ICR 9.2

Interventional Cardiology Review Volume 9 • Issue 2 • Summer 2014

Volume 9 • Issue 2 • Summer 2014

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TAVR and LAA Occlusion: A Stitch in Time?

Sameer Gafoor, Luisa Heuer, Jennifer Franke, Stefan Bertog, Laura Vaskelyte, Ilona Hofmann and Horst Sievert

Absorb BVS Implantation in Bifurcation Lesions: Current Evidence and Practical Recommendations Robin P Kraak, Maik Grundeken, Robbert de Winter and Joanna Wykrzykowska

Differences in Outcomes and Indications between Sapien and CoreValve TAVI Prostheses Alia Noorani and Vinayak Bapat A

B

D

Alcohol Septal Ablation for the Treatment of Hypertrophic Obstructive Cardiomyopathy D1 Constantinos O’Mahony, Saidi Mohiddin and Charles Knight

A

B

LAD

Echocardiographic Findings in Left Ventricular Outflow Tract Obstruction

LAD

Optical Coherence C Tomography Image

E

C

D1

F

G

ISSN: 1756-1477

Provisional Single-scaffold Placement in a Coronary Bifurcation Lesion

Main Bifurcation D Lesion Treated with ABSORB Bioresorbable Vascular Scaffold

D1

H

D1

I

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Our Claim to FAME

The Results Are in

FAME 2 Trial

Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease

86% relative risk reduction for urgent revascularization in the FFR-guided PCI arm.

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1. De Bruyne B, Pijls N, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease.

N Engl J Med. 2012;367(11):991-1001.

2. St. Jude Medical. Data on File.

Product referenced is approved for CE Mark.

Rx Only Please review the Instructions for Use prior to using these devices for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. PressureWire is designed, developed and manufactured by St. Jude Medical Systems AB. PressureWire, ST. JUDE MEDICAL, the nine-squares symbol and MORE CONTROL. LESS RISK. are registered and unregistered trademarks and service marks of St. Jude Medical, Inc. and its related companies. Š2012 St. Jude Medical, Inc. All rights reserved.

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Volume 9 • Issue 2 • Summer 2014

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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

Editorial Board Fernando Alfonso

Juan Granada

Marko Noc

Cardiac Department, Hospital Universitario de La Princesa, Madrid

CRF Skirball Research Center, New York

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

A Pieter Kappetein

London Chest Hospital, Barts Health NHS Trust, London

Jeffrey Popma Beth Israel Deaconess Medical Center, Boston

Demosthenes Katritsis

Elliot Smith

Olivier Bertrand

Athens Euroclinic, Athens, Greece

Quebec Heart-Lung Insitute, Laval University, Quebec

Tim Kinniard

London Chest Hospital, Barts Health NHS Trust, London

University Hospital of Wales, Cardiff

Lars Søndergaard

Lutz Buellesfeld

Ajay Kirtane

Rigshospitalet - Copenhagen University Hospital, Copenhagen

University Hospital, Bern

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

Jonathan Byrne

Didier Locca

King’s College Hospital, London

Lausanne University Hospital, Lausanne

Antonio Colombo

Roxana Mehran

San Raffaele Hospital, Milan

Carlo DiMario Royal Brompton & Harefield NHS Foundation Trust, London

Eric Eeckhout

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

Nicolas Van Mieghem

Mount Sinai Hospital, New York

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Jeffrey Moses

Renu Virmani

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

CVPath Institute, Maryland

Darren Mylotte

Centre Hospitalier Universitaire Vaudois, Lausanne

Gregg Stone

Galway University Hospitals, Galway

Mark Westwood London Chest Hospital, Barts Health NHS Trust, London

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

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Liam O’Neill liam.oneill@radcliffecardiology.com •

Cover image

3d render Heart atrium - back view © Maya2008 | shutterstock.com

Radcliffe Cardiology

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Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved

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Established: June 2006 Frequency: Tri-annual Current issue: Summer 2014

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 and European Cardiology Review. n

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Radcliffe Cardiology

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Contents

Foreword 76 Simon Kennon

Coronary

77 Risks of Stroke After Coronary Artery Bypass Graft – Recent Insights and Perspectives

Tullio Palmerini, Carlo Savini and Marco Di Eusanio

84 ABSORB BVS Implantation in Bifurcation Lesions – Current Evidence and Practical Recommendations

Robin P Kraak, Maik J Grundeken, Robbert J de Winter and Joanna J Wykrzykowska

89 Clinical Impact of Stent Design

Rebecca L Noad, Colm G Hanratty and Simon J Walsh

94 Current Antithrombotic Therapy in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Interventions

Gabriele Pesarini, Sara Ariotti and Flavio Ribichini

102 Use of Thrombectomy Devices in Primary Percutaneous

Interventions for ST-elevation Myocardial Infarction – An Update

Krishnaraj S Rathod, Stephen M Hamshere, Tawfiq R Choudhury,

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Daniel A Jones and Anthony Mathur

INTERVENTIONAL CARDIOLOGY REVIEW

10/05/2014 19:47

Let’s co-create to innovate interventional cardiology!

IN T ER V EN T ION A L CA RDIOLOGY

Interventional Cardiologist

R&D Alvimedica

Alvimedica is a young, agile company devoted to developing minimally-invasive medical technologies in close cooperation with medical professionals such as yourself: physicians looking for next-level innovations in the operating room. Our ‘co-creation approach’ results in a range of products aiming to meet needs so far unmet in interventional cardiology.

Certainly we can offer you worldclass DES, BMS, guidewires and diagnostic, guiding and balloon catheters. But Alvimedica also brings you the exclusive polymer-free, balloon expandable DES stent: Cre8™! Our commitment to improving interventional procedures through innovation

Visit our booth F8/F9 at EuroPCR

is driven by our sincere care for patients’ quality of life and our goal to positively impact clinical outcomes. As our motto says: we want to help physicians bring their patients ‘Back to Life!’ as soon as possible, and based on safe medical practices.

www.alvimedica.com

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Contents

Structural 108 Alcohol Septal Ablation for the Treatment of Hypertrophic Obstructive Cardiomyopathy

Constantinos O’Mahony, Saidi A Mohiddin and Charles Knight

115 Review of Data and Discussion – Who Should Undergo Patent Foramen Ovale Closure in 2014?

Amit Bhan and Brian Clapp

121 Differences in Outcomes and Indications between Sapien and CoreValve Transcatheter Aortic Valve Implantation Prostheses A lia Noorani and Vinayak Bapat

Transcatheter Aortic Valve Replacement and Left Atrial Appendage 126 Occlusion – A Stitch in Time?

S ameer Gafoor, Luisa Heuer, Jennifer

Franke, Stefan Bertog, Laura Vaskelyte,

Ilona Hofmann and Horst Sievert

Transcatheter Aortic Valve Implantation Without 130 General Anaesthetic S imon Kennon and Zhan Lim

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You’re invited to attend our scientific sessions at EuroPCR 2014!

www.alvimedica.com

Alvimedica.indd 7

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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.

I

n this issue of Interventional Cardiology Review, the structural section contains an excellent paper on alcohol septal ablation for hypertrophic cardiomyopathy, discussing both clinical and procedural issues. Clapp brings us up to date with a review of current indications for

PFO closure and Bapat discusses the different outcomes and indications for Sapien and CoreValve TAVI procedures. Gafoor considers the rationale for combined TAVI and left atrial appendage occlusion procedures and I have also contributed a short review of data regarding TAVI procedures performed without general anaesthetic.

In the coronary section, there is a review of the risks of stroke following CABG as well as two excellent technical articles on the use of absorbable stents in bifurcation lesions and the clinical impact of stent design. In addition, the central role of thrombus in acute coronary syndromes is highlighted with a comprehensive review of antithrombotic therapy for patients with acute coronary syndromes undergoing percutaneous coronary interventions. n

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Coronary

Risks of Stroke After Coronary Artery Bypass Graft – Recent Insights and Perspectives Tullio Pa lm e r i n i , 1 Ca r l o S a v i n i 2 a n d M a r c o D i E u s a n i o 2 1. Dipartimento Cardio-Toraco-Vascolare, Unità Operativa di Cardiologia; 2. Dipartimento Cardio-Toraco-Vascolare, Unità Operativa di Cardiochirurgia, Policlinico S. Orsola, Bologna, Italy

Abstract Stroke is one of the most devastating complications after coronary artery bypass graft (CABG) surgery, entailing permanent disability, a 3–6 fold increased risk of mortality, an incremental hospital resource consumption and a longer length of hospital stay. Notwithstanding advances in surgical, anaesthetic and medical management across the last 10 years, the risk of stroke after CABG has not significantly declined, likely because an older and sicker population is now deemed suitable to undergo CABG. The pathogenesis of stroke is multifactorial, but two variables are believed to play a major role – cerebral embolisation of atheromatous debris arising from the ascending aorta during surgical manipulation and hypoperfusion during surgery. Identification of vulnerable patients at increased risk of stroke before CABG is of paramount importance for the surgical decision-making approach and informed consent. Several models including demographic, clinical and procedural variables have been developed to risk-stratify the hazard of stroke in patients undergoing CABG, but identification of severe atherosclerosis of the ascending aorta and pre-existing cerebrovascular disease are key determinants for appropriate risk stratification and decision-making. Atherosclerotic disease of the ascending aorta can be identified before surgery using transoesophageal echocardiography, computed tomography and magnetic resonance imaging. However, intra-operative ultrasound scanning of the ascending aorta is the diagnostic tool with the best sensitivity and specificity for the detection of atheromatous debris in the ascending aorta. Although many investigators have advocated the use of off-pump CABG to minimise the risk of peri-operative stroke, results from randomised trials and meta-analyses have been inconsistent. Anaortic approaches, including total arterial revascularisation with in situ grafting of both mammary arteries, or the use of the HEARTSTRING® seal device avoid any manipulation of the aorta, thus potentially minimising the risk of stroke in high-risk patients. Assessment and treatment of severe carotid artery disease, and aggressive and prompt treatment of post-operative atrial fibrillation are other important strategies that should be routinely implemented to reduce the risk of stroke in patients undergoing CABG.

Keywords Stroke, coronary artery bypass, atheroembolism, off-pump, aorta Disclosure: The authors have no conflicts of interest to declare.

Received: 4 April 2014 Accepted: 22 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):77–83 Correspondence: Tullio Palmerini, Dipartimento Cardio-Toraco-Vascolare, Unità Operativa di Cardiologia, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy.

E: tulliopalmerini@hotmail.com

Neurological dysfunction following coronary artery bypass graft (CABG) surgery can manifest as stroke, encephalopathy including delirium and post-operative cognitive dysfunction. Stroke is one of the most devastating complications after CABG surgery, entailing permanent disability and a 3–6 fold increased risk of death with a case-fatality rate up to 20 %.1,2 It is also associated with incremental hospital resource consumption and a longer length of hospital stay.

It has been estimated among a population of 114,233 Medicare beneficiaries that the occurrence of stroke entails an incremental cost of US$18,552 and an incremental length of hospital stay of seven days.3 The risk of stroke after CABG varies across studies ranging from 0.0 % to 5.2 %,4,5 depending on study design, patient risk profile, operative techniques and the length of study follow-up. Although advances in surgical, anaesthetic and medical management have occurred across the last 10 years, the risk of stroke after CABG has not significantly

© RADCLIFFE CARDIOLOGY 2014

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declined, likely because an older and sicker population is now deemed suitable to undergo CABG surgery.6 In addition, stroke represents a dismal point against CABG when deciding the optimal strategy of revascularisation between CABG and percutaneous coronary intervention (PCI) in patients with multivessel coronary artery disease. Specifically, in a recent meta-analysis including 19 randomised controlled trials with 10,944 patients, CABG was associated with significantly higher 30-day and one-year rates of stroke compared with PCI.7 Interestingly, the difference in the risk of stroke between the two strategies of revascularisation seemed more evident in patients with unprotected left main coronary artery disease or multivessel coronary artery disease than in patients with single vessel coronary artery disease.7 In addition, in a recently published meta-regression analysis including 20 randomised controlled trials comparing PCI versus CABG in patients with stable angina, a significant interaction

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Coronary between female gender and stroke risk reduction with PCI was apparent.8

Pathogenesis The pathogenesis of stroke is multifactorial, but two variables are believed to play a major role – cerebral embolism and hypoperfusion during surgery. Some studies suggested that panvasacular inflammation may also play a role, especially in the setting of acute coronary syndromes.9 Cerebral embolism is by far the most common cause of peri-operative stroke accounting for 50–75 % of cases.

Cerebral emboli arise from either the ascending aorta during surgical manipulation or from the heart due to atrial fibrillation.

The prevalence of atherosclerotic disease in the ascending aorta varies across studies, depending on the patient population, the criteria used to define the disease, and the diagnostic tool implemented to detect the disease, with case rates up to 38 % in some studies.10 This prevalence has significantly increased in recent years, likely due to better diagnostic methods and an increasing population of elderly. Peripheral vascular disease, age, hypertension and diabetes have been reported to be independent predictors of atherosclerotic disease of the ascending aorta.11 A high correlation between atherosclerosis of the ascending aorta and atheroembolism during CABG surgery has been established by several studies.5,12–14 In a prospective multicentre study including more than 2,000 patients, atherosclerosis of the ascending aorta was the strongest independent predictor of stroke associated with CABG.5 In the study by Bergman et al., extensive atherosclerotic disease of the ascending aorta was associated with a 31 % risk of post-operative stroke.12 The risk depends on the presence, location and extent of disease when the aorta is surgically manipulated.15 Embolisation of atheromatous debris from the aorta is likely to occur at the time of cannulation of the aorta for establishing cardiopulmonary bypass, when the aortic clamp is applied or released, or when proximal graft anastomoses are performed using side-biting clamp.

