEMI patients receiving primary PCI demonstrates a reduction in mortality and MACEs, driven by a reduction in major bleeding in patients who had their procedure via the radial rather than femoral route.38 The magnitude of the mortality benefit seen by pursuing a default radial strategy is related to the baseline bleeding risk of an individual

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Adjuvant pharmacological agents also help determine the likelihood of major bleeding following PCI and therefore outcome. GPIs are potent antiplatelet agents effective in improving ischaemia-related outcomes in PCI,40–42 measured as reduction of a composite clinical end point (death, reinfarction or repeat revascularisation) at the price of an increased risk of major haemorrhage. An initial rise in popularity, due to this evidence, has been followed by a fall in GPI use due to their cost, the bleeding complications and data, such as the HORIZONS-AMI trial.12 HORIZONS-AMI demonstrated less major bleeding and a mortality benefit for using bivalirudin (a direct thrombin inhibitor) versus heparin and GPI. More recently, the HEAT trial43 did not show a mortality benefit or reduced major bleeding for bivalirudin and, indeed, unfractionated heparin alone had a comparable outcome to bivalirudin. The HEAT trial employed much more contemporary practice than HORIZONSAMI; well deployed, third-generation drug-eluting stents were used via a radial approach (80 %), with high use (90 %) of newer

We should tailor our procedural practices and pharmacological therapies used in PCI procedures undertaken on an individual patient basis, balancing risk of ischaemia or failure of the procedure with the risk of bleeding. Pre-procedural assessment of a patient’s bleeding risk should be part of our routine assessment of a patient. Analysis of over a million PCIs recorded in the US CathPCI registry was used to develop and validate a PCI bleeding risk prediction score and simplified bedside tool. Entering only 10 variables, such as age, sex, body mass index (BMI), renal function and pre-procedural haemoglobin level, yields a score and a percentage bleeding risk on which a clinician can act.47 Other bleeding risk scores have also been developed to predict non-CABG–related TIMI major bleeding in patients undergoing PCI in the elective and acute setting, such as the Mehran score, through a patient-level pooled analysis of the REPLACE-2, ACUITY and HORIZONS-AMI trials.21 The risk score consists of seven variables: serum creatinine level, age, sex, presentation, white blood cell count, cigarette smoking and anticoagulant agent use. While many of these scores may identify patients at risk of bleeding complications the requirement of laboratory results such as creatinine, haemoglobin levels and white blood cell count for their calculation means that they cannot be used in the highest-risk patients, such as primary, PCI or other emergent cases where such lab results may not be available at the time of the PCI. Nevertheless, a high bleeding risk score should encourage bleeding avoidance strategies, such as a transradial approach and avoidance of high bleeding risk pharmacological agents, such as GPIs. Similarly, if the femoral route is required for arterial access, care should be taken using micro-puncture techniques and ultrasound guidance and vascular closure devices considered.48

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Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention

Conclusion PCI represents a delicate balance between minimising thrombotic complications without significantly increasing haemorrhagic event rates. PCI necessitates the use of highly potent antithrombotic and anticoagulant drugs, as well as requiring arterial access and

1. Kwok CS Rao SV, Myint PK, et al., Major bleeding after percutaneous coronary intervention and risk of subsequent mortality: a systematic review and meta-analysis, Open Heart , 2014;1:e000021. 2. Chhatriwalla AK, Amin AP, Kennedy KF, et al., Association between bleeding events and in-hospital mortality after percutaneous coronary intervention, JAMA , 2013;309:1022–9. 3. Subherwal S, Peterson ED, Dai D, et al., Temporal trends in and factors associated with bleeding complications among patients undergoing percutaneous coronary intervention: a report from the National Cardiovascular Data CathPCI Registry, J Am Coll Cardiol , 2012;59:1861–9. 4. Mehta SR, Jolly SS, RIVAL Investigators, Effects of radial versus femoral artery access in patients with acute coronary syndromes with or without ST-segment elevation, J Am Coll Cardiol , 2012;60:2490–9. 5. Stone GW, Witzenbichler B, Guagliumi G, et al., Bivalirudin during primary PCI in acute myocardial infarction, N Engl J Med , 2008;358:2218–30. 6. Giugliano RP, Giraldez RR, Morrow DA, et al., Relationship between bleeding and outcomes in patients with ST-elevation myocardial infarction inthe ExTRACT-TIMI25 trial, Eur Heart J , 2010;31:2103–10. 7. Mehran R, Rao SV, Bhatt DL, et al., Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium, Circulation , 2011;123:2736–47. 8. Bovill EG, Terrin ML, Stump DC, et al., Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial, Ann Intern Med , 1991;115:256–65. 9. Mega JL BE, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM; ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial, Lancet , 2009;374:29–38. 10. Sabatine MS, Morrow DA, Giugliano RP, et al., Association of haemoglobin levels with clinical outcomes in acute coronary syndromes, Circulation , 2005;111:2042–9. 11. Amlani SNT, Afzal R, Pal-Sayal R, et al., Mortality and morbidity following a major bleed in a registry population with acute ST elevation myocardial infarction, J Thromb Thrombolysis , 2010;30:434–40. 12. Mehran R, Lansky AJ, Witzenbichler B, et al., Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial, Lancet , 2009;374:1149–1159. 13. Moscucci M, Fox KA, Cannon CP, et al., Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE), Eur Heart J , 2003;24:1815–23. 14. Spencer FA, Moscucci M, Granger CB, et al., Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction?, Circulation , 2007;116:2793–801. 15. Mehran R, Rao SV, Bhatt DL, et al., Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium, Circulation , 2011;123:2736–47. 16. Jolly SS, Yusuf S, Cairns J, et al., Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial, Lancet , 2011;377:1409–20. 17. Kinnaird TD, Stabile E, Mintz GS, et al., Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions, Am J Cardiol , 2003;92:930–5.

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instrumentation. Bleeding complications are therefore an inevitable consequence of PCI. Awareness of the predictors and importance of major peri-procedural bleeding as well as the judicious use of efficacious bleeding avoidance strategies will optimise ouctomes of PCI procedures undertaken. n

18. Manoukian SV, Feit F, Mehran R, et al., Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY trial, J Am Coll Cardiol , 2007;49:1362–8. 19. Rao SV, Eikelboom JA, Granger CB, et al., Bleeding and blood transfusion issues inpatients with non-ST-segment elevation acute coronary syndromes, Eur Heart J , 2007;28:1193e204. 20. Chhatriwalla AK, Amin AP, Kennedy KF, et al., Association between bleeding events and in-hospital mortality after percutaneous coronary intervention, AMA , 2013;309:1022–9. 21. Mehran R, Pocock S, Nikolsky E, et al., Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials, JACC Cardiovasc Interv , 2011;4:654–64. 22. Mehta SK, Frutkin AD, Lindsey JB, et al., Bleeding in patients undergoing percutaneous coronary intervention: the development of a clinical risk algorithm from the National Cardiovascular Data Registry, Circ Cardiovasc Interv , 2009;2:222–9. 23. Spencer FA, Moscucci M, Granger CB, et al., Does comorbidity account for the excess mortality in patients with major bleeding in acute myocardial infarction?, Circulation , 2007;116:2793–801. 24. Abbas AE, Brodie B, Dixon S, et al., Incidence and prognostic impact of gastrointestinal bleeding after percutaneous coronary intervention for acute myocardial infarction, Am J Cardiol , 2005;96:173–6. 25. Doyle BJ, Ting HH, Bell MR, et al., Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005, JACC Cardiovasc Interv , 2008;1:202–9. 26. Verheugt FW, Steinhubl SR, Hamon M, et al., Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention, JACC Cardiovasc Interv , 2011;4:191–7. 27. Dangas GD, Claessen BE, Mehran R, et al., Clinical outcomes following stent thrombosis occurring in-hospital versus outof-hospital: results from the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, J Am Coll Cardiol , 2012;59:1752–9. 28. Doyle BJ, Rihal CS, Gastineau DA, et al., Bleeding blood transfusion and increased mortality after percutaneous coronary intervention, J Am Coll Cardiol , 2009;53:2019–27. 29. Smith KJ, Bleyer AJ, Little WC, et al., The cardiovascular effects of erythropoietin, Cardiovasc Res, 2003;59:538–48. 30. Corwin HL, Gettinger A, Fabian TC, et al., Efficacy and safety of epoetin alfa in critically ill patients, N Engl J Med , 2007;357:965–76. 31. Najjar SS, Rao SV, Melloni C, et al., Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial, JAMA, 2011;305:1863–72. 32. Chase AJ, Fretz EB, Warburton WP, et al., Association of the arterial access site at angioplasty with transfusion and mortality: the M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg), Heart , 2008;94:1019–25. 33. Rao SV, Jollis JG, Harrington RA, et al., Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes, JAMA , 2004;292:1555–62. 34. Robinson SD, Janssen C, Fretz EB, et al., Non-red blood cell transfusion as a risk factor for mortality following percutaneous coronary intervention, Int J Cardiol , 2012;157:169–73. 35. Kwok CS, Sherwood MW, Watson SM, et al., Blood

transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: A systematic review and meta-analysis, JACC Int , 2015; in press. 36. Yacoub D, Hachem A, Theoret JF et al., Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/ p38 mitogen-activation protein kinase signaling pathway, Atherioscler Thromb Vasc Biol , 2010;30:2424–33. 37. Mamas MA, Ratib K, Routledge H, et al.; British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research, Influence of arterial access site selection on outcomes in primary percutaneous coronary intervention; are the results of randomized trials achievable in clinical practice?, JACC Int , 2013;6:698–706. 38. Mamas MA, Ratib K, Routledge H, et al., Influence of access site selection on PCI related adverse events in STEMI patients; meta-analysis of randomized controlled trials, Heart , 2012;98:303–11. 39. Mamas MA, Anderson SG, Carr M, et al., on behalf of the British Cardiovascular Intervention Society and the National Institute for Cardiovascular Outcomes Research, Baseline bleeding risk and arterial access site practice in relation to procedural outcomes following percutaneous coronary intervention, JACC , 2014;64:1554–64. 40. Brener SJ, Barr LA, Burchenal JE, et al., Randomized, placebocontrolled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators, Circulation , 1998;98:734–41. 41. Montalescot G, Barragan P, Wittenberg O, et al.; ADMIRAL Investigators, Abciximab before direct angioplasty and stenting in myocardial infarction regarding acute and longterm follow-up. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction, N Engl J Med , 2001;344:1895–903. 42. Stone GW, Grines CL, Cox DA, et al., Controlled abciximab and device investigation to lower late angioplasty complications (CADILLAC) investigators. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction, N Engl J Med , 2002;346:957–66. 43. Shahzad A, Mars C, Kemp I et al., Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial, Lancet , 2014;S0140–6736. 44. Montalescot G, Wiviott SD, Braunwald E, et al., Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38):double-blind, randomised controlled trial, Lancet , 2009;373:723–31. 45. Steg PG, James S, Harrington RA, et al., Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis, Circulation , 2010;122:31–41. 46. Yusuf S, Mehta SR, Chrolavicius S, et al., Comparison of fondaparinux and enoxaparin in acute coronary syndromes, N Engl J Med , 2006;354:1464–76. 47. Rao SV, McCoy LA, Spertus JA, et al., An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: A report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry, J Am Coll Cardiol Intv , 2013;6:897–904. 48. Gedikoglu M, Oguzkurt L, Gur S, et al., Comparison of ultrasound guidance with the traditional palpation and fluoroscopy method for the common femoral artery puncture, Catheter Cardiovasc Interv , 2013;82:1187–92.

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Coronary Adjunctive Pharmacotherapy

Contemporary Antiplatelet Strategies in the Treatment of STEMI using Primary Percutaneous Coronary Intervention Sri R av e e n Ka n d a n a n d Th o m a s W J o h n s o n Bristol Heart Institute, Bristol, UK

Abstract Reperfusion therapy for patients presenting with an acute ST-segment elevation myocardial infarction (STEMI) involves primary percutaneous coronary intervention (PPCI) and concomitant oral antiplatelet and intravenous antithrombotic pharmacotherapy. There is a conflict between the desire to reduce the time between first medical contact and coronary re-canalisation and achieving effective platelet inhibition with oral antiplatelet agents. This review outlines the currently available antiplatelet treatments, and their place within the therapeutic timeline of a patient presenting with STEMI. Additionally, we focus on current challenges associated with effective antiplatelet treatment, including acute stent thrombosis (AST), the effect of morphine, platelet function assessment and concomitant anticoagulant therapy.

Keywords Primary percutaneous coronary intervention, antiplatelet therapy, ST-elevation myocardial infarction Disclosure: Dr. Kandan has no conflicts of interest to declare. Dr. Johnson has received consultancy and speaker fees from AstraZeneca, Daiichi-Sankyo and Correvio. Received: 16 December 2014 Accepted: 4 February 2015 Citation: Interventional Cardiology Review, 2015;10(1):26–31 Correspondence: Thomas W Johnson, BSc, MBBS, MD, FRCP, Bristol Heart Institute, Upper Maudlin Street, Bristol BS2 8HW, UK. E: tom.johnson@uhbristol.nhs.uk

Antiplatelet Therapy

Clopidogrel

Current guidelines support the early administration of oral antiplatelet agents upstream of angiographic assessment and intervention.1 Aspirin is commonly given by the first medical contact and additional oral antiplatelet drugs are administered on arrival in hospital (see Figure 1).

Clopidogrel is a thienopyridine – a pro-drug requiring two cytochromep450 dependent steps to generate an active metabolite – which binds irreversibly to the P2Y12 adenosine diphosphate (ADP) receptor on platelets (see Figure 2). Genetic polymorphisms in the cytochrome P450 (CYP) enzymes can lead to lower levels of the active clopidogrel metabolite, diminished platelet inhibition and a higher rate of major adverse cardiovascular events (MACE), including stent thrombosis. Approximately 30 % of healthy subjects have been shown to be carriers of a reduced function CYP2C19 allele.5

Aspirin The efficacy of aspirin in acute ST-segment elevation myocardial infarction (STEMI) was first demonstrated in the Second International Study of Infarct Survival (ISIS-2).2 In ISIS-2, 17,187 patients were randomised within 24 hours of an acute STEMI to receive oral aspirin 160 mg/day for 30 days, intravenous streptokinase, both agents or neither drug. Compared with placebo, aspirin therapy resulted in a highly significant reduction in vascular mortality (23 % odds reduction [OR]), equivalent to streptokinase monotherapy (25 % OR). The combination of aspirin and streptokinase offered even greater benefit (42 % OR). Aspirin therapy was also associated with significant reductions in the incidence of non-fatal re-infarction (1.0 versus 2.0 %) and stroke (0.3 versus 0.6 %) with no increase in the risk of major bleeding or haemorrhagic stroke. Aspirin has excellent bioavailability and this is enhanced by use of uncoated aspirin, administered chewed or crushed to establish a high blood level quickly (time to peak concentration [Tmax] 20–30 minutes).3 Interestingly, there is a significant geographic variation in the dosing of aspirin. In Europe, the recommended oral loading dose is 150–300 mg (or intravenous [i.v.] 80–150 mg) followed by 75–100 mg by mouth (p.o.) daily.1 US STEMI guidelines recommend 162–325 mg loading followed by 81–325 mg daily.4

Johnson_FINAL.indd 26

Use of clopidogrel in STEMI patients has evolved from initial trials in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) (Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial [PCI-CURE])6 and patients with STEMI treated with fibrinolysis before PCI (PCI-clopidogrel as adjunctive reperfusion therapy trial [PCI-CLARITY]).7 In PCI-CURE, ACS patients undergoing PCI benefited from combined treatment with clopidogrel and aspirin, achieving a 31 % reduction in cardiovascular death and MI at 30 days. In PCI-CLARITY, clopidogrel pre-treatment in STEMI patients undergoing fibrinolysis led to a 46 % reduction in the 30-day rate of cardiovascular death, recurrent MI or stroke compared with placebo, without an increase in bleeding. The recommended clopidogrel loading dose in STEMI patients is 600 mg. Results from the Intracoronary stenting and antithrombotic regimen: Choose between 3 high oral doses for immediate clopidogrel effect (ISAR-CHOICE) trial8 showed that in patients undergoing PCI, loading with 600 mg of clopidogrel (compared with 300 mg) resulted in higher plasma concentrations of the active metabolite and lower

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Contemporary Antiplatelet Strategies in the Treatment of STEMI using PPCI

values for ADP-induced platelet aggregation 4 hours after drug administration. The clinical benefit of a 600 mg loading dose in STEMI patients undergoing PPCI was demonstrated in the Antiplatelet therapy for reduction of myocardial damage during angioplasty (ARMYDA)-6 MI,9 Clopidogrel and aspirin optimal dose usage to reduce recurrent events – seventh organisation to assess strategies in ischemic symptoms (CURRENT-OASIS) 7 10 and Harmonising outcomes with revascularisation and stents in acute myocardial infarction (HORIZONS-AMI)11 trials. In ARYMDA-6 MI, high dose loading reduced infarct size with improved cardiac function, and 30-day MACE rates. Similarly, in subgroup analyses of the CURRENT-OASIS 7 and HORIZONS-AMI trials, STEMI patients loaded with clopidogrel 600 mg, prior to PPCI, had a significant reduction in stent thrombosis and myocardial infarction, without any increase in bleeding events.

Figure 1: Timeline of a STEMI Patient Requiring PPCI and Pharmacotherapy Options Symptom Onset

Aspirin (Morphine, Oxygen Therapy)

First Medical Contact

}

Diagnosis and Decision for PPCI Arrival at PPCI Centre

Clopidogrel or Prasugrel or Ticagrelor DTB Time* 39 mins

Heparin or Bivalirudin +/- GP IIb/IIIa Inhibitor

PPCI

Prasugrel Prasugrel is a third-generation thienopyridine, sharing the same active metabolite as clopidogrel (see Figure 2), and despite partial reliance on CYP2C19, achieves faster and more potent platelet inhibition (a 60 mg loading dose of prasugrel reaches maximal plasma concentration at 30 minutes in healthy volunteers).12 Prasugrel has a very low rate of nonresponders in comparison with clopidogrel.13

CTB Time* 113 mins

Antiplatelet Therapy pre-PPCI

Aspirin + Clopidogrel or Prasugrel or Ticagrelor (Warfarin and (N)OACs)

Post PPCI

*Median times based on British Cardiovascular Intervention Society Audit Returns 2013. CTB = call to balloon; DTB = door to balloon; GPIIb/IIIa = glycoprotein IIb/IIIa; (N)OAC = nonvitamin K antagonist oral anticoagulants; PPCI = primary percutaneous coronary intervention.

Figure 2: Molecular Targets of Drug Therapy on the Activated Platelet

The clinical superiority of prasugrel over clopidogrel in ACS was Prasugrel

Clopidogrel CP450 CP450

CP450

active metabolite Ticagrelor

P2Y12

GPIIb/IIIa Inhibitors

demonstrated in the TRial to assess Improvement in Therapeutic Outcomes by optimising platelet inhibitioN – Thrombolysis in Myocardial Infarction-38 (TRITON–TIMI 38) study.14 Prasugrel, administered following angiography, reduced the composite primary endpoint (cardiovascular death, non-fatal MI or stroke) in patients undergoing PCI for STEMI or moderate-high risk ACS. In the pre-specified STEMI subgroup (3,534 patients), the risk reduction was 21 % (prasugrel 10 % versus clopidogrel 12.4 %) at 15 months, without a significant increase in non-coronary artery bypass graft (CABG)-related bleeding.15 The risk of stent thrombosis was also significantly lower. Prasugrel is contraindicated in patients with prior stroke/transient ischaemic attack (TIA), and is not recommended in patients aged ≥75 years or in patients with lower body weight (<60 kg), as there was no net clinical benefit in these subsets. A reduced maintenance dose of 5 mg could be considered in these patients.

Ticagrelor A new chemical class called CycloPentylTriazoloPyrimidine is partly formed by Ticagrelor, which, in contrast to thienopyridines, causes reversible inhibition of the P2Y12 receptor and does not require hepatic metabolism for its activity (see Figure 2).16 Similar to prasugrel, ticagrelor provides more rapid, potent and consistent platelet inhibition over clopidogrel. In the PLATelet inhibition and patient Outcomes (PLATO) trial,17 ticagrelor (compared with clopidogrel) reduced the composite primary endpoint (cardiovascular death, non-fatal MI or stroke) and also reduced cardiovascular mortality in STEMI and moderate–high risk ACS patients. In the STEMI subgroup, this primary endpoint was reduced from 10.8 % in the clopidogrel group to 9.4 % in the ticagrelor group (relative risk [RR] reduction of 13 %). In addition, overall mortality was reduced from 6 % to 4.9 % without a higher risk of major bleeding. Dyspnoea is a frequently reported side effect of ticagrelor. In PLATO, 13.8 % of patients on ticagrelor reported dyspnoea compared with 7.8 %

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Platelet Activation AA

Abxicimab Eptifibatide Tirofiban

TXA2 COX-1

Aspirin AA = arachidonic acid; COX-1 = cyclooxygenase-1; CYP450 = cytochrome P450; P2Y12 = purinergic receptor P2Y; GPIIb/IIIa = glycoprotein IIb/IIIa; TXA2 = thromboxane A2.

treated with clopidogrel.17 However few patients (0.9 %) discontinued the drug because of dyspnoea; importantly, there were no associated lung abnormalities and the mortality benefit persisted in this group.18 Contrary to the PLATO experience, a recent study of ticagrelor compliance in ACS patients demonstrated that dyspnoea was the commonest reason for drug discontinuation, occurring in 9.1 % of cases.19 The European Society of Cardiology (ESC) and American College of Cardiology Foundation/American Heart Association (ACCF/AHA) recommendations for antithrombotic strategies in patients with STEMI undergoing primary PCI are summarised in Table 1. Prasugrel, ticagrelor and clopidogrel (600 mg loading dose) are all class I, level B options in both guidelines, but the ESC expresses a clear preference for the newer antiplatelet agents, stating that clopidogrel should only be used when prasugrel or ticagrelor are either not available or contraindicated.

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Coronary Adjunctive Pharmacotherapy Table 1: Recommendations for Antithrombotic Treatment Strategies in Patients with STEMI Undergoing Primary PCI Recommendations

Class of Recommendation ESC1

ACCF/AHA3

Recommended in all patients regardless of initial treatment strategy

In Europe: Loading dose 150–300mg oral (or 80–150mg i.v.), maintenance dose 75–100mg daily long term

Antiplatelet Therapy Aspirin

In America: Loading dose 162–325mg oral, maintenance 81–325mg daily long term (81 mg preferred with

Ticagrelor – Class IIa) P2Y12 Inhibitor Recommended in addition to aspirin and maintained over 12 months

Give at time of first medical contact (ESC); as early as possible or at time of PCI (AHA/ACCF)

Prasugrel (60 mg loading dose, 10 mg daily dose) if no contraindication (i.e. prior stroke/TIA)

Ticagrelor (180 mg loading dose, 90 mg twice daily dose) if no contraindication

Clopidogrel (600 mg loading dose, 75 mg daily dose). ESC: only when prasugrel or ticagrelor are not

Should be considered for bail-out or evidence of no re-flow or a thrombotic complication

IIa

Upstream use may be considered for high-risk patients undergoing transfer for primary PCI

IIb

IIa

Options:

available or contraindicated GPIIb/IIIa Inhibitor

Options are: abxicimab, eptifibatide (with double bolus) or tirofiban (with a high bolus dose) Anticoagulant Therapy Recommended in all patients in addition to antiplatelet therapy Options: Unfractionated heparin (70–100 U/kg i.v. bolus when no GPIIb/IIIa inhibitor is planned; 50–70 U/kg i.v. bolus with GPIIb/IIIa inhibitor) Bivalirudin 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for up to 4 hours post procedure Bivalirudin is preferred over UFH with GPIIb/IIIa receptor antagonist in patients at high risk of bleeding Enoxaparin i.v. 0.5 mg/kg with or without GPIIb/IIIa inhibitor

IIa IIa

Antiplatelet Therapy after PCI in Patients Requiring Oral Anticoagulation In patients with a firm indication for oral anticoagulation (e.g. atrial fibrillation with CHA2DS2-VASc score ≥2,

venous thromboembolism, LV thrombus or mechanical valve prosthesis), oral anticoagulation is recommended in addition to antiplatelet therapy In patients with ACS and atrial fibrillation at low bleeding risk (HAS-BLED ≤2), initial triple therapy of (N)OAC and

IIa

ASA (75–100 mg/day) and clopidogrel 75 mg/day should be considered for a duration of 6 months irrespective of stent type followed by (N)OAC and aspirin 75–100 mg/day or clopidogrel (75 mg/day) continued up to 12 months In patients requiring oral anticoagulation at high bleeding risk (HAS BLED ≥3), triple therapy of (N)OAC and ASA

IIa

(75–100 mg/day) and clopidogrel 75 mg/day should be considered for a duration of 1 month irrespective of stent type followed by (N)OAC and aspirin 75–100 mg/day or clopidogrel (75 mg/day) continued up to 12 months The use of ticagrelor and prasugrel as part of initial triple therapy is not recommended

III

ACCF/AHA = American College of Cardiology Foundation/American Heart Association; ACS = acute coronary syndrome; ASA = acetylsalicylic acid; CHA2DS2-VASc = Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65 – 74 and Sex category [Female]); ESC = European Society of Cardiology; GPIIb/IIIa = glycoprotein IIb/IIIa; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol; INR = international normalized ratio; LV = left ventricular; (N)OAC = (non-vitamin K antagonist) oral anticoagulant; PCI = percutaneous coronary intervention; STEMI = ST elevation myocardial infarction; TIA = transient ischaemic attack; UFH = unfractionated heparin.