Cerebral emboli often co-exist with intra-operative hypoperfusion, which impairs the clearance of microemboli16 and may be responsible of bilateral watershed infarcts after CABG.17 Cerebral hypoperfusion may be exacerbated by the co-existence of carotid artery stenosis, which is another important risk factor for intra-operative stroke.18 Chronic atrial fibrillation is a risk factor for cerebral embolism, and in patients undergoing CABG the peri-operative period may be at increased risk of stroke due to the necessity to modulate anticoagulant therapy. In addition, recent studies have suggested that new onset atrial fibrillation in the peri-operative period is also a risk factor for post-CABG stroke.19 Atrial fibrillation develops in 15–30 % of patients undergoing CABG,20,21 and although initial reports suggested that it was a self-limited phenomenon with no relevant clinical sequelae, a recent study including 8,058 patients undergoing CABG, suggested that new onset atrial fibrillation was associated with significantly higher rates of stroke and long-term mortality.19

Risk Stratification Identification of vulnerable patients at increased risk of stroke before CABG is of paramount importance for the surgical decision-making approach and informed consent. The risk of stroke before CABG has been extensively scrutinised leading to the identification of several

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risk factors. Age, diabetes, hypertension, peripheral vascular disease, renal failure, left ventricular dysfunction and non-elective surgery have consistently been reported as risk factors of peri-operative stroke in patients undergoing CABG surgery.22,23 All these risk factors can be assessed before surgery, so the information can assist informed decision-making by patients, their family and their physicians. The combination of these variables has generated several risk stratification tools that can be implemented before surgery, to determine the individual probability of stroke in patients undergoing CABG. In the Charlesworth score, generated from 33,000 consecutive patients undergoing isolated CABG, seven variables are integrated, including age, diabetes, left ventricular ejection fraction <40 %, female gender, priority of surgery, renal dysfunction and peripheral vascular disease.22 In the simpler model generated by McKhann et al. only three variables are considered: age, hypertension and history of stroke.6 More recently, Hornero et al. generated and validated a new risk model (Pack2 score), including priority of surgery, peripheral vascular disease, preoperative cardiac failure/left ventricular ejection fraction <40 % and chronic kidney failure.23 Interestingly, in patients with Pack2 score ≥2, off-pump CABG significantly reduced the risk of stroke compared with on-pump CABG, whereas no difference was apparent between the two strategies of revascularisation in patients with Pack2 score <2. Further studies should externally validate this score and assess whether it is useful in clinical practice to select the optimal strategy of revascularisation between on-pump and off-pump CABG in high-risk patients.

However, while these risk stratification tools are important because they factor the additive effect of several variables, they also share a major limitation in disregarding two important risk factors – atherosclerotic disease of the ascending aorta12 and pre-existing cerebrovascular disease.6 As the impact of these two factors on the risk of post-operative stroke is substantial, they should always be scrutinised before deciding the optimal strategy of coronary revascularisation.

Severe atherosclerosis of the ascending aorta is often an unexpected intra-operative finding during CABG, when preoperative risk stratification has not been accurate. It represents a challenge for the surgeon, who may need to change the operative strategy. A variety of methods can be used before surgery to diagnose severe atherosclerosis in the ascending aorta, including computed tomography scanning, transoesophageal echocardiography or magnetic resonance imaging.

Intra-operative ultrasonographic scanning of the aorta can also be used to detect atherosclerotic changes in the entire ascending aorta. It is a rapid, safe and sensitive method, and some studies have reported that it is more accurate than both transoesophageal echocardiography14 and computed tomography in detecting atheromatous debris in the ascending aorta.24 Assessment of the neurological risk profile of patients before CABG is another essential step to make accurate risk stratification. The neurological profile of the patient should be carefully characterised, seeking for a history of stroke, the presence of initial neurocognitive disorders, or the presence of pre-existing cerebrovascular disease.6 Recent studies have also suggested that detection of cerebral ischaemia by magnetic resonance imaging before CABG is strongly associated with the risk of post-operative stroke.25,26 Screening of carotid artery disease with echo Doppler before CABG should also be performed, especially in high-risk patients.

INTERVENTIONAL CARDIOLOGY REVIEW

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Risks of Stroke After Coronary Artery Bypass Graft – Recent Insights and Perspectives

The Value of Off-pump Coronary Artery Bypass Graft in Reducing the Risk of Stroke The observation that atherosclerosis of the ascending aorta is a major determinant of stroke after CABG has led some investigators to advocate the use of off-pump CABG to reduce surgical manipulation of the aorta. Several studies have compared clinical outcomes of patients treated with on-pump versus off-pump CABG, and results have been controversial. In general, observational studies have consistently suggested an association between off-pump CABG and stroke reduction, but this association has not been confirmed in several randomised controlled trials (RCTs).

Specifically, in a propensity matched analysis involving more than 42,000 patients, there was a 35 % reduction in the risk of stroke in patients treated with off-pump CABG compared with those treated with on-pump CABG.27 In sharp contrast, in the recently published CABG Off or On Pump Revascularization Study (CORONARY), no significant difference in stroke rates was apparent between patients treated with on-pump CABG versus those treated with off-pump CABG. Similar results were apparent in two other recently published RCTs: German Off-Pump Coronary Artery Bypass Grafting in Elderly Patients (GOPCABE)28 trial and PRAGUE 6 trial.29 Several other RCTs comparing off-pump versus on-pump CABG have been performed, and results are summarised in Table 1.

In order to clarify relative safety and efficacy of off-pump versus on-pump CABG, several meta-analyses have been performed, but results have been controversial too. In particular, in the meta-analysis by Afilalo et al., 30 including 59 RCTs with 8,961 patients, there was a significantly lower 30-day risk of stroke with off-pump CABG compared with on-pump CABG. In sharp contrast, in the broader meta-analysis by Moller et al.,31 including 86 RCTs with 10,716 patients, there was no significant difference in the risk of stroke at long-term follow-up. Evaluation of different timepoints, study selection and different methodology likely explain discrepancies. It should be noted that neither of these two metaanalyses included the CORONARY trial, which with 4,752 patients enrolled, is the largest RCT performed to date.

In the largest meta-analysis performed to date, including the CORONARY trial and analysing the risk of stroke in 22,279 patients, Palmerini et al. showed that patients treated with off-pump CABG had a significantly lower 30-day risk of stroke than patients treated with on-pump CABG. However, when the analyses were restricted to high quality studies, studies with either >100 or >1,000 patients, or to studies with definition or adjudication of stroke by a clinical events committee, the precision of the point estimate was reduced, suggesting that the overall result may have been affected by studies with substantial risk of bias. Most notably, the odds ratio (95 % confidence interval [CI]) for stroke in trials of off-pump versus on-pump CABG enrolling >1,000 patients was 1.10 (0.67, 1.72).

These data therefore do not clearly support the hypothesis of a significant reduction in the risk of stroke with routine implementation of off-pump CABG compared with on-pump CABG. With an absolute risk reduction of 0.1 % and a relative risk reduction of 11.0 % with off-pump CABG versus on-pump CABG observed in the CORONARY trial, more than 300,000 patients would be necessary to assess whether off-pump CABG truly

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reduces the risk of stroke compared with on-pump CABG with test power of 80 % and alpha (α)=0.05.

Anaortic Off-pump Coronary Artery Bypass Graft Approaches As discussed above, RCTs and meta-analyses do not consistently support the hypothesis that routine implementation of off-pump CABG might reduce the risk of stroke compared with on-pump CABG. However, the specific technique used to perform off-pump CABG in those RCTs has not been reported in detail.7 Off-pump CABG in fact encompasses a variety of surgical techniques that entails different levels of aortic manipulation, including partial or side clamping of the aorta, use of the HEARTSTRING® Proximal Seal System (MAQUET, San Jose, CA, US)32 and total arterial revascularisation without cross-clamping.

Partial clamping entails surgical manipulation, and does not eliminate the clamp-related risk of stroke. In sharp contrast, anaortic approaches avoids any clamping of the aorta during off-pump procedure by performing in situ grafting using both mammary arteries and/or T- or Y-grafting. Several studies have suggested that anaortic approaches may minimise the risk of stroke in patients undergoing CABG. In a meta-analysis including 12 observational studies, the anaortic approach was associated with a significant reduction in the risk of stroke compared with both conventional CABG and off-pump CABG with partial clamping.33 In addition, Halbersma et al. showed very low rates of stroke in a cohort of 400 consecutive patients undergoing off-pump CABG with anaortic approaches.34 When the results were analysed in the perspective of the surgical arm of the Synergy between percutaneous coronary intervention with Taxus and Cardiac Surgery (SYNTAX) trial,35 a clear trend was apparent, suggesting a reduction of the risk of stroke in patients treated with anaortic approaches compared with patients treated with conventional CABG (0.8 % in the study by Halbersma et al. versus 2.2 % in the surgical arm of the SYNTAX trial). Moreover, the 0.8 % risk of stroke associated with anaortic approaches34 closely matched the 0.6 % risk of stroke associated with stenting in the SYNTAX trial.35 Another device that can be used to minimise aortic manipulation is the HEARTSTRING seal. The HEARTSTRING seal is delivered at the site of circular aortotomy to avoid uncontrolled spurting of blood while the graft is sutured. 32 After completion of the anastomosis and before tightening of the suture, the device is removed. In a propensity score matched analysis including 4,314 patients, Emmert at al. showed that the occurrence of stroke was significantly lower in patients treated with anaortic approaches using the HEARTSTRING device compared with patients treated with off-pump CABG using partial clamping.36 Moreover, the HEARTSTRING device had similar rates of stroke as total in situ arterial revascularisation, which avoids any touch of the aorta and therefore is considered the gold standard technique to minimise the risk of stroke.

Can We Minimise the Risk of Stroke After Coronary Artery Bypass Graft? Techniques and Patient Selection Accurate risk stratification and careful selection of the strategy of revascularisation are key factors to minimise the risk of stroke. The presence of severe atherosclerotic disease of the ascending aorta may be associated with a stroke rate up to 45 % if no modifications in the operative technique are implemented. 37 Depending on the

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Coronary Table 1: Randomised Clinical Trials Comparing Off-pump Versus On-pump Coronary Artery Bypass Graft Study Primary Endpoint Study Design

Number of Patients

Al-Ruzzeh, 2006

1) NCF at 6 weeks;

Single-centre, superiority (NCF);

178

2) Angiografic graft patency at 3 months

equivalence (angiographic

Results Off-pump superior to on-pump CABG

graft patency)

Ascione, 2005

Peri-procedural retinal microvascular

Single-centre superiority

damage

on-pump CABG

Ascione, 2006

Peri-procedural function of the small

Off-pump superior to on-pump

intestine, liver and pancreas

Single-centre superiority

20 40

Off-pump superior to

CABG for liver and pancreatic

function

BBS, 2010

All-cause mortality, MI, cardiac arrest,

On-pump as safe as

cardiogenic shock, stroke, coronary

reintervention at 30 days

Blacher, 2005

Peri-procedural lymphocyte activation

Single-centre, superiority

28

Superiority not shown

Caputo, 2002

Peri-procedural inflammatory marker

Single-centre, superiority

40

Off-pump superior to

release

on-pump CABG

Carrier, 2003

In-hospital death, MI, neurological injury,

Off-pump superior to

renal and respiratory insufficiency

on-pump CABG

Cavalca, 2006

Peri-procedural oxidative stress

Off-pump superior to

Single-centre, safety study

Single-centre, superiority Single-centre superiority

341

65 50

off-pump CABG

on-pump CABG

CORONARY, 2012

Death, stroke, MI, renal failure at 30 days

Multicentre, superiority

4,752

Superiority not shown

Czerny, 2000

Post-operative inflammatory marker and

Single-centre, superiority

30

Lower cTn release in

cTn release

off-pump CABG

Czerny, 2001

Completeness of revascularisation

Equivalence between off-pump

Single-centre

80

and on-pump CABG

Diegeler, 2000

Off-pump superior to

Peri-procedural NCF impairment

Single-centre, superiority

40

on-pump CABG

DOORS, 2010

Death, stroke, MI at 30 days

Multicentre, non-inferiority

900

Non-inferiority not shown

Formica, 2009

Peri-procedural inflammatory marker release

Single-centre, superiority

60

Superiority not shown

Gasz, 2004

Peri-procedural inflammatory marker release

Single-centre, superiority

20

Off-pump superior to

on-pump CABG

Gasz, 2005

Off-pump superior to

Peri-procedural inflammatory marker release

Single-centre superiority

30

on-pump CABG

Gerola, 2004

Peri-procedural all-cause mortality, MI,

Equivalence between off-pump

pulmonary complications, bleeding,

wound complications, NCF

Gonenc, 2006

Peri-procedural oxidative stress

Multicentre

Single-centre

160

42

and on-pump CABG Off-pump CABG decreases

impairment of oxidant/

antioxidant balance

GOPCABE, 2013

Death, stroke, MI, repeat revascularisation,

renal replacement therapy

Gulielmos, 2000

Peri-procedural inflammatory marker and

cTn release

on-pump CABG

Hernandez, 2007

NCF at hospital discharge

Single-centre, superiority

204

Superiority not shown

Jares, 2007

Peri-procedural coagulation parameters

Single-centre, superiority

20

Off-pump superior to

measured with TEG

on-pump CABG

JOCRI, 2005

Cardiac death, MI, CHF, TVR at 3 years

Off-pump non-inferior to

Multicentre, superiority

2,539

Superiority not demonstrated

Single-centre

20

Off-pump superior to

Multicentre, non-inferiority

167

on-pump CABG

Johansson-Synnergren, Peri-procedural inflammatory marker release Single-centre

Off-pump CABG reduces

52

2003

and endothelial function

complement activation

Khan, 2004

Graft patency at 3 months

Graft patency lower in the

Single-centre

103

off-pump CABG

Kochamba, 2000

Off-pump as safe as

Peri-procedural outcome

Single-centre, safety study

58

on-pump CABG

Kunes, 2007

On-pump CABG associated

Peri-procedural inflammatory marker release

Single-centre, superiority

34

with higher release of

pentraxin 3

Lee, 2003

In-hospital all-cause death, stroke and

Off-pump superior to

length of stay, intra-aortic balloon support

post-operatively

Legare, 2004

Peri-procedural death, MI, stroke, AF,

deep sternal wound infection

Lingaas, 2006

Graft patency at 12 months

Single-centre, superiority

60

Single-centre, superiority

300

Superiority not shown

Single-centre

120

Equivalence between off-pump

80

Palmerini_edited_version2.indd 80

on-pump CABG

and on-pump CABG

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Table 1: Continued Study Primary Endpoint Study Design

Number of Patients

Results

Malik, 2006

50

Off-pump superior to

Peri-procedural CPK-MB release

Single-centre, superiority

on-pump CABG

Mandak, 2008

Off-pump superior to

Peri-procedural tissue metabolism

Single-centre, superiority

40

on-pump CABG

MASS III, 2010

Similar incidence of the

Death, MI, Stroke, TVR at 5 years

Single-centre

308

PE between off-pump versus

on-pump CABG

Matata, 2000

Peri-procedural inflammatory marker release

Off-pump CABG significantly

and oxidative stress

reduced the PE

Medved, 2008

In-hospital mortality or morbidity

Similar incidence of the

Single-centre Single-centre

20 60

PE between off-pump versus

on-pump CABG

Michaux, 2006

LVEF and diastolic function (tricuspid and

Similar incidence of the

mitral E/A ratio)

Single-centre

50

PE between off-pump versus

on-pump CABG

Modine, 2010

Off-pump CABG attenuates

Peri-procedural renal injury

Single-centre

71

peri-procedural renal injury

Motallebzadeh, 2004

Off-pump CABG significantly

Peri-procedural cerebral injury

Single-centre

35

reduced the PE

Motallebzadeh, 2007

NCF better in the

Peri-procedural NCF

Single-centre

212

off-pump CABG

Muneretto, 2003

Similar incidence of the

Early and midterm outcomes

Single-centre

176

PE between off-pump versus

on-pump CABG

Nesher, 2006

Peri-procedural inflammatory marker

Off-pump CABG reduced the

and CPK-MB release

incidence of the PE

Niranjan, 2006

Autologous blood transfusion and

Similar incidence of the

post-operative complications

Single-centre Single-centre

125 80

PE between off-pump versus

on-pump CABG

OCTOPUS, 2007

NCF at 3 months

Multicentre, superiority

281

Superiority not shown

Ozkara, 2007

Peri-procedural PAI-1 release

Single-centre

44

Off-pump CABG associated

with higher level of PAI-1

Parolari, 2003

No difference in the

Peri-procedural oxygen metabolism

Single-centre

25

PE between off-pump and

on-pump CABG

Parolari, 2005

Peri-procedural plasma P-selectin and

TF levels

Penttila, 2001

Peri-procedural changes in myocardial

metabolism

Single-centre, superiority

29

Superiority not shown

Single-centre

22

Off-pump CABG associated with better myocardial energy

preservation

PRAGUE-4, 2004

Death, MI, stroke, RF requiring haemodialysis

No difference in the

at 30 days

Single-centre

388

PE between off-pump and

on-pump CABG

PRAGUE-6, 2013

Off-pump superior to

Death, MI, stroke, new RF

Single-centre

206

on-pump CABG

Rachwalik, 2006

Peri-procedural respiratory function

Single-centre

42

NA

Rainio, 2007

Peri-procedural retinal micro-embolism

Single-centre

20

Off-pump CABG reduced the

incidence of the PE

Rasmussen, 2007

Off-pump CABG reduced the

Peri-procedural inflammatory marker release

Single-centre

35

Single-centre

Peri-procedural inflammatory marker,

CPK-MB and cTn release

myocardial injury

ROOBY, 2009

All-cause death, reoperation, new mechanical Multicentre, superiority

2,203

Superiority not shown

support, coma, stroke, cardiac arrest, RF

requiring dialysis at 30 days. All-cause death,

MI, TLR at 1 year

Sahlman, 2003

Peri-procedural inflammatory and

50

Off-pump CABG reduced the

CPK-MB release

incidence of the PE

Sajja, 2007

Peri-procedural renal function

Off pump CABG associated

Single-centre Single-centre

40

incidence of the PE

Rastan, 2005

116

Off-pump CABG attenuates

with better renal function

Selvanayagam, 2004

Off-pump CABG associated

Peri-procedural LVEF

Single-centre

60

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Number of Patients

Results

SMART, 2003

Completeness of revascularisation and

197

Similar incidence of the PE

graft patency at 30 days

Single-centre

between off-pump and

on-pump CABG

Sousa Uva, 2010

On-pump superior to

Graft patency at 5 weeks

Single-centre, superiority

150

off-pump CABG

Tang, 2002

Similar incidence of the

Peri-procedural renal injury

Single-centre

40

PE between off-pump and

on-pump CABG

Tatoulis, 2006

PE similar between off-pump

Systemic vascular resistance at 12 hours

Single-centre

100

and on-pump CABG

Vedin, 2006

PE similar between off-pump

NCF at 6 months

Single-centre

80

and on-pump CABG

Velissaris, 2003

PE similar between off-pump

Peri-procedural gastric mucosa oxygenation

Single-centre

54

and on-pump CABG

Vural, 1995

PE similar between off-pump

Peri-procedural haemodynamic assessment

Single-centre

50

and on-pump CABG

Wan, 2004

Off-pump CABG attenuates

Peri-procedural inflammatory marker release Single-centre

37

marker release

Wandschneider, 2000

Off-pump CABG attenuates

Peri-procedural inflammatory marker release

Single-centre

108

marker release

Wehlin, 2004

Off-pump CABG attenuates

Peri-procedural inflammatory marker release

Single-centre

37

marker release

Zamvar, 2002

Off-pump CABG attenuates

NCF at 10 weeks

Single-centre

60

NC dysfunction

AF = atrial fibrillation; ARF = acute renal failure; CABG = coronary artery bypass graft; CHF = congestive heart failure; CORONARY = CABG Off or On Pump Revascularization Study; CPK = creatine phosphokinase; cTn = cardiac troponin; DOORS = Danish On-Pump versus Off-Pump Randomization Study; GOPCABE = German Off-Pump Coronary Artery Bypass Grafting in Elderly Patients study; JOCRI = Japanese Off-pump Coronary Revascularization Investigation; LVEF = left ventricular ejection fraction; MASS III = Medicine, Angioplasty,or Surgery Study; MI = myocardial infarction; NA = not available; NCF = neurocognitive function; PAI-1 = Plasminogen activator inhibitor-1; PE = primary endpoint; RF = renal failure; ROOBY = Randomized On/ Off Bypass study; SMART = Surgical Management of Arterial Revascularization Therapies; TEG = thromboelastography; TF = tissue factor; TLR = target lesion revascularisation; TVR = target vessel revascularization.

individual risk profile of patients, several options can be considered to minimise the risk of stroke. If the risk of stroke appears prohibitive with CABG, and anaortic approaches cannot be used, PCI should be considered as an alternative. In case of severe atherosclerotic disease of the ascending aorta, off-pump CABG with anaortic approaches should be implemented. Total arterial revascularisation with in situ grafting using both mammary arteries and/or T- or Y-grafting should be considered the gold standard to minimise the risk of stroke.

When complete revascularisation cannot be achieved with total arterial revascularisation, use of the HEARTSTRING device may help in minimising aortic manipulation. Use of intra-operative epiaortic ultrasound, which can precisely characterise site and extension of atherosclerotic disease, may help the surgical decision-making approach. In the study by Bolotin et al., intra-operative findings of atherosclerotic disease of the ascending aorta with epiaortic ultrasound led to a change in the surgical strategy in 28 % of cases.10 Moreover, in cases in which on-pump CABG cannot be avoided, epiaortic ultrasound may help in identifying a relatively disease-free portion of the aorta to minimise the risk of atheroembolism when clamping or cannulating the aorta.

Despite some studies suggesting a potential benefit of anaortic approaches for high-risk patients, this technique has not been widely embraced. For several reasons, including the technical requirements for performing graft anastomoses with the beating heart and the concern for long-term patency, most surgeons worldwide still prefer to perform CABG with cardiopulmonary bypass.38 Thus, much of

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the evidence derived from the aforementioned studies has been contributed by highly experienced centres with surgeons that have developed high proficiency in performing off-pump CABG. Whether this technique can be safely extended to all cardiac surgical centres, remains to be determined.

Use of epiaortic filters has also been advocated as another possible strategy to minimise the risk of cerebral embolism in patients with severe atherosclerotic disease of the ascending aorta, who are not deemed suitable for anaortic approaches. The filter is inserted through a modified arterial cannula immediately before releasing the cross-clamp, and it remains in the aorta until cardiopulmonary bypass is discontinued. In a study involving 77 patients, implantation of the filters proved to be feasible, safe and uneventful.39 Particulate emboli were retrieved in 44 patients, the predominant origin of which was atheromatous. In a randomised trial including 1,289 patients, particulate emboli were detected in 598 (96.8 %) of 618 successfully deployed filters.40 In addition, a significant reduction in post-operative renal complications was apparent in patients in whom filters were implanted compared with the control group.

More controversial appears the management of patients with carotid artery disease that have to undergo CABG. The prevalence of severe carotid disease in this setting is around 6–12 %.41 Three approaches are commonly used: carotid endarterectomy followed by CABG, combined carotid endarterectomy and CABG, and more recently carotid stenting followed by CABG. In a propensity matched analysis of 350 patients in which these three approaches were compared, Shishehbor et al. showed significantly lower long-term rates of

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all-cause death, myocardial infarction and stroke in patients treated with carotid stenting followed by CABG in comparison with both carotid endarterectomy followed by CABG (adjusted hazard ratio [HR] 0.33, 95 % CI 0.15–0.77; p=0.01) and combined carotid endarterectomy and CABG (HR 0.35, 95 % CI 0.18–0.70).42 However, due to the observational nature of the study, these data should be considered hypothesis generating, and further randomised trials are warranted.

Optimal blood pressure management, prompt recognition and treatment of new onset atrial fibrillation, prevention of rewarming temperature >37°C,43 use of alpha-stat pH management44 and prevention of hyperglycaemia during surgery45 are other recommendations that should be considered depending on the individual risk profile of patients.

1. Dacey LJ, Likosky DS, Leavitt BJ, et al., Perioperative stroke and long-term survival after coronary bypass graft surgery, Ann Thorac Surg , 2005;79:532–6; discussion 537.

2. Tarakji KG, Sabik JF 3rd, Bhudia SK, et al., Temporal onset, risk factors, and outcomes associated with stroke after coronary artery bypass grafting, JAMA , 2011;305:381–90.

3. Brown PP, Kugelmass AD, Cohen DJ, et al., The frequency and cost of complications associated with coronary artery bypass grafting surgery: results from the United States Medicare program, Ann Thorac Surg , 2008;85:1980–6.

4. Goy JJ, Kaufmann U, Goy-Eggenberger D, et al., A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs Internal Mammary Artery, Mayo Clin Proc , 2000;75:1116–23.

5. Roach GW, Kanchuger M, Mangano CM, et al., Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators, N Engl J Med , 1996;335:1857–63.

6. McKhann GM, Grega MA, Borowicz LM Jr, et al., Stroke and encephalopathy after cardiac surgery: an update, Stroke , 2006;37:562–71.

7. Palmerini T, Biondi-Zoccai G, Reggiani LB, et al., Risk of stroke with coronary artery bypass graft surgery compared with percutaneous coronary intervention, J Am Coll Cardiol , 2012;60:798–805.

8. D’Ascenzo F, Barbero U, Moretti C, et al., Percutaneous coronary intervention versus coronary artery bypass graft for stable angina: Meta-regression of randomized trials, Contemp Clin Trials , 2014;38:51–8.

9. Grau AJ, Boddy AW, Dukovic DA, et al., Leukocyte count as an independent predictor of recurrent ischemic events, Stroke , 2004;35:1147–52.

10. Bolotin G, Domany Y, de Perini L, et al., Use of intraoperative epiaortic ultrasonography to delineate aortic atheroma, Chest , 2005;127:60–5.

11. Davila-Roman VG, Barzilai B, Wareing TH, et al., Intraoperative ultrasonographic evaluation of the ascending aorta in 100 consecutive patients undergoing cardiac surgery, Circulation , 1991;84:III47–53.

12. Bergman P, van der Linden J, Atherosclerosis of the ascending aorta as a major determinant of the outcome of cardiac surgery, Nat Clin Pract Cardiovasc Med , 2005;2:246–51.

13. Blauth CI, Macroemboli and microemboli during cardiopulmonary bypass, Ann Thorac Surg , 1995;59:1300–3.

14. Dávila-Román VG, Murphy SF, Nickerson NJ, et al., Atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic events and mortality, J Am Coll Cardiol , 1999;33:1308–16.