Glycoprotein IIb/IIIa Inhibitors Glycoprotein IIb/IIIa inhibitors (GPIs) provide rapid, potent platelet inhibition. Their use in PPCI has spanned the evolution of PCI and pharmacological therapies; consequently, it is challenging to relate the data to current practice with more potent oral antiplatelet therapies. Initial data supported the combined role of stenting and abciximab administration to minimise target vessel revascularisation,20 and preangiographic commencement of therapy appeared advantageous.21 However, in the dual antiplatelet therapy (DAPT) era, early use of abciximab resulted in an increased rate of bleeding.22 Subsequent analysis has demonstrated a continued benefit in early administration of GPIs in high-risk patients,23 particularly if presenting early or to a non-interventional centre.24 Contemporary trials provide conflicting results, the ONgoing Tirofiban in Myocardial infarction Evaluation 2

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(ON-TIME 2) trial,25 utilising pre-hospital initiation of high bolus dose tirofiban, in addition to aspirin, heparin and high-dose clopidogrel, reduced MACE at 30 days with no significant increase in major bleeding. However, the HORIZONS-AMI26 trial demonstrated superiority of bivalirudin versus unfractionated heparin (UFH) and GPI in terms of a composite of major bleeding and MACE. Consequently, current guidelines1,4 suggest restricting GPI use for ‘bailout’ in the event of angiographic evidence of massive thrombus, slow-/no-reflow or a thrombotic complication.

Adjunctive Antithrombotic Pharmacotherapy during PPCI In addition to the array of oral antiplatelet therapy options in PPCI, there is continued debate regarding the optimal combination of antithombotic

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therapy. UFH and bivalirudin are most commonly used and the European guidelines for STEMI support their use with a Class I indication.27 The evidence supporting use of bivalirudin derived from HORIZONSAMI,26 which demonstrated that bivalirudin compared with UFH and routine use of GPIs was associated with a reduction in mortality and major bleeding at 30 days, with a survival benefit that extended to 3 years. Further support for bivalirudin’s bleeding safety was demonstrated in the open-label European Ambulance ACS Angiography (EUROMAX) trial,28 comparing pre-hospital administration of bivalirudin versus UFH or low-molecular-weight heparin (LMWH) with optional use of GPI (58.5 % routine use). However, both trials were associated with an increased rate of AST with the use of bivalirudin and the elevated bleeding rate observed in the UFH arm of both studies has been attributed to the high rates of GPI use. The recently published How Effective are Antithrombotic Therapies in primary percutaneous coronary intervention (HEAT-PPCI) trial29 was designed to specifically address the criticisms levelled at previous bivalirudin trials, specifically the efficacy of bivalirudin monotherapy against UFH with GPI use restricted to true ‘bail-out’ (13 % and 15 %, respectively). The study demonstrated a primary efficacy outcome (allcause mortality, cerebrovascular accident, re-infarction or unplanned target lesion revascularisation) of 8.7 % in the bivalirudin group versus 5.7 % in the heparin group (RR 1.52, 95 % confidence interval [CI] 0.9– 2.13). This reduction in major adverse ischaemic events with heparin was not associated with an increase in bleeding complications. Definite or probable stent thrombosis occurred more often with bivalirudin (3.4 versus 0.9 %, RR 3.91, 95 % CI 1.61–9.52). In the light of these new data, the most recent ESC guidelines on revascularisation have downgraded their recommendation for the use of bivalirudin to Class IIa1.

Acute Stent Thrombosis The increased rate of AST observed with bivalirudin therapy has been attributed to the relatively short half life of bivalirudin (t1/2=25 minutes),30 resulting in a waning effect of the drug within 2 hours of withdrawal. The risk of AST is further exacerbated by the observed delay in platelet inhibition observed in STEMI patients treated with oral P2Y12 inhibitors. The Rapid Activity of Platelet Inhibitor Drugs (RAPID) Primary PCI study31 evaluated 50 patients with STEMI undergoing PPCI with bivalirudin monotherapy, randomised to prasugrel or ticagrelor at standard loading doses. There was no significant difference in residual platelet reactivity between both drugs but the study showed that effective platelet inhibition within 2 hours of loading was only achieved in half of patients. Four hours were required to achieve effective platelet inhibition in the majority of patients.

Morphine Effect on Platelet Activity The RAPID investigators assessed the effect of opiate use on platelet reactivity. The use of morphine significantly affected the activity of prasugrel and ticagrelor, independently predicting high residual platelet reactivity 2 hours post-loading dose (odds ratio 5.29; p=0.012).31 The effect has been confirmed in a randomised controlled trial of 24 healthy subjects receiving 600 mg of clopidogrel with placebo or 5 mg of intravenous morphine. Morphine was shown to delay clopidogrel absorption, decrease plasma levels of the active metabolite and delayed the maximal inhibition of platelet aggregation by 2 hours.32 Furthermore, the opiate effect on platelet inhibition does not appear restricted to patients experiencing opiate-related nausea/vomiting.33

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The negative interaction between morphine and oral antiplatelet agents is also supported by the Administration of ticagrelor in the cathlab or in the ambulance for new STEMI to open the coronary artery (ATLANTIC) trial,34 which demonstrated that the primary end point of ST-segment resolution was significantly improved with prehospital administration of ticagrelor in opiate-naïve patients. These findings challenge current guidance to administer analgesia early, on first medical contact.27

Methods to Enhance Platelet Inhibition Studies to overcome the potential delay in platelet inhibition, associated with immediate pre-procedural loading of oral antiplatelet therapy, have been undertaken. The ATLANTIC investigators addressed this question by randomising 1,862 patients presenting within 6 hours of STEMI onset to pre-hospital versus in-hospital treatment with ticagrelor.34 Pre-hospital ticagrelor did not improve pre-PCI coronary perfusion but appeared to be safe and was associated with a reduction in post-procedural AST. The median time between the two loading doses (pre-hospital versus in-hospital) was 31 minutes. Alternatives to upstream administration of an oral antiplatelet therapy include manipulation of the pharmacokinetic properties of oral agents or use of an intravenous platelet inhibitor. The Mashed Or Just Integral Tablets of ticagrelOr (MOJITO) study35 tested the effect of crushing ticagrelor to accelerate drug absorption and demonstrated a significant enhancement of platelet inhibition 1 hour following drug ingestion. A larger scale trial with clinical endpoints would be necessary to validate these results. Cangrelor is an intravenous adenosine triphosphate (ATP) analogue, which reversibly inhibits the P2Y12 receptor without requiring hepatic conversion.36 The attraction of cangrelor is therefore its very rapid onset of action and short halflife (3–5 minutes) allowing rapid platelet inhibition and quick reversal. Two early trials (Cangrelor versus standard therapy to achieve optimal management of platelet inhibition [CHAMPION]-PCI37 and CHAMPIONPLATFORM38) evaluating cangrelor in patients undergoing PCI failed to show clinical superiority over clopidogrel. The more recent CHAMPION-PHOENIX39 trial randomised 11,145 patients undergoing urgent or elective PCI to intravenous cangrelor or clopidogrel 600 or 300 mg loading (56 % stable angina/18 % STEMI). At 48 hours the rate of composite primary efficacy endpoint (death, MI, ischaemiadriven revascularisation or stent thrombosis) occurred less in the cangrelor group (4.7 % versus 5.9 %) and the rate of stent thrombosis was significantly lower (0.8 % cangrelor versus 1.4 % clopidogrel). Although the study demonstrated benefit with use of cangrelor, there were significant limitations in the trial design, favouring the study drug arm. The control group only received clopidogrel once the anatomy was delineated, and 30 % of the cohort were administered the drug post-PCI. Consequently, the higher rate of peri-procedural MI in the control group is not surprising.

Antiplatelet Strategies in Patients on Oral Anticoagulation A significant proportion of patients undergoing PPCI may already be anticoagulated on a vitamin K antagonist (VKA) or a non-vitamin K antagonist oral anticoagulants ((N)OAC) at the time of the procedure. These patients are at increased risk of bleeding and often the international normalized ratio (INR) levels are not available. There is no clear evidence on the optimal antithrombotic pharmacotherapy for these patients. The 2014 ESC/EACTS guidelines on myocardial revascularisation1 recommends that PPCI in this setting should be

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Coronary Adjunctive Pharmacotherapy performed via a radial approach with use of additional parenteral anticoagulation regardless of the timing of the last dose of oral anticoagulant. Bivalirudin may be preferred due to its short half-life and should be discontinued immediately after PPCI. GPIs should generally be avoided unless for bail-out situations.

Duration of Dual Antiplatelet Therapy post-PPCI DAPT (aspirin + a P2Y12 inhibitor) is recommended for 1 year in patients undergoing PPCI for STEMI. This recommendation is based on the early CURE study40 (clopidogrel) and is supported by more recent results from TRITON-TIMI 38 (Prasugrel)15 and PLATO (Ticagrelor).17 Regardless of stent type, extended DAPT for 1 year reduces the risk of stent thrombosis, re-infarction and cardiovascular mortality6 with the more potent DAPTs associated with the greatest post-ACS clinical benefit.41 Recent data have highlighted that extended DAPT confers further protection against ischaemic events but at the expense of additional bleeding risk.42 In stark contrast, the Global-Leaders trial (NCT01813435) is currently enrolling patients to either 1 month DAPT with aspirin and ticagrelor, and then ticagrelor monotherapy for 23 month or 12 months DAPT with aspirin and ticagrelor/clopidogrel with aspirin monotherapy between 12 and 24 months. We await the results with interest.

thrombus, mechanical valve prosthesis). Triple therapy with an oral anticoagulant, aspirin 75–100 mg and clopidogrel 75 mg should be limited in duration depending on the clinical setting, thromboembolic risk (CHA2DS2-VASc score) and bleeding risk (HAS-BLED score). The WOEST trial43, which randomised 573 patients either to dual therapy or triple therapy, showed that in patients on oral anticoagulants the use of clopidogrel without aspirin was safe. TIMI bleeding and allcause mortality was lower in the dual therapy group with no increase in the rate of thrombotic events. The 2014 ESC/EACTS guidelines on myocardial revascularisation1 recommends 1 month of triple therapy for ACS patients at high bleeding risk (HAS-BLED >3) and 6 months for patients at lower bleeding risk, followed by dual therapy (oral anticoagulant and clopidogrel or aspirin) for a minimum of 12 months (see Table 1). The use of prasugrel and ticagrelor as part of triple therapy should be avoided44 and gastric protection with a proton pump inhibitor should be implemented.

Conclusion

Antiplatelet Therapy after PCI in Patients Requiring Oral Anticoagulation

Successful revascularisation of patients presenting with STEMI requires rapid transfer to a PCI capable unit and concomitant treatment with antiplatelet and antithrombotic drugs. A delicate balance exists between thrombosis and bleeding and a perfect combination of agents is yet to be found. An intimate relationship between the intravenous antithrombotic and oral antiplatelet agents exists and these must be

A proportion of patients on DAPT post-PPCI will have a firm indication for long-term anticoagulation (atrial fibrillation with Cardiac failure, Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65 – 74 and Sex category [Female]) [CHA2DS2VASc] score ≥2, venous thromboembolism, left ventricular [LV]

considered in the selection/tailoring of treatment. Oral antiplatelet therapies provide long-term platelet inhibition but are hampered by delayed onset of action in acutely unwell patients. Future strategies may include upstream administration of drugs by the first medical contact or acute treatment with an intravenous platelet inhibitor. n

1. Authors/Task Force Members, Windecker S, Kolh P, et al., 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. 2. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2, Lancet , 1988;332:349–60. 3. Sagar KA, Smyth MR, A comparative bioavailability study of different aspirin formulations using on-line multidimensional chromatography, J Pharm Biomed Anal , 1999;21:383–92. 4. O’Gara PT, Kushner FG, Ascheim DD, et al.; American College of Cardiology Foundation/American Heart Association Task Force on Practice G, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Circulation , 2013;127:e362–425. 5. Mega JL, Close SL, Wiviott SD, et al., Cytochrome p-450 polymorphisms and response to clopidogrel, N Engl J Med , 2009;360:354–62. 6. Mehta SR, Yusuf S, Peters RJ, et al.; Clopidogrel in Unstable angina to prevent Recurrent Events trial I, Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study, Lancet , 2001;358:527–33. 7. Sabatine MS, Cannon CP, Gibson CM, et al.; Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction I, Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study, JAMA , 2005;294:1224–32. 8. von Beckerath N, Taubert D, Pogatsa-Murray G, et al., Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial, Circulation , 2005;112:2946–50. 9. Patti G, Barczi G, Orlic D, et al., Outcome comparison of 600- and 300- mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study, J Am Coll Cardiol , 2011;58:1592–9.

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10. Mehta SR, Tanguay JF, Eikelboom JW, et al., Double-dose versus standard-dose clopidogrel and high-dose versus lowdose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial, Lancet , 2010;376:1233–43. 11. Dangas G, Mehran R, Guagliumi G, et al., Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial, J Am Coll Cardiol, 2009;54:1438–46. 12. Brandt JT, Payne CD, Wiviott SD, et al., A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation, Am Heart J , 2007;153:66 e9–16. 13. Grosdidier C, Quilici J, Loosveld M, et al., Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications, Am J Cardiol , 2013;111:985–90. 14. Wiviott SD, Braunwald E, McCabe CH, et al., Prasugrel versus clopidogrel in patients with acute coronary syndromes, N Engl J Med , 2007;357:2001–15. 15. Montalescot G, Wiviott SD, Braunwald E, et al., Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial, Lancet , 2009;373:723–31. 16. Capodanno D, Dharmashankar K, Angiolillo DJ, Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist, Expert Rev Cardiovasc Ther , 2010;8:151–8. 17. Wallentin L, Becker RC, Budaj A, et al.,Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N Engl J Med , 2009;361:1045–57. 18. Storey RF, Becker RC, Harrington RA, et al., Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes, Eur Heart J , 2011;32:2945–53. 19. Gaubert M, Laine M, Richard T, et al., Effect of ticagrelorrelated dyspnea on compliance with therapy in acute coronary syndrome patients, Int J Cardiol , 2014;173:120–1. 20. Stone GW, Grines CL, Cox DA, et al., Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction, N Engl J Med , 2002;346:957–66. 21. Montalescot G, Barragan P, Wittenberg O, et al., Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction, N Engl J Med , 2001;344:1895–903.

22. Ellis SG, Tendera M, de Belder MA, et al., Facilitated PCI in patients with ST-elevation myocardial infarction, N Engl J Med , 2008;358:2205–17. 23. De Luca G, Navarese E, Marino P, Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials, Eur Heart J , 2009;30:2705–13. 24. Herrmann HC, Lu J, Brodie BR, et al., Benefit of facilitated percutaneous coronary intervention in high-risk ST-segment elevation myocardial infarction patients presenting to nonpercutaneous coronary intervention hospitals, JACC Cardiovasc Interv , 2009;2:917–24. 25. ten Berg JM, van’t Hof AW, Dill T, et al., Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome, J Am Coll Cardiol , 2010;55:2446–55. 26. Stone GW, Witzenbichler B, Guagliumi G, et al., Bivalirudin during primary PCI in acute myocardial infarction, N Engl J Med , 2008;358:2218–30. 27. Task Force on the management of STseamiotESoC, Steg PG, James SK, 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. 28. Steg PG, van ‘t Hof A, Hamm CW, et al., Bivalirudin started during emergency transport for primary PCI, N Engl J Med , 2013;369:2207–17. 29. Shahzad A, Kemp I, Mars C, et al., Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial, Lancet , 2014;384:1849–58. 30. Robson R, The use of bivalirudin in patients with renal impairment, J Invasive Cardiol , 2000;12 Suppl. F:33F-6. 31. Parodi G, Valenti R, Bellandi B, et al., Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study, J Am Coll Cardiol , 2013;61:1601–6. 32. Hobl EL, Stimpfl T, Ebner J, et al., Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial, J Am Coll Cardiol , 2014;63:630–5. 33. Parodi G, Bellandi B, Xanthopoulou I, et al., Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention, Circ Cardiovasc Interv , 2015;8.

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34. Montalescot G, van ‘t Hof AW, Lapostolle F, et al., Prehospital ticagrelor in ST-segment elevation myocardial infarction, N Engl J Med , 2014;371:1016–27. 35. Parodi G, Xanthopoulou I, Bellandi B, et al., Ticagrelor crushed tablets administration in STEMI patients: The Mashed Or Just Integral Tablets of ticagrelOr (MOJITO) study, Eur Heart J , 2014;35(Suppl.):1030. 36. Ferreiro JL, Ueno M, Angiolillo DJ, Cangrelor: a review on its mechanism of action and clinical development, Expert Rev Cardiovasc Ther , 2009;7:1195–201. 37. Harrington RA, Stone GW, McNulty S, et al., Platelet inhibition with cangrelor in patients undergoing PCI, N Engl J Med , 2009;361:2318–29.

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38. Bhatt DL, Lincoff AM, Gibson CM, et al., Intravenous platelet blockade with cangrelor during PCI, N Engl J Med , 2009;361:2330–41. 39. Bhatt DL, Stone GW, Mahaffey KW, et al., Effect of platelet inhibition with cangrelor during PCI on ischemic events, N Engl J Med , 2013;368:1303–13. 40. Yusuf S, Zhao F, Mehta SR, et al., Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation, N Engl J Med , 2001;345:494–502. 41. Bellemain-Appaix A, Brieger D, Beygui F, et al., New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis, J Am Coll Cardiol, 2010;56:1542–51.

42. Mauri L, Kereiakes DJ, Yeh RW, et al., Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents, N Engl J Med , 2014;371:2155–66. 43. Dewilde WJ, Oirbans T, Verheugt FW, et al., Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial, Lancet , 2013;381:1107–15. 44. Sarafoff N, Martischnig A, Wealer J, et al., Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation, J Am Coll Cardiol , 2013;61:2060–6.

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Coronary Primary Angioplasty and High Risk PCI

Preventive Percutaneous Coronary Intervention in ST-elevation Myocardial Infarction – The Primacy of Randomised Trials David S Wald 1 and Jonathan P Bestwick 2 1. Professor of Cardiology; 2. Lecturer in Medical Statistics, Wolfson Institute of Preventive Medicine, London, UK

Abstract Randomised trials show a benefit of preventive (non-infarct artery) percutaneous coronary intervention in patients with acute ST elevation myocardial infarction, but non-randomised studies do not. The evidence on each is quantified and assessed. The primacy of randomised trials reveals the danger of using non-randomised studies that can, as in this case, give the wrong answer.

Keywords STEMI, preventive PCI, non-infarct artery Disclosure: The authors have no conflicts of interest to declare. Received: 2 December 2014 Accepted: 4 February 2015 Citation: Interventional Cardiology Review, 2015;10(1):32–4 Correspondence: David S Wald, Queen Mary University of London, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK. E: d.s.wald@qmul.ac.uk

The management of patients with acute ST-elevation myocardial infarction (STEMI) relies on restoring blood flow to the occluded infarct artery. Prompt percutaneous coronary intervention (PCI) and stenting of the stenosis causing the occlusion reduces the risk of cardiac death and recurrent infarction.1 In about half of patients,2 stenoses are identified in non-infarct arteries at the time of the PCI, leading some operators to extend the procedure and carry out an immediate ‘preventive PCI’ in the non-infarct arteries, on the basis that this may prevent future serious cardiac events. Until recently, however, clinical guidelines recommended that PCI be limited to the infarct artery, because of concern that the benefit of preventive PCI may not outweigh the risks of the extended procedure.3,4 This recommendation was based on non-randomised studies in which the outcome of patients with STEMI and multivessel disease who received immediate preventive PCI at the time of their infarct artery PCI was compared with the outcome of patients treated by infarct artery PCI alone. In these studies, doctors determined who received preventive PCI and who did not. Figure 1 shows a metaanalysis plot of 16 such studies (42,817 patients, median follow-up 12 months).5–20 The summary estimate in the non-randomised studies is not statistically significant but suggests a possible increased risk of all-cause death or non-fatal MI in the preventive PCI group (odds ratio 1.24, 95 % confidence interval [CI] 0.97–1.60; p=0.085). The use of all-cause rather than cardiac death as an outcome is a limitation, because it includes non-cardiac causes that are not influenced by PCI (e.g. cancer) and dilutes the relevant cardiac outcomes, but only one study7 reported cause-specific death. A more serious limitation, in the non-randomised studies, is selection bias: the extent to which patients who received preventive PCI, for example, were sicker than those receiving infarct artery-only PCI and were therefore heading for a worse outcome regardless of the treatment strategy adopted. Selection bias is not avoided by increasing study size or by adjusting

Wald_FINAL.indd 32

for confounding, because not all confounding factors are measured or known, so even in large propensity score-matched studies11,14 it is not possible to be sure which treatment is better. Selection bias is avoided in a randomised trial, since the use of preventive PCI is determined by random allocation rather than physician choice. Four such trials (979 patients, median follow-up 18 months),21–24 in which cardiac deaths were reported in all but one23, have been completed and a meta-analysis plot of these trials is also shown in Figure 1. The relative risk of cardiac death or non-fatal MI is 0.39 (95 % CI 0.23–0.69; p<0.001), showing that selection bias is an important source of error in the non-randomised studies and indicating that preventive PCI, performed as an immediate extension of the infarct artery PCI, reduces the risk of cardiac death and MI by about 60 %. How can these findings be reconciled with the view that PCI improves symptoms but not prognosis?25–27 The value of angioplasty has been studied in different groups of patients with coronary artery disease. The evidence of benefit in reducing the risk of cardiac death and MI in patients with STEMI is known.1 In patients with non-STEMI, there is a short-term hazard but a long-term benefit.28 In patients with stable angina, prior studies have shown no evidence of prognostic benefit.26–27 This gradation of effect may, at least in part, be due to the fact that PCI causes adverse cardiac events as well as preventing them, and in a lower-risk group, for example, in patients with angina rather than a MI, the benefit may not outweigh the harm. In patients with STEMI, coronary artery plaque rupture remote from the infarct artery has been demonstrated in autopsy29,30 and intravascular ultrasound studies,31–34 which suggess that plaque instability is not a localised vascular event but a generalised process throughout the coronary tree. In an angiographic study of 253 patients with STEMI, the finding of multiple complex coronary artery lesions (>50 % stenosis) remote from the infarct artery

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Preventive Percutaneous Coronary Intervention in ST-elevation Myocardial Infarction

In the PRAMI trial the evidence of benefit emerged early on.24 The curves in the Kaplan–Meier plot (see Figure 2) diverged within a few days and the maximum effect was evident within a few months, suggesting that the immediacy of preventive PCI is important and that staged preventive PCI (undertaken after a few weeks) may not be as effective. The same observations were apparent in the Complete Versus culprit-Lesion only PRimary PCI Trial (CVLPRIT) trial22 in which all but about a quarter of patients in the preventive PCI group had immediate preventive PCI, the remainder having a staged procedure within a few days. Neither of the two trials was designed to compare immediate versus staged preventive PCI. Such a trial, if judged necessary, would need to be large to demonstrate a difference in outcome on top of the 60 % reduction in cardiac death or MI from preventive PCI alone. The results of PRAMI24 and CvLPRIT22 have prompted a rethink in the way we manage non-infarct artery stenoses in STEMI. The European Revascularisation Guidelines were recently changed (September 2014) and now recommend that immediate preventive PCI be considered in selected patients with STEMI,37 but do not indicate how this selection should be made. The use of a physiological measure of blood flow, such as fractional flow reserve (FFR), may be better than visual angiographic assessment in guiding preventive PCI,38 but it may also worsen outcomes if non-flow limiting stenoses are left untreated and become the sites of future infarction. Three trials of preventive PCI in patients with STEMI are in progress that are using FFR to decide which non-infarct artery stenoses to treat.39–41 No trial is designed to directly compare FFR with angiography in STEMI to determine which, if either, is better in guiding preventive PCI. Further research would be needed to resolve this uncertainty. A limitation of the trials of preventive PCI, as in all randomised trials, is that they only provide an average effect of treatment. Some patients will benefit more from preventive PCI than others, but in the absence of knowing who they are, no special selection can be recommended. The trials excluded patients with cardiogenic shock, previous coronary artery bypass graft (CABG), significant stenosis of the left main stem or in whom the only non-infarct artery disease was a chronic total occlusion. Therefore, while the benefits of preventive PCI may apply in these selected groups, there

1. Keeley EC, Boura JA, Grines CL, Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials, Lancet , 2003;361:13–20. 2. Park D-W, Calre RM, Schulter PJ, et al., Extent, location, and clinical significance of non–infarct-related coronary artery disease among patients with ST-elevation myocardial

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Figure 1: Immediate Preventive Percutaneous Coronary Intervention versus Infarct Artery-only Percutaneous Coronary Intervention – Outcomes in Non-randomised Studies (All-cause Death or Myocardial Infarction) and in Randomised Trials (Cardiac Death or Myocardial Infarction) Study, first author

Events/number of patients Preventive PCI No preventive PCI

Effect size (95 % CI)

Non-randomised studies*

Toma5 Dziewierz6 Xu7 Varani8 Roe9 Cavender10 Iqbal11 Jin12 Qarawani13 Hannan14 Khattab15 Rahman16 Corpus17 Kong18 Seo19

11/1,984 27/217 57/707 11/70 6/120 6/105 10/156 15/147 14/79 25/79 246/3,134 1321/25,802 41/403 164/2,418 24/901 7/215 6/25 12/95 54/503 59/503 8/45 4/28 51/578 122/1,449 52/354 37/152 31/1,350 5/632 62/217 8/82 25/208 Estavez-Loueiro20 1/59

2.44 (1.55, 3.83) 2.04 (0.89, 4.66) 1.74 (0.19, 21.10) 1.66 (0.67, 4.28) 1.61 (0.68, 3.86) 1.58 (1.37, 1.82) 1.56 (1.11, 2.22) 1.23 (0.44, 2.99) 1.20 (0.23, 12.19) 1.10 (0.73, 1.67) 1.08 (0.08, 10.06) 0.97 (0.66, 1.43) 0.94 (0.48, 1.75) 0.27 (0.08, 0.90) 0.20 (0.05, 0.57) 0.13 (0.00, 0.81)

Overall (l2 = 5.8 %; p=0.002)

1.24 (0.97, 1.60)

Randomised trials**

0.64 (0.03, 40.09) 0.41 (0.16, 1.07) 0.40 (0.12, 1.16) 0.36 (0.18, 0.73)

1/17 14/146 17/84 27/231

2/52 6/150 6/65 11/234

Di Mario21 Gershlick22 Politi23 Wald24

0.39 (0.23, 0.63)

Overall (l2 = 0.0 %; p=0.988) 0.1 Preventive PCI better

10 Preventive PCI worse

*All-cause death or myocardial infarction (MI) (cardiac death reported in only one of the 16 studies);7 **Cardiac death or MI (cardiac death reported in all but one trial).22 CI = confidence interval; PCI = percutaneous coronary intervention.