15. van der Linden J, Hadjinikolaou L, Bergman P, Lindblom D, Postoperative stroke in cardiac surgery is related to the location and extent of atherosclerotic disease in the ascending aorta, J Am Coll Cardiol , 2001;38:131–5.

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Conclusions Notwithstanding the remarkable improvement in surgical, anaesthetic and medical management, the risk of stroke after CABG has not significantly declined. Risk stratification is of the utmost importance for identifying vulnerable patients. Specifically, pre-existing cerebrovascular disease and atherosclerosis of the ascending aorta are major determinants of the risk of peri-operative stroke, and should be always carefully scrutinised. RCTs and meta-analysis do not clearly support routine implementation of offpump CABG as a strategy to minimise the risk of stroke. Observational studies have suggested that anaortic approaches might reduce the risk of stroke compared with conventional CABG in patients with severe atherosclerosis of the ascending aorta. Further randomised controlled trials are warranted to confirm this hypothesis. n

16. Caplan LR, Hennerici M, Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke, Arch Neurol , 1998;55:1475–82.

17. Gottesman RF, Sherman PM, Grega MA, et al., Watershed strokes after cardiac surgery: diagnosis, etiology, and outcome, Stroke , 2006;37:2306–11.

18. Naylor AR, Mehta Z, Rothwell PM, Bell PR, Carotid artery disease and stroke during coronary artery bypass: a critical review of the literature, Eur J Vasc Endovasc Surg , 2002;23:283–94.

19. Horwich P, Buth KJ, Légaré JF, New onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery, J Card Surg , 2013;28:8–13.

20. Amar D, Shi W, Hogue CW Jr, et al., Clinical prediction rule for atrial fibrillation after coronary artery bypass grafting, J Am Coll Cardiol , 2004;44:1248–53.

21. Villareal RP, Hariharan R, Liu BC, et al., Postoperative atrial fibrillation and mortality after coronary artery bypass surgery, J Am Coll Cardiol , 2004;43:742–8.

22. Charlesworth DC, Likosky DS, Marrin CA, et al., Development and validation of a prediction model for strokes after coronary artery bypass grafting, Ann Thorac Surg , 2003;76:436–43.

23. Hornero F, Martin E, Rodríguez R, et al., A multicentre Spanish study for multivariate prediction of perioperative in-hospital cerebrovascular accident after coronary bypass surgery: the PACK2 score, Interact Cardiovasc Thorac Surg , 2013;17:353–8.

24. Bergman P, van der Linden J, Forsberg K, Ohman M, Preoperative computed tomography or intraoperative epiaortic ultrasound for the diagnosis of atherosclerosis of the ascending aorta?, Heart Surg Forum , 2004;7(3):E245–9; discussion E249.

25. Mathisen L, Andersen MH, Hol PK, et al., Preoperative cerebral ischemic lesions predict physical health status after on-pump coronary artery bypass surgery, J Thorac Cardiovasc Surg , 2005;130:1691–7.

26. Matsuura K, Mogi K, Sakurai M, et al., Impact of preexisting cerebral ischemia detected by magnetic resonance imaging and angiography on late outcome after coronary artery bypass surgery, Ann Thorac Surg, 2011;91:665–70.

27. Puskas JD, Edwards FH, Pappas PA, et al., Off-pump techniques benefit men and women and narrow the disparity in mortality after coronary bypass grafting, Ann Thorac Surg , 2007;84:1447–54; discussion 1454–6.

28. Diegeler A, Börgermann J, Kappert U, et al., Off-pump versus on-pump coronary-artery bypass grafting in elderly patients, N Engl J Med , 2013;368:1189–98.

29. Hlavicka J, Straka Z, Jelinek S, et al., PRAGUE-6 Trial, OffPump Versus On-Pump Coronary Artery Bypass Graft Surgery in Patients With EuroSCORE ≥6. Available at: http:// clinicaltrialresults.org/Slides/ACC%202013/Hlavicka_ PRAGUE-6_ACC%202013.pdf (accessed 27 April 2014).

30. Afilalo J1, Rasti M, Ohayon SM, et al., Off-pump vs. on-pump coronary artery bypass surgery: an updated meta-analysis and meta-regression of randomized trials, Eur Heart J, 2012;33(10):1257–67.

31. Møller CH1, Penninga L, Wetterslev J, et al., Off-pump versus on-pump coronary artery bypass grafting for ischaemic heart disease, Cochrane Database Syst Rev, 2012;3:CD007224.

32. Emmert MY, Grünenfelder J, Scherman J, et al., HEARTSTRING enabled no-touch proximal anastomosis for off-pump coronary artery bypass grafting: current evidence and technique, Interact Cardiovasc Thorac Surg , 2013;17:538–41.

33. Edelman JJ, Yan TD, Bannon PG, et al., Coronary artery bypass grafting with and without manipulation of the ascending aorta--a meta-analysis, Heart Lung Circ , 2011;20:318–24.

34. Halbersma WB, Arrigoni SC, Mecozzi G, et al., Four-year outcome of OPCAB no-touch with total arterial Y-graft: making the best treatment a daily practice, Ann Thorac Surg , 2009;88:796–801.

35. Serruys PW, Morice MC, Kappetein AP, et al., Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease, N Engl J Med , 2009;360:961–72.

36. Emmert MY, Seifert B, Wilhelm M, et al., Aortic no-touch technique makes the difference in off-pump coronary artery bypass grafting, J Thorac Cardiovasc Surg , 2011;142:1499–506.

37. Mills NL, Everson CT, Atherosclerosis of the ascending aorta and coronary artery bypass. Pathology, clinical correlates, and operative management, J Thorac Cardiovasc Surg , 1991;102:546–53.

38. Kerendi F, Morris CD, Puskas JD, Off-pump coronary bypass surgery for high-risk patients: only in expert centers?, Curr Opin Cardiol , 2008;23:573–8.

39. Reichenspurner H, Navia JA, Berry G, et al., Particulate emboli capture by an intra-aortic filter device during cardiac surgery, J Thorac Cardiovasc Surg , 2000;119:233–41.

40. Banbury MK, Kouchoukos NT, Allen KB, et al., Emboli capture using the Embol-X intraaortic filter in cardiac surgery: a multicentered randomized trial of 1,289 patients, Ann Thorac Surg , 2003;76:508–15; discussion 515.

41. Berens ES, Kouchoukos NT, Murphy SF, Wareing TH, Preoperative carotid artery screening in elderly patients undergoing cardiac surgery, J Vasc Surg , 1992;15:313–21; discussion 322–3.

42. Shishehbor MH, Venkatachalam S, Sun Z, et al., A direct comparison of early and late outcomes with three approaches to carotid revascularization and open heart surgery, J Am Coll Cardiol , 2013;62:1948–56.

43. Grigore AM, Grocott HP, Mathew JP, et al., The rewarming rate and increased peak temperature alter neurocognitive outcome after cardiac surgery, Anesth Analg , 2002;94:4–10.

44. Murkin JM, Martzke JS, Buchan AM, et al., A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. II. Neurologic and cognitive outcomes, J Thorac Cardiovasc Surg , 1995;110:349–62.

45. McAlister FA, Man J, Bistritz L, et al., Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes, Diabetes Care, 2003;26:1518–24.

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ABSORB BVS Implantation in Bifurcation Lesions – Current Evidence and Practical Recommendations R obin P K ra a k , Ma ik J Gru n d e k e n , R o b b e r t J d e Wi n t e r a n d J o a n n a J Wy k r z y k o w s k a AMC Heartcenter, Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands

Abstract The introduction of the ABSORB bioresorbable vascular scaffold (BVS) provides a new tool for stenting in interventional cardiology. Initially, relatively simple coronary artery lesions were treated with this novel device; nowadays, we are gaining clinical experience when treating a wide variety of lesions with the ABSORB BVS, including bifurcation lesions. Unfortunately, data are limited in terms of the use of the ABSORB BVS in coronary bifurcation lesions, so little is known about the safety and feasibility of these procedures. Bench testing and case reports showed that single provisional scaffold placement is feasible with fenestration of the scaffold towards the side branch and sequential non-compliant balloon inflation in the side and main branches. However, no prospective randomised clinical data with optical coherence tomography (OCT) imaging for different bifurcation stenting techniques are available. Based on the available data and our own experience we would recommend the use of the provisional single scaffold technique and only to fenestrate the scaffold if a severely pinched ostium combined with impaired flow seen on angiogram.

Keywords Percutaneous coronary interventions, bioresorbable vascular scaffold, bifurcation lesions, optical coherence tomography Disclosure: Joanna J Wykrzykowska receives consultancy fees from Abbott Vascular. The AMC Heartcenter received a restricted research grant from Abbott Vascular.

The remaining authors have no conflicts of interest to declare.

Received: 2 April 2014 Accepted: 23 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):84–8 Correspondence: Joanna J Wykrzykowska, Academic Medical Center – University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

E: j.j.wykzykowska@amc.uva.nl

In the past three decades, significant progress has been made in the treatment of coronary artery disease. From the introduction of balloon angioplasty by Andreas Grüntzig in 19771 to metallic drugeluting stents with thin stent struts coated with cytotoxic or cytostatic drugs,2,3 with biocompatible/biodegradable polymers,4 with or without endothelial progenitor cell-capturing technology.5 However, current standard treatment with metallic stents has its shortcomings, such as late in-stent restenosis, late and very late stent thrombosis, impaired vasomotion in the stented segment6–8 and hindrance of repeat revascularisations. To potentially overcome the shortcomings of metallic stents, fully bioabsorbable stents (i.e. scaffolds) were developed.9 After preclinical testing and clinical evaluation in relatively simple coronary artery lesions,10–12 the ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS) received CE-mark approval on 14 December 2010 and is since then increasingly being used in clinical practice across Europe and the rest of the world. This adoption in clinical practice led to a broad extension of, officially offlabel, indications in which the ABSORB BVS is being used, such as ST-segment elevation myocardial infarction (STEMI),13 chronic totally occluded (CTO) arteries and bifurcation lesions.

The use of bioresorbable technology in coronary bifurcation lesions may have potential benefits compared with metallic stents.

For example, bioresorbable scaffolds could prevent permanent obstruction of a side branch (SB) after full absorption of the struts in front of this SB, leading to increased blood flow in the SB. Another

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potential benefit of the ABSORB BVS in bifurcation lesions might be a lower risk of late stent thrombosis, due to the absorption of non-apposed SB (NASB) struts at long term. These NASB struts are known to be often uncovered and thus a potential nidus for stent thrombosis.14 However, in all preclinical and clinical trials on the BVS, patients with SB ≥2 mm were excluded from enrolment, so limited data are available about the use of the BVS in bifurcation lesions.

Therefore, the ‘Instructions for use’ of the ABSORB BVS does not indicate the use of the device in lesions involving a SB >2.5 mm. This led to some practical concerns about the use of the ABSORB BVS in coronary bifurcation lesions. For example, does the ABSORB BVS, with a strut thickness of 150 µm, allow for the same bifurcation techniques being used in metallic stent? Is the BVS, due to the lactic acid material, easier to fracture? This article will focus on data provided from in vitro and in vivo assessment of the ABSORB BVS in coronary bifurcation lesions and will provide practical recommendations based on these data and our own experience.

In vitro evaluation Džavík and Colombo recently reported several bifurcation bench tests in which the ABSORB BVS is evaluated in a synthetic arterial model.15 Bifurcation stenting techniques tested included provisional stenting with final kissing balloon inflation (FKBI), modified T-stenting with a FKBI, double or two-step crush technique, mini-crush technique and culotte technique. The investigators used non-compliant (NC) balloons only, to prevent overexpansion of the scaffold due to increased

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Figure 1: In vitro Bench Test of the Double-crush Procedure A

B

C

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In vitro model of a double-crush procedure (A), with a 3.0x18 mm ABSORB bioresorbable vascular scaffold (BVS) in the main vessel and a 2.5x28 mm scaffold in the side branch, showed a small area of carinal malapposition (arrow). Micro-computed tomography reconstruction showed a good paving of the main branch lumen with one strut protruding into the lumen (B); however, no protruding struts in the side branch BVS (C). View through the main branch BVS into the side branch revealed good opening and coverage of the side branch ostium (D). Source: Džavík and Colombo, 2014.15 Copyright Elsevier. LAD = left anterior descending; RCx = right circumflexus artery.

balloon diameters. All procedures were assessed visually and by scanning electron microscopy (single scaffold techniques) and by microcomputed tomography (two scaffold techniques).

The investigators did not see any malapposition or strut fractures after FKBI in provisional stenting of a 3.0x18 mm BVS. FKBI in the provisional stenting technique was performed with a 2.5x20 mm balloon in the SB and 3.0x20 mm balloon in the main branch, both inflated at 8 atmospheres. Strut fractures were observed when FKBI was performed after T-stenting technique using a 3.0x18 mm BVS in the main branch (MB) and a 2.5x18 mm BVS in the SB and 3.0x20 mm (MB) and 2.5x20 mm (SB) balloons inflated at 10 atmospheres. The double- and mini-crush techniques both resulted in mild protrusions of BVS struts in the main branch. Even so, the double-crush technique showed a small area of malapposition between the carina and the two overlying scaffolds (see Figure 1). Likewise, a small area of malapposition was seen if the culotte technique was used, this technique also led to a thick circumferential two-layer scaffold wall in the proximal segment of the MB as well as a bulky BVS neocarina.

Based on their observations, the authors recommended to use provisional stenting in the majority of cases, with sequential noncompliant balloon inflation in the SB and the MB and reserving FKBI only if absolutely necessary. Restricted use of planned two-stent techniques, like crush or culotte, was recommended as more bench testing is needed to evaluate the feasibility of these techniques.

These recommendations are supported by other bench test studies, performed by White et al. presented at Transcatheter Cardiovascular Therapeutics (TCT) 2013.16

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In vivo Evaluation Systematic evaluation of side branches ≤2 mm jailed by the ABSORB BVS was performed by Okamura et al.17 Furthermore, few case reports described the treatment of true bifurcations lesions with involvement of SB ≥2 mm.18–21 To allow full assessment of the ABSORB BVS SB struts, optical coherence tomography (OCT) was used in all these reports.

OCT allows visualisation of the vessel wall and the ABSORB BVS struts at high resolution22 and with a high degree of reproducibility.23 Okamura et al. assessed jailed side branch struts at baseline with three-dimensional (3D) OCT reconstruction, allowing the SB orifices to be evaluated visually. In total, 40 SB ostia of 25 patients enrolled in the ABSORB Cohort B study were analysed. In total, 24 orifices were jailed and showed different degrees and patterns of compartmentalisation (Type V, T and H) (see Figure 2).

Further insight in the use of the ABSORB BVS in coronary artery bifurcation lesions emerges from case reports combined with OCT images. Okamura et al. described a patient with an obstructed SB of ≤2 mm. Serial OCT imaging was performed at 2-year follow up showing an open SB ostium with intimal bridges creating a neocarina, persisting after absorption of the scaffold.24 Van Geuns et al. demonstrated the feasibility of crossing the ABSORB BVS struts into the SB with a coronary guidewire after deployment of a 3.0x18 mm ABSORB BVS in a left anterior descending (LAD) artery bifurcation lesion (Medina classification 1,1,0).21 Gogas et al. were first to describe side branch balloon dilatation of a LAD/second diagonal bifurcation lesion (Medina 1,1,1) treated with a single ABSORB BVS in the main branch. After deployment of a 3.0x18 mm ABSORB BVS

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Coronary Figure 2: Three-dimensional Assessment of Non-jailed and Jailed Side Branch

Figure 3: Three-dimensional Optical Coherence Tomography Evaluation of a Left Main Bifurcation Lesion Treated with ABSORB Bioresorbable Vascular Scaffold

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Extra-luminal views (A) and intraluminal views (B) from three-dimensional offline reconstructions shows non-jailed and Types V, T, and H jailed ≤2 mm side branch (SB).

Source: Okamura et al., 2010.17 Copyright Elsevier.

in the midLAD, there was impaired flow and pinching of the ostium of the second diagonal, after which the scaffold was fenestrated towards the SB and dilated with a 1.5x12 mm Trek-compliant balloon.

2D OCT images and offline 3D-OCT reconstructions showed an open ostium of the SB and well-apposed struts in the SB segment.20 Finally, Grundeken et al. showed a successful deployment of a 3.5x18 mm ABSORB BVS in the left main coronary artery (LMCA) in the direction of the LAD, crossing the left circumflexus artery (LCx). However, after placement of the scaffold plaque shift towards the ostium of the LCx was observed on angiography. Therefore, the BVS was fenestrated towards the LCx and the LCx ostium was dilated with 2.0x20mm and 2.5x15mm Sapphire II compliant balloons at 8 atmospheres.

Offline 3D-OCT reconstructions of the scaffold before fenestration showed multiple struts jailing the ostium of the LCx. After dilatation of the LCx ostium there is an opening of the stent cell seen towards the LCx without scaffold disruption (see Figure 3). These case reports illustrated that implantation of the ABSORB BVS and scaffold fenestration towards the SB with subsequent SB post-dilatation is feasible. Furthermore, these cases described the role of OCT to guide optimal scaffold placement.

Practical Recommendations Although more clinical studies are needed to verify the optimal strategy in bifurcation lesions using ABSORB BVS, we would like to make the

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Initial angiography showed a left main coronary artery (LMCA) lesion (A), after placement of a 3.5 × 18 mm ABSORB bioresorbable vascular scaffold (BVS). (B) Plaque shift (white arrow) was observed towards the left circumflexus artery (LCx) (C). Therefore, the BVS was fenestrated towards the LCx with a traverse wire and the LCx ostium was dilated with 2.0x20 mm and 2.5x15 mm Sapphire II compliant balloons at 8 atmospheres (D). Final angiogram showed a good result (E). Longitudinal two-dimensional optical coherence tomography (OCT) pullback (I) indicating the viewing points at the LCx ostium of figures (F), (G), (H), (J), (M) and (N). Offline three-dimensional reconstructions before fenestration showed multiple BVS struts jailing side branch (H), (K), (M) and dividing the LCx ostium in five compartments (F). After fenestrating the ABSORB BVS, with guidewire positioned through the distal cell (G) (J), the ABSORB could be opened without BVS deformity at the level of the carina (L) (N). Source: Grundeken MJ et al., 2013.18 Copyright Elsevier.

following recommendations based on previously described data and our own experience. In accordance with the recommendation of the European Bifurcation Club, based on randomised data on one- versus two-stent techniques using metallic stents, we would recommend the provisional single stenting technique in the majority of the lesions (see Figure 4), as previously suggested by Džavík and Colombo.15 Adequate lesion preparation and optimal sizing of the ABSORB BVS is essential prior to scaffold placement. Stent sizing with metallic stents is recommended to be based on the distal diameter with subsequent postdilatation of the proximal main branch with a larger balloon to ensure stent apposition in the proximal main branch (proximal optimisation technique [POT]).25 This technique is considered to prevent carinal shift and subsequent ostial pinching of the SB. However, postdilation of the BVS with balloons >0.5 mm larger than the BVS size is discouraged due to the increased risk of strut fractures. Therefore, we recommend to choose the BVS size based on the proximal diameter.

Intravascular imaging, such as intravascular ultrasound (IVUS) or OCT, or online quantitative coronary angiography (QCA) can be used for optimal sizing of the ABSORB BVS.

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ABSORB BVS Implantation in Bifurcation Lesions â&#x20AC;&#x201C; Current Evidence and Practical Recommendations

Figure 4: Provisional Single-scaffold Placement in a Coronary Bifurcation Lesion

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Initial angiography of a 64-year-old male patient without a medical history showed a Medina 0,1,1 left anterior descendens (LAD)/first diagonal branch (D1) lesion (A). After pre-dilatation with a 2.0x20 mm balloon of both the LAD (12 atm) and ostium of D1 (10 atm), a 3.0x18 mm ABSORB bioresorbable vascular scaffold (BVS) was delivered in the LAD (B) and (C). Subsequently, the scaffold was post-dilated with a 3.0x12 mm non-compliant balloon at 16 atmospheres. Final angiography showed a good result in the LAD and a slightly pinched ostium of the D1 (D). Two-dimensional optical coherence tomography (OCT) images showed some non-apposed side branch struts, and an open ostium of D1 (E) and (F). Offline three-dimensional reconstructions showed a pinched ostium of the D1, probably because of carina shifting (G), multiple BVS struts jailing the side branch (H) and (I) and dividing the D1 ostium in three compartments. Due to TIMI III flow in the D1 at final angiogram, the scaffold was not fenestrated. At 9-months follow-up the patients is still without complaints.

After deployment of the scaffold, we recommend to guide further need for fenestration and post-dilatation of the scaffold on the angiographic result and OCT images. If a lesion after deployment of the scaffold has a severely pinched ostium on angiography combined with impaired flow, Thrombolysis In Myocardial Infarction (TIMI) flow 1 or 2, we recommend the fenestration of the scaffold towards the SB. Online 3D-OCT reconstructions, which are available at the newest OCT consoles, could guide the optimal guidewire position during recrossing towards the SB. Recrossing through the most distal compartment is recommended, as distal recrossing leads to a reduction of incomplete stent apposition (ISA) at baseline in metallic stents.26 In our experience, fenestration of the scaffold towards the SB is feasible with a 2.0 mm or a 2.5 mm balloon in the SB ostium to a maximum of 6 to 8 atmospheres.

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Final OCT pullback after fenestration could be performed to detect whether the scaffold is well apposed in the whole stented area and to control for any struts out of the expected range. The latter is a sign of strut fracture, which could be treated with additional stenting.

Due to lack of clinical data, we recommend repeat angiography to be performed combined with OCT at 9 months after scaffold placement, even if the patient is without any complaints. This allows assessment of the TIMI flow in the SB and MB, intimal tissue bridging in front of the SB and intimal formation in the distal MB. Treatment of ABSORB BVS re-stenosis has not been investigated in clinical trials; however, Nakatani et al. showed a case series of six patients with in-stent restenosis who have been treated with additional stenting using Xience drug-eluting stents.27

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Coronary Discussion The ABSORB BVS is currently being used in daily clinical practice around the world. Unfortunately, very limited data are available about the use of the BVS in coronary bifurcation lesions. Several case reports have shown that treatment of bifurcation lesions and fenestration of the scaffold towards the side branch is feasible, which is supported by in vitro testing. However, all recommendations made in the treatment of coronary bifurcation lesions are not supported by any long-term clinical or in vivo data and are solely based on either expert opinion or limited in vitro data.

Džavík and Colombo are the first to publish in vitro benchmark testing. The tests performed are extensive; however, only one or two experiments were performed in each bifurcation stenting procedure.

For example, a double-crush procedure could be successful once or twice but what if the experiment is repeated multiple times, will these results still hold? Although silicone models provide us with valuable insights into BVS geometry, in vitro models almost always have their limitations, which makes it difficult to deduce these results in terms of in vivo use. Silicone models are in general more rigid compared with coronary arteries, which makes it harder to overstretch and fracture the ABSORB BVS. Furthermore, the radial force of these models differ from coronary arteries, which makes assessment of non-apposed struts less reliable.

Okamura et al. provided a detailed description of how the ABSORB BVS obstructs SB orifices at baseline and the patterns of compartmentalisation and the number of compartments obstructing the SB. These observations are intellectually interesting; however, it is uncertain what implications it has for everyday clinical practice.

Furthermore, the clinical outcome in relation with the pattern of

1. Gruntzig A, Transluminal dilatation of coronary-artery stenosis, Lancet , 1978;1:263.

2. Stone GW, Rizvi A, Newman W, et al., Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease, N Engl J Med , 2010;362:1663–74.

3. Stefanini GG, Kalesan B, Serruys PW,et al., Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial, Lancet , 2011;378:1940–8.

4. Separham A, Sohrabi B, Aslanabadi N, Ghaffari S, The twelvemonth outcome of biolimus eluting stent with biodegradable polymer compared with an everolimus eluting stent with durable polymer, J Cardiovasc Thorac Res , 2011;3:113–6.

5. Woudstra P, de Winter RJ, Beijk MA, Next-generation DES: the COMBO dual therapy stent with Genous endothelial progenitor capturing technology and an abluminal sirolimus matrix, Expert Rev Med Devices , 2014;11:121–35.

6. Nakazawa G, Otsuka F, Nakano M, et al., The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents, J Am Coll Cardiol , 2011;57:1314–22.

7. Joner M, Finn AV, Farb A, et al., Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk, J Am Coll Cardiol , 2006;48:193–202.

8. Maier W, Windecker S, Kung A, et al., Exercise-induced coronary artery vasodilation is not impaired by stent placement, Circulation , 2002;105:2373–7.

9. Oberhauser JP, Hossainy S, Rapoza RJ, Design principles and performance of bioresorbable polymeric vascular scaffolds.

EuroIntervention , 2009;5 Suppl. F:F15–F22.

10. 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.

11. Serruys PW, Onuma Y, Ormiston JA, et al., Evaluation of the second generation of a bioresorbable everolimus drug-

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compartmentalisation and number of compartments is still unknown and needs further investigation.

Moreover, the effect of different bifurcation stenting procedures at follow up is unknown. Different stenting procedures could alter the endothelial shear stress patterns and coronary blood flow in different ways, hypothetically leading to different neointimal formation patterns at 1-year follow up.28 The effect of all these factors could alter the neo-intimal bridge formation in front of the side branch in two ways. At follow-up this could potentially lead to increased neo-intimal formation with obstruction of the SB, although also non-covered NASB struts can persist.

Due to the lack of data, we believe that there is an urgent need for prospective randomised clinical data with OCT imaging for different bifurcation stenting techniques using the ABSORB BVS. In the absence of these data we recommend the use of the single scaffold provisional stenting strategy in coronary artery bifurcation lesions as is recommended by the European bifurcation club for metallic stents.

Conclusion Based on case reports and in vitro testing ABSORB BVS placement in coronary bifurcation lesions seems to be feasible. The potential theoretical advantage of BVS of better access to side branches due to the disappearance over time of obstructing struts needs to be confirmed. Complex multiple BVS-bifurcation constructions, such as Culotte or Crush, are unattractive due to mechanical properties and strut size of currently available devices. Further research should be performed to detect the optimal bifurcation stenting procedure for this novel devices. n

eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes, Circulation , 2010;122:2301–12.

12. Serruys PW, Onuma Y, Dudek D, et al.,Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary artery stenosis: 12-month clinical and imaging outcomes, J Am Coll Cardiol , 2011;58:1578–88.

13. Kajiya T, Liang M, Sharma RK, et al., Everolimus-eluting bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI), EuroIntervention , 2013;9:501-504.

14. Gutierrez-Chico JL, Regar E, Nuesch E, et al., Delayed coverage in malapposed and side-branch struts with respect to well-apposed struts in drug-eluting stents: in vivo assessment with optical coherence tomography, Circulation , 2011;124:612–23.