Figure 2: Kaplan–Meier Curves for the Primary Outcome (Composite of Cardiac Death, Non-Fatal Myocardial Infarction or Refractory Angina) in the Preventive Angioplasty in Myocardial Infarction (PRAMI) Trial 24

Proportion without any primary outcome

was associated with a 10.6-fold excess risk of recurrent acute coronary syndrome within 1 year.35 The simplest, albeit speculative, explanation for the preventive benefit of PCI in such patients is by stabilising plaques prone to rupture and spontaneous thrombosis,36 so reducing subsequent infarction. There is uncertainty whether the benefit outweighs the risk of PCI in stenoses <50 %, since these were not included in the randomised trials. Preventive PCI may also reduce ischaemia by improving coronary flow in severe stenoses and by preventing progression over time, explaining the observed reduction in refractory angina. The concordance between the components of the primary outcomes in Preventive Angioplasty in Myocardial Infarction (PRAMI) (hazard ratios 0.34 [0.11–1.08], 0.32 [0.13–0.75] and 0.35 [0.18–0.69] for cardiac death, non-fatal myocardial infarction and refractory angina, respectively)24 suggests that both mechanisms may be similarly important in the prevention of future cardiac events.

1.00 0.90

Preventive PCI

0.80

No preventive PCI

0.70 Hazard ratio 0.35 (95 % confidence interval 0.21–0.58)

0.60 0.50 0

18 24 12 Months since randomisation

is uncertainty. In others, for whom the non-infarct artery stenoses are judged treatable by PCI, the evidence from the trials completed so far, is clear – that immediate preventive PCI confers substantial clinical benefit. The primacy of randomised trials reveals the danger of using non-randomised studies, which can, as in this case, give the wrong answer. n

infarction, JAMA , 2014;312:2019–27. 3. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur Heart J , 2012;33:2569–619. 4. O’Gara PT, Kushna FG, Ascheim DD, et al., 2013 ACCF/

AHA guideline for the management of ST-elevation myocardial infarction: executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines, Circulation , 2013;127:529–55. 5. Toma M, Buller CE, Westerhout CM, et al., for the APEX-AMI Investigators, Non-culprit coronary artery percutaneous

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Coronary Primary Angioplasty and High Risk PCI coronary intervention during acute ST-segment elevation myocardial infarction: insights from the APEX-AMI trial, Eur Heart J , 2010;31:1701–7. 6. Dziewierz A, Siudak Z, Rakowski T, et al., Impact of multivessel coronary artery disease and noninfarctrelated artery revascularization on outcome of patients with ST-elevation myocardial infarction transferred for primary percutaneous coronary intervention (from the EUROTRANSFER registry), Am J Cardiol , 2010;106:342–7. 7. Xu F, Chen YG, Li JF, et al., Multivessel Percutaneous Coronary Intervention in Chinese Patients with Acute Myocardial Infarction and Simple Nonculprit Arteries, Am J Med Sci , 2007;333:376–80. 8. Varani E, Balducelli M, Aquilina M, et al., Single or Multivessel Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction Patients, Catheter Cardiovasc Interv , 2008;72:927–33. 9. Roe MT, Cura FA, Joski PS, et al., Initial experience with multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction, Am J Cardiol , 2001;88:170–3. 10. Cavender MA, Milford-Beland S, Roe MT, et al., Prevalence, predictors, and in-hospital outcomes of non-infarct artery intervention during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (from the National Cardiovascular Data Registry), Am J Cardiol , 2009;104:507–13. 11. Iqbal MB, Ilsley C, Kabir T, et al., Culprit vessel versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment-elevation myocardial infarction and multivessel disease: real-world analysis of 3984 Patients in London, Circ Cardiovasc Qual Outcomes , 2014;7:936–43. 12. Jin Z, Rha SW, Chen KY, et al., Culprit-lesion revascularization versus complete revascularization in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention with drugeluting stents. Poster session presented at: Angioplasty Summit-TCT Asia Pacific; 2007 Apr 25–27; Seoul, South Korea. 13. Qarawani D, Nahir M, Abboud M, et al., Culprit only versus complete coronary revascularization during primary PCI, Int J Cardiol , 2008;123:288–92. 14. Hannan EL, Samadashvili Z, Walford G, et al., Culprit vessel percutaneous coronary intervention versus multivessel and staged percutaneous coronary intervention for ST-segment elevation myocardial infarction patients with multivessel disease, J Am Coll Cardiol Intv, 2010;3:22-31. 15. Khattab AA, Abdel-Wahab M, Röther C, et al., Multi-vessel stenting during primary percutaneous coronary intervention for acute myocardial infarction. A single-center experience,

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Clin Res Cardiol , 2008;97:32–8. 16. Rahman M, Nfor T, Allaqaband S, et al., Clinical and angiographic outcomes in patients with ST-segment elevation myocardial infarction undergoing single versus multiple vessel percutaneous coronary intervention, JACC , 2010;55(10A):A98.E921. 17. Corpus RA, House JA, Marso SP, et al., Multivessel percutaneous coronary intervention in patients with multivessel disease and acute myocardial infarction, Am Heart J , 2004;148:493–500. 18. Kong JA, Chou ET, Minutello RM, et al., Safety of single versus multi-vessel angioplasty for patients with acute myocardial infarction and multi-vessel coronary artery disease: report from the New York State Angioplasty Registry, Coron Artery Dis , 2006;17:71–5. 19. Seo J-S, Park D-W, Kim SS, et al., Long-term outcomes of culprit only versus complete revascularization during primary percutaneous coronary intervention, J Am Coll Cardio l, 2009;53(10s1):A1–A99. 20. Estevez-Loureiro R, Rodriguez-Vilela A, Salgado-Fernandez J, et al., Effect of multivessel revascularization during primary percutaneous coronary intervention on outcomes of patients with ST-segment elevation myocardial infarction. Oral abstract presented at: 2010 Angioplasty Summit Transcatheter Cardiovascular Therapeutics Asia Pacific; 2010 Apr 28–29; Seoul, South Korea. 21. Di Mario C, Mara S, Flavio A, et al., Single vs multivessel treatment during primary angioplasty: results of the multicentre randomised HEpacoat for culprit or multivessel stenting for Acute Myocardial Infarction (HELP AMI) study, Int J Cardiovasc Intervent , 2004;6:128–33. 22. Gershlick AH, The Complete versus Lesion only Primary PCI Trial. Available at: http://www.escardio.org/about/press/ esc-congress-2014/press-conferences/Documents/gershlick. pdf (accessed 1 February 2015). 23. Politi L, Sgura F, Rossi R, et al., A randomised trial of targetvessel versus multi-vessel revascularisation in ST-elevation myocardial infarction: major adverse cardiac events during long-term follow-up, Heart , 2010;96:662–7. 24. Wald DS, Morris JK, Wald NJ, et al., for the PRAMI investigators, Randomized trial of preventive angioplasty in myocardial infarction, N Engl J Med , 2013;369:1115–23. 25. Hochman JS, Steg PG, Does preventive PCI work?, N Engl J Med , 2007;356:15. 26. Parisi AF, Folland ED, Hartigan P, A comparison of angioplasty with medical therapy in the treatment of singlevessel coronary artery disease, N Engl J Med , 1992;326:10–6. 27. Boden WE, O’Rourke RA, Teo KK, et al., Optimal medical therapy with or without PCI for stable coronary disease, N Engl J Med , 2007;356:1503–16. 28. Mehta SR, Cannon CP, Fox KA, et al., Routine vs selective

invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials, JAMA , 2005;293:2908–17. 29. Falk E, Shah PK, Coronary plaque disruption, Circulation , 1995;92:657–71. 30. Davies MJ, Thomas A, Thrombosis and acute coronaryartery lesions in sudden cardiac ischemic death, N Engl J Med , 1984;310:1137–40. 31. Schoenhagen P, Stone GW, Nissen SE, et al., Coronary plaque morphology and frequency of ulceration distant from culprit lesions in patients with unstable and stable presentation, Arterioscler Thromb Vasc Biol , 2003;23:1895–900. 32. Rioufol G, Finet G, Ginon I, et al., Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study, Circulation , 2002;106:804–8. 33. Hong MK, Mintz GS, Lee CW, et al., Comparison of coronary plaque rupture between stable angina and acute myocardial infarction: a three-vessel intravascular ultrasound study in 235 patients, Circulation , 2004;110:928–33. 34. Rioufol G, Gilard M, Finet G, et al., Evolution of spontaneous atherosclerotic plaque rupture with medical therapy: longterm follow-up with intravascular ultrasound, Circulation , 2004;110:2875–80. 35. Goldstein JA, Demetriou D, Grines CL, et al., Multiple complex coronary plaques in patients with acute myocardial infarction, N Engl J Med , 2000;343:915–22. 36. Meier B, Plaque sealing by coronary angioplasty, Heart, 2004;90:1395–8. 37. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2014 ESC/ EACTS Guidelines on myocardial revascularization, European Heart Journal , 2014;35:2541–619. 38. Tonino PAL, De Bruyne B, Pijls NHJ, et al., Fractional flow reserve versus angiography for guiding percutaneous coronary intervention, N Engl J Med , 2009;360:213–24. 39. Complete vs Culprit-only Revascularization to Treat Multivessel Disease After Primary PCI for STEMI (COMPLETE). Available at: https://clinicaltrials.gov/ct2/show/NCT017404 79?term=COMPLETE+culprit&rank=2 (accessed 1 February 2015). 40. Primary PCI in patients with ST-elevation myocardial infarction and multivessel disease: Treatment of Culprit Lesion Only or Complete Revascularization (PRIMULTI). Available at: https:// clinicaltrials.gov/ct2/show/NCT01960933?term=COMPLETE+cu lprit&rank=5 (accessed 1 February 2015). 41. Comparison Between FFR guided revascularization versus conventional strategy in acute STEMI patients with MVD. (CompareAcute). https://clinicaltrials.gov/ct2/show/ NCT01399736?term=COMPARE-acute&rank=1 (accessed 1 February 2015).

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Interventional Strategies in Thrombus Management for ST Elevation Myocardial Infarction M i c h a e l Ts a n g 1 a n d S a n j i t J o l l y 2 1. Interventional Cardiology Fellow; 2. Associate Professor, McMaster University and Population Health Research Institute, Hamilton Health Sciences, Hamilton, Canada

Abstract The major limitation of modern primary percutaneous coronary intervention (PPCI) is distal embolisation of thrombus and microvascular obstruction. Microvascular flow, as measured by myocardial blush grade (MPG), predicts mortality after PPCI. Despite initial enthusiasm, current evidence does not support routine use of Intracoronary over intravenous glycoprotein 2b3a inhibitors during PPCI for ST elevation myocardial infarction (STEMI) to improve clinical outcomes. Manual thrombectomy (MT) improves MPG and reduces distal embolisation in meta-analyses of small trials. A single-centre trial (N=1071), the Thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction study (TAPAS) trial showed a mortality reduction, which led guidelines to recommend routine manual aspiration. However, the largest randomised trial (Thrombus aspiration in ST-elevation myocardial infarction in Scandinavia [TASTE] trial, N=7021) showed no difference in mortality and only trends towards reduction in myocardial infarction (MI) and stent thrombosis. The TASTE trial had much lower than expected mortality and so was likely underpowered for modest but important treatment effects (20–30 % RRR). The Thrombectomy with PCI versus PCI alone in patients with STEMI undergoing primary PCI (TOTAL) trial (N=10,700) will determine if MT reduces important clinical events during PPCI. Thrombus management remains an important area of research in STEMI.

Keywords Primary percutaneous intervention, thrombus thombectomy, microvascular perfusion, ST elevation myocardial infarction, interventional strategies Disclosure: Dr Jolly has received grant support from Medtronic. Dr Tsang has no conflicts of interest to declare. Received: 14th April 2014 Accepted: 19th August 2014 Citation: Interventional Cardiology Review, 2015;10(1):35–8 Correspondence: Dr Sanjit Jolly, Associate Professor, McMaster University and Population Health Research Institute, Hamilton Health Sciences, David Braley Research Building Rm C3-118 237 Barton Street East, Hamilton, Canada L8L 2X2. E: Sanjit.Jolly@phri.ca

Many advances have been made in the management of ST elevation myocardial infarction (STEMI) over the past three decades.1 This is owed to insight into role that thrombus has in the obstruction of the infarct-related artery (IRA) and the subsequent cascade of the myocardial ischaemia, cell oedema and myocardial necrosis. The institution of reperfusion therapy has revolutionised the care of patients with STEMI decreasing morbidity and mortality.2–5 This therapy, whether it be pharmacologic in the case of fibrinolysis or mechanical in the case of percutaneous coronary intervention (PCI), aims at restoring patency of the IRA and ultimately tissue perfusion. However, even with modern primary PCI, distal embolisation of thrombus is common and about a third of patients have impaired microvascular perfusion despite TIMI 3 flow in infarct vessel.6 This article will review the importance of thrombus in STEMI and approaches to management: mechanical and pharmacologic.

The Importance of Thrombus in the Pathophysiology of ST Elevation Myocardial Infarction Mechanism of Acute Coronary Syndrome in the Formation of Thrombus The pathophysiology of acute coronary syndrome (ACS) is rupture or erosion of the fibrous cap overlying lipid rich plaques within the arterial tree.1 This event exposes pro-inflammatory substances, ultimately resulting in platelet aggregation and formation of obstructive

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thrombus.1,7 Angiographic evidence of thrombus formation can be seen in more than 90 % of patients who present with ST elevation myocardial infarction (STEMI).8 Plaque rupture usually produces combination of red (cross-linked fibrin and red blood cells) and white (platelet aggregates) thrombus.9 Reperfusion therapy has become the cornerstone in the treatment of STEMI.10–13 The basis of this strategy is to restore epicardial blood flow either by the fibrinolysis of thrombus or by mechanical displacement of thrombus in the case of percutaneous coronary intervention (PCI).

The Effectiveness of Reperfusion Therapy – Early Success in Thrombus Management The effectiveness of thrombolytic therapy has been well demonstrated in the Second international study of infarct survival (ISIS-2) study. This landmark randomised trial of 17,187 patients compared streptokinase alone, aspirin alone, the combination of aspirin and streptokinase vs neither in patients with suspected acute myocardial infarction (AMI).2 ISIS-2 demonstrated that streptokinase reduced mortality by 25 % and the combination of aspirin and streptokinase reduced mortality by 39 per cent.2 However, one of the limitations of fibrinolytic therapy is that reperfusion of the infarct artery is only successful in 50–60 % of cases.14 In comparison, primary PCI achieves TIMI 3 flow in 80–90 % of cases and meta-analyses of randomised trials show that PPCI compared to fibrinolysis reduces mortality.5,15

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Coronary Primary Angioplasty and High Risk PCI Table 1: Definition for Levels of Myocardial Blush Grade as Seen by Angiography Myocardial Blush Angiographic Finding Grade 0 Absence of myocardial blush or contrast density 1

Minimal myocardial blush or contrast density

Moderate myocardial blush or contrast density but less

than that obtained from the ipsilateral non-infarct

related coronary artery

Normal myocardial blush or contrast density,

comparable with that obtained during angiography of a

contralateral or ipsilateral non-infarct-related artery

Definitions adopted from Van’t Hof et al.15

Figure 1: The Relationship Between Myocardial Blush Grade and Survival in After Successful Percutaneous Intervention (Restoration of Thrombolysis in Myocardial Infarction [TIMI]-3 Flow) in Acute Myocardial Infarction 20

1 year cumulative mortality (%)

18 16 14

18.3 %

*p=0.004

16.2 %

12 10 8 6

6.8 %

Microvascular Perfusion There has been increasing focus on looking beyond flow in infarct artery to microvascular perfusion. ST resolution (STR) is considered a non-invasive measure of tissue perfusion.15 After PPCI, it has been shown that there was a reduction of mortality with more complete STR – in those with absent STR (<30 %) the mortality rate is 8.4 % whereas those with partial STR (30–70%) and complete STR (>70 %) have a mortality of 5.0 and 5.6 % respectively.19 Microvascular flow can also be assessed by the myocardial blush grade (MBG), an angiographic measure of microvascular perfusion. As shown in (see Table 1) MBG is graded from 0 (absence of blush) to 3 (normal myocardial blush). Blush assessment requires a longer than average cine run to determine if blush clears.15 MBG has been shown to be an independent predictor of ST segment resolution, Killip Class after primary PCI and mortality.15 Compared to MBG of three, an MBG of zero or one has an eight-fold higher risk of long-term mortality (3 vs 23 % at two years, p< 0.0001).15 Interestingly, in the same study up to 67 % of patients with TIMI 3 flow had MBG of 0 or 1 which again suggests that epicardial blood flow does not necessarily imply tissue level perfusion.15 Even among those with TIMI 3 flow after angioplasty, an MBG grade of 0 or 1 may be associated with an increase for mortality (relative risk 4.7; 95 % CI 2.3 to 9.5; p< 0.001) (see Figure 1).18,20 This data has led to new paradigm that TIMI 3 flow is not enough; we must find methods to improve microvascular perfusion during PPCI.

Myocardial blush grade 0 or 1 – no or minimal blush or contrast density seen in the myocardium supplied by culprit artery after angioplasty. Blush grade 2 – moderate blush or contrast density, and blush grade 3 – normal blush or contrast density when compared with non-culprit artery. Figure was adapted from data produced by Stone GW, et al.18

Abnormal tissue perfusion in the presence of a patent epicardial artery is a phenomenon which is referred to as “No Reflow”.6 TIMI flow of less than three after an artery has been opened during PPCI is the most common finding which can be associated with no reflow. It is also an independent predictor of long-term cardiac death (relative risk [RR] 5.25, 95 % confidence interval [CI] 1.85 to 14.9, p=0002).21

Microvascular vs Macrovascular ReperfusionImplications on Clinical Reperfusion

Pharmacological Strategies in Thrombus Management

Patency in Infarct-related Artery After Acute Myocardial Infarction and Outcome

The Role of Adjunctive Glycoprotein IIb IIIa Inhibitors (GP IIb IIIa Inhibitors): Intracoronary Abciximab

Previously, patency of infarct-related artery after thrombolysis has been defined by the Thrombolysis in myocardial infarction (TIMI) research group.16 The TIMI system grades antegrade flow seen angiographically. Grade 0 denotes no perfusion as seen by absence of contrast flow through stenosis.16 Grade 1 flow means there is contrast seen through stenosis but the artery fails to completely fill the entirety of the artery.16 Grade 2 flow indicates complete filling of the artery with contrast past the stenosis but the rate of flow is less than that seen in a normal artery, or contrast clearance is delayed compared to that seen in a normal artery.16 Grade 3 indicates that artery fills and clears of contrast completely at a rate comparable to a normal artery.16 The open artery hypothesis that relates an improvement in survival to establishing normal flow in the IRA and hence patency of the artery has been demonstrated in previous studies.17 TIMI grade 3 is associated with a marked reduction in 30-day mortality, with an odds ratio of 0.44 (95 % CI, 0.24 to 0.79).17 There appears to be stepwise improvement in outcomes with ranging from TIMI 0–3 after primary PCI.15,18 However, TIMI flow as a prognostic tool after PPCI is less useful because more than 90 % of patients have TIMI 3 flow at end of PPCI.15

Localised directed intracoronary (IC) administration of Abciximab in the infarct-related artery has attracted some recent research interest. There is theoretical advantage to this route of administration of providing a higher concentration of active drug at the site of thrombus given that Abciximab has a short plasma half-life. The intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction (INFUSE AMI) (N=452) study was a 2x2 factorial design randomising patients with STEMI on a background of dual antiplatelet therapy and Bivalarudin to thrombectomy plus IC abciximab (via clearway catheter), aspiration thrombectomy without IC abciximab, no aspiration thrombectomy plus IC abciximab and no aspiration thrombectomy plus no IC abciximab. This study showed a 2.8 % reduction in infarct size (p= 0.03) but also a numerical but not significant increase in TIMI major bleeding (2.2 vs 0.5 %; p =0.40).22 The significantly larger Abciximab intracoronary vs Intravenous drug application in ST-elevation myocardial infarction trial (AIDA STEMI) trial (N= 2065) comparing IC bolus (via guide catheter) vs intraveous abciximab in patients with STEMI showed no difference in the composite primary endpoint (all cause mortality, recurrent infarction or new congestive heart failure at 90 days (7.0 vs 7.6 %; odds ratio [OR] 0.91; 95 % CI 0.64-1.28; p=0.58).23

2 0

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0/1 2 3 Patients with TIMI -3 Flow Stratified by Myocardial Blush Grade

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The primary difference in the two trials is lack of abciximab in control group in INFUSE AMI. At the current time, the evidence does not support routine use of IC abciximab but future large scale randomised trials are needed if locally directed therapy (i.e. via clearway catheter) improves clinical outcomes.

Covered Stents There has been recent exploration of a bare metal stent (BMS) platform covered with a polyethylene terephthalate mesh (Mguard™ stent) that aims to trap thrombus and hence prevent distal embolisation.24 There has been one multicentre randomised study (n=433) comparing the efficacy of Mguard stent to conventional stents in STEMI. Both bare metal stents (BMS) or drug eluting stents (DES) at the operators discretion were allowed in the control arm. The primary outcome of complete STR post-procedure was significantly better in the patients randomised to the MGuard stenting arm compared with conventional stenting (57.8 % vs 44.7 %, absolute difference 13.2 %; 95 % CI 3.1 %–23.3 %; p=0.008). Limitations of the Mguard is coverage of side branches with mesh and bulkiness of device. The MASTER II trial is underway (N=1114), and is a larger trial testing Mguard vs BMS or DES in STEMI with a primary outcome of ST resolution. Ultimately, larger clinical outcome trials are needed to determine if this strategy of trapping thrombus with a mesh covered stent improves clinical outcomes and it would be optimal to have a drug eluting version to avoid restenosis.

Thrombectomy – Manual and Mechanical The rationale of thrombectomy is that if one can remove thrombus prior to deploying stent, there will be improvement in the myocardial blush grade and the risk of distal embolisation and no reflow can be reduced.25 There are two major types of thrombectomy – mechanical and manual aspiration.

Manual Thrombectomy Manual thrombectomy uses very simple devices that are essentially long tubes with syringes on the end. The Thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction study (TAPAS) trial was a single-centre trial (N=1071) that showed that in patients with STEMI, routine manual thrombectomy compared to PCI alone reduced impaired microvascular perfusion (primary outcome MBG zero or one) by 35 % (p< 0.001) and a trend toward reduced in cardiac mortality at 30 days (2.1 % versus 4.0 %; risk ratio, 0.52; 95 % CI, 0.26 to 1.07, p=0.07). At one-year follow-up this difference in cardiac death became statistically significant (3.6 % in thrombus aspiration group vs 6.7 % in the PCI alone group; hazard ratio (HR) 1.93; 95 % CI 1.11-3.37; p=0.02).26 Subsequent meta-analyses showed reductions in mortality but this was driven by the TAPAS trial.27 Based on the TAPAS trials, both the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) provided a class IIa recommendation for routine use of manual aspiration in primary PCI.12,28 The most recent and largest trial, the Thrombus aspiration in ST-elevation myocardial infarction in Scandinavia (TASTE) trial, a multicentre study randomising 7244 patients to thrombus aspiration versus PCI alone.29 The enrolment and randomisation was done within the infrastructure of the Swedish coronary angiography and angioplasty registry (SCAAR).29 Based on actual mortality rates in the Swedish registry, there was an expected 452 events to have an 80 % power to detect a 30 % relative risk reduction (RR).29 There was no significant difference in the primary outcome of all cause mortality

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at 30 days between thrombus aspiration plus PCI vs PCI alone (2.8 vs 3.0 %, hazard ratio 0.94, confidence interval [CI] 0.72 to 1.22, p=0.63).29 There were trends towards reduction in hospitalisation due to recurrent MI (0.5 % vs 0.9 % respectively; HR 0.61; 95 % CI, 0.34–1.07; p=0.09) and stent thrombosis (0.2 % vs 0.5 % respectively; HR 0.47; 95 % CI 0.20-1.02, p=0.06).29 TASTE had less than half the original number of planned events and so was underpowered for modest but clinically important reductions (20–30 % RRR) in all cause mortality. As a result, further data is needed. The ongoing randomised trial of routine aspiration Thrombectomy with PCI versus PCI alone in patients with STEMI undergoing primary PCI (TOTAL) is an event driven trial that will recruit 10,700 patients. The primary outcome will be cardiovascular death, MI, cardiogenic shock and class IV heart failure up to 180 days.30 The hypothesis of the trial is that by reducing thrombus burden at site of stent implantation, thrombectomy can prevent MI and stent thrombosis and by preventing no reflow, thrombectomy can prevent cardiogenic shock, heart failure and death. The TOTAL trial will definitively answer the question of whether routine aspiration thrombectomy reduces important clinical outcomes in primary PCI.

Mechanical Thrombectomy The most commonly used device employed for mechanical thrombectomy is the Angiojet rheolytic thrombectomy (RT) catheter.31 This device uses high velocity saline jets to break up thrombus and active suction to remove thrombus. There have been to randomised trials comparing Angiojet to conventional PCI in STEMI but have yielded conflicting results. The AngioJet rheolytic thrombectomy in patients undergoing primary angioplasty for acute myocardial infarction (AIMI) trial (n= 480) showed a 27 % increase in infarct size (p=0.03), no difference in STR or MBG and increase in mortality with routine use of Angiojet.32 The AngioJet rheolytic thrombectomy before direct infarct artery stenting with direct stenting alone in patients with acute myocardial infarction (JETSTENT) trial (n=501) showed that patients receiving routine RT before direct stenting (DS) compared with DT alone had a 7 % increase in STR (p= 0.04) but no significant improvement in infarct size. Unexpectedly the overall major adverse cardiovascular events (MACE) rates at six months were lower in the RT before DS compared to DS alone (11.2 % versus 19.4 %; p=0.011). The primary difference in the trials is the selection of patients with high thrombus burden in the JETSTENT vs all comers. It may be that the Angiojet is beneficial in those with large thrombus burden and not in those patients with minimal thrombus. A recent optical coherence tomography (OCT) trial suggests that the Angiojet when compared to manual thrombectomy may be more effective at thrombus removal.33 Future large-scale trials are needed to determine the effect of the modern Angiojet on clinical outcomes in the subset of patients with high thrombus burden after wire crossing.