15. Džavík V, Colombo A, The absorb bioresorbable vascular scaffold in coronary bifurcations: insights from bench testing.

JACC Cardiovasc Interv , 2014;7:81–8.

16. White JM, Bifurcation strategies with the Absorb BVS Resorbable Scaffold. In: TCT, San Francisco, CA, USA, 2013.

17. Okamura T, Onuma Y, Garcia-Garcia HM, et al., 3-dimensional optical coherence tomography assessment of jailed side branches by bioresorbable vascular scaffolds: a proposal for classification. JACC Cardiovasc Interv , 2010;3:836–44.

18. Grundeken MJ, Kraak RP, de Bruin DM, Wykrzykowska JJ, Three-dimensional optical coherence tomography evaluation of a left main bifurcation lesion treated with ABSORB(R) bioresorbable vascular scaffold including fenestration and dilatation of the side branch, Int J Cardiol, 2013;168e107–e108.

19. Dzavik V, Muramatsu T, Crooks N, et al., Complex bifurcation percutaneous coronary intervention with the Absorb bioresorbable vascular scaffold. EuroIntervention , 2013;9:888.

20. Gogas BD, van Geuns RJ, Farooq V, et al., Three-dimensional reconstruction of the post-dilated ABSORB everolimus-eluting

bioresorbable vascular scaffold in a true bifurcation lesion for flow restoration. JACC Cardiovasc Interv , 2011;4:1149–50.

21. van Geuns RJ, Gogas BD, Farooq V, et al., 3-dimensional reconstruction of a bifurcation lesion with double wire after implantation of a second generation everolimuseluting bioresorbable vascular scaffold, Int J Cardiol , 2011;153:e43–e45.

22. Gutierrez-Chico JL, Serruys PW, Girasis C, et al., Quantitative multi-modality imaging analysis of a fully bioresorbable stent: a head-to-head comparison between QCA, IVUS and OCT, Int J Cardiovasc Imaging , 2012;28:467–78.

23. Gomez-Lara J, Brugaletta S, Diletti R, et al., Agreement and reproducibility of gray-scale intravascular ultrasound and optical coherence tomography for the analysis of the bioresorbable vascular scaffold, Catheter Cardiovasc Interv , 2012;79:890–902.

24. Okamura T, Serruys PW, Regar E, Cardiovascular flashlight.

The fate of bioresorbable struts located at a side branch ostium: serial three-dimensional optical coherence tomography assessment, Eur Heart J , 2010;31:2179.

25. Stankovic G, Lefevre T, Chieffo A, et al., Consensus from the 7th European Bifurcation Club meeting, EuroIntervention , 2013;9:36–45.

26. Okamura T, Onuma Y, Yamada J, et al., 3D optical coherence tomography: new insights into the process of optimal rewiring of side branches during bifurcational stenting, EuroIntervention , 2014;pii: 20130514–02.

27. Nakatani S, Onuma Y, Ishibashi Y, et al., Early (before 6 months), late (6-12 months) and very late (after 12 months) angiographic scaffold restenosis in the ABSORB Cohort B trial, EuroIntervention , 2014;pii: 20130829-09..

28. Bourantas CV, Papafaklis MI, Kotsia A, et al., Effect of the endothelial shear stress patterns on neointimal proliferation following drug-eluting bioresorbable vascular scaffold implantation: an optical coherence tomography study, JACC Cardiovasc Interv , 2014;7:315–24.

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Coronary

Clinical Impact of Stent Design R ebec c a L N o a d , 1 Co l m G H a n ra t t y 2 a n d S i m o n J Wa l s h 2 1. Specialist Registrar in Cardiology; 2. Consultant Cardiologist, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK

Abstract The introduction and widespread adoption of drug-eluting stents into routine clinical practice has seen tremendous changes in the practice of interventional cardiology. For a prolonged period, manufacturers have focused research on drugs and polymers that are the key to the prevention of in-stent restenosis. However, stent platform design and its clinical implications have now come back to the fore. This has occurred for numerous reasons, but has primarily been driven by the need for modern stents to perform well in increasingly demanding clinical scenarios. This paper reviews the historical evolution of stent platform design. Current manufacturing processes and materials are also explored. Geometric stent construction and its implications for longitudinal stability and the longer term risks of stent fracture are reviewed. Finally, the implications of the specific stent chosen for different clinical applications including the treatment of bifurcations and left main disease are also summarised. This article will familiarise cardiologists with the crucial impact of each of these factors on modern day practice, as well as acute and long-term outcomes for patients.

Keywords Stent design, longitudinal compression, stent fracture, stent thrombosis, left main stem stenting Disclosure: Colm G Hanratty is a consultant to Boston Scientific. Simon J Walsh is a consultant to Abbott Vascular, Biosensors and Boston Scientific. Rebecca L Noad has no conflicts of interest to declare.

Received: 2 April 2014 Accepted: 28 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):89–93 Correspondence: Simon J Walsh, Consultant Cardiologist, Belfast City Hospital, 51 Lisburn Road, Belfast, BT9 7AB, Northern Ireland, UK. E: simon.walsh@belfasttrust.hscni.net

As the role of percutaneous coronary intervention (PCI) has evolved, inevitably, so too has the technology associated with this specialty.

Initially, plain old balloon angioplasty (POBA) was developed as a strategy to ‘stretch’ focal stenoses within the coronary arteries leading to a relief from ischaemia and angina. Whilst potentially of great benefit to some patients, POBA was beset by a series of Achilles’ heels. These included early, unpredictable and abrupt vessel closure due to coronary dissection, subacute recoil of the dilated coronary lesion with the stenosis recurring relatively early, and later restenosis due to the healing response invoked by vascular injury from the procedure. Ultimately, supplementary technologies were needed to resolve these issues and this led to the concept of deploying bare metal stents (BMS) in the coronary artery. Early BMS were developed to more reliably treat short, focal areas of disease. The aim of using these devices was to cover disruption and stabilise dissection associated with POBA, thus preventing abrupt vessel closure. In addition, the vessel was scaffolded to prevent early recoil and the initial results from widespread adoption of coronary intervention with BMS led to benefits for patients.1 One feature of early BMS was that they were relatively bulky and stiff devices. This reflected their initial function for the treatment of focal and straightforward coronary lesions. As the practice of interventional cardiology evolved to meet the needs of patients with more complex coronary lesions, so too did the stents.

There was an explosion of different manufacturers, stent designs and technologies.2 Therefore, early platforms quickly improved, becoming easier to deliver and thus more user-friendly. Whilst the majority of these devices were constructed from stainless steel, there was a

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range of stent cell construction (open versus closed), cell geometry, strut thickness and different materials were also explored (such as gold, carbon and a variety of others).

However, it soon became clear that BMS were beset by the late complication of in-stent restenosis (ISR). This late ‘healing phenomenon’ led to loss of the treated vessel lumen and a recurrence of ischaemia.

Repeat procedures (target lesion revascularisation [TLR] and target vessel revascularisation [TVR]) became a frequent occurrence after PCI with BMS. It also became apparent that ISR was associated with many of the design features of these devices. These included longer stent length, smaller stent diameter, a high metal:artery ratio and strut thickness.3–5 Clinical features such as the presence of diabetes also contributed to stent failure.3 There were both early and long-term adverse consequences of ISR for patients.6,7 These events also led to a clinical disadvantage for patients with multivessel disease who were treated by PCI compared with those who were offered coronary artery bypass grafting (CABG).8,9 Ultimately, this brought about the development of drug-eluting stents (DES). These devices were first introduced in the pivotal Randomized Study with the Sirolimus-Coated Bx Velocity BalloonExpandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL) trial.10 DES had polymers and a variety of different drugs coated onto stents to stop late lumen loss.

The therapeutic goal was to reduce the inflammatory and healing response that occurred after stent implantation, with the aim of

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Coronary preventing ISR and its clinical consequences. DES were very effective in reducing levels of ISR relative to BMS and their use quickly became widespread. However, their introduction and dissemination meant that the original design concepts that applied BMS now also needed to facilitate timed and consistent drug delivery. By this time, the design goals that previously applied to stent manufacture had been expanded and significantly altered. Investigations of different drugs, polymers and their combinations became prominent and essentially superseded platform design as manufacturers sought to produce increasingly safe and effective devices.

One significant effect of DES was that patients with a previously difficult disease, such as those with diabetes or multivessel disease, could be treated.11,12 As a result, more and more challenging lesions became amenable to PCI. In addition, stent design was also pushed forwards by operator feedback that led manufacturers to encompass potentially desirable properties in their products. These included improved radiographic visibility, flexibility, device deliverability and conformity to the vessel. In general, the overall trend in design goals was to produce thinner stents that are more flexible but where the key mechanical property of the stent (the radial strength and hence the scaffold within the vessel) has been preserved.

Stent platform design and manufacture has now come back under the clinical spotlight for a variety of reasons. These include the expanding use of these devices in previously ‘taboo’ clinical areas (bifurcations, chronic total occlusions, left main disease) with an increasingly complex demand placed on their mechanical performance. It has become apparent that these properties are paramount not only with regard to the mechanical properties of the stents but also to clinical outcomes in these challenging clinical scenarios.

Stent Materials, Design, Longitudinal Strength and Stent Fracture Metallic stents are manufactured by different processes. These include laser cut slotted tubes, multilink hoops and the sinusoidal continuous wire, which is a single unit that is wound, folded and welded into shape. The stent must apply sufficient radial force on the wall of the diseased coronary artery so that the vessel lumen is restored to a near normal diameter whilst subsequently scaffolding the vessel and preventing collapse of the artery in the longer term.

Desirable performance characteristics include low elastic recoil, conformability, high visibility and ease of deliverability. The latter is a complex parameter influenced by the flexibility afforded by the stent itself, the properties of the delivery balloon system and the overall crossing profile of the entire device.

Mechanical engineering is a science of compromise. Therefore, altering any single feature of a stent inevitably affects other properties.

There is a complex interaction between every feature of stent design and how the device behaves in clinical practice.13 The radio-opacity of a stent is mainly dictated by the material (usually a metallic alloy) from which it is constructed, where the resistance to penetration

by X-ray is proportional to the cube of the atomic number of the elements that make up the alloy.13 There are a range of metallic alloys that are employed in commonly used stents. These include stents that are constructed from 316L stainless steel, cobalt chromium alloys (MP35N and L605) and platinum chromium alloys (see Figure 1 and Table 1 for examples). The alloy that the stent is constructed from will not only alter the radio-opacity but also the elastic modulus (a

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material’s tendency to be deformed elastically or non-permanently when a force is applied to it), yield strength (the stress at which a material exhibits plastic or permanent deformation) and tensile strength (the maximum stress that a material can withstand whilst stretched or pulled before its cross-sectional area significantly contracts).14 In clinical terms, these latter features dictate the overall radial strength of the stent itself, in addition to its susceptibility to recoil. These two features are not mutually exclusive. However, these properties are crucial for both the acute and long-term performance of the stent. The evolution away from stainless steel towards other alloys has been to allow the stent struts to become thinner whilst maintaining the overall radial strength of the device.

Most recently, bioresorbable stents have been introduced to the clinical arena. The most extensively studied stent is currently the Absorb™ (Abbott Vascular, Santa Clara, CA, US). This stent is manufactured from a poly-L-lactic acid (PLLA) polymer. This semi-crystalline polymer is constructed from a number of linked sinusoidal hoops with stent struts that are 150 µm thick.15 This particular stent cannot be seen radiographically and has two small metallic markers sited at the distal and proximal stent edges for intra-procedural identification. A number of other bioresorbable materials and platforms are under investigation at various stages,15 although a review of these materials and devices is beyond the scope of this article. Nevertheless, the same mechanical constraints and desirable properties are also directly applicable to these devices.

A major factor in stent design is the geometry of the stent cell structure (see Table 1). This is dictated by the number and pattern of connectors between rings or hoops. Reducing the number of fixed connectors is potentially desirable as this improves flexibility, delivery and decreases the metal:artery ratio. However, this also potentially impacts negatively on longitudinal strength. It has recently become apparent that longer, thinner and more flexible stents can be less stable in their longitudinal axis. These stents can be ‘compressed’ or distorted along the length of the device creating a ‘concertina’ effect or longitudinal stent deformation (LSD).16,17 This phenomenon is now well-understood and usually relates to an interaction between guiding catheters and stents deployed in the aorto-ostial position, or stents that are relatively undersized after initial deployment that are subsequently ‘caught’ and distorted by secondary equipment that is passed into the coronary vessel.14,16 With regard to longitudinal stability, there are several technical design factors that are associated with an increased susceptibility to LSD. It has been shown that at compressive forces of 50 gF (0.5 N) or less, it is possible to shorten18 or elongate19 modern metallic stents. Stent alloy and strut thickness appear to be somewhat less important with regard to susceptibility to LSD. The construction of the device, number of connectors between rings and their geometrical distribution across the device dictate the longitudinal strength of the platform. In general, more connectors between rings correlate with increasing longitudinal strength. Where connectors are present, those that are in longitudinal alignment confer increasing strength, whilst offset connectors are less strong. However, there is a significant downside to increasing the longitudinal strength of the device. This will increase the ‘stiffness’ of the stent, therefore reducing its deliverability to and conformability within the vessel.

Whilst unrecognised, LSD has the potential to be clinically disastrous for the patient. However, these events appear to be relatively rare.