Intracoronary Thrombolysis Prior to Manual Thrombectomy There has only been one randomised study investigating the effect of IC thrombolytic delivery prior to aspiration thrombectomy. The Delivery of thrombolytIcs before thrombectomy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (DISSOLUTION) trial (n=102) compared IC thrombolytic delivery (urokinase at 200, 000 U) via a microcatheter prior to aspiration thrombectomy compared with IC normal saline control

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Coronary Primary Angioplasty and High Risk PCI via microcatheter prior to aspiration thrombectomy in patients with large thrombus.34 It showed that patients treated with IC thrombolytic upfront prior to aspiration thrombectomy compared to control showed a higher rate of TIMI 3 flow (90 vs 66 %; p=0.008), higher rate of MBG 2 or 3 (68 vs 45 %; p=0.028) and higher rate of STR >70 % (82 vs 55 %, p=0.006) It also showed a significantly lower rate of MACE at six months in the upfront IC thombolytic group compared to control (6 % vs 21 %; p=0.044) but this was entirely driven by a reduction in re-hospitalisation for heart failure. Thrombolysis prior to thrombectomy allowed greater volume of aspirate from manual thrombectomy.

1. Nabel EG and Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med , 2012;366:54–63. 2. [No authors listed]. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. J Am Coll Cardiol 1988;12(6 Suppl A):3A–13A. 3. [No authors listed]. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet 1986;1:397–402. 4. Wilcox, RG, et al. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:525–30. 5. Keeley EC, Boura JA, Grines CL, Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet , 2003;361:13–20. 6. Jaffe R, et al. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention. Circulation 2008;117:3152–6. 7. Eagle KA, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004;110:e340–437. 8. DeWood MA, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897–902. 9. Mukherjee D and Moliterno DJ, Achieving tissue-level perfusion in the setting of acute myocardial infarction. Am J Cardiol 2000;85:39C–46C. 10. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349–60. 11. Zijlstra F, et al. Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999;341:1413–9. 12. Steg PG, 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.

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Further larger randomised trials are needed to validate these findings and test safety and efficacy of IC lytics as an adjunct to PCI.

Conclusion Rapid reperfusion therapy has led to marked to reductions in mortality in STEMI. However, therapies focused at preventing thrombus embolisation have failed to show improvements in mortality but so far trials have been underpowered. The largest trial of manual thrombectomy, the TOTAL trial, will inform us of the effect of routine manual thrombectomy on clinical outcomes in STEMI. n

13. Levine GN, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation , 2011;124:e574–651. 14. Cannon CP, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 1998; 98:2805–14. 15. van ‘t Hof, AW, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation , 1998;97:2302–6. 16. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group. N Engl J Med 1985;312:932–6. 17. Simes RJ, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation, 1995;91:1923–8. 18. Stone GW, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591–7. 19. Farkouh ME, et al. Relationship between ST-segment recovery and clinical outcomes after primary percutaneous coronary intervention: the HORIZONS-AMI ECG substudy report. Circ Cardiovasc Interv , 2013;6:216–23. 20. Henriques JP, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003;107:2115–9. 21. Morishima I, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000;36:1202–9. 22. Stone GW, et al. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 2012;307:1817–26. 23. Thiele H, et al. Intracoronary versus intravenous bolus abciximab during primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: a randomised trial. Lancet 2012;379:923–31. 24. Stone GW, et al. Prospective, Randomized, Multicenter Evaluation of a Polyethylene Terephthalate Micronet Mesh-

Covered Stent (MGuard) in ST-Segment Elevation Myocardial Infarction: The MASTER Trial. J Am Coll Cardiol, 2012;pii:S0735– 1097(12)04506-8. [ePub ahead of print]. 25. Mongeon FP, et al. Adjunctive thrombectomy for acute myocardial infarction: A bayesian meta-analysis. Circ Cardiovasc Interv , 2010;3:6–16. 26. Vlaar PJ, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet 2008;371:1915–20. 27. Bavry AA, Kumbhani DJ, Bhatt DL, Role of adjunctive thrombectomy and embolic protection devices in acute myocardial infarction: a comprehensive meta-analysis of randomized trials. Eur Heart J 2008;29:2989–3001. 28. O’Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140. 29. Frobert O, et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med 2013;369:1587–97. 30. Jolly SS, et al. Design and rationale of the TOTAL trial: a randomized trial of routine aspiration ThrOmbecTomy with percutaneous coronary intervention (PCI) versus PCI ALone in patients with ST-elevation myocardial infarction undergoing primary PCI. Am Heart J 2014;167:315–321 e1. 31. Migliorini A, et al. Comparison of AngioJet rheolytic thrombectomy before direct infarct artery stenting with direct stenting alone in patients with acute myocardial infarction. The JETSTENT trial. J Am Coll Cardiol 2010;56:1298–306. 32. Ali A, et al. Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study. J Am Coll Cardiol 2006;48:244–52. 33. Parodi G, et al. Comparison of manual thrombus aspiration with rheolytic thrombectomy in acute myocardial infarction. Circ Cardiovasc Interv , 2013;6:224–30. 34. Greco C, et al. Usefulness of local delivery of thrombolytics before thrombectomy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (the delivery of thrombolytics before thrombectomy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention [DISSOLUTION] randomized trial). Am J Cardiol 2013;112:630–5.

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Coronary Cardiogenic Shock

The Role of Percutaneous Haemodynamic Support in High-risk Percutaneous Coronary Intervention and Cardiogenic Shock Dagmar M Ouweneel, Bimmer E Claessen, Krischan D Sjauw and José PS Henriques AMC Heartcenter, Academic Medical Center, Amsterdam, The Netherlands

Abstract The experience and usage of percutaneous cardiac assist devices in cardiogenic shock as well as high-risk percutaneous coronary intervention have increased over the years. Nonetheless, there is still little evidence of clinical benefit of these devices other than immediate haemodynamic improvement. Despite the fact that these devices are used to treat a rather complex patient population, clinical testing remains important in order to evaluate their true impact on clinical outcome before being adopted into clinical practice. Therefore, this review shows an overview of the current experience and evidence of the available percutaneous cardiac assist devices.

Keywords Cardiogenic shock, myocardial infarction, high-risk PCI, percutaneous coronary intervention, mechanical circulatory support Disclosure: The Academic Medical Center has received a research grant from Abiomed. Dr. Henriques has received honoraria/speaking fees from Abiomed. Received: 8 December 2014 Accepted: 29 January 2015 Citation: Interventional Cardiology Review, 2015;10(1):39–44 Correspondence: José PS Henriques, AMC Heartcenter, Academic Medical Center – University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E: j.p.henriques@amc.uva.nl

The main goal of mechanical cardiac assistance is to provide haemodynamic support in case of an endangered coronary or systemic circulation by increasing or maintaining coronary and systemic blood flow. In addition to haemodynamic support, mechanical cardiac assistance may also provide myocardial protection by unloading the ventricle. The experience with percutaneous mechanical support devices is mainly gathered in patients with cardiogenic shock (CS) or during high-risk percutaneous coronary intervention (PCI). CS is a physiological state in which inadequate tissue perfusion results from cardiac dysfunction, most commonly due to acute myocardial infarction. Non-ischaemic causes include myocarditis, end-stage cardiomyopathy or sustained arrhythmias. CS remains the leading cause of death for hospitalised patients after ST-segment elevation myocardial infarction (STEMI).1 If CS occurs after STEMI, it is mostly a consequence of decreased myocardial contractility due to the infarction, resulting in a cascade of decreased cardiac output (CO), hypotension and decreased coronary blood flow, which will further reduce contractility and CO. This vicious circle may not only lead to further myocardial ischaemia, but also to diminished organ perfusion and ultimately multiple organ failure and death. Patients with complex or high-risk coronary lesions due to extensive and diffuse multivessel, left main or last remaining coronary artery disease, who previously were not considered suitable for PCI, are increasingly treated with PCI. In patients who have been refused for cardiac surgery, PCI is increasingly considered as an alternative. During these high-risk procedures, haemodynamic compromise and complications can occur rapidly, for which support of a mechanical cardiac assist device can be helpful, particularly in patients with poor

Henriques_FINAL.indd 39

left ventricular (LV) function. Although the exact role of mechanical cardiac assistance in periprocedural risk management of complex and high-risk PCI procedures remains debatable, a growing number of high-risk PCI procedures are being performed with mechanical cardiac assistance.

Haemodynamic Support The primary objective of cardiac support is the maintenance of haemodynamic stability. This is achieved by maintaining or improving coronary and systemic blood flow in order to ensure sufficient CO and adequate organ perfusion. The improvement of coronary and microvascular blood flow could also accelerate recovery of stunned myocardium after ischaemia. The SHOCK-trial investigators have shown that cardiac power output (CPO) is the best haemodynamic parameter to predict mortality in case of CS.2 This parameter takes the CO and the mean arterial pressure into account, based on the assumption that both adequate CO and blood pressure are necessary for sufficient end-organ perfusion. Haemodynamic support devices should be able to maintain both CO as well as blood pressure to provide adequate organ perfusion, ideally without the use of concomitant vasopressor or inotrope therapy.

Myocardial Protection Some mechanical assist devices protect the myocardium by increasing oxygen delivery and reducing the oxygen demand, thereby preventing myocardial damage. This is achieved by a combination of increasing the aortic pressure and unloading the ventricle. Depending on the device, unloading is achieved through direct unloading of the left ventricle or by decreasing the preload of the left ventricle. Unloading the left ventricle results in a decreased LV end-diastolic pressure and peak LV wall stress,

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Coronary Cardiogenic Shock Figure 1: Percutaneous Assist Devices

(A) Intra-aortic balloon counterpulsation; (B) The Impella is inserted percutaneously and positioned across the aortic valve in the left ventricle; (C) The TandemHeart ventricular assist device, which is placed in the left ventricle using a trans-septal cannula. (D) The venous access is connected to an extracorporeal membrane oxygenation (ECMO) system with an integrated centrifugal pump and membrane oxygenator (artificial lung) and connected to the arterial inflow access. From Werdan et al.3 With permission.

which in turn leads to decreased microvascular resistance, myocardial work load and myocardial oxygen consumption. By decreasing microvascular resistance, coronary blood flow is increased, as the latter is the result of the pressure difference between the proximal and distal vascular bed. In conclusion, the ideal cardiac assist device protects

several limitations to the IABP. The augmentation of CO is likely to be insufficient for patients with severe CS. Also, to provide haemodynamic support it requires a certain level of LV function. Finally, the function of the IABP relies on synchronisation with the cardiac cycle, which might not be reliable in case of cardiac arrhythmias in critically ill patients.

the myocardium by increasing coronary perfusion and decreasing myocardial workload.

Impella

Mechanical Assist Devices Over the past decades, many LV support devices have been developed, such as surgical bridge-to-transplant or destination therapy devices as well as temporary (percutaneous) bridge-to-recovery devices. During an acute critical presentation, a less-invasive percutaneous approach is preferable as it provides a quick and easy deployment. The ideal device is instantly accessible and should be associated with a low complication rate, as sometimes complications outweigh the potential beneficial effects. Complications associated with any (percutaneous) LV assist device include limb ischaemia, embolisation of atherosclerotic or thrombotic material, stroke, infection and haemolysis. In the following sections, the most common and currently used percutaneous devices are described: the intra-aortic balloon pump (IABP), TandemHeart (Cardiac Assist Inc., Pittsburgh, PA, US), ECMO (extracorporeal membrane oxygenation) and Impella (Abiomed Europe GmbH, Aachen, Germany). These devices differ in insertion technique as well as working mechanism.

Intra-aortic Balloon Pump The IABP was, since its introduction in 1968, the most frequently used and broadly available cardiac assist device. The IABP is inserted percutaneously in the femoral artery and the balloon is positioned in the descending thoracic aorta distal to the left subclavian artery and proximal to the renal artery branches (see Figure 1A).3 The balloon is synchronised to the cardiac cycle and is rapidly inflated during diastole and rapidly deflated during early systole by input and removal of helium gas. The IABP is assumed to increase coronary and systemic blood flow due to augmentation of the diastolic blood pressure during inflation of the balloon. Deflation of the balloon decreases myocardial oxygen demand by decreasing afterload and ventricular wall tension, while slightly increasing coronary bloodflow.4 The IABP generates an increase of CO up to approximately 0.3–0.5 l/min. There are

Henriques_FINAL.indd 40

The Impella is a micro-axial rotary pump that is placed across the aortic valve expelling aspirated blood from the left ventricle into the ascending aorta (see Figure 1B). Currently, there are three versions of the Impella system available. The Impella 2.5 and Impella CP can provide up to 2.5 l/min and 3.5–4.0 l/min, respectively, and are percutaneously inserted. The Impella 5.0 can deliver up to 5.0 l/min but requires a surgical cutdown of the femoral or axillary artery. The device has a pigtail-catheter at the tip to ensure stable positioning in the left ventricle and to avoid adhering to the myocardium. The direct unloading of the left ventricle is an important feature of the Impella. The unloading effect of the Impella 2.5 was demonstrated by a reduction in end-diastolic wall stress and immediate decrease in pulmonary capillary wedge pressure (PCWP).5–7 The Impella-induced increase in coronary bloodflow probably results from both an increased perfusion pressure and a decreased LV volume-related intra-myocardial resistance. In an experimental setting, haemodynamic support and unloading with the Impella has been demonstrated to reduce infarct size.8 The Impella 5.0 should result in even more unloading due to the substantially larger contribution to overall circulation. In contrast to the IABP, the Impella works independently of LV function and cardiac rhythm.

TandemHeart TandemHeart is a trans-septal ventricular assist device that is inserted through the femoral vein and right atrium into the left atrium via an atrial septum puncture (see Figure 1C). The outflow cannula is inserted through the femoral artery and positioned at the level of the aortic bifurcation. It has a continuous flow centrifugal pump with a maximal rotation speed of 7,500 revolutions per minute, which can deliver up to 4 l/min. The haemodynamic effects of the TandemHeart are an increase of CO and mean arterial blood pressure (MAP) and a decrease of PCWP, central venous pressure (CVP) and pulmonary artery pressure (PAP). This results in reduced filling pressures in the left and right ventricle, a reduced cardiac workload and a lower oxygen demand.9–11 However, it should be

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The Role of Percutaneous Haemodynamic Support in High-risk PCI and Cardiogenic Shock

noted, that without direct LV unloading, the increased MAP translates to increased LV afterload, which partially offsets the potential benefit of the lower cardiac workload. The main concerns are the complications (bleeding and limb ischaemia) and the complex insertion procedure.

Figure 2: Impella RP

Percutaneous Extracorporeal Membrane Oxygenation ECMO can be achieved percutaneously and is a modified heart–lung machine, which can be used for several days (see Figure 1D). The ECMO system generally consists of a centrifugal pump, a heater and an oxygenator. Venous blood flows from the right atrium into a centrifugal pump and oxygenator and is guided via an outflow cannula in the femoral artery into the descending aorta. The advantage of ECMO over the other percutaneous devices is its ability to provide support in case of RV (RV) failure, to provide higher blood flow rates (up to 4.5 l/min depending on the cannula size) and to oxygenate the blood. Complications associated with ECMO are a systemic inflammatory response, renal failure, limb ischaemia and bleeding complications. Although ECMO can provide substantial haemodynamic support, it also increases both afterload and preload of the left ventricle, increasing the oxygen demand and impeding myocardial protection.12 However, patient transportation with ECMO is relatively easy, which makes it possible to start ECMO support outside the hospital.13

Right Ventricular Assist Devices RV dysfunction has been shown to be a predictor of mortality in STEMI patients with and without CS.14,15 Although the majority of diagnostic and therapeutic approaches for CS are predominantly directed at the left ventricle, there are also assist devices that support the right ventricle. First of all the IABP has been thought to alleviate the RV but clear evidence is absent and due to its limited LV support it is unlikely that the IABP will assist the RV in a meaningful manner. The TandemHeart has an alternative set-up in which it can serve as a RV assist device.16 ECMO can also be used for RV or biventricular failure, as it displaces blood volume from the venous to the arterial circulation and oxygenates the blood. The disadvantage is that LV afterload is increased because there is no direct unloading of the left ventricle. The Impella RP, a specific Impella to support the right ventricle, has recently received a CE-mark in Europe. The Impella RP is placed percutaneously through the femoral vein and advanced in an antegrade fashion across the pulmonic valve into the pulmonary artery (see Figure 2). The Impella RP can provide flow up to 5 l/min for an anticipated duration of 14 days.17

Evidence The current experience with percutaneous mechanical support devices is mainly in patients with CS or during high-risk PCI.

High-risk Percutaneous Coronary Intervention During PCI, haemodynamic compromise and complications can occur rapidly, for which support of a mechanical cardiac assist device can be helpful, particularly in patients with poor LV function. Support of a mechanical assist device might be an appealing treatment strategy, however, iatrogenic complications due to this invasive therapy should not outweigh the potential benefits. The exact role of mechanical support devices during high-risk PCI, the indication as well as the optimal device, is still open to debate. There is no generally accepted guideline-based definition for high-risk PCI, but it usually includes features such as a reduced LV function (ejection fraction [EF] <30 %), procedural complexity and procedural ischaemic risk, such as in left main PCI or last remaining vessel PCI.

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The Impella RP is inserted percutaneously. The inflow portion of the catheter resides in the inferior vena cava, and a flexible cannula traverses the right atrium, tricuspid valve and pulmonic valve. The outflow portion of the catheter resides in the main pulmonary artery. The figure was provided by Abiomed.

When looking at the use of IABP in high-risk PCI, a few registries showed a potential benefit.18,19 Perera and colleagues performed a multicentre randomised controlled trial in high-risk PCI using prophylactic IABP placement before the procedure. They showed that usage of IABP did not reduce 28-day major adverse cardiac and cardiovascular events (MACCE).20 Patients undergoing elective IABP placement had fewer procedural complications, however, the rates of access complications and minor bleeding was higher. However, longterm follow up of these patients did show a difference in mortality.21 Regarding the use of Impella 2.5 during high-risk PCI, a few registries showing safety and feasibility of Impella 2.5 during high-risk PCI.22–25 There is one randomised controlled trial (PROTECT II), which showed no difference between Impella 2.5 and IABP on major adverse events on 30 and 90 days. However, this trial was prematurely discontinued for futility and therefore underpowered. Subgroup analysis showed significantly lower major adverse event rates in the Impella 2.5 group after excluding the first patients per group at each site, suggesting a learning curve associated with the initial introduction of the Impella 2.5.26 The learning curve shows that clinical trials should better address the training aspect of new devices, especially when compared with more established devices. The learning curve should also be taken into account when starting to work with a new device, especially in unstable patients. Increased utilisation of percutaneous assist devices in this elective setting will provide an important opportunity for operators to become familiar with these new devices. With increasing experience, operators also will feel more comfortable with the use in an acute setting.

Cardiogenic Shock Intra-aortic Balloon Pump Until recently, there were no large randomised controlled clinical trials investigating IABP therapy in the setting of STEMI complicated

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Coronary Cardiogenic Shock Table 1: Comparison of Devices ECMO

TandemHeart

Impella 2.5

Impella CP

Impella 5.0

Impella RP

Pump mechanism Pneumatic

IABP

Centrifugal

Axial flow

Cannula size

18–21 F inflow;

21 F inflow;

13 F, 9 F catheter

14 F, 9 F catheter

22 F, 9 F catheter

23 F, 9 F catheter

15–22 F outflow

15–17 F outflow

shaft

shaft; surgical cut-

shaft

7–9 F

down Insertion

Descending

Inflow cannula into 21 F inflow cannula

12 F catheter

technique

aorta via the

the right atrium via into left atrium via

placed retrograde placed retrograde

retrograde across

placed antegrade

femoral artery

the femoral vein;

femoral vein and

across the aortic

the aortic valve via

through the femoral

outflow cannula

trans-septal puncture valve via the

valve via the

a surgical cut-down

vein crossing

into descending

and 15–17 F outflow

femoral artery

of the femoral

the tricuspid and

aorta via femoral

cannula into femoral

artery

pulmonary valve

artery

0.5–1.0 l/min

> 4.5 l/min

4 l/min

2.5 l/min

3.5–4.0 l/min

5.0 l/min

4.0 l/min

Implantation time

++++

Risk of limb

+++

Anticoagulation

+++

Haemolysis

Requires stable

Yes

+++

++++

Haemodynamic

femoral artery

14 F catheter

21 F catheter placed 23 F catheter

support

ischaemia

heart rhythm Post-implantation management complexity +

Relative qualitative grading concerning time (‘implantation time’);

++++

risk (‘risk of limb ischaemia’);

+++

intensity (‘anticoagulation’, ‘post-implantation management complexity’);

severity (‘haemolysis’). Adapted from Ouweneel and Henriques.46

by CS. A meta-analysis of cohort studies published in 2009 concluded that there was insufficient evidence to support the previously strong guideline recommendation for IABP therapy in the setting of STEMI complicated by CS. The meta-analysis supported IABP therapy adjunctive to thrombolysis, but showed an increase in mortality for IABP therapy concomitant to primary PCI. More important the meta-analysis showed that the studied available observational data were importantly hampered by bias and confounding.27 A recently published Cochrane individual–patient–data meta-analysis of randomised controlled trials on patients with myocardial infarction complicated by CS, included six eligible and two ongoing studies with a total of 190 patients.28 The authors concluded that these few randomised trials were not able to show convincing evidence for either benefit of harm. The recently performed large randomised controlled multicentre IABP-SHOCK II trial randomised a total of 600 patients with STEMI complicated by CS, between IABP and medical therapy.29,30 No difference was found in 30-day all-cause mortality nor in other clinical endpoints. This trial confirmed the findings of the previously performed meta-analysis, showing no improved clinical outcome in patients treated with IABP concomitant to primary PCI in the setting of STEMI complicated by CS.

TandemHeart Only a few small studies are performed using the TandemHeart but none of them were powered on mortality.9,10,31 These studies showed an improvement in haemodynamic values, mixed venous oxygen saturation and urine output and the two randomised controlled trials confirmed the superior improvement of haemodynamic parameters compared with IABP therapy. However, complications such as severe bleeding, arrhythmias and limb ischaemia occurred more often when using the TandemHeart than in cases of IABP. Although both studies were not

Henriques_FINAL.indd 42

powered to detect differences in mortality, no difference in mortality was found, which is also shown in a meta-analysis including both trials.32

Extracorporeal Membrane Oxygenation Veno-arterial ECMO has been used successfully for several years in refractory CS, caused by myocarditis, postcardiotomy, myocardial infarction or heart transplantation.33 Described survival rates depend highly on the aetiology of the CS. In the setting of acute myocardial infarction, there are no randomised controlled trials. However, there are several cohort studies suggesting advantage from early use of ECMO.34,35 The usage of ECMO during resuscitation seems to increase, not only when resuscitation is performed inside a hospital, but also outside the hospital.13 The time from cardiac arrest to ECMO flow seems to be a critical determinant of outcome. However, no randomised trials have been performed yet.36

Impella Only a few studies have reported on Impella usage in CS patients. Meyns et al. showed initial safety and feasibility in six patients with severe CS after maximal inotropic support and IABP therapy.7 They showed decreased PCWP and blood lactate levels and increased MAP and CO after usage of Impella. The ISAR-SHOCK randomised trial compared IABP with Impella 2.5 in CS patients.37 They showed increased cardiac index, CO and MAP in patients treated with Impella compared with IABP-treated patients. Also, they found that the overall cardiac power index (CPI) was slightly higher in Impella patients but the endogenous CO of the left ventricle was significantly lower because of the additional work of the device. Serum lactate levels were lower in the Impella group compared with the IABP group. No difference in mortality, major bleeding, distal limb ischaemia, arrhythmias and infections were found. The

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long-term effects of Impella support are described in the setting of STEMI-treated PCI and showed no aortic valve damage.38 Also, the Impella group patients showed more LVEF recovery compared with control patients. In severe CS, the Impella 5.0 may result in superior haemodynamic support. Engström et al. described the experience with the use of the Impella 2.5 and 5.0 and suggest that Impella 5.0 placement should be considered for profound CS patients.39 Either immediate insertion of Impella 5.0 or a quick upgrade to Impella 5.0 after initial 2.5 Impella was advised to be considered in cases with severe shock without signs of recovery. There are two ongoing randomised controlled trials evaluating Impella CP in the setting of CS: i.e. IMPRESS in Severe Shock (Impella CP versus IABP, NTR3450) and the Danish Cardiogenic Shock Trial (Impella CP versus optimal medical therpay, NCT01633502).

Combined Therapies There are several cases describing a combination of ECMO and Impella therapy. It was found that the increased LV load due to the retrograde aortic blood return via the arterial cannula of ECMO could be counteracted by the use of Impella, which unloads the left ventricle.40–42 There have also been several reports on combining Impella with IABP therapy.43,44 However, the forward flow of the Impella may be degraded during diastole due to the diastolic pressure augmentation from the IABP. Although the combined use of IABP and Impella might theoretically increase coronary flow, due to a variety of technical reasons its combined use is not recommended. These reasons may range from misinterpretation of Impella alarms and the repetitious reductions of flow during IABP operation, which may prolong red cell transit times and thus increasing shear stress possibly leading to haemolysis. For patients with severe right heart failure, a combination of an Impella RP and a LV assist device has been described.17,45

Guidelines Recently, the guidelines on the role of mechanical circulatory support in patients with STEMI complicated by CS have significantly changed. The European guidelines of 2010 recommended the use of IABP (class I/C) in patients with CS, whereas the guidelines of 2014 do not recommend the routine use of IABP anymore (class III/A) (see Table 1).46 The main reasons for changing the guidelines are the publication of a meta-analysis and a large randomised controlled trial evaluating the clinical benefit of the IABP, both showing no beneficial effect on 30-day mortality.27,29 The 2013 US guidelines recommend to assess the need for inotropic therapy, IABP or both on an individual basis, as observational data are conflicting. The superior haemodynamic support of LV assist devices is mentioned, but with the annotation that the experience is limited. In these guidelines, IABP has a class IIa recommendation in patients who do not quickly stabilize with pharmacological therapy. Alternative LV assist devices may be considered in patients with refractory CS (class IIb). An overview of recommendations of using mechanical assist devices in CS is shown in Table 2.47–51

Future Perspectives The experience of usage of mechanical assist devices is expanding rapidly. The indications include not only acute CS patients and highrisk PCI, but also as a bridge-to-transplant in advanced heart failure patients. In the forthcoming years, the development and the usage of percutaneous assist devices will increase and haemodynamic support will be used more frequently as an additional treatment in several patient groups. As recent studies were not able to show a

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Table 2: Previous and Current Guidelines A) European Guidelines47–49 Year Device

Recommendation

2010

I/C

IABP

IABP insertion is recommended in patients

with haemodynamic instability (particularly

those in cardiogenic shock and with

mechanical complications)

LV assist

III/B

devices

pumps is not recommended

2012

IABP

Intra-aortic balloon pumping may be

IIb/B

Routine use of percutaneous centrifugal

considered (in patients with cardiogenic

shock [Killip class IV])

LV assist

LV assist devices may be considered for

devices

IIb/C

circulatory support in patients in

refractory shock

2014

Routine use of IABP in patients with

IABP

III/A

cardiogenic shock is not recommended

LV assist

Short-term mechanical circulatory support

devices

IIb/C

in ACS patients with cardiogenic shock may be considered

B) American Guidelines50,51 Year Device

Recommendation

2011

I/B

IABP

A haemodynamic support device is

recommended for patients with

cardiogenic shock after STEMI who

do not quickly stabilise with

pharmacological therapy

LV assist

A haemodynamic support device is

devices

I/B

recommended for patients with

cardiogenic shock after STEMI who

do not quickly stabilise with

pharmacological therapy

2013

The use of IABP counterpulsation can be

IABP

IIa/B

useful for patients with cardiogenic shock

after STEMI who do not quickly stabilise

with pharmacological therapy

LV assist

Alternative LV assist devices for circulatory

devices

IIb/C

support may be considered in patients with refractory cardiogenic shock

ACS = acute coronary syndrome; IABP = intra-aortic balloon pump; LV = left ventricular; STEMI = ST-segment elevation myocardial infarction.

survival benefit of the frequently used IABP in CS after myocardial infarction, the experience with other assist devices will expand in this setting. Other assist devices have not yet shown their benefit on survival, and are usually not available outside expert centres. As many attending cardiologists often feel the need to do more than just initiate pharmaceutical inotropic support, IABP will probably continue to be used until alternatives are widely available. However, it is important that other assist devices show clinical effectiveness before they become common clinical practice. For usage of mechanical assist devices during high-risk PCI, there are two important questions that need to be answered. First, the question rises in terms of the role of mechanical circulatory support during these procedures. Is there a clinical benefit and, if so, in which patients? Second, which support device is the most optimal in this setting? The complications should not outweigh the possible clinical benefit of these invasive devices. Future developments on mechanical assist devices need to focus on minimising insertion-point-related complications like limb-ischaemia

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Coronary Cardiogenic Shock and severe bleeding by reducing the device size while maintaining sufficient haemodynamic support. Also thrombo-embolic complications should be reduced and the associated morbidity needs to be minimised. New mechanical support devices, such as the pulsatile ECMO (Pulsecath) and the Reitan catheter pump (Cardiobridge), are being developed. The usage of percutaneous RV assist devices in case of RV failure is in development but only little experience is available. Choosing the appropriate mechanical support device may depend on the degree of support needed. In consequence, subgroups of patients regarding the severity of CS have to be defined to allow a

1. Goldberg RJ, Spencer FA, Gore JM, et al., Thirty-year trends (1975 to 2005) in the magnitude of, management of, and hospital death rates associated with cardiogenic shock in patients with acute myocardial infarction: a population-based perspective, Circulation , 2009;119(9):1211–9. 2. Fincke R, Hochman JS, Lowe AM, et al., Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry, J Am Coll Cardiol , 2004;44(2):340–8. 3. Werdan K, Gielen S, Ebelt H, Hochman JS, Mechanical circulatory support in cardiogenic shock, Eur Heart J, 2014;35(3):156–67. 4. Scheidt S, Wilner G, Mueller H, et al., Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a co-operative clinical trial, N Engl J Med , 1973;288(19):979–84. 5. Sjauw KD, Remmelink M, Baan J Jr, et al., Left ventricular unloading in acute ST-segment elevation myocardial infarction patients is safe and feasible and provides acute and sustained left ventricular recovery, J Am Coll Cardiol , 2008;51(10):1044–6. 6. Remmelink M, Sjauw KD, Henriques JP, et al., Effects of left ventricular unloading by Impella recover LP2.5 on coronary hemodynamics, Catheter Cardiovasc Interv , 2007;70(4):532–7. 7. Meyns B, Dens J, Sergeant P, et al., Initial experiences with the Impella device in patients with cardiogenic shock – Impella support for cardiogenic shock, Thorac Cardiovasc Surg , 2003;51(6):312–7. 8. Meyns B, Stolinski J, Leunens V, et al., Left ventricular support by catheter-mounted axial flow pump reduces infarct size, J Am Coll Cardiol , 2003;41(7):1087–95. 9. Thiele H, Sick P, Boudriot E, et al., Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock, Eur Heart J, 2005;26(13):1276–83. 10. Burkhoff D, Cohen H, Brunckhorst C, O’Neill WW, A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock, Am Heart J , 2006;152(3):469–8. 11. Thiele H, Lauer B, Hambrecht R, et al., Reversal of cardiogenic shock by percutaneous left atrial-to-femoral arterial bypass assistance, Circulation , 2001;104(24):2917–22. 12. Kawashima D, Gojo S, Nishimura T, et al., Left ventricular mechanical support with Impella provides more ventricular unloading in heart failure than extracorporeal membrane oxygenation, ASAIO J , 2011;57(3):169–76. 13. Beurtheret S, Mordant P, Paoletti X, et al., Emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-RESCUE program), Eur Heart J, 2013;34(2):112–20. 14. Hamon M, Agostini D, Le Page O, et al., Prognostic impact of right ventricular involvement in patients with acute myocardial infarction: meta-analysis, Crit Care Med , 2008;36(7):2023–33. 15. Engstrom AE, Vis MM, Bouma BJ, et al., Right ventricular dysfunction is an independent predictor for mortality in ST-elevation myocardial infarction patients presenting with cardiogenic shock on admission, Eur Heart J, 2010;12(3):276–82. 16. Atiemo AD, Conte JV, Heldman AW, Resuscitation and recovery from acute right ventricular failure using a percutaneous right ventricular assist device, Catheter Cardiovasc Interv , 2006;68(1):78–82. 17. Cheung AW, White CW, Davis MK, Freed DH, Short-term mechanical circulatory support for recovery from acute right ventricular failure: clinical outcomes, J Heart Lung Transplant, 2014;33(8):794–9.

Henriques_FINAL.indd 44

better discrimination between patient groups and devices to detect beneficial or harmful effects on outcome in different subgroups.

Conclusion The ideal device generates sufficient haemodynamic support to prevent end-organ failure, but also myocardial protection to prevent myocardial ischaemia and has a low complication rate. The experience and usage of percutaneous cardiac assist devices in CS as well as high-risk PCI has increased over the past years. However, there is still little evidence of clinical benefit of these invasive devices and it is important that they prove their clinical benefit before they become common clinical practice. n

18. Mishra S, Chu WW, Torguson R, et al., Role of prophylactic intra-aortic balloon pump in high-risk patients undergoing percutaneous coronary intervention, J Am Coll Cardiol , 2006;98(5):608–12. 19. Briguori C, Sarais C, Pagnotta P, et al., Elective versus provisional intra-aortic balloon pumping in high-risk percutaneous transluminal coronary angioplasty, Am Heart J , 2003;145(4):700–7. 20. Perera D, Stables R, Thomas M, et al., Elective intra-aortic balloon counterpulsation during high-risk percutaneous coronary intervention: a randomized controlled trial, JAMA , 2010;304(8):867–74. 21. Perera D, Stables R, Clayton T, et al., Long-term mortality data from the balloon pump-assisted coronary intervention study (BCIS-1): a randomized, controlled trial of elective balloon counterpulsation during high-risk percutaneous coronary intervention, Circulation , 2013;127(2):207–12. 22. Sjauw KD, Konorza T, Erbel R, et al., Supported high-risk percutaneous coronary intervention with the Impella 2.5 device the Europella registry, J Am Coll Cardiol , 2009;54(25):2430–4. 23. Henriques JP, Remmelink M, Baan J Jr, et al., Safety and feasibility of elective high-risk percutaneous coronary intervention procedures with left ventricular support of the Impella Recover LP 2.5, J Am Coll Cardiol , 2006;97(7):990–2. 24. Burzotta F, Paloscia L, Trani C, et al., Feasibility and long-term safety of elective Impella-assisted high-risk percutaneous coronary intervention: a pilot two-centre study, J Cardiovasc Med (Hagerstown), 2008;9(10):1004–10. 25. Dixon SR, Henriques JP, Mauri L, et al., A prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial U.S. experience, JACC Cardiovasc Interv , 2009;2(2):91–6. 26. Henriques JP, Ouweneel DM, Naidu SS, et al., Evaluating the learning curve in the prospective Randomized Clinical Trial of hemodynamic support with Impella 2.5 versus Intra-Aortic Balloon Pump in patients undergoing high-risk percutaneous coronary intervention: a prespecified subanalysis of the PROTECT II study, Am Heart J , 2014;167(4):472–9 e5. 27. Sjauw KD, Engstrom AE, Vis MM, et al., A systematic review and meta-analysis of intra-aortic balloon pump therapy in ST-elevation myocardial infarction: should we change the guidelines?, Eur Heart J , 2009;30(4):459–68. 28. Unverzagt S, Machemer MT, Solms A, et al., Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock, Cochrane Database Syst Rev , 2011(7):CD007398. 29. Thiele H, Zeymer U, Neumann FJ, et al., Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial, Lancet , 2013;382(9905):1638–45. 30. Thiele H, Zeymer U, Neumann FJ, et al., Intraaortic balloon support for myocardial infarction with cardiogenic shock, N Engl J Med, 2012;367:1287–96. 31. Kar B, Gregoric ID, Basra SS, Iet al., The percutaneous ventricular assist device in severe refractory cardiogenic shock, J Am Coll Cardiol , 2011;57(6):688–96. 32. Sjauw KD, Engstrom AE, Henriques JP, Percutaneous mechanical cardiac assist in myocardial infarction. Where are we now, where are we going?, Acute Card Care , 2007;9(4):222–30. 33. Abrams D, Combes A, Brodie D, Extracorporeal membrane oxygenation in cardiopulmonary disease in adults, J Am Coll Cardiol , 2014;63(25 Pt A):2769–78. 34. Sakamoto S, Taniguchi N, Nakajima S, Takahashi A, Extracorporeal life support for cardiogenic shock or cardiac arrest due to acute coronary syndrome, Ann Thorac Surg , 2012;94(1):1–7.

35. Sheu JJ, Tsai TH, Lee FY, et al., Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock, Crit Care Med , 2010;38(9):1810–7. 36. Fagnoul D, Combes A, De Backer D, Extracorporeal cardiopulmonary resuscitation, Curr Opin Crit Care , 2014;20(3):259–65. 37. Seyfarth M, Sibbing D, Bauer I, et al., A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction, J Am Coll Cardiol , 2008;52(19):1584–8. 38. Engstrom AE, Sjauw KD, Baan J, et al., Long-term safety and sustained left ventricular recovery: long-term results of percutaneous left ventricular support with Impella LP2.5 in ST-elevation myocardial infarction, EuroIntervention , 2011;6(7):860–5. 39. Engstrom AE, Cocchieri R, Driessen AH, et al., The Impella 2.5 and 5.0 devices for ST-elevation myocardial infarction patients presenting with severe and profound cardiogenic shock: the Academic Medical Center intensive care unit experience, Crit Care Med , 2011;39(9):2072–9. 40. Chaparro SV, Badheka A, Marzouka GR, et al., Combined use of Impella left ventricular assist device and extracorporeal membrane oxygenation as a bridge to recovery in fulminant myocarditis, ASAIO J , 2012;58(3):285–7. 41. Koeckert MS, Jorde UP, Naka Y, et al., Impella LP 2.5 for left ventricular unloading during venoarterial extracorporeal membrane oxygenation support, J Card Surg, 2011;26(6):666–8. 42. Cheng A, Swartz MF, Massey HT, Impella to unload the left ventricle during peripheral extracorporeal membrane oxygenation, ASAIO J , 2013;59(5):533–6. 43. Cubeddu RJ, Lago R, Horvath SA, et al., Use of the Impella 2.5 system alone, after and in combination with an intraaortic balloon pump in patients with cardiogenic shock: case description and review of the literature, Eurointervention , 2012;7(12):1453–60. 44. Wiktor DM, Sawlani N, Kanthi Y, et al., Successful combined use of Impella Recover 2.5 device and intra-aortic balloon pump support in cardiogenic shock from acute myocardial infarction, ASAIO J , 2010;56(6):519–21. 45. Hunziker P, Hunziker L, Percutaneous biventricular cardiac assist device in cardiogenic shock, Eur Heart J , 2013;34(22):1620. 46. Ouweneel DM, Henriques JPS, Percutaneous cardiac support devices for cardiogenic shock: current indications and recommendations, Heart , 2012;98(16):1246–54. 47. Wijns W, Kolh P, Danchin N, et al., Guidelines on myocardial revascularization, Eur Heart J , 2010;31(20):2501–55. 48. 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(20):2569–619. 49. Windecker S, Kolh P, 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 CardioThoracic Surgery (EACTS), Eur Heart J, 2014;35(37):2541–619. 50. Levine GN, Bates ER, Blankenship JC, et al., 2011 ACCF/AHA/ SCAI Guideline for Percutaneous Coronary Intervention: A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions, Circulation , 2011;124(23):e574-e651. 51. O’Gara PT, Kushner FG, Ascheim DD, et al., 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol , 2013;61(4):e78–140.

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Structural Patent Foramen Ovale

Percutaneous Closure of Patent Foramen Ovale – Data from Randomized Clinical Trials and Meta-Analyses Stefa n S t o r t e c k y a n d S t e p h a n Wi n d e c k e r Swiss Cardiovascular Centre Bern, Department of Cardiology, University Hospital, Bern, Switzerland

Abstract Data from epidemiologic studies have indicated a close association between the presence of a patent foramen ovale (PFO) and cryptogenic stroke that is suggestive of paradoxical embolism as the underlying cause. Percutaneous closure of PFO has been proposed for the secondary prevention among patients suffering from paradoxical embolism. While observational data support this strategy, three randomized trials investigating percutaneous PFO closure with medical therapy have failed to detect a statistically significant reduction of the primary endpoint of recurrent ischemic cerebrovascular events, peripheral embolism, and death in the intention-to-treat analysis. Several reasons have been discussed as basis for the negative primary study results, including long recruitment rates, low number of recurrent events, and the use of different devices. In order to provide an answer to these unresolved factors, several meta-analyses have been published that have provided conflicting results. This article will review the available evidence of percutaneous PFO closure, will provide an overview on randomized clinical trials, and summarize the evidence from meta-analyses.

Keywords Cerebrovascular events, cryptogenic, stroke, patent foramen ovale, PFO, percutaneous closure Disclosure: Dr. Stortecky has no conflicts of interest to declare. Dr. Windecker reports having received research grants to the institution from Abbott, Biotronik, Boston Scientific, Edwards Lifesciences, The Medicines Company, Medtronic, and St Jude, and speaker fees from Abbott, Astra Zeneca, Bayer, Biotronik, Biosensors, Boston Scientific, and Eli Lilly. Received: 15 December 2014 Accepted: 10 February 2015 Citation: Interventional Cardiology Review, 2015;10(1):45–8 Correspondence: Stefan Stortecky, Department of Cardiology, Swiss Cardiovascular Centre Bern, Bern University Hospital, 3010 Bern, Switzerland. E: stefan.stortecky@insel.ch

Cerebrovascular events are associated with high rates of morbidity and mortality and are considered the global second leading cause of death.1 The majority of strokes are ischemic, although the etiology remains unknown in a considerable number of patients,2 commonly referred to as “non-defined” or “cryptogenic.” 3 Data from epidemiologic studies point towards a relevant association between the prevalence of a patent foramen ovale (PFO) and the occurrence of cryptogenic stroke or embolism.4 Thus, paradoxical embolism via PFO has been suggested as plausible mechanism and etiology of cryptogenic cerebrovascular or other embolic events in a considerable number of patients.5 However, the true prevalence of paradoxical embolism is unknown, as the clinical diagnosis of proved or impending events remains difficult.6 Percutaneous PFO closure has been proposed as effective treatment for the secondary prevention of recurrent cerebrovascular or peripheral embolism, and several devices have been introduced into clinical practice. Observational studies investigating percutaneous PFO closure for patients with presumed paradoxical embolism suggested a substantial benefit in the secondary prevention of recurrent neurologic and vascular events over medical therapy,7,8 and even a mortality benefit during long-term follow-up when comparing patients after device closure with patients before or without PFO closure.7

Stortecky_FINAL.indd 45

Randomized Evidence—PFO Closure versus Medical Therapy Two devices for percutaneous PFO closure (STARFlex, NMT Medical, Boston, MA, US; Amplatzer PFO Occluder, St Jude Medical, Plymouth, MN) have been investigated in three randomized clinical trials and compared with medical therapy among patients with cryptogenic stroke or embolism.9–11

CLOSURE I Trial The first randomized trial investigating whether percutaneous PFO closure is effective in the secondary prevention of recurrent ischemic stroke was the multicenter CLOSURE I trial.9 PFO closure was performed with the STARFlex closure device, and medical therapy consisted of either warfarin (target international normalized ratio [INR] 2–3) or acetylsalicylic acid (325 mg/d) as implemented by the treating neurologist. A total of 909 patients with a previous history of stroke or transient ischemic attack (TIA) were included in this study and randomized in a 1:1 fashion to either undergo PFO closure or medical therapy between 2003 and 2008. The primary endpoint of the study was assessed after 2 years and consisted of a composite endpoint of stroke or TIA within 2 years, death of any cause during the first 30 days, and death of neurologic cause after 30 days up to 2 years of follow-up. After 2 years of follow-up, no difference was observed in the primary endpoint between percutaneous PFO

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Structural Patent Foramen Ovale closure and medical therapy (adjusted hazard ratio [HR] 0.78, 95 % confidence interval [CI] 0.45–1.35; p=0.37). While the low event rates have been noted, procedural and device specific attributes and complications attracted considerable attention. Effective closure of PFO closure with the STARFlex device was achieved in only 87 % of patients after 2 years of follow-up and device-associated thrombus was as frequent as 1.1 % of patients and considered responsible for recurrent stroke in two patients. Of note, the risk for new onset of atrial fibrillation was almost eightfold increased among PFO closure patients compared with those allocated to medical treatment (5.7 % versus 0.7 %; p<0.001), two-thirds of which have been observed in the first week after the intervention.

PC Trial The Amplatzer PFO Occluder was investigated in the PC trial, which was initiated in 2000 as a multicenter, randomized clinical trial.10 A total of 414 patients have been recruited and randomized to either PFO closure using the Amplatzer PFO Occluder (n=204) or medical therapy (n=210). After a mean follow-up duration of 845 patient-years in the closure group and 835 patient-years in the medical therapy group, the predefined combined primary endpoint of all-cause death, recurrent stroke, TIA, or peripheral embolism had occurred in seven patients of the closure group compared with 11 patients in the medical therapy group (HR 0.63; 95 % CI 0.24–1.62; p=0.34). Recruitment was protracted over almost 9 years, and the event rate was low in both treatment arms. Of note, a numerical difference in recurrent stroke was observed with an 86 % relative risk reduction in the Amplatzer PFO Occluder compared with the medical therapy group (HR 0.14, 95 % CI 0.02–1.17; p=0.07) after implementing the endpoint definition applied in the RESPECT trial.

RESPECT Trial The RESPECT trial was conducted between 2003 and 2011 as multicenter, randomized clinical trial to investigate the effectiveness of PFO closure with the Amplatzer PFO Occluder in the secondary prevention of ischemic vascular events. In the overall patient cohort of 980 patients and after a maximum follow-up duration of 8.1 years of follow-up, the primary endpoint recurrent stroke or death within either 30 days after the intervention or 45 days after randomization was observed in nine patients of the PFO closure group compared with 16 patients of the medical therapy group (HR 0.49, 95 % CI 0.22–1.11; p=0.08). While the intention-to-treat analysis provided a numerical difference in the primary endpoint between treatment groups, the per-protocol analysis (HR 0.37, 95 % CI 0.14–0.96; p=0.03) and the as-treated analysis (HR 0.27, 95 % CI 0.10–0.75; p=0.007) favored percutaneous PFO closure over medical therapy. Of note, the treatment effect was particularly pronounced among patients with high-risk PFO criteria as defined by the presence of a substantial shunt (0.8 % versus 4.3 %; p=0.012) or atrial septal aneurysm (1.1 % versus 5.3 %; p=0.016) at baseline. None of the patients had signs of device-related thrombus during echocardiographic follow-up in RESPECT and the PC trial. A nonsignificant twofold increased risk for new onset of atrial fibrillation was noted in the closure group compared with patients receiving medical therapy alone (3.0 % vs 1.5 %; p=0.13), but this was not associated with adverse events.

Randomized Evidence—PFO Closure Devices Most recently, long-term data from a randomized controlled trial investigating clinical outcomes and device-specific differences of three PFO occluder devices (Amplatzer PFO Occluder, STARFlex, or

Stortecky_FINAL.indd 46

HELEX, (WL Gore and Associates, Flagstaff, AZ) became available,12 and provided further information for the ongoing debate. A total of 660 patients with previous cryptogenic stroke and PFO were recruited and randomized to closure with one of these closure devices. No differences were observed in technical success between devices; however, significant differences in effective PFO closure rates were observed (Amplatzer versus STARFlex versus HELEX, 98.6 % versus 96.8 % versus 91.8 %; p=0.0012) during follow-up assessment. The primary composite endpoint, recurrent cerebral ischemia, death from neurologic cause, or paradoxical embolism within 5 years after the index procedure was observed in 1.4 %, 6.0 %, and 4.0 % of patients, respectively (p=0.04). Furthermore, there were significant differences in device-associated thrombus formation (0 % versus 5.0 % versus 0.5 %, respectively; p<0.0001) and new-onset of atrial fibrillation (3.6 % versus 12.3 % versus 2.3 %, respectively; p<0.0001) during the followup duration of 5 years.

Meta-analyses Summarizing Randomized Evidence Several meta-analyses with various statistical approaches and different composite endpoints have been published to date, summarizing the available evidence from randomized clinical trials (see Table 1). By combining the results of the three randomized trials investigating PFO closure compared with medical therapy, Wolfrum et al. came to the conclusion that PFO closure does not appear to be superior in patients with cryptogenic stroke or embolism, 13 showing a nonsignificant relative risk (RR) reduction of 44 % in the primary intention-to-treat (RR 0.66, 95 % CI 0.37–1.19) and in the per protocol analysis (RR 0.66, 95 % CI 0.32–1.38). Similarly, Kitsios et al. failed to show a significant reduction for the endpoint stroke (HR 0.55, 95 % CI 0.26–1.18); however, a significant effect was observed when analyzing the composite primary outcomes (HR 0.67, 95 % CI 0.44– 1.00). By using the same trial data and in contrast to the previous analyses, Rengifo-Moreno et al. was able to prove a relevant benefit in the reduction of cerebrovascular events (recurrent stroke and TIA; HR 0.59, 95 % CI 0.36–0.97) and furthermore in the combined endpoint of death and vascular events (HR 0.67, 95 % CI 0.44–1.00). Moreover, in a subgroup analysis the authors point towards a potential beneficial effect of percutaneous PFO closure among patients with substantial PFO shunt (HR 0.35, 95 % CI 0.12–1.03), however, this did not reach statistical significance.14 Capodanno et al. reported no beneficial effect for percutaneous PFO closure when compared with medical therapy in the secondary prevention of stroke (HR 0.62, 95 % CI 0.34–1.11).15 However, separating the data according to the PFO device used showed a significant reduction of stroke (HR 0.44, 95 % CI 0.20–0.95) among patients receiving the Amplatzer PFO Occluder, suggesting a device-specific effect on clinical outcomes. A variation in effectiveness and safety between different devices has been further emphasized after the availability of the long-term data of a randomized head-to-head comparison of the three most frequently used devices.12 Using the data of this head-to-head comparison, potential device specific effects on clinical outcomes were investigated by performing a network meta-analysis (see Table 1).13–33 Overall, the results of this analysis indicated a clinically relevant difference in effectiveness between the Amplatzer and the STARFlex device.16 Accordingly, the probability to be best in preventing recurrent cerebrovascular events was 77.1 % for the Amplatzer, 20.9 % for the Helex, and 1.7 % for the STARFlex PFO

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Percutaneous Closure of Patent Foramen Ovale

Table 1: Meta-analyses Investigating Percutaneous PFO Closure Results (ITT) Author

Year

Wolfrum M et al.13

2014

Recurrent Stroke (95 % CI)

Subgroup Analyses Composite Endpoint (95 % CI)

RR 0.66 (0.37–1.19) –

Description

(95 % CI)

RR 0.66 (0.32–1.38)

–

Amplatzer only

RR 0.44 (0.20–0.94

–

Amplatzer only

OR 0.46 (0.21–0.98)

–

RR 0.71 (0.22–2.27)

Substantial shunt

–

RR 0.37 (0.09–1.45)

Amplatzer only

HR 0.44 (0.21–0.94)

–

HR 0.64 (0.41–0.98)

Amplatzer only (PP)

–

HR 0.64 (0.44–0.97)

PP analysis

HR 0.62 (0.40–0.95)

–

As treated analysis

HR 0.61 (0.40–0.95)

–

Amplatzer only

HR 0.54 (0.29–1.01))

–

Amplatzer only

RR 0.48 (0.23–1.02)

–

2014

OR 0.64 (0.37–1.10) –

Dentali F et al.18

2014

RR 0.66 (0.37–1.19) RR 0.71 (0.48–1.06) Atrial septal aneurysm

2013

HR 0.62 (0.36–1.07) –

Riaz IB et al.20

2013

–

Khan AR et al.21

2013

HR 0.66 (0.43–1.01) PP analysis

HR 0.67 (0.44–1.00) –

Composite Endpoint

PP analysis

Hernandez J et al.17

Pandit A. et al.19

Recurrent Stroke

Zhang B et al.22

2013

RR 0.66 (0.37–1.19) –

Hakeem A et al.23

2013

RR 0.66 (0.35–1.24) RR 0.71 (0.48–1.06) PP analysis

–

RR 0.66 (0.43–1.00)

Nagaraja V et al.24

2013

OR 0.65 (0.36–1.19) –

Atrial septal aneurysm

RR 0.7 (0.21–2.33)

–

Substantial shunt

RR 0.35 (0.09–1.41)

–

HR 0.62 (0.38–1.00)

Substantial shunt

–

HR 0.35 (0.12–1.03)

Atrial septal aneurysm

–

HR 0.68 (0.32–1.42)

Rengifo-Moreno P et al.14

2013

HR 0.62 (0.36–1.07) HR 0.67 (0.44–1.00) PP analysis

Pineda AM et al.25

2013

OR 0.65 (0.36–1.20) OR 0.70 (0.47–1.05) As treated analysis

–

OR 0.62 (0.41–0.94)

Chen L et al.26

2013

–

Ntaios G et al.27

2013

OR 0.64 (0.37–1.10) –

Amplatzer only

OR 0.46 (0.21–0.98)

–

Kwong JS et al.28

2013

OR 0.65 (0.36–1.20) –

Amplatzer only

OR 0.47 (0.22–1.02)

–

Kitsios GD et al.29

2013

HR 0.55 (0.26–1.18) HR 0.67 (0.44–1.00) Amplatzer only

HR 0.38 (0.14–1.02)

HR 0.44 (0.17–1.12)

Capodanno D et al.30

2013

HR 0.62 (0.36–1.11) –

Amplatzer only

HR 0.44 (0.20–0.95)

–

Spencer FA et al.31

2014

RR 0.61 (0.34–1.07) –

Amplatzer only

RR 0.44 (0.21–0.93)

–

Stortecky S et al.16

2014

–

Amplatzer only

RR 0.39 (0.17–0.84)

–

StarFlex only

RR 1.01 (0.44–2.41)

–

Helex only

RR 0.71 (0.17–2.78)

–

RR 0.70 (0.47–1.04) –

–

Udell JA et al.32

2014

RR 0.66 (0.37–1.19) RR 0.73 (0.50–1.07) Amplatzer only

RR 0.48 (0.23–1.02)

0.64 (0.37–1.11)

Pickett CA et al.33

2014

RR 0.62 (0.35–1.11) RR 0.67 (0.44–1.01) PP analysis

–

RR 0.64(0.41–0.98)

RR 0.44 (0.21–0.95)

–

Amplatzer only

AT = as treated; HR = hazard ratio; ITT = intention to treat; PP = per protocol; RR = risk ratio or relative risk; OR = odds ratio. Depicted are analyses from random effect models as presented.

closure device, and only 0.4 % for medical therapy alone. Differences in device design and material resulted in a significant reduction of recurrent stroke when using the Amplatzer (RR 0.39, 95 % CI 0.17–0.84), whereas the STARFlex (RR 1.01, 95 % CI 0.44–2.41) and the Helex device (RR 0.71, 95 % CI 0.17–2.78) were not able to show a statistically significant secondary preventive effect. Conversely, the implantation of the Amplatzer device was associated with a twofold increased risk and the STARFlex with a sevenfold increased risk for new-onset atrial fibrillation compared with medical therapy alone.