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Figure 1: Examples of Some Drug-eluting and Bare Metal Stents

The drug eluting stent is listed above, with the corresponding bare metal version annotated below. The material that the stents are manufactured from and strut thickness are noted. These are drawn to scale. Strut thickness refers to the axis measured as if from the lumen to the vessel wall.

Table 1: Examples of Commonly Used Metallic Drug-eluting Stents Manufacturer Abbott Vascular (CA, US)

Drug-eluting Stents Xience Prime™

Material Cobalt chromium (L605)

Drug Everolimus

Connectors/Ring 3

Geometry

Biosensors (Singapore)

Biomatrix™

Stainless steel (316L)

Biolimus

2

Boston Scientific (MA, US)

Promus Element™

Platinum chromium

Everolimus

2

Medtronic (MN, US)

Integrity Resolute™

Cobalt chromium (MP35N)

Zotarolimus

2

The manufacturer, alloys, drugs eluted, number of connectors between rings and stent geometry are outlined.

Where LSD does occur, a three-pronged approach is required to manage the stent deformation. Ideally, preventative measures should be undertaken, such as prudent guide catheter selection in ostial lesions to allow for sufficient support without excessive guide engagement. Choosing a stent of an appropriate size and careful proximal stent optimisation (usually with softer semi-compliant balloons in our practice), particularly in the left main stem, will help to ensure that secondary devices are unlikely to catch on struts and cause deformation. Secondly, a low threshold is required for suspecting stent deformation, particularly when there is resistance in delivering post-dilation balloons. Careful fluoroscopy examination and or additional imaging with intravascular ultrasound (IVUS)/optical coherence tomography (OCT) may be necessary to diagnose this problem.16 Finally, if longitudinal stent compression has occurred, cautious post-dilation should be attempted. Small diameter balloons may initially be required to cross the damaged stent, and these can be gradually upsized as necessary. This method has been used with success in our experience.16 Further proximal stent deployment may be needed in the setting of vessel damage.14,16 It is worth noting that this phenomenon can also occur with bioresorbable platforms (see

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Figure 2). Should this occur, OCT will be necessary to demonstrate the complication.

Nevertheless, there is a clear trade-off with increasing the stiffness of a stent. Whilst longitudinal stability rises with the number of stent connectors, the risk of stent fracture increases as the stent becomes stiffer. Therefore, older stent platforms are much more susceptible to this phenomenon. In one clinical study, the 6-connector Cypher stent was more than four-times more likely to fracture than newer platforms.20 The incidence of stent fracture with the Nobori™ 2-connector Biolimus eluting stent (Terumo Corporation, Tokyo, Japan) is reported at >4 % per lesion at nine-month angiographic assessment in a study of >1,000 patients.21 This may relate to the exact shape of the connector between rings for this particular stent. Fracture has also been described in the thinner strut, 3-connector Xience™ stents (Abbott Vascular, Santa Clara, CA, US) where a combination of LSD and stent fracture were also associated with adverse clinical events.22 This was particularly likely to occur at areas of stent overlap.

Another study has suggested an incidence of stent fracture in Xience stents at almost 3 % in a large cohort of >1,000 patients undergoing

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Coronary Figure 2: Optical Coherence Tomography Images of a Well-deployed Bioresorbable Vascular Scaffold (A) and the Same Stent After Longitudinal Deformation Caused by a Guide Catheter (B)

Table 2: Stent Models Within Different Manufacturer’s Platforms and Manufacturer Recommended Over-expansion Limits Manufacturer Platform Model’s Over-expansion

Nominal Limit Expansion Abbott Vascular Xience 2.25 mm 3.25 mm (CA, US)

Xpedition™

2.50 mm

2.75 mm

3.00 mm

3.25 mm

3.50 mm

4.00 mm

Biosensors

2.25 mm

Biomatrix

4.00 mm

4.50 mm 3.50 mm

(Singapore) Flex™ 2.50 mm

3.00 mm

3.50 mm

4.00 mm

Boston Scientific

Promus

2.25 mm

2.75 mm

(MA, US)

Premier™

2.50 mm

3.50 mm

4.50 mm

2.75 mm

3.00 mm

3.50 mm

4.00 mm

5.75 mm

2.25 mm

3.50 mm

Synergy™

2.50 mm

2.75 mm

3.00 mm

3.50 mm

4.00 mm

5.75 mm

Medtronic

Resolute

2.25 mm

3.50 mm

(MN, US)

Integrity™

2.50 mm 2.75 mm

3.00 mm

3.50 mm

4.00 mm

4.25 mm

4.75 mm

follow-up angiography between 6 and 9 months.23 Stent fracture is likely to lead to ISR, acute or chronic occlusion and is certainly not a benign phenomenon.20–23 These events are predisposed by certain features within the lesion or vessel. These include treating the right coronary artery, using longer stents, areas of tortuosity, calcification, stent malapposition and stenting at hinge points.

Therefore, whilst LSD can occur as a sudden and dramatic event that complicates a PCI, this can usually be managed and resolved

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Stent Models Across a Product Range, Bifurcations and Over-expansion It is imperative that cardiologists are intimately familiar with the stents that they use. A differing range of stents occur within the various manufacturer product ranges (see Table 2). Understanding the differences between the stents within these product ranges is key to obtaining a good clinical outcome for the patient. This is becoming more important as the lesion complexity increases. For example, using a two-stent strategy at a bifurcation could potentially have a vastly different mechanical result depending on which product is chosen. If a 2.5 mm diameter product is brought from a side branch back into a much larger diameter main vessel, the final expansion in the proximal main vessel and stent cell diameter (and thus lumen achieved in the main vessel) will be very different than if a 3 mm or 4 mm version of the ‘same stent’ is deployed in the side branch instead.

Understanding the implications of these choices is crucial. This is particularly pertinent when the left main stem (LMS) is being treated.

4.25 mm

provided that it is recognised. Our experience is that patients do well over the long term when this is the case. In contrast, stent fracture is much more difficult to predict and it also seems to be a more common phenomenon than was previously considered to be the case. Furthermore, there is a high chance of an adverse outcome with stent fracture. Whilst LSD is certainly not desirable, the trade-off of a more flexible and conformable stent platform with less axial stability may be worthwhile if these platforms prevent later complications that are likely to occur in significant numbers. This is becoming increasingly relevant in the era of treating long segments of disease with stents that can be as long as 48 mm and the frequent need for overlapping stents (as is common when treating chronic total occlusions). Newer approaches have been adopted more recently.

For example, the Promus Premier™ and Synergy™ II stent models (Boston Scientific, Natick, MA, US) aim to retain flexibility through the body of the stent by using two offset connectors. However, the most proximal three rings are linked by extra connectors to provide resistance to LSD.

With LMS intervention, over-expansion of current stent platforms is frequently required as the devices are brought back from smaller diameter daughter vessels (LAD or left circumflex). Despite bench testing demonstrating that current drug-eluting stent platforms can maintain structural integrity beyond the nominal expansion diameter,24 there are theoretical concerns that over-expansion may affect drug delivery and cause mechanical disruption of the stent.

The first concern regarding over-expansion is that it may damage the stent polymer, leading to uneven drug elution, with a potential for later ISR.25 Bench testing of over-expansion of first generation DES found that balloon dilation induced only minor polymer coating abnormalities, which have also been noted on undeployed DES.26,27 It is also possible to replicate this polymer damage by delivering stents through tortuous and calcified vessels. Another concern with respect to over-expansion is the risk of mechanical disruption of the stent. Stent fracture is possible with overly aggressive stent expansion.

A further mechanical issue with over-expansion that has been queried is of the potential for stent recoil. This is a theoretical concern due to a reduction in metal:artery ratio and an alteration of the scaffold itself.

Stent recoil has been described when treating atheromatous vessels.28 However, in the LMS the usual reason for over-expansion is apposition

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Clinical Impact of Stent Design

to the non-diseased vessel wall rather than scaffolding flow limiting plaque. Furthermore, the radial strength of the stent paradoxically increases as it is over-expanded. This is due to straightening of both the ring and connectors, thus leading to greater strength, not less.

Our experience of LMS PCI is that this is typically a very large vessel.

In a study of 125 patients, the mean cross-sectional area of the distal LMS was 22.6 mm2 (standard deviation [SD] ± 5.4 mm2) and mean maximal vessel diameter was 5.7 mm (SD ± 0.7 mm).29 Therefore, the vast majority of patients would consequently require post-dilation beyond the nominal diameter of all of the large vessel platforms of current generation DES during LMS PCI. We also performed a further prospective clinical study where all patients who underwent IVUS-guided LMS PCI and stent post-dilation beyond suggested expansion limits were entered into a registry. In 31 patients, mean maximal stent diameters of >5.0 mm were reliably achieved (using Biomatrix Flex™ 9 crown and Promus Element Large vessel platforms) with 5.5 mm and 6.0 mm post-dilation balloons. No intra-procedural complications occurred and in 13.4 months of follow-up only one patient experienced clinical ISR.29 This indicates excellent short-term efficacy and no increased complication rate with over-expansion of current generation DES in the LMS. These results compliment the bench data of Foin et al., but in the clinical arena.24 It should be noted that under-expansion or incomplete stent apposition of BMS or DES is strongly associated with ISR and stent thrombosis.30–32 We would suggest that leaving undersized and unapposed or malapposed stents in the LMS should be avoided at all costs.

1. Rankin JM, Spinelli JJ, Carere RG, et al., Improved clinical outcome after widespread use of coronary-artery stenting in Canada, N Engl J Med, 1999;341:1957–65.

2. Colombo A, Stankovic G, Moses JW, Selection of coronary stents, J Am Coll Cardiol, 2002;40:1021–33.

3. Cutlip DE, Chauhan MS, Baim DS, et al., Clinical restenosis after coronary stenting: perspectives from multicenter clinical trials, J Am Coll Cardiol, 2002;40:2082–9.

4. Kastrati A, Mehilli J, Dirschinger J, et al., Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial, Circulation, 2001;103;2816–21.

5. Briguori C, Sarais C, Pagnotta P, et al., In-stent restenosis in small coronary arteries: impact of strut thickness, J Am Coll Cardiol, 2002;40:403–9.

6. Chen MS, John JM, Chew DP, et al., Bare metal stent restenosis is not a benign clinical entity, Am Heart J, 2006;151:1260–4.

7. Doyle B, Rihal CS, O’Sullivan CJ, et al., Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents, Circulation, 2007;116:2391–8.

8. Serruys PW, Unger F, Sousa JE, et al., Comparison of coronaryartery bypass surgery and stenting for the treatment of multivessel disease, N Engl J Med , 2001;344:1117–24.

9. The SoS Investigators, Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multi-vessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial, Lancet, 2002;360:965–70.

10. Morice MC, Serruys PW, Sousa JE, et al., A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization, N Engl J Med, 2002;346:1773–80.

11. Serruys PW, Morice MC, Kappetein AP, et al., Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease, N Engl J Med, 2009;360:961–72.

12. Serruys PW, Silber S, Garg S, et al., Comparison of zotarolimus-eluting and everolimus-eluting coronary stents, N Engl J Med, 2010;7:363:136–46.

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Conclusions and Future Directions The evolution of the role of stents has resulted in a significant change in stent design, primarily driven by the requirements of the disease that is being treated. Stent design is crucial for acute and long-term outcomes for patients and it is critical that cardiologists have a complete understanding of the design features of the devices that they are implanting.

It is likely that LMS PCI and the treatment of large vessel bifurcations will become a mainstream application of PCI over the forthcoming years. Manufacturers may need to consider producing dedicated platforms for the treatment of these vessels. As more patients with multivessel disease are treated greater attention will also need to be placed on longer-term outcomes in more demanding clinical settings.

The risks of latent stent fracture may assume a more prominent role in clinical studies in future. Ultimately, as the clinical practice of PCI continues to evolve, manufacturers and clinicians will have to work closely in partnership to make sure that the devices that are implanted can provide excellent safety and long-term efficacy for patients. The importance of stent design has been re-emphasised and is likely to become increasingly relevant in future, where the patient and lesion being treated are likely to mandate very careful selection of the stents that are deployed in each individual setting. The focus should be shifted away from producing ever more deliverable stent platforms and should be moved back to the fundamental properties of what the device has been built to achieve. n

13. Finet G, Rioufol G, Coronary stent longitudinal deformation by compression: is this a new global stent failure, a specific failure of a particular stent design or simply an angiographic detection of an exceptional PCI complication?, EuroIntervention, 2012;8:177–81.

14. Shand J, Ramsewak A, Spence M, et al., The ‘concertina effect’ and the limitations of current drug-eluting stents: is it time to revisit and prioritize stent design over efficacy?, Interv Cardiol, 2012;4:325–35.

15. Onuma Y, Serruys PW, Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization?, Circulation, 2011;123:779–97.

16. Hanratty CG, Walsh SJ, Longitudinal compression: a “new” complication with modern coronary stent platforms -- time to think beyond deliverability?, EuroIntervention, 2011;7:872–7.

17. Pitney M, Pitney K, Jepson N, et al., Major stent deformation / pseudofracture of 7 Crown Endeavor/Micro Driver stent platform: incidence and causative factors, EuroIntervention, 2011;7:256–62.

18. Prabhu S, Schikorr T, Mahmoud T, et al., Engineering assessment of the longitudinal compression behaviour of contemporary coronary stents, EuroIntervention, 2012;8:275–81.

19. Ormiston JA, Webber B, Webster MW, Stent longitudinal integrity bench insights into a clinical problem, JACC Cardiovasc Interv, 2011;4:1310–7.

20. Park MW, Chang K, Her SH, et al., Incidence and clinical impact of fracture of drug-eluting stents widely used in current clinical practice: comparison with initial platform of sirolimus-eluting stent, J Cardiol, 2012;60:215–21.