Future Outlook Three randomized trials are currently registered and recruiting patients, with the aim to contribute to our understanding of safety and efficacy of PFO closure when compared with medical therapy: • D EFENSE-PFO (NCT01550588): comparing PFO closure with the Amplatzer device with medical therapy in 210 patients during a follow-up duration of 2 years. • Gore REDUCE trial (NCT00738894): compares PFO closure with the Helex PFO occlude in 664 patients with an estimated mean follow-up of 6 years.

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• C LOSE trial (NCT00562289): allocates 900 patients to either PFO closure with different devices, or antiplatelet/ antithrombotic therapy. The recently published evidence of specific inter-device comparisons on clinical outcomes will make the interpretation of the results difficult, unless the setup of the trial allows stratification by type of device.

Summary Randomized clinical trials and the large number of meta-analyses have been performed to further inform the discussion on the effectiveness of percutaneous PFO closure in the secondary prevention of cryptogenic stroke and embolism. While the available evidence points towards a potential treatment effect in favor of percutaneous PFO closure, there still remain substantial uncertainties. In addition to device-specific differences that may impact on clinical outcomes owing to differences in closure success and predisposition for thrombus formation and atrial arrhythmias, appropriate patient selection remains crucial. Although not specifically examined in dedicated randomized trials, patients with certain echocardiographic high-risk criteria, such as atrial septal aneurysm and other anatomical and functional characteristics

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Structural Patent Foramen Ovale of the PFO, which are associated with increased shunt size, as well as the presence of an Eustachian valve or a Chiari network, contribute to an increased risk of recurrent embolic events and may benefit most from percutaneous PFO closure. However, additional

5. 6.

10.

11.

12.

13.

Lozano R, Naghavi M, Foreman K, et al., Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010, Lancet , 2012;380:2095–128. Sacco RL, Ellenberg JH, Mohr JP, et al., Infarcts of undetermined cause: the NINCDS Stroke Data Bank, Ann Neurol , 1989;25:382–90. Handke M, Harloff A, Olschewski M, et al., Patent foramen ovale and cryptogenic stroke in older patients, N Engl J Med , 2007;357:2262–8. Lechat P, Mas JL, Lascault G, et al., Prevalence of patent foramen ovale in patients with stroke, N Engl J Med , 1988;318:1148–52. Windecker S, Stortecky S, Meier B, Paradoxical embolism, J Am Coll Cardiol , 2014;64:403¬15. Hargreaves M, Maloney D, Gribbin B, Westaby S, Impending paradoxical embolism: a case report and literature review, Eur Heart J , 1994;15:1284–5. Wahl A, Juni P, Mono ML, et al., Long-term propensity scorematched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism, Circulation , 2012;125:803–12. Agarwal S, Bajaj NS, Kumbhani DJ, et al., Meta-analysis of transcatheter closure versus medical therapy for patent foramen ovale in prevention of recurrent neurological events after presumed paradoxical embolism, JACC Cardiovasc Interv , 2012;5:777-89. Furlan AJ, Reisman M, Massaro J, et al., Closure or medical therapy for cryptogenic stroke with patent foramen ovale, N Engl J Med , 2012;366:991–9. Meier B, Kalesan B, Mattle HP, et al., Percutaneous closure of patent foramen ovale in cryptogenic embolism, N Engl J Med , 2013;368:1083–91. Carroll JD, Saver JL, Thaler DE, et al., Closure of patent foramen ovale versus medical therapy after cryptogenic stroke, N Engl J Med , 2013;368:1092–100. Hornung M, Bertog SC, Franke J, et al., Long-term results of a randomized trial comparing three different devices for percutaneous closure of a patent foramen ovale, Eur Heart J , 2013;34:3362–9. Wolfrum M, Froehlich GM, Knapp G, et al., Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis, Heart , 2014;100:389–95.

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randomized studies comparing PFO closure with medical therapy are unlikely to answer these open questions conclusively, given the low rates of recurrent events, and unrealistically large treatment effect assumptions used for sample size considerations. n

14. Rengifo-Moreno P, Palacios IF, Junpaparp P, et al., Patent foramen ovale transcatheter closure versus medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials, Eur Heart J , 2013;34:3342–52. 15. Capodanno D, Milazzo G, Vitale L, et al., Updating the evidence on patent foramen ovale closure versus medical therapy in patients with cryptogenic stroke: a systematic review and comprehensive meta-analysis of 2,303 patients from three randomised trials and 2,231 patients from 11 observational studies, EuroIntervention , 2014;9:1342–9. 16. Stortecky S, da Costa BR, Mattle HP, et al., Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis, Eur Heart J , 2015;36:120–8. 17. Hernandez J, Moreno R, Percutaneous closure of patent foramen ovale: “Closed” door after the last randomized trials?, World J Cardiol , 2014;6:1–3. 18. Dentali F, Gianni M, Mumoli N, et al., Efficacy and safety of patent foramen ovale closure in patients with a cryptogenic stroke: Systematic review and meta-analysis, Thromb Haemost , 2014;111. 19. Pandit A, Aryal MR, Pandit AA, et al., Amplatzer PFO occluder device may prevent recurrent stroke in patients with patent foramen ovale and cryptogenic stroke: A Meta-Analysis Of Randomised Trials, Heart Lung Circ , 2014;23:303–8. 20. Riaz IB, Dhoble A, Mizyed A, et al., Transcatheter patent foramen ovale closure versus medical therapy for cryptogenic stroke: a meta-analysis of randomized clinical trials, BMC Cardiovasc Disord , 2013;13:116. 21. Khan AR, Bin Abdulhak AA, Sheikh MA, et al., Device closure of patent foramen ovale versus medical therapy in cryptogenic stroke: a systematic review and meta-analysis, JACC Cardiovasc Interv , 2013;6:1316–23. 22. Zhang B, Zhou J, Li H, et al., Transcatheter closure of patent foramen ovale does not reduce the risk of recurrent ischemic stroke versus medical therapy alone: a meta-analysis of randomized controlled trials, Int J Cardiol , 2013;169:e106–8. 23. Hakeem A, Marmagkiolis K, Hacioglu Y, et al., Safety and efficacy of device closure for patent foramen ovale for secondary prevention of neurological events: Comprehensive systematic review and meta-analysis of randomized controlled trials, Cardiovasc Revasc Med , 2013;14:349–55.

24. Nagaraja V, Raval J, Eslick GD, et al., Is transcatheter closure better than medical therapy for cryptogenic stroke with patent foramen ovale? A meta-analysis of randomised trials, Heart Lung Circ , 2013;22:903–9. 25. Pineda AM, Nascimento FO, Yang SC, et al., A meta-analysis of transcatheter closure of patent foramen ovale versus medical therapy for prevention of recurrent thromboembolic events in patients with cryptogenic cerebrovascular events, Catheter Cardiovasc Interv , 2013;82:968–75. 26. Chen L, Luo S, Yan L, Zhao W, A systematic review of closure versus medical therapy for preventing recurrent stroke in patients with patent foramen ovale and cryptogenic stroke or transient ischemic attack, J Neurol Sci , 2014;337:3–7. 27. Ntaios G, Papavasileiou V, Makaritsis K, Michel P, PFO closure versus medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and metaanalysis, Int J Cardiol , 2013;169:101–5. 28. Kwong JS, Lam YY, Yu CM, Percutaneous closure of patent foramen ovale for cryptogenic stroke: a meta-analysis of randomized controlled trials, Int J Cardiol , 2013;168:4132–8. 29. Kitsios GD, Thaler DE, Kent DM, Potentially large yet uncertain benefits: a meta-analysis of patent foramen ovale closure trials, Stroke , 2013;44:2640–3. 30. Capodanno D, Milazzo G, Vitale L, et al., Updating the evidence on patent foramen ovale closure versus medical therapy in patients with cryptogenic stroke: asystematic review and comprehensive meta-analysis of 2,303 patients from three randomised trials and 2,231 patients from 11 observational studies, EuroIntervention , 2012;91342–9. 31. Spencer FA, Lopes LC, Kennedy SA, Guyatt G, Systematic review of percutaneous closure versus medical therapy in patients with cryptogenic stroke and patent foramen ovale, BMJ Open , 2014;4:e004282. 32. Udell JA, Opotowsky AR, Khairy P, et al., Patent foramen ovale closure vs medical therapy for stroke prevention: metaanalysis of randomized trials and review of heterogeneity in meta-analyses, Can J Cardiol , 2014;30:1216–24. 33. Pickett CA, Villines TC, Ferguson MA, Hulten EA, Percutaneous closure versus medical therapy alone for cryptogenic stroke patients with a patent foramen ovale: meta-analysis of randomized controlled trials, Tex Heart Inst J , 2014;41:357–67.

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Structural Transcatheter Aortic Valve Implantation

LE ATION.

Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation R oberto Spina , 1 Ch r i s A n t h o n y, 2 D a v i d WM M u l l e r 3 a n d D a v i d Ro y 4 1. Interventional Cardiology Fellow; 2. Cardiology Specialist Registrar; 3. Head, Cardiac Catheterization Laboratories; 4. Interventional Cardiologist, Department of Cardiology, St Vincent’s Hospital, Sydney, Australia

declare. o declare.

Abstract Transcatheter aortic valve replacement with either the balloon-expandable Edwards SAPIEN XT valve, or the self-expandable CoreValve prosthesis has become the established therapeutic modality for severe aortic valve stenosis in patients who are not deemed suitable for surgical intervention due to excessively high operative risk. Native aortic valve regurgitation, defined as primary aortic incompetence not associated with aortic stenosis or failed valve replacement, on the other hand, is still considered a relative contraindication for transcatheter aortic valve therapies, because of the absence of annular or leaflet calcification required for secure anchoring of the transcatheter heart valve. In addition, severe aortic regurgitation often coexists with aortic root or ascending aorta dilatation, the treatment of which mandates operative intervention. For these reasons, transcatheter aortic valve replacement has been only sporadically used to treat pure aortic incompetence, typically on a compassionate basis and in surgically inoperable patients. More recently, however, transcatheter aortic valve replacement for native aortic valve regurgitation has been trialled with newer-generation heart valves, with encouraging results, and new ancillary devices have emerged that are designed to stabilize the annulus–root complex. In this paper we review the clinical context, technical characteristics and outcomes associated with transcatheter treatment of native aortic valve regurgitation.

Keywords TAVI, TAVR, transcatheter aortic valve implantation, transcatheter aortic valve aortic replacement, aortic regurgitation, Jena Valve, Core Valve, Acurate TA Valve Disclosure: The authors have no conflicts of interest to declare. Received: 12 December 2014 Accepted: 31 January 2015 Citation: Interventional Cardiology Review, 2015;10(1):49–54 Correspondence: David Roy, Interventional Cardiologist, Department of Cardiology, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. E: deproy@hotmail.com

Transcatheter aortic valve replacement (TAVR) with either the balloonexpandable Edwards SAPIEN XT valve (Edwards Lifesciences, Irvine, California), or the self-expandable CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) has become the established therapeutic modality for severe aortic valve stenosis in patients who are not deemed suitable for surgical intervention due to excessively high operative risk. In the pivotal Placement of Aortic Transcatheter Valves (PARTNER) randomized trial, TAVR with the Edwards SAPIEN valve prosthesis, compared with conventional therapy, decreased the rate of death at 1 year, reduced cardiac symptoms, and was associated with improvement in valve function.1 Medium-2 and longer-term3 follow-up studies of the PARTNER trial patient cohort demonstrated sustained benefit of TAVR over standard therapy in terms of mortality, functional status, and hemodynamic performance of the aortic valve. In addition, in high-risk patients with severe aortic stenosis (AS), transcatheter aortic valve implantation and surgical replacement of the aortic valve were associated with similar rates of survival at 1 year4 and 2 years.5 Native aortic valve regurgitation (NAVR), defined as primary aortic regurgitation not associated with AS or failed surgical or TAVR, is still considered a relative contraindication for transcatheter aortic valve therapies. In fact, in the PARTNER trial, patients with severe (grade ≥3) aortic incompetence were excluded from the study, because of the

Roy_FINAL.indd 49

absence of annular or leaflet calcification required for secure anchoring of the transcatheter heart valve and the associated risk for valve dislocation.1 In addition, severe aortic regurgitation often is accompanied by aortic root or ascending aorta dilatation, the treatment of which mandates operative intervention. In recent years, TAVR has been sporadically used to treat NAVR in surgically inoperable patients. Initial reports described transcatheter deployment of the Medtronic CoreValve prosthesis or the Edwards SAPIEN XT valve to treat NAVR on a compassionate basis,6–9 and in special settings such as left ventricular (LV) assist device,10,11 or heart transplantation.12 The initial experience has been comprehensively reviewed by Roy et al.13 More recently, TAVR for isolated aortic regurgitation has been performed with newer-generation valves, such as the JenaValve (JenaValve Technology, Munich, Germany), the ACURATE TA valve (Symetis, Ecublens, Switzerland), and the Medtronic Engager valve (Medtronic 3F Therapeutics, Inc., Santa Ana, California, US).14 In addition, new ancillary devices such as the Helio dock have emerged that are specifically designed to stabilize the annulus–root complex, and have been trialled in conjunction with older-generation transcatheter aortic valve prostheses.15

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Structural Transcatheter Aortic Valve Implantation Table 1: Guideline Recommendations for Surgery in Patients with Aortic Incompetence Indication Symptomatic patients

ACC/AHA ESC Class I Class I

Undergoing CABG or surgery on aorta or other valve

Class I

Asymptomatic patients

Class I

LV systolic dysfunction (EF <50 %)

Class I

Severe LV dilatation (LVEDD >75 mm or ESD >55 mm) Class IIa

–

Severe LV dilatation (LVEDD >75 mm or ESD >55 mm) Class IIb

Class IIa

ACC = American College of Cardiology; AHA = American Heart Association; CABG = coronary artery bypass graft; EF = ejection fraction; ESC = European Society of Cardiology; ESD = endsystolic dimension; LV – left ventricular; LVEDD = left ventricular end-diastolic dimension.

Figure 1: The Jena Valve

The JenaValve transapical system consists of a porcine root valve mounted on a low-profile self-expanding nitinol stent. The porcine root leaflets are connected to flexible stent posts designed to reduce leaflet stress in diastole. Reprinted from Eurointervention, Vol. 8, Treede et al., copyright (2012), with permission from Europa Digital & Publishing.

Figure 2: Jena Valve Deployment

The JenaValve transcatheter heart valve (A) and its implantation in illustration (B to D) and fluoroscopy (E to H). Release of the positioning feelers and placement into the aortic sinuses enables anatomic orientation (B and F). After correct orientation has been verified in two different fluoroscopic angulations, release of the lower stent part facilitates the clipping of the native aortic valve leaflets to the device and expansion of the stent allowing for secure anchoring even in the absence of valve calcium (C and G). Release of the upper stent part completes deployment of the valve prosthesis (D and H). Reprinted with permission from J Am Coll Cardiovasc Interven, Vol 7, Sieffert et al., Copyright (2014).

Aortic Regurgitation and Indications for Valve Replacement NAVR arises from failure of the aortic valve leaflets to appose during ventricular diastole, a process that may occur because of leaflet damage or distortion or from dilatation of the ascending root. Whereas a fibro-calcific degenerative process accounts for the large majority of cases of AS, the aetiologic spectrum of aortic incompetence is much broader. Globally, rheumatic heart disease accounts for a large burden

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of isolated aortic incompetence. In the developed world, degenerative and congenital conditions, such as bicuspid aortic valve, are more common causes of isolated aortic regurgitation.16 Enlargement of the aortic root and ascending aorta can occur concurrently and are frequently interdependent. The prevalence estimates of NAVR vary widely depending of the definition of aortic regurgitation used and the characteristics of the population: 2–30 %.16 The prevalence of significant NAVR in the general population is estimated at 1 %.16 Patients with mild aortic regurgitation rarely develop significant symptoms or LV dysfunction: even severe aortic regurgitation can remain indolent for a prolonged period of time. Symptoms may develop, however, once the imbalance between diastolic LV distension, myocardial muscle mass, and systolic wall tension leads to progressive LV dilatation and systolic dysfunction. Prognosis in patients with severe aortic regurgitation is associated with both the presence of symptoms and LV dysfunction. In a study of 246 patients with moderate of severe aortic regurgitation, 10-year mortality was closely associated with symptoms: those in New York Heart Association (NYHA) class II–IV had an annual mortality of 25 % compared with the 3 % mortality seen in asymptomatic patients.17 In addition, patients with LV dysfunction had a threefold greater mortality than those with preserved function.17 A long-term postoperative study has demonstrated improved survival when patients undergo early AVR after onset of mild symptoms, mild LV dysfunction (ejection fraction [EF] 45 % to 50 %), or end-systolic dimension 50 to 55 mm rather than waiting for more severe symptoms or more severe LV dysfunction to develop.18 Accordingly, the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines recommend aortic valve replacement when symptoms supervene, or once LV dilatation (LV end-systolic diameter >55 mm) or LV dysfunction (LVEF <50 %) develop (see Table 1).19

TAVR for Native Aortic Valve Regurgitation— Experience with the First-generation Transcatheter Heart Valves Initial attempts at catheter-based treatment of NAVR in patients deemed surgically inoperable used first-generation transcatheter heart valves, such as the CoreValve and the Edwards SAPIEN valve. The CoreValve has hitherto been the preferred valve because of its technical and design characteristics. In particular, self-expandable valves, such as the CoreValve, offer high and permanent recoil forces that are thought to provide better stability in the noncalcified native aortic valve apparatus compared with the balloon-expandable transcatheter valves. Though neither valve was designed to treat this condition, successful cases have been reported.

Edwards SAPIEN The Edwards SAPIEN heart valve system, which consists of a tri-leaflet bovine pericardial valve and a balloon-expandable, stainless steel support frame, has been used infrequently in the treatment of aortic regurgitation. One report describes the trans-apical deployment of a 29 mm valve via mini-thoracotomy and under cardiopulmonary bypass for a patient who developed severe aortic incompetence despite a structurally normal valve following LV assist device implantation.10 The procedure required substantial over-sizing (29 mm valve for a 21 mm annulus that would normally require a 23 mm valve). No residual aortic incompetence was noted, but no follow-up data

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Table 2: Registry Reports of Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation First-generation Transcatheter Heart Valves Registry report

Number of

patients

TAVI device

Procedural

30-day

success

mortality

30-day stroke

Requirement for

Permanent pacemaker

Residual AR ≥II

second procedure implantation

Roy et al.21

CoreValve

74.4 %

9.3 %

4.7 %

18.6 %

16.3 %

21 %

Testa et al.22

CoreValve

79 %

23 %

0 %

19.2 %

5 %

23 %

Second-generation Transcatheter Heart Valves Seiffert et al.30 31 JenaValve 96.8 %

12.9 %

0 %

6.4 %

Wendt et al.32

0 %

ACURATE TA

100 %

AR = aortic regurgitation; TAVI = transcatheter aortic valve implantation.

were provided. Another case report documented procedural failure, with deployment of a 26 mm Edwards SAPIEN valve prosthesis in a patient with severe AR and an aortic annulus diameter of 26 mm, followed by valve dislocation soon after deployment and embolization into the left ventricle.20 A 29 mm CoreValve was then deployed successfully after retrieval of the embolized Edwards SAPIEN valve.

CoreValve The CoreValve prosthesis consists of a tri-leaflet biological valve sewn into a self-expanding nitinol frame. An international registry study demonstrated the feasibility and potential procedural difficulties when using TAVI for severe AR21 (see Table 2). The study described 43 patients who underwent TAVR for NAVR with the CoreValve between 2011 and 2012 at 14 centers worldwide. All patients had pure severe AR and were deemed surgically inoperable with mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), 26.9±17.9 %; and mean STS (Society of Thoracic Surgeons) score, 10.2±5.3 %. Although procedural success was high, with successful implantation of a TAVR in 42 out of 43 (97.7 %) patients (one conversion to open heart surgery), eight patients (18.6 %) required a second valve during the index procedure for residual aortic regurgitation. Post-procedure aortic regurgitation grade II or higher was present in nine patients (21 %), meaning that the Valve Academic Research Consortium (VARC)-defined procedure success was reduced to 74.4 %.21 At 30 days, the major stroke incidence was 4.7 %, and the allcause mortality rate was 9.3 %. At 12 months, the all-cause mortality was 21.4 % (six out of 28 patients). Also of interest was the finding that the need for a second valve was limited to patients without aortic valve calcification. This study demonstrated the feasibility of this technique and highlighted the potential procedural difficulties in treating NAVR with TAVR. In a large CoreValve registry from Italy, 1,557 consecutive patients undergoing TAVR, of whom 26 (1.6 %) presented with AR, were prospectively followed and baseline clinical characteristics and clinical outcomes compared22 (see Table 2). Patients with AR were significantly younger (mean age 73±10 versus 82±6), more frequently suffered from advanced heart failure symptoms (NYHA Class III/IV 95 % versus 73 %), and had a higher incidence of severe pulmonary hypertension (SPAP >60 mmHg, 31 % versus 10 %) compared with patients with AS. Logistic EuroSCORE and STS scores were similar between the two groups and VARC-defined device success was lower in the AR group (79 % versus 96 %). At 1 month, patients treated for AR had a higher overall mortality (23 % versus 5.9 %, odds ratio [OR] 4.22) and cardiac mortality (15.3 % versus 4 %, OR 4.01). At 12 months, overall and cardiac mortality remained higher for patients who underwent TAVR for AR compared with AS (31 % versus 19 %, hazard ratio [HR] 2.1, and 19.2 % versus 6 %, HR 3.1, respectively).22

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Table 3: Aetiology of Aortic Incompetence in the Four Combined Registry Series (n=108) Sclerotic degenerative

67 (62 %)

Aortic aneurysm/annular dilatation

15 (13.9 %)

Sequelae of endocarditis

10 (9.3 %)

Takayasu’s arteritis, rheumatoid vasculitis

5 (4.6 %)

Post-radiation therapy

3 (2.8 %)

Aortic dissection

3 (2.8 %)

Rheumatic heart disease

1 (0.9 %)

Other

4 (3.7 %)

Figure 3: The ACURATE TA Valve

The ACURATE TA device consists of a self-expandable nitinol stent, available in three sizes, which acts as an anchoring structure within the aortic annulus through its upper and lower crowns (A). The ACURATE valve is designed to achieve precise anatomical fixation in the subcoronary and suprannular position. The transcathether heart valve system is designed to allow sheathless delivery (28-French equivalent) through the apex of the left ventricle. Reproduced with permission from Symetis.

Figure 4: The Medtronic Engager

A B

The Medtronic Engager valve is composed of three bovine pericardium leaflets sewn to a polyester sleeve and mounted on a compressible and self-expanding nitinol frame (A). The stent assembly consists of a shaped main frame and a support frame, coupled together to form the commissural posts of the valve. The Engager seals the annulus by capturing the native leaflets with the control arms and conforms to the anatomy of the aortic annulus with the self-expanding frame, it prevents valve migration and minimises paravalvular regurgitation (B, C). Reproduced with permission from Medtronic.

TAVR for Native Aortic Valve Regurgitation— Experience with the Newer-generation Transcatheter Heart Valves A number of newer-generation transcatheter heart valves have been developed in recent years23 (see Table 2). Four devices that may be particularly suited for catheter-based treatment of aortic regurgitation are the JenaValve, ACURATE TA valve, the Medtronic Engager valve, and

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Structural Transcatheter Aortic Valve Implantation Figure 5: J-Valve Deployment

Intra-procedural fluoroscopy and the animation of valve implantation process. Panel A, E: The delivery sheath (black arrow) is delivered to the supra-annular plan. Panel B, F: Three graspers (small black arrow) are then released and pulled back gently into the aortic sinuses. Panel C, G: The valve is retrieved into the annular plan with the help of positioning graspers. Panel D, H: The valve deployed. Reprinted with permission from Heart, Lung Circ, Copyright (2014).

Figure 6:The Helio Transcatheter Aortic Dock

1. Dock

3. SAPIen XT value

Several initial reports demonstrated feasibility and successful treatment of aortic regurgitation using the JenaValve.25–30 In the largest series of 31 patients, transapical TAVR with a JenaValve for the treatment of NAVR was performed in 31 patients in nine German centers.30 Average age at time of procedure was 74 years, and all patients were deemed at high risk for cardiac surgery, with an average logistic EuroSCORE of 23.6 %. Procedural success was achieved in 30 out of 31 cases, with one patient requiring a second valve implantation due to valve dislocation. Two patients underwent either surgical or further transcatheter valvular re-interventions because of infective endocarditis or for increasing paravalvular regurgitation. All-cause mortality was 12.9 % and 19.3 % at 30 days and 6 months, respectively. Cerebrovascular events did not occur during follow-up, and a significant improvement in NYHA class was observed and persisted up to 6 months. Post-procedural aortic regurgitation was none/trace in 28 of 31 and mild in three of 31 patients. At present, the JenaValve is the only transcatheter valve that has been CE-marked for treatment of both AS and aortic regurgitation.

ACURATE TA Valve The ACURATE TA device (Symetis SA Ecublens, Switzerland) consists of a self-expandable nitinol stent, available in three sizes, which acts as an anchoring structure within the aortic annulus through its upper and lower crowns23,31,32 (see Figure 3). The ACURATE valve is designed to achieve precise anatomical fixation in the subcoronary and suprannular position. A three-leaflet porcine valve is fixed to the lower part of the nitinol stent. A double polyethylene skirt covers the inner and outer surface of the stent body, thus reinforcing the porcine valve and avoiding direct contact between the biological tissue and the metal stent struts. The transcathether heart valve system is designed to allow sheathless delivery (28-French equivalent) through the apex of the left ventricle. Intra-procedural balloon valvuloplasty is generally not required for deployment, and implantation is carried out without rapid pacing.

2. Native leaflets The Helio dock consists of a self-expandable nitinol stent with a polyethylene skirt. The dock is designed to be positioned inside the aortic root and is intended to secure the balloonexpandable Sapien XT heart valve to the aortic annulus by incorporating and entrapping the native cusps. Reprinted from EuroIntervention, Vol. 9, Barbanti et al., Copyright (2013), with permission from Europa Digital & Publishing.

the J-valve. In fact, the lack of calcification of the valvular apparatus confers greater stability to some newer-generation valves, and hence allows these devices to work more effectively. These valves share several characteristics. They are deployed primarily transapically; they are self-seating; they are anatomically oriented into the commissures; and they can be deployed in animal models in the orthotopic position because of their lower radial force compared with other TAVR devices.

The JenaValve The JenaValve transapical system consists of a porcine root valve mounted on a low-profile self-expanding nitinol stent24 (see Figure 1). The porcine root leaflets are connected to flexible stent posts designed to reduce leaflet stress in diastole. In contrast to devices expanding within the aortic annulus, the JenaValve relies on an active clip fixation of the native aortic valve leaflets, thereby reducing the radial force applied on surrounding cardiac and aortic structures24 (see Figure 2). This design also prevents coronary compromise by the native leaflets or stent struts, and does not interfere with future coronary intervention. Because the valve deploys in an anatomically aligned position, rapid pacing and balloon inflation is not required during implantation.

Roy_FINAL.indd 52

Wendt et al. describe procedural characteristics and clinical outcomes in a series of six patients with severe native aortic valve incompetence and two patients with aortic regurgitation secondary to failed aortic root repair, all of whom were deemed surgically inoperable in view of mean logistic EuroSCORE and STS scores of 34 % and 7.3 %, respectively.32 Procedural success was 100 % and no complications satisfying the VARC-2 criteria occurred in the peri-procedural period. Residual aortic incompetence post-procedure, as documented by transesophageal echocardiography, was at most grade I at three and six months’ follow-up. At 12 months’ follow-up, all-cause mortality, cardiovascular mortality, and cerebrovascular event rates were zero.32 Currently the ACURATE transcatheter valve is only available for transapical implantation, but a transfemoral version, the ACURATE TF, is undergoing clinical trials. Given the encouraging initial results, the ACURATE TA transcatheter heart valve might become more widely tested in the treatment of NAVR.

Medtronic Engager The Medtronic Engager aortic valve system (Medtronic 3F Therapeutics, Inc., Santa Ana, California, US) is a second-generation TAVR bioprosthesis combined with a delivery system designed for over-the-wire transapical implantation of the valve. The valve is composed of three bovine pericardium leaflets sewn to a polyester sleeve and mounted on a compressible and self-expanding nitinol frame23,33 (see Figure 4). The stent assembly consists of a shaped main

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Transcatheter Aortic Valve Replacement for Native Aortic Valve Regurgitation

frame and a support frame, coupled together to form the commissural posts of the valve. The Medtronic Engager valve obtained CE (Conformité Européenne) mark in 2013, after the pivotal multicentre trial demonstrated feasibility and acceptable safety profile in 125 patients with inoperable AS.23 Because the Engager seals the annulus by capturing the native leaflets with the control arms and conforms to the anatomy of the aortic annulus with the self-expanding frame, it prevents valve migration and minimizes paravalvular regurgitation (see Figure 4). Although primarily intended for the treatment of severe AS, it has the potential to develop a role in the treatment of aortic regurgitation, given its unique technical design. Indeed, the Engager has been successfully used to treat noncalcific, severe aortic insufficiency in an inoperable patient with an excellent final echocardiographic result.34 However, the patient required permanent pacemaker implantation, a complication that occurred in a significant number of patients (28 %) recruited into the initial multicentre trial previously alluded to.33

J-valve The J-valve system (Jie-cheng Medical Technology, Suzhou, China) is a newly developed second-generation transcatheter heart valve designed for anterograde transapical implantation characterised by three U-shaped graspers that facilitate anatomically correct valve implantation and provide axial as well as radial fixation by embracing the native valve leaflets35 (see Figure 5). The first-inhuman implantation for a high-risk patient with severe NAVR was successful and excellent valve function was demonstrated at followup35 (see Figure 5).

Ancillary Devices Helio Dock The Helio transcatheter dock (Edwards Lifesciences, Irvine, California, US) is an ancillary device that is intended to confer greater annular stability to the Edwards SAPIEN XT valve.15,36 The dock consists of a self-expandable nitinol stent with a polyethylene skirt (see Figure 6). The dock is designed to be positioned inside the aortic root and is intended to secure the balloon-expandable SAPIEN XT heart valve to the aortic annulus by incorporating and entrapping the native cusps. Following the first in-human successful report, a feasibility study of the procedure was demonstrated in a small series of four patients with severe primary AR deemed inoperable.37–39 Although initial results were encouraging, the dock technique has not gained traction, presumably due to the complexity of the technique and imminent availability of next-generation valves. At present, the manufacturer has discontinued production of the Helio dock.

Technical Considerations Patient Selection The use of TAVR for NAVR should still be limited to inoperable patients or those with prohibitive surgical risk due to age, frailty, or co-morbid conditions, as the clinical evidence accumulated thus far is not sufficient to establish noninferiority of TAVR compared with surgical treatment. From the Italian CoreValve registry, compared with inoperable patients with AS, patients who underwent TAVR for NAVR were younger, had more advanced NYHA class symptoms despite standard medical therapy, more frequently had SPAP, and had larger LV end-systolic as well as end-diastolic volumes. In the combined four largest series of TAVR for AR (a total of 108 patients), the predominant

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etiology of aortic incompetence was sclerotic-degenerative in 62 % of patients, followed by aortic aneurysm or dilatation in 13.9 % (see Table 3), with radiation therapy, infective endocarditis, rheumatic heart disease, vasculitis, and connective tissue diseases accounting for the remainder. The significant number of patients with aortic aneurysms is surprising, given that aortic regurgitation with concomitant aortopathy would normally mandate consideration of thoracic aortic surgical replacement with or without valve surgery. Acute aortic incompetence is generally attributable to dissection of the ascending aorta or infective endocarditis, and is not likely to be amenable to satisfactory transcatheter treatment.

Diagnostic Work-up Multimodality imaging, consisting of transthoracic and transesophageal echocardiography, and multidetector computed tomography imaging has been used increasingly in preparation for TAVR with the firstgeneration transcatheter valves, and is now accepted as standard practice. Contrast-enhanced multislice computed tomography is particularly useful for assessing valve and annular anatomy and aortic root morphology and should now be considered standard practice for planning TAVR procedures where available. Effective aortic annulus diameters, areas, and perimeters are often derived from multiplanar reconstruction of computed tomography data and/or from the midesophageal long-axis view in transesophageal echocardiography. In cases of NAVR, where precise valve dimensions are essential to prevent valve dislocation, multimodality imaging is essential.

Procedural Details The newer-generation transcatheter valves are designed for implantation predominantly via the transapical route in the hybrid cardiac catheterization laboratory. Rapid or burst pacing is generally not required, as is balloon inflation and dilatation. Compared with TAVR for AS, TAVR for aortic incompetence has proved to be more technically challenging as reflected by the higher rate of valve-in-valve procedures required, and the lower rate of procedural success. The absence of annular or cusp calcification translates into a lack of fluoroscopic markings that may make valve positioning more arduous compared to patients with calcific AS. The use of two pigtail catheters, the tips of which are positioned in the noncoronary and left coronary cusps may facilitate deployment.

Unresolved Matters and Future Directions The experience in using the transcatheter approach to treat NAVR is limited but is expanding. Patients with mixed aortic valve disease with severe stenosis and at least moderate regurgitation have been successfully treated with both of the commercially available TAVR devices, but NAVR without stenosis is still considered a relative contraindication in published guidelines. Significant native aortic regurgitation is uncommon, and high-risk or inoperable patients with such pathology are few. Hence, the potential for this technology to expand exists, but is not of the same magnitude as with AS. Newer-generation valve designs that use leaflet pinning or stabilization mechanisms are showing promise but experience with these devices is still limited. Larger registries, longer follow-up periods, and randomized clinical trials are necessary to gather sufficient evidence and experience to consider the widespread use of TAVR for NAVR. n

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Structural Transcatheter Aortic Valve Implantation 1. Leon MB, Smith CR, Mack M, et al., Trans-catheter aortic-valve implantation for aortic stenosis in patients who canot undergo surgery, N Eng J Med , 2010;363:1597–607 2. Makker R, Fontana G, Jilaihawi H, et al., Transcatheter aorticvalve replacement for inoperable severe aortic stenosis, N Eng J Med , 2012;366:1696–704 3. Kapadia S, Tuzcu M, Makkar R, et al., Long-term outcomes of inoperable patients with aortic valve stenosis randomly assigned to Transcatheter aortic valve replacement or standard therapy, Circulation , 2014;130:1483–92 4. Smith C, Leon M, Mack M, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Eng J Med , 2011;364:2187–98 5. Kodali S, Williams M, Smith C, et al., Two-year outcomes after Transcatheter or surgical aortic-valve replacement, N Eng J Med , 2012;366:1686–95. 6. Ducrocq G, Himbert D, Hvass U, Vahanian A, Compassionate aortic valve implantation for severe aortic regurgitation, J Thorac Cardiovasc Surg , 2010;140:930–2. 7. Dhillon PS, Kakouros N, Brecker SJ, Transcatheter aortic valve replacement for symptomatic severe aortic valve regurgitation, Heart , 2010;96:810. 8. Krumsdorf U, Haass M, Pirot M, et al., Technical challenge of transfemoral aortic valve implantation in a patient with severe aortic regurgitation, Circ Cardiovasc Interv , 2011 1;4:210–1. 9. Chiam PT, Ewe SH, Chua YL, Lim YT, First transcatheter aortic valve implantation for severe pure aortic regurgitation in Asia, Singapore Med J , 2014;55:103–5. 10. D’Ancona G, Pasic M, Buz S, et al. TAVI for pure aortic valve insufficiency in a patient with a left ventricular assist device, Ann Thorac Surg , 2012;93:e89–91. 11. Krause R, Metz D, Bushnaq H, Direct aortic transcatheter aortic valve implantation for pure aortic valve regurgitation after implantation of a left ventricular assist device, J Thorac Cardiovasc Surg , 2014;147:e38–41. 12. Zanuttini D, Armellini I, Bisceglia T, et al., Transcatheter aortic valve implantation for degenerative aortic valve regurgitation long after heart transplantation, Ann Thorac Surg, 2013;96:1864–6. 13. Roy D, Sharma S, Brecker S, Native aortic regurgitation: transcatheter therapeutic options, Eurointervention, 2013:9S55-62 14. Babaliaros V, Cribier A, The expansion of transcather

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technology to treat aortic insufficiency, J Am Coll Cardiovasc Interv , 2014;7:1175–6. 15. Tofield A, Feasibility trial reports deployment of new device for TAVI in aortic insufficiency, Eur Heart J, 2013;34:2578. 16. Goldbarg SH, Halperin JL. Aortic regurgitation: disease progression and management, Nat Clin Pract Cardiovasc Med , 2008;5:269–79. 17. Dujardin K, Enriquez-Sarano M, Schaff HV, et al., Mortality and morbidity of aortic regurgitation in clinical practice: a longterm follow-up study, Circulation , 1999;99:1851–7. 18. Tornos P, Sambola A, Permanyer-Miralda G, et al., Long-term outcome of surgically treated aortic regurgitation: influence of guideline adherence toward early surgery, J Am Coll Cardiol , 2006;47:1012–7. 19. Bonow RO, Chronic mitral regurgitation and aortic regurgitation: have indications for surgery changed?, J Am Coll Cardiol , 2013;61:693–701 20. Pacchioni A, Reimers B, Sorropago G, Multiple TAVI for aortic regurgitation in true porcelain aorta, EuroPCR presentation 2011, Paris, France. 21. Roy D, Laborde JC, Brecker SJ, Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation, J Am Coll Cardiol , 2013;61:1577–84. 22. Testa L, Latib A, Rossi ML, De Marco F, CoreValve implantation for severe aortic regurgitation: a multicentre registry, EuroIntervention , 2014;10:739–45. 23. Taramasso M, Pozzoli A, Latib A, et al., New devices for TAVI: technologies and initial clinical experiences, Nat Rev Cardiol , 2014;11:157–67. 24. Treede H, Rastan A, Ferrari M, et al., JenaValve, EuroIntervention , 2012;8 Suppl Q:Q88–93. 25. Schlingloff F, Schäfer U, Frerker C, et al., Transcatheter aortic valve implantation of a second-generation valve for pure aortic regurgitation: procedural outcome, haemodynamic data and follow-up, Interact Cardiovasc Thorac Surg , 2014;19:388–93. 26. Seiffert M, Diemert P, Koschyk D, et al., Transapical implantation of a second-generation transcatheter heart valve in patients with noncalcified aortic regurgitation, J Am Coll Cardiovasc Interv , 2013; 6:590–7. 27. Bleiziffer S, Mazzitelli D, Nöbauer C, et al., Successful treatment of pure aortic insufficiency with transapical implantation of the

JenaValve, Thorac Cardiovasc Surg , 2013;61:428–30. 28. Schlingloff F, Frerker C, Schäfer U, Bader R, Transapical aortic valve (JenaValve) implantation for severe aortic insufficiency and aortic aneurysm, J Thorac Cardiovasc Surg , 2013;146:e40–1. 29. Schlingloff F, Schäfer U, Frerker C, et al., Transcatheter aortic valve implantation of a second-generation valve for pure aortic regurgitation: procedural outcome, haemodynamic data and follow-up, Interact Cardiovasc Thorac Surg , 2014;19:388–93. 30. Seiffert M, Bader R, Kappert U, et al., Initial German experience with transapical implantation of a second-generation transcatheter heart valve for the treatment of aortic regurgitation, JACC Cardiovasc Interv , 2014;7:1168–74. 31. Huber C, Wenaweser P, Windecker S, Carrel T, Transapical transcatheter aortic valve implantation using the secondgeneration self-expanding Symetis ACURATE TA valve, Multimed Man Cardiothorac Surg , 2014 [Epub ahead of print]. 32. Wendt D, Kahlert P, Pasa S, et al., Transapical transcatheter aortic valve for severe aortic regurgitation: expanding the limits, JACC Cardiovasc Interv , 2014;7:1159–67. 33. Sündermann SH, Holzhey D, Bleiziffer S, Second-generation transapical valves: the Medtronic Engager system, Multimed Man Cardiothorac Surg , 2014;2014. 34. Kiefer P, Seeburger J, Mohr FW, Holzhey DM, Transcatheter aortic valve replacement for isolated aortic valve insufficiency: experience with the Engager valve, J Thorac Cardiovasc Surg , 2014;147:e37–8. 35. Zhu D, Hu J, Meng W, Guo Y, Successful transcatheter aortic valve implantation for pure aortic regurgitation using a new second generation self-expanding J-ValveTM System - The First in-Man Implantation, Heart Lung Circ , 2014 [Epub ahead of print]. 36. Barbanti M, Ye J, Pasupati S, et al., The Helio transcatheter aortic dock for patients with aortic regurgitation, EuroIntervention , 2013;9 Suppl:S91. 37. Pasupati S, Devlin G, Davis M, et al., Transcatheter solution for pure aortic insufficiency, JACC Cardiovasc Imaging , 2014;7:315–8. 38. Pasupati S, A novel approach to aortic insufficiency: Edwards Helio System—feasibility trial. Presented at EuroPCR 2013. 39. Webb, J. Helio (Giovani): a dedicated transcatheter valve system for aortic insufficiency. Presented at EuroPCR 2013.

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Structural Transcatheter Aortic Valve Implantation

LE ATION.

The Current Situation and the Future of Emergent Cardiac Surgery in TAVI Holg e r E g g e b r e c h t a n d A x e l S c h m e r m u n d CCB-Cardioangiologisches Centrum Bethanien and AGAPLESION Bethanien-Krankenhaus, Frankfurt, Germany

Abstract Transcatheter aortic valve implantation (TAVI) has become a beneficial treatment for patients with aortic valve stenosis deemed at high or even prohibitive risk for open surgery. The risk for severe complications is low (ranging between 0.2 % and 1.0 %); nevertheless, in approximately 1 % of patients emergency cardiac surgery (ECS) is required during TAVI. Aortic injury, embolization of the TAVI prosthesis, and myocardial injury are among the most frequent complications necessitating ECS. Mortality rates of ECS during TAVI are high, ranging between 45 % and 67 %, owing to the comorbid and fragile health status of TAVI patients. Therefore, avoidance of complications appears to be of utmost importance to improve outcomes. This review analysis the current literature in terms of incidence, causes, and outcomes of ECS during TAVI.

Keywords Transcatheter aortic valve implantation, TAVI, TAVR, surgery, aortic valve replacement Disclosure: The authors have no conflicts of interest to declare. Received: 2 December 2014 Accepted: 3 February 2015 Citation: Interventional Cardiology Review, 2015;10(1):55–7 Correspondence: Holger Eggebrecht, MD, Cardioangiological Center Bethanien (CCB), Im Prüfling 23, 60389 Frankfurt, Germany. E: h.eggebrecht@ccb.de

Transcatheter aortic valve implantation (TAVI) has become a highly effective and beneficial treatment option for patients with severe symptomatic aortic valve stenosis. The randomized Placement of AoRtic TraNscathetER Valves (PARTNER) trials have shown that (1) TAVI using the balloon-expandable Edwards Sapien valve implanted via the transfemoral (TF) or transapical (TA) route is superior with respect to outcomes compared with standard therapy in inoperable patients and that (2) TAVI is at least non-inferior to surgical aortic valve replacement (AVR) in high-risk patients.1,2 More recently, the randomized US pivotal CoreValve high-risk study has reported that TAVI exclusively via the transvascular (83 % TF, 17 % trans-subclavian) approach using the selfexpandable Medtronic/CoreValve prosthesis is in fact superior to open surgery in such high-risk patients.3

hours after TAVI.6 Nevertheless, definitions may be heterogenous throughout the literature.7 It may further be speculated that in some very-high-risk TAVI cases, ECS is not even attempted due to the anticipated bad outcome. Therefore, comparison of ECS rates between different studies may be hampered.

Risk for Emergent Cardiac Surgery during TAVI

In a meta-analysis of 46 published studies comprising a total of 9,251 TAVI patients, ECS was required in 102 (1.1 %) patients.6 ECS rates were higher among patients undergoing TA TAVI compared with those undergoing TF TAVI.6,7 Contemporary national and international TAVI registries have yielded similar rates of ECS during TAVI. In the most recent report from the AQUA registry comprising 10,409 patients undergoing TAVI in Germany in 2013, ECS with sternotomy was required in 94 (0.9 %) patients.5 The FRANCE 2 registry reported that 12 out of 3,195 TAVI patients (0.4 %) were converted to open surgery.8 In a report from the initial US commercial experience, 94 (1.2 %) out of 7,710 patients underwent conversion to open heart surgery for TAVI complications.9 The international SOURCE registry using the balloonexpandable Edwards Sapien valve similarly reported an ECS rate of 1.2 %.10 More recently, the risk for ECS appeared even lower with a single (0.1 %) patient among a total of 995 patients included into the international ADVANCE registry.11 These patients were exclusively undergoing TF TAVI, using the self-expandable Medtronic/CoreValve prosthesis.11

The most recent Valve Academic Research Consortium (VARC)-2 consensus document lists ECS among other TAVI-related complications, defined as any conversion to open sternotomy during the TAVI procedure secondary to any procedure-related complication. In the published literature, ECS is often defined as any cardiothoracic surgical intervention requiring cardiopulmonary bypass and sternotomy for urgent aortic valve replacement, repair of myocardial perforation or aortic injury, or pericardial drainage performed during or within 24

Single-center experiences involving smaller numbers of patients have suggested higher ECS rates of up to 2.8 % or even 4.9 %.12,13 These numbers may in part be related to different definitions of ECS12 but also to the sites‚‘ TAVI experience/learning curve.14 Griese et al.12 reported that 20 (4.9 %) of 411 patients undergoing TAVI between 2009 and 2012 at their institution required ECS, including four patients who switched to TA TAVI (n=1) or femoral cardiopulmonary bypass for

With rapidly increasing experience, TAVI globally has become a safe clinical routine procedure. In Germany, 30-day mortality rates have almost been halved since 2008 (see Figure 1), according to data from the German obligatory quality assurance registry (AQUA registry).4 Although the risk for severe complications such as annular rupture, ventricular perforation, or aortic injury during TAVI is low, ranging between 0.2 % and 1.0 % (see Table 1),5 some of these complications may ultimately require emergency cardiac surgery (ECS).

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Structural Transcatheter Aortic Valve Implantation Table 1: Risk for Severe Complications and Emergent Cardiac Surgery during TAVI 5 Coronary obstruction

All Patients TF TAVI (n=10,049) (n=7,602) 40 (0.4 %) 32 (0.4 %)

TA TAVI (n=2,807) 8 (0.3 %)

Aortic dissection

21 (0.2 %)

18 (0.2 %)

8 (0.1 %)

Annular rupture

45 (0.4 %)

37 (0.5 %)

8 (0.3 %)

Pericardial tamponade

101 (1.0 %)

92 (1.2 %)

8 (0.3 %)

Valve embolisation

40 (0.4 %)

27 (0.4 %)

13 (0.5 %)

94 (0.9 %)

Emergent cardiac surgery (sternotomy)

NS = not specified; TA = transapical; TF = transfemoral; TAVI = transcatheter aortic valve implantation.

Figure 1: Development of In-hospital Mortality after Transcatheter Aortic Valve Implantation in Germany, According to the Obligatory Quality Assurance Registry 4 11000 10.41 % 9.15 % 8250

7.5 %

8.25 %

7.1 % 7210 5.8 %

4837

5500

11 % 10409

9332

5.7 % 5.5 %

2558

2750

Mortalityn

2009

2010

2011

2012

0% 2013

Mortalityn

TAVI Complications Requiring Emergent Cardiac Surgery Complications that occur during TAVI and require ECS include ventricular injury with tamponade (e.g. right or left ventricular perforation due to pacer lead or stiff guide wire), injury to the ascending aorta (e.g. perforation, dissection), rupture of the device landing zone (i.e. annular rupture), coronary obstruction, severe (para-)valvular regurgitation, and prosthesis embolization/migration into the left ventricle or aorta.7 The risk for these complications is generally low, ranging between 0.2 % and 1.0 % (see Table 1). In the German TAVI registry, which included 1,975 patients between 2009 and 2011, leading causes for ECS during TAVI were aortic injury (21 % of ECS cases), prosthesis embolization (21 %), and myocardial perforation (17 %).7 Similar distributions have been reported from the US TAVI registry, which included prosthesis embolization (23 % of ECS cases), aortic injury (13 %), and myocardial perforation (12 %), but also annular rupture (14 %) among the most frequent ECS causes.9 In the SOURCE registry of 2,307 patients, again prosthesis embolization (33 % of ECS cases) and aortic injury (26 %) were the main causes for ECS.10

Outcomes after Emergent Cardiac Surgery Patients currently selected for TAVI are usually elderly, co-morbid, and fragile patients deemed either inoperable or at least high risk for

Eggebrecht_FINAL.indd 56

(i.e. lower EuroSCORE) may have better outcomes even after ECS for TAVI complications.14

Conclusion and Glimpse into the Future

cardiogenic/hemorrhagic shock (n=3), but no sternotomy. There was also a strikingly high rate of ventricular perforation with either the pacing lead or the stiff guidewire with failed transcutaneous puncture ultimately necessitating ECS.12

It has been suggested that the severity of the specific TAVI complication that necessitates ECS has an effect on postoperative outcomes. In the German TAVI registry, the highest mortality was observed in patients undergoing ECS for aortic perforation or dissection: four (80 %) out of five patients died despite ECS.7 High mortality rates after ECS were also reported for annular rupture (50–100 %) and cardiac tamponade (50–100 %).7,10,15,16 By contrast, outcomes of patients with severe aortic regurgitation undergoing ECS appeared to be better: postoperative mortality ranged between 0 % and 33 %.7,10 As patients with severe aortic regurgitation are usually hemodynamically more stable than patients with overt annular rupture and tamponade, it may be speculated that not only the complexity of the complication, but also the hemodynamic status of the patient allowing for example more urgent/semi-elective instead of bail-out emergency surgery has an impact on postoperative outcomes. The analysis of Seiffert et al.13 further suggests that patients with a lower baseline risk

2.75 %

634 0 2008

elective open heart surgery. It is therefore not surprising that mortality of emergency heart surgery for complications occurring acutely during the TAVI procedure is high. In fact, mortality among patients requiring ECS during TAVI may be as high as 67 %, thus being approximately ninefold higher than in patients undergoing uncomplicated TAVI.6 Other studies reported somewhat better outcomes after ECS, but the 30-day mortality rates still varied between 45 % and 52 %.7,10,12

ECS is currently required in approximately 1 % of patients undergoing TAVI and may be more frequent among those undergoing TA TAVI procedures. The Medtronic/CoreValve experience, which already excludes prosthesis embolization and annular rupture, suggests that the risk for ECS can be reduced to 0.1 % of TAVI patients.11 Currently, leading causes for ECS during TAVI are aortic injury, prosthesis embolization, and myocardial perforation, as well as annular rupture. Even in centers with an on-site cardiac surgery department and thus short reaction times in such bail-out situations, postoperative mortality of ECS is high (45–67 %), owing to the comorbid and fragile health status of inoperable or high-risk patient cohort currently selected for TAVI instead of open surgery. Therefore, minimizing ECS risk is the best way to improve outcomes. It may be anticipated from the historical development of percutaneous coronary intervention that the need for ECS during TAVI may similarly decrease in the near future. Technical improvements in valve design such as the development of retrievable, repositionable TAVI devices may prevent prosthesis embolization and thus the need for ECS. Development of dedicated, pre-shaped stiff TAVI guidewires may reduce the risk for ventricular perforation. Better pre-procedural planning by routine use of contrast-enhanced computed tomography allows for better positioning, thus avoiding coronary obstruction and minimizing the risk for oversizing-induced annular rupture as well as paravalvular regurgitation by better prosthesis size selection. Paravalvular leak is further addressed by technical developments in valve design. The increasing tendency to avoid balloon valvuloplasty before valve implantation may reduce annular rupture. Similarly, miniaturization and improved flexibility of the delivery systems may help to reduce ECS for complications such as aortic perforation or dissection. Increasing operator experience and growing confidence in the procedure will further reduce the risk for ECS.

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The Current Situation and the Future of Emergent Cardiac Surgery in TAVI

Table 2: Rates of Emergency Cardiac Surgery during Transcatheter Aortic Valve Implantation as Reported in the Literature Authors/Study

Years of Patient Inclusion

Emergency Cardiac Surgery Rate

Mortality

Eggebrecht et al.; metanalysis6

2004–2011

102/9,251 (1.1 %)

67.1 %

Eggebrecht et al.; SOURCE registry10

2007–2009

27/2,307 (1.2 %)

51.9 %

Seiffert et al.; German single center experience (Hamburg)13

2008–2012

13/458 (2.8 %)

38.5 %

Griese et al.; German single center

2009–2012

20/411 (4.9 %)

30 days: 35 %

experience (Bad Neustadt)12

In-hospital: 45 %

Hein et al.; German TAVI registry7

2009–2011

24/1,975 (1.2 %)

46 %

Linke et al.; ADVANCE study11

2010–2011

1/995 (0.1 %)

–

Gilard et al.; FRANCE-28

2010–2011

12/3,195 (0.4 %)

Mack et al.; initial US commercial experience9

2011–2013

94/7,710 (1.2 %)

NG = not given.

The 2012 valvular heart disease guidelines of the European Society of Cardiology mandate that TAVI should only be performed in hospitals with both cardiology and cardiac surgery department on-site. The requirement of an on-site cardiac surgery department as a prerequisite for TAVI has been approved with the highest level of recommendation (class 1); however, based on expert consensus only (level of evidence C). Scientific data to support this recommendation do not exist. Since 2012, TAVI has rapidly evolved and has made substantial technical (e.g., 14 F Sapien 3 prosthesis) as well as procedural (i.e., growing operator‚Äôs experience and

1. Leon MB, Smith CR, Mack M, et al., Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med , 2010;363:1597‚Äì607. 2. 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‚Äì98. 3. Adams DH, Popma JJ, Reardon MJ, et al., Transcatheter aorticvalve replacement with a self-expanding prosthesis, N Engl J Med , 2014;370:1790‚Äì8. 4. AQUA ‚Äì Institut f√ºr angewandte Qualit√§tsf√∂rderung und Forschung im Gesundheitswesen GmbH. Qualit√§tsreport 2013. Available at: https://www sqg de/sqg/upload/CONTENT/ Qualitaetsberichte/2013/AQUA-Qualitaetsreport-2013 pdf 2014 (accessed February 9, 2015). 5. AQUA ‚Äì Institut f√ºr angewandte Qualit√§tsf√∂rderung und Forschung im Gesundheitswesen GmbH. HCH-AORTKATH - Aortenklappenchirurgie, isoliert (Kathetergest√ºtzt)Bundesauswertung zum Erfassungsjahr 2013. Available at: https://www sqg de/downloads/Bundesauswertungen/2013/ bu_Gesamt_HCH-AORT-KATH_2013 pdf 2014 (accessed February 9, 2015).

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Eggebrecht_FINAL.indd 57

confidence) progress to become a routine procedure, which is highly beneficial for patients at high risk for open surgery. In 2013, >10,000 TAVI procedures were performed in Germany, which was more than the number of isolated AVR. The risk for severe complications necessitating ECS during TAVI is low and will further decrease. If required, outcomes of ECS are bleak, mostly due to the risk profile of the patients currently considered for TAVI. Therefore ECS does thus not really serve as a valid safety net. Avoidance of complications by experienced operators appears to be more appropriate to improve outcomes of TAVI. n

6. Eggebrecht H, Schmermund A, Kahlert P, et al., Emergent cardiac surgery during transcatheter aortic valve implantation (TAVI): a weighted meta-analysis of 9,251 patients from 46 studies, EuroIntervention , 2013;8:1072‚Äì80. 7. Hein R, Abdel-Wahab M, Sievert H, et al., Outcome of patients after emergency conversion from transcatheter aortic valve implantation to surgery, EuroIntervention , 2013;9:446‚Äì51. 8. Gilard M, Eltchaninoff H, Iung B, et al., Registry of transcatheter aortic-valve implantation in high-risk patients, N Engl J Med , 2012;366:1705‚Äì15. 9. Mack MJ, Brennan JM, Brindis R, et al., Outcomes following transcatheter aortic valve replacement in the United States, JAMA , 2013;310:2069‚Äì77. 10. Eggebrecht H, Mehta RH, Kahlert P, et al., Emergent cardiac surgery during transcatheter aortic valve implantation (TAVI): insights from the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry, EuroIntervention , 2013 {Epub ahead of print]. 11. Linke A, Wenaweser P, Gerckens U, et al., Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study, Eur Heart J, 2014;35:2672–84.

12. Griese DP, Reents W, Kerber S, et al., Emergency cardiac surgery during transfemoral and transapical transcatheter aortic valve implantation: incidence, reasons, management, and outcome of 411 patients from a single center, Catheter Cardiovasc Interv , 2013;82:E726‚ÄìE733. 13. Seiffert M, Conradi L, Baldus S, et al., Severe intraprocedural complications after transcatheter aortic valve implantation: calling for a heart team approach, Eur J Cardiothorac Surg , 2013;44:478‚Äì84; discussion 484. 14. Eggebrecht H, Schmermund A, Mehta RH, Reducing severe intraprocedural complications during transcatheter aortic valve implantation with an interdisciplinary heart team approach, Eur J Cardiothorac Surg , 2014;45:203‚Äì4. 15. Pasic M, Unbehaun A, Dreysse S, et al., Rupture of the device landing zone during transcatheter aortic valve implantation: a life-threatening but treatable complication, Circ Cardiovasc Interv , 2012;5:424‚Äì32. 16. Schymik G, Heimeshoff M, Bramlage P, et al., Ruptures of the device landing zone in patients undergoing transcatheter aortic valve implantation: an analysis of TAVI Karlsruhe (TAVIK) patients, Clin Res Cardiol , 2014;103:912‚Äì20.

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Structural Tricuspid Valve Repair

Indications for Surgery for Tricuspid Regurgitation Yan Topilsky Director of Echo Lab, Tel Aviv Medical Center, Israel

Abstract Despite the fact that tricuspid regurgitation (TR) can result in significant symptoms, patients are rarely referred for isolated surgical repair, or replacement, and most surgeries are performed in the context of other planned cardiac surgery. In this article, we review the different causes of TR, the natural history of untreated severe TR, indications and timing for isolated TR surgery, indications for TR surgery performed at the time of left-sided valve surgery, and surgical approaches for correction of TR.

Keywords Tricuspid regurgitation, effective regurgitant orifice (ERO), pulmonary arterial systolic pressure, left ventricle, right ventricle Disclosure: The author has no conflicts of interest to declare. Received: 27 October 2014 Accepted: 3 February 2015 Citation: Interventional Cardiology Review, 2015;10(1):58–60 Correspondence: Yan Topilsky, Division of Cardiovascular Diseases and Internal Medicine, Tel Aviv Medical Center, 6 Weizmann Street, Tel Aviv, Israel. E: topilskyyan@gmail.com

In contrast to aortic or mitral diseases, there has been far less discussion on indications for tricuspid valve repair or replacement. Despite the fact that tricuspid regurgitation (TR) can result in significant symptoms, it remains undertreated. Patients are rarely referred for isolated surgical repair, or replacement, and most surgeries are performed in the context of other planned cardiac surgery. In this article, we will review the causes and natural history of untreated severe TR, indications and surgical approaches for correction of TR.

Causes, Assessment and Natural History Approximately 80 % of cases of TR are functional due to right ventricular (RV) enlargement resulting in annular dilation, or leaflet tethering.1 RV dilatation is secondary to left heart failure, other valvular causes, RV volume or pressure overload. Less-common causes of TR are organic and include rheumatic, congenital, endocarditis, traumatic/iatrogenic, pacemaker or defibrillator leads interfering with leaflet coaptation, or myxomatous degeneration of the tricuspid valve. A unique cause of TR is isolated TR, the result of marked tricuspid annular dilatation due to degenerative condition of the annulus and/or right atrium.1,2

Without treatment, TR may deteriorate over time, leading to worse symptoms, biventricular heart failure and death. Several trials investigated the impact of TR, in and by itself, or in conjunction with other valvar diseases, on survival and cardiac outcomes.5–8 In a large retrospective analysis of <5,000 patients by Nath et al.,8 it was shown that severe (and even moderate) TR is associated with worse survival even when adjusted for pulmonary artery systolic pressure (PASP), left ventricular ejection fraction (LVEF), RV size and function. The limitations of all these studies were that the considerable matter of multiple co-morbidities affected survival (severe pulmonary hypertension, poor LV function, organic valve disease right and left-sided), so that it was difficult to prove whether TR in and by itself independently affects survival, or is it a surrogate for associated conditions.

Indications and Timing of Tricuspid Valve Surgery Because indications for TR surgery differ significantly whether it is performed at the time of left-sided valve surgery, or in isolation, we will discuss them separately.

Isolated Tricuspid Regurgitation Surgery With TR, patients may experience fatigue and decreased exercise tolerance as a result of decreased cardiac output or the ‘classic symptoms’ of right-sided heart failure from elevated right atrial pressures, such as peripheral oedema, ascites, congestive liver and decreased appetite. Atrial fibrillation is also common as a result of right atrial enlargement. Echocardiography is routinely used to assess the severity of TR in clinical practice. This is performed in an integrative manner using color Doppler, assessing the morphology of continuous wave Doppler recordings across the valve, pulsed wave Doppler of the hepatic veins, measurement of vena contracta width and calculation of effective regurgitant orifice (ERO) using the proximal-isovelocity-surfacearea (PISA) method.3 Serial assessments of TR must be interpreted in the patient’s clinical context, because severity can be affected by multiple factors, such as volume status, respiratory cycle and after-load.4

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Recently we have shown that severe (ERO >0.4 cm2), isolated (without significant co-morbidities, structural valve disease, significant PASP elevation by Doppler or overt cardiac cause) TR is associated with excess mortality and morbidity,9 thus warranting heightened attention to diagnosis and quantification of TR, and suggesting that it should be treated aggressively. Furthermore, several publications have shown that isolated tricuspid valve surgery can be performed with an acceptable operative mortality if patients undergo surgery before the onset of advanced heart failure symptoms, or severe RV dysfunction.5,10–12 Based on the recent data the practice has evolved to include more surgical treatment of TR even when it is isolated.13 Recent guidelines recommended (Class IIa indication) that isolated tricuspid valve surgery can be performed for patients with symptoms due to severe primary TR, including congestive hepatopathy, preferentially before onset of

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Indications for Surgery for Tricuspid Regurgitation

Figure 1: Indications for Surgery 16

Tricuspid Regurgitation

Progressive functional (TR) Stage B Mild

Moderate

At time of left-sided valve surgery

TA Dilation*

PHTN without TA dilation

TV Repair (IIa)

TV Repair (IIb)

Class I

Class IIa

Asymptomatic severe TR Stage C Functional At time of left-sided valve surgery

Symptomatic severe TR Stage D

Primary

Reoperation

Progressive RV dysfunction

TV Repair or TVR (I) Class IIb

Preserved RV function PHTN not severe

Functional

Primary

At time of left-sided valve surgery

TV Repair or TVR (IIb)

TV Repair or TVR (I)

TV Repair or TVR (IIa)

Class IIa

Class IIb

Class I

PHTN = pulmonary hypertension; TA = tricuspid annular; TV = tricuspid valve; TVR = target-vessel revascularisation; RV = right ventricular.

significant RV dysfunction.14–16 It should be noted that the optimal timing of isolated tricuspid valve surgery for asymptomatic patients with severe

Tricuspid Regurgitation Surgery at the Time of Left-sided Valve Surgery

TR is controversial. The US guidelines have suggested a conservative approach that includes serial assessments of RV size and function that may indicate the need for corrective surgery (Class IIb indication) in selected patients with severe TR, continued deterioration of RV and low surgical risk. On the other hand, the European recent guidelines16 are more specific since they clearly state “Surgery should be considered in asymptomatic or mildly symptomatic patients with severe isolated primary TR and progressive RV dilatation or deterioration of RV function (Class IIa indication).”

It is agreed that severe TR of either a primary or functional nature may not predictably improve after treatment of the left-sided valve lesion and reduction of RV after-load.7,14,15 It is also known that adding tricuspid valve repair during left-sided surgery does not add appreciably to the risks of surgery. Furthermore, it was shown that reoperation for severe, isolated TR after left-sided valve surgery is associated with a peri-operative mortality rate up to 25 %.14,15 Thus, because of the hazards imposed by reoperation, the unpredictable nature of TR after successful mitral surgery and the simplicity and low morbidity imposed by adding a cerclage stitch or annuloplasty band on the tricuspid annulus during left-sided surgery have influenced decisionmaking in favour of repair of functional TR initially at the time of leftsided valve surgery. The question remains: when to deal with tricuspid correction during left-sided surgery? Left uncorrected at the time of left-sided valve surgery, moderate and even mild degrees of functional TR may progress over time in approximately 25 % of patients and result in reduced long-term functional outcome and survival.7,20,21 Risk factors for persistence or progression of TR include tricuspid annulus dilatation (>40 mm or 21 mm/m2 on transthoracic echocardiogram [TTE], or >70 mm on direct intra-operative inspection), significant RV dysfunction or dilatation, significant tricuspid leaflet tethering, atrial fibrillation or pulmonary hypertension at the time of left-sided valve surgery, rheumatic or functional aetiology of mitral disease or history of right heart failure.7,20,21 Based on these data the recent guidelines committee has advocated tricuspid valve repair for patients with severe TR (Class I indication), or mild, moderate functional TR at the time of left-sided valve surgery with either tricuspid annular dilatation or prior evidence of right heart failure (Class IIa indication). Furthermore, tricuspid valve repair should be considered (Class IIb indication) in patients with moderate functional TR and pulmonary hypertension at the time of left-sided valve surgery. Nevertheless, not all mitral diseases are similar. In two recent large series from the Mayo Clinic it was shown that in patients who underwent mitral valve repair for isolated degenerative leaflet prolapse that had moderate or less coexistent functional TR at the time of surgery, TR regressed until the third year in the majority of patients following successful

Another important and controversial question pertains to whether to re-operate just for severe TR in patients who have undergone previous left-sided valve surgery. Isolated tricuspid valve surgery for severe TR after previous left-sided surgery has historically been performed relatively late in the natural history of the disease, only when patients became severely symptomatic with signs of right heart failure. Because of the delay in surgery, mortality rates for re-operative tricuspid surgery late after left-sided valve surgery have been exceedingly high (10–25 %).14,15 This high mortality was likely related to the advanced nature of RV failure encountered at the time of the second procedure, residual pulmonary hypertension, LV dysfunction and other valve abnormalities. The sobering results seen with tricuspid valve repair at reoperation inject a note of caution into its performance and may encourage replacement with an ageappropriate (mechanical or biological) prosthesis. Recently, several advanced centers of excellence17,18 have reported good peri-operative mortality rates (as low as 4 %), and reasonable long-term outcome with tricuspid valve reoperation when performed early and before severe RV dysfunction occurs. Thus, although the US guidelines15,19 advocate that reoperation for isolated TR may be considered only for persistent symptoms related to TR in patients who have undergone previous left-sided surgery, and the presence of either severe pulmonary hypertension or significant RV dysfunction constitutes a relative contraindication to reoperation, the European guidelines16 are more permissive and recommend surgery in this setting also in asymptomatic patients if there are signs of RV dilatation/dysfunction.

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Structural Tricuspid Valve Repair and durable degenerative mitral valve repair, irrespective of annular diameter, and only one tricuspid valve repair for severe symptomatic TR was necessary 4.5 years after the initial MV operation.22,23 On the other hand, 29 % of the patients who had 5-year follow up at that study had at least moderate–severe TR at the end of follow up. Based on these data, the indications for tricuspid repair, at the time of mitral repair for mitral valve prolapsed, continue to be debatable. Some believe that early correction of mitral regurgitation for mitral valve prolapsed, without concomitant tricuspid repair, is reasonable because it may diminish the late occurrence of functional TR,24 while others support a more aggressive approach, requiring tricuspid repair whenever the annulus is dilated, similar to patients with functional, or rheumatic, mitral regurgitation.7,16

Repair or Replace The last factor pertaining to tricuspid valve surgery is whether to replace or repair the valve, how to repair and whether to use a bioprosthetic or mechanical prosthesis whenever we replace. Singh et al. have shown in their seminal report that tricuspid valve repair is associated with better peri-operative, midterm and event-free survival than tricuspid valve replacement, at least in patients with organic tricuspid disease. Despite more TR in the repair group during follow up, reoperation rates and functional class were similar. Thus, it is common practice that repair should be pursued whenever possible in patients with TR.25 In terms of the mode of repair, the debate continues, with most surgeons preferring placement of an annuloplasty ring because it is associated with improved survival and event-free survival compared with De Vega annuloplasties.26,27 Nevertheless, others believe that bi-cuspidisation annuloplasty is equally effective as ring annuloplasty at eliminating TR, but is simpler and less expensive.28 However, the durability of tricuspid valve repair, even when using annuloplasty rings may be limited in some patients. The Cleveland Clinic group has shown that increased preoperative tricuspid leaflet

1. Topilsky Y, Khanna A, Le Tourneau T, et al., Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension, Circ Cardiovasc Imaging , 2012;5(3):314–23. 2. Kasai A, Nishikawa H, Ono N, et al., [Clinical evaluation of severe idiopathic tricuspid regurgitation], J Cardiol , 1990;20(4):937–44. 3. Zoghbi WA, Enriquez-Sarano M, Foster E, et al., Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography, J Am Soc Echocardiogr , 2003;16(7):777–802. 4. Topilsky Y, Tribouilloy C, Michelena HI, et al., Pathophysiology of tricuspid regurgitation: quantitative Doppler echocardiographic assessment of respiratory dependence, Circulation , 2010;122(15):1505–13. 5. Messika-Zeitoun D, Thomson H, Bellamy M, et al., Medical and surgical outcome of tricuspid regurgitation caused by flail leaflets, J Thorac Cardiovasc Surg , 2004;128(2):296–302. 6. Sagie A, Schwammenthal E, Newell JB, et al., Significant tricuspid regurgitation is a marker for adverse outcome in patients undergoing percutaneous balloon mitral valvuloplasty, J Am Coll Cardiol , 1994;24(3):696–702. 7. Dreyfus GD, Corbi PJ, Chan KM, Bahrami T, Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair?, Ann Thorac Surg , 2005;79(1):127–32. 8. Nath J, Foster E, Heidenreich PA, Impact of tricuspid regurgitation on long-term survival, J Am Coll Cardiol , 2004;43(3):405–9. 9. Topilsky Y, Nkomo VT, Vatury O, et al., Clinical outcome of isolated tricuspid regurgitation, JACC Cardiovasc Imaging , 2014;7(12):1185–94. 10. Kim YJ, Kwon DA, Kim HK, et al., Determinants of surgical outcome in patients with isolated tricuspid regurgitation, Circulation , 2009;120(17):1672–8. 11. Topilsky Y, Khanna AD, Oh JK, et al., Preoperative factors associated with adverse outcome after tricuspid valve

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tethering height and area, low LVEF and increased RV pressure were related to worse TR during follow up, and predicted early and mid-term adverse outcomes of ring annuloplasty. Thus patients with significant tethering, significant distortion of the valve, LV and RV dysfunction or severe pulmonary hypertension may require tricuspid valve replacement to avoid long-term repair failure and adverse clinical outcomes. A recent meta-analysis tried to address the question of whether patients requiring tricuspid replacement should have a mechanical or a biological valve. Surprisingly, there were no major differences between the insertion of a mechanical or biological tricuspid valve. The reoperation rate was similar with bio-prosthetic degeneration rate being equivalent to the mechanical thrombosis rate. Conversely, up to 95 % of patients with a bio-prosthesis still received anticoagulation. Survival was equivalent between biological and mechanical valves, thus a mechanical tricuspid prosthesis is reasonable in patients less than 60 years of age who do not have a contraindication to anticoagulation, just like in patients undergoing aortic or mitral valve replacement.29

Conclusions In the absence of clinical trials, present guidelines are based on expert opinion. The surgical indications for TR are considered more actively if: 1) Another cardiac operation is considered, especially at the time of left-sided valve surgery. 2) If functional TR is severe, particularly based on quantitative criteria such as ERO ≥40 mm2. 3) When the patient is symptomatic from the TR, especially with congestive signs directly related to the TR, or marked reduction of functional capacity measured without other cause than the TR. Nevertheless, it is essential to consider surgery only if the co-morbid conditions are not overwhelming, RV dysfunction is not irreversible, and life expectancy is at least several years. n

replacement, Circulation , 2011;123(18):1929–39. 12. Moller JE, Pellikka PA, Bernheim AM, et al., Prognosis of carcinoid heart disease: analysis of 200 cases over two decades, Circulation , 2005;112(21):3320–27. 13. Badano LP, Agricola E, Perez de Isla L, et al., Evaluation of the tricuspid valve morphology and function by transthoracic real-time three-dimensional echocardiography, Eur J Echocardiogr , 2009;10(4):477–84. 14. Nishimura RA, Otto CM, Bonow RO, et al., 2014 AHA/ACC guideline for the management of patients with valvular 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(22):2438–88. 15. Nishimura RA, Otto CM, Bonow RO, et al., 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines, Circulation , 2014;129(23):e521–643. 16. Vahanian A, Alfieri O, Andreotti F, et al., Guidelines on the management of valvular heart disease (version 2012), Eur Heart J , 2012;33(19):2451–96. 17. Kuwaki K, Morishita K, Tsukamoto M, Abe T, Tricuspid valve surgery for functional tricuspid valve regurgitation associated with left-sided valvular disease, Eur J Cardiothorac Surg , 2001;20(3):577–82. 18. Pfannmuller B, Misfeld M, Borger MA, et al., Isolated reoperative minimally invasive tricuspid valve operations, Ann Thorac Surg , 2012;94(6):2005–10. 19. Nishimura RA, Otto CM, Bonow RO, et al., 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol , 2014;63(22):e57–185. 20. Chopra HK, Nanda NC, Fan P, et al., Can two-dimensional

echocardiography and Doppler color flow mapping identify the need for tricuspid valve repair?, J Am Coll Cardiol , 1989;14(5):1266–74. 21. Fukuda S, Gillinov AM, McCarthy PM, et al., Determinants of recurrent or residual functional tricuspid regurgitation after tricuspid annuloplasty, Circulation , 2006;114(Suppl. 1):I582–587. 22. Rajbanshi BG, Suri RM, Nkomo VT, et al., Influence of mitral valve repair versus replacement on the development of late functional tricuspid regurgitation, J Thorac Cardiovasc Surg , 2014;148(5):1957–62. 23. Yilmaz O, Suri RM, Dearani JA, et al., Functional tricuspid regurgitation at the time of mitral valve repair for degenerative leaflet prolapse: the case for a selective approach, J Thorac Cardiovasc Surg , 2011;142(3):608–13. 24. Suri RM, Topilsky Y, The role of cognitive dissonance in the management of functional tricuspid regurgitation at the time of degenerative mitral valve repair, J Thorac Cardiovasc Surg , 2014;148(6):2810–2. 25. Singh SK, Tang GH, Maganti MD, et al., Midterm outcomes of tricuspid valve repair versus replacement for organic tricuspid disease, Ann Thorac Surg , 2006;82(5):1735–1741; discussion 1741. 26. McCarthy PM, Bhudia SK, Rajeswaran J, et al., Tricuspid valve repair: durability and risk factors for failure, J Thorac Cardiovasc Surg , 2004;127(3):674–85. 27. Tang GH, David TE, Singh SK, et al., Tricuspid valve repair with an annuloplasty ring results in improved long-term outcomes, Circulation , 2006;114(Suppl. 1):I577–581. 28. 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 Sur g, 2007;133(1):117–26. 29. Kunadian B, Vijayalakshmi K, Balasubramanian S, Dunning J, Should the tricuspid valve be replaced with a mechanical or biological valve?, Interact Cardiovasc Thorac Surg, 2007;6(4):551–7.

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