21. Kuramitsu S, Iwabuchi M, Yokoi H, et al., Incidence and clinical impact of stent fracture after the Nobori biolimus-eluting stent implantation, J Am Heart Assoc, 2014;3(2):e000703.

22. Inaba S, Mintz GS, Yun KH, et al., Mechanical complications of everolimus-eluting stents associated with adverse events: an intravascular ultrasound study, EuroIntervention, 2014;9:1301–8.

23. Kuramitsu S, Iwabuchi M, Haraguchi T, et al., Incidence and clinical impact of stent fracture after everolimus-eluting stent

implantation, Circ Cardiovasc Interv, 2012;5:663–71.

24. Foin N, Sen S, Allegria E, et al., Maximal expansion capacity with current DES platforms: a critical factor for stent selection in the treatment of left main bifurcations?, EuroIntervention, 2013;8:1315–25.

25. Weimer M, Butz T, Schmidt W, et al., Scanning electron microscopic analysis of different drug eluting stents after failed implantation: from nearly undamaged to major damaged polymers, Catheter Cardiovasc Interv, 2010;75:905–11.

26. Basalus MW, Tandjung K, van Westen T, et al., Scanning electron microscopic assessment of coating irregularities and their precursors in unexpanded durable polymer-based drugeluting stents, Catheter Cardiovasc Interv, 2012;79:644–53.

27. Basalus MW, Tandjung K, VAN Apeldoorn AA, et al., Effect of oversized partial postdilatation on coatings of contemporary durable polymer-based drug-eluting stents: a scanning electron microscopy study, J Interv Cardiol, 2011;24:149–61.

28. Aziz S, Morris JL, Perry RA, Stables RH, Stent expansion: a combination of delivery balloon underexpansion and acute stent recoil reduces predicted stent diameter irrespective of reference vessel size, Heart, 2007;93:1562–6.

29. Shand JA, Sharma D, Hanratty C, et al., A prospective intravascular ultrasound investigation of the necessity for and efficacy of postdilation beyond nominal diameter of 3 current generation DES platforms for the percutaneous treatment of the left main coronary artery, Catheter Cardiovasc Interv, 2013 [Epub ahead of print].

30. Hassan AK, Bergheanu SC, Stijnen T, et al., Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis, Eur Heart J, 2010;31:1172–80.

31. Fujii K, Carlier SG, Mintz GS, et al., Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study, J Am Coll Cardiol, 2005;45:995–8.

32. Cook S, Wenaweser P, Togni M, et al., Incomplete Stent Apposition and Very Late Stent Thrombosis After Drug-Eluting Stent Implantation, Circulation, 2007;115:2426–34.

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Coronary

Current Antithrombotic Therapy in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Interventions Ga briele Pe s a r i n i , S a ra A r i o t t i a n d F l a v i o Ri b i c h i n i Division of Cardiology, Department of Medicine, University of Verona, Italy

Abstract Acute coronary syndromes (ACS) represent a life-threatening complication of the systemic atherosclerotic process, affecting the coronary circulation. Thrombosis, defined as an uncontrolled activation of the endogenous thrombogenetic reparative process, often follows atherosclerotic plaque damage and is mainly engaged by two main pathways: platelet aggregation and coagulation. Therefore, antithrombotic therapy to modulate either pathway plays an important role for the reduction of ischaemic adverse events in ACS patients.

Since the advent of aspirin and warfarin, numerous antiaggregant and anticoagulant molecules have been developed to achieve this goal, but their anti-ischaemic efficacy is often obtained at the price of augmented bleedings, which are known to be strong predictors of adverse outcome. This article briefly reviews the physiopathological mechanisms of thrombosis and presents an overview of the available literature supporting the use of these major drugs, as well as the European Society of Cardiology recommendations for their utilisation in the setting of non-ST and ST-elevation myocardial infarction undergoing invasive treatment.

Keywords Acute coronary syndromes, antiaggregants, anticoagulants, bleeding, thrombosis Disclosure: The authors have no conflicts of interest to declare.

Received: 6 April 2014 Accepted: 27 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):94â&#x20AC;&#x201C;101 Correspondence: Gabriele Pesarini, Cardiovascular Interventional Unit, Division of Cardiology, Department of Medicine, University of Verona, Piazzale Aristide Stefani 1, 37126, Verona, Italy. E: gabriele.pesarini@ospedaleuniverona.it

Haemostasis is a complex phenomenon defined as the chain of mechanisms able to maintain the integrity of a closed, high-pressure circulatory system after vascular damage.1 Thrombogenesis represents the main process assuring haemostasis at each level of the vascular system, and its accurate regulation guarantees the correct balance between blood flow and damage repair. An uncontrolled thrombin formation may occur in different pathological situations, finally leading to the dangerous process of thrombosis.

Atherosclerosis development and its complication into an acute coronary syndrome (ACS) recognises different pathogenetic mechanisms that involve inflammation, endothelial dysfunction, platelet activation and, finally, thrombus formation.2 ST-segment elevation myocardial infarction (STEMI) is paradigmatic of inappropriate thrombogenic response. In fact, a complete thrombotic occlusion of epicardial coronary vessels is present in the vast majority of cases.3 The currently recommended treatment of ACS is based upon early mechanical reperfusion and prompt use of potent antithrombotic drugs aimed to obtain the best chances of vessel patency restore and significant reduction of acute and late cardiovascular events.4â&#x20AC;&#x201C;6 Furthermore, the widespread use of intracoronary devices, such as drug-eluting stents during percutaneous coronary intervention (PCI), also implies the necessity for prevention of potentially lifethreathening device-related complications, such as early, late and very late stent thrombosis. On the other hand, the need for fast reperfusion and thrombosis inhibition must be balanced with the individual risk of

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bleeding for each subject, as this complication is a well-recognised cause of morbidity and mortality in post-PCI patients.7 With the development of more potent and rapidly acting antithrombotic agents, the choice of the right therapy for each patient should be the result of a careful consideration of the individual clinical and operative risk.

Major Mechanisms of Thrombus Formation Thrombogenesis in ACS is often initiated by complications of vulnerable atherosclerotic plaques that are prone to rupture, mainly due to their elevated content of lipids and apoptotic cells, leading to a necro-fatty core and a thin-cap fibrous coverage.8 The loss of endothelial coverage leads to exposure of several factors that trigger the two main pathways of thrombus formation: coagulation and platelets activation. Figure 1 summarises the major actors of thrombogenesis as well as the drugs sites of interaction with the physiological process. Animal models9 suggest that platelets recruitment in the injury site and their activation are driven by two main mechanisms: the first may be independent of the coagulation cascade. In fact, exposure of the von Willebrand factor (vWF) and subendothelial collagen, captures the platelets respectively by interaction with platelet glycoprotein (GP) Ib-V-IX and GP VI, which seems to be also the main responsible for their thrombin-independent activation. The second pathway involves tissue factor (TF) release and its binding to factor VIIa that activates factor IX, leading to thrombin generation and, finally, platelets activation via protease-activatedreceptor 1 (PAR-1) that also triggers amplification of the response by release of adenosine diphosphate (ADP), serotonine and thromboxane A2 (TXA2).1 In particular, TXA2 is synthetised from arachidonate by the

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Antithrombotic Therapy in Acute Coronary Syndromes

Figure 1: Schematic Representation of the Main Mechanisms of Thrombogenesis, As Described in the Text Aspirin

Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor

2

ADP

P

AD

r

Abciximab Tirofiban Eptifibatide

te na do i h ac Ar

TPα TPβ

YI2

P2

ATP Histamine Serotonin

TXA

ADP

CO X

GPIIbIIIa

GPI

D gra ense nu les

P2Y

12r

GPIIbIIIa

Fibrinogen

/4

PAR1

b

GPIV G

Bivalirudin Dabigatran

IIa

Thrombin

v vWF

Collagen Col gen Fibrin

Apixaban Rivaroxaban Otamixaban LMWH

Va-Xa

UFH LMWH Xa

Fibrin

AT-III

Fibrin

Prothrombin Prot tth hrombin bi TF-VIIa

Fondaparinux

Circulaating TF C T Circulating Vit. K γ-glutamill-carboxylase

VKA

IXa

X

VII TF-VIIa

II, VII, IX, X

VIIa

IX

T TF

In bold, the drugs interacting with the various key steps of aggregation and coagulation. AT = antithrombin; COX = cyclo-oxygenase; GP = glycoprotein; LMWH = low molecular weight heparin; TF = tissue factor; TXA2 = thromboxane A2; UFH = unfractioned heparin; VKA = vitamin K antagonists; vWF = von Willebrand factor.

cyclo-oxygenase (COX) pathway, while ADP is released by the dense granules of the platelets. Both these important mediators enhance platelets activation by autocrine and paracrine actions, interacting with G-protein coupled receptors, namely TPα and TPβ for TXA2, and P2Y1 and P2Y12 for ADP. All the effectors finally trigger aggregation activating the IIb/IIIa (αIIbβ3) integrin receptor for fibrinogen and vWF, but platelet activation is not uniform in the early phases of thrombus formation.10 Therefore, initial thrombus is a dynamic entity, with continuous platelets activation, adhesion and separation, rendering the clot architecture and shape extremely variable.

Coagulation is the other major pathway of thrombus formation, and its activation relays mainly on the release and exposure of TF, a membrane protein that is constitutively expressed by fibroblasts and smooth muscle cells, while it is inducible on monocytes and endothelial cells.11 Furthermore, it is known that TF is also present in circulating blood, on the surface of tiny cell-derived vescicular structures that can be captured by the P-selectin expressed by activated platelets.12 This form of TF is usually inactive, and can be cleaved into the active form by disulphide isomerase expressed by platelets and endothelial cells at the injury site, probably being the main enzyme responsible for fibrin deposition inside the thrombus.13 Once in the active form, TF forms complexes with circulating factor VIIa that are able to activate factors VII, IX and X: the binding of factor Xa to factor V promotes the production of small quantities of thrombin that probably ignites the burst of the subsequent coagulation process.14 In fact, the initial

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small amount of thrombin can activate both factors V and VII, leading to efficient conversion of prothrombin into thrombin itself by the more active complex Xa-Va. As thrombin availability is the main limiting factor for the coagulative chain burst, the final step of the conversion of fibrinogen into fibrin is greatly enhanced after the early ignition phase, and this process further propagates the thrombus, eventually leading to pathological thrombosis.

Inhibiting Platelets Aggregation As previously stated, platelet activation leading to the autocrine and paracrine release of active mediators and subsequent aggregation, represents one of the two main pathways for thrombus formation.

Over the years, several molecules have been discovered and used to inhibit platelet activation, but all these compounds focus on three key stages of the process: inibition of TXA2 formation, blockage of the P2Y12 ADP receptor and blockage of the IIbIIIa integrin.

Aspirin Acetylsalicylic acid (ASA) irreversibly blocks both COX-1 and COX-2 (more weakly) by acetylation of their active site,15 thus preventing prostaglandin (PGs) and thromboxane production from platelets-membrane arachidonate. In particular, COX-1 inhibition reduces prostaglandin H2 (PGH2), which is a metabolic precursor of TXA2, a potent platelet activator. Being the first synthesised effective antithrombotic agent, ASA still plays an unquestionable role in the treatment of vascular thrombosis and major cardiovascular events prevention. In classic

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Coronary studies, such as the Physicians’ Health Study,16 ASA reduced acute MI (AMI) occurrence in a large cohort of male US physicians asymptomatic for cardiac ischaemia. ASA efficacy on hard endpoints in patients with AMI has been then confirmed in the large ISIS-2 trial,17 showing survival benefits comparable with those achieved by strepokinase fibrinolysis.

Furthermore, ASA decreased rates of re-infarctions and non-fatal strokes at mid-term follow-up in the same study. Long-term benefits of chronic antithrombotic therapy with ASA has also been analysed and confirmed with dosages of 75–325 mg/day.18 In older studies, ASA proved useful for hard-endpoints prevention also in the setting of unstable angina.19 Therefore, for the treatment of both non-STEMI (NSTEMI) and STEMI patients undergoing PCI, the European Society of Cardiology (ESC) recommends administering an initial loading dose of 150–300 mg of ASA, unless contraindicated, followed by a long-term maintenance dose of 75–100 mg daily (Class:I; LOE:B). ASA is also recommended in ACS patients, independently of the treatment strategy.5,6

Ticlopidine The first-generation thienopydirine ticlopidine, usually administered at a dose of 250 mg twice daily, has been widely replaced by newer agents mainly due to its known adverse haematological effects (neutropenia, purpura).

Clopidogrel The second-generation PDY12 receptor blocker drug, clopidogrel bisulfate, is a prodrug activated in the liver by a cytochrome-mediated two-step oxidation. Importantly, 85 % of the administered dose is inactivated by estherase-mediated competing reactions.20 The active compound binds permanently to a free cysteine on P2Y12, inactivating it for all the platelet’s lifespan. The clinical use of clopidogrel in non-ST-elevation (NSTE)-ACS has been investigated in the large CURE trial, which evidenced a significant reduction in a composite of cardiovascular death, recurrent AMI or strokes when a 300 mg loading dose followed by 75 mg daily of the drug was associated to ASA in terms of ASA alone (9.3 % versus 11.4 %; p<0.001).21 In the CURRENT-OASIS 7 trial a double loading dose of 600 mg followed by 6 days of 150 mg daily of clopidogrel proved superior in preventing cardiovascular deaths/AMI and stroke (3.9 % versus 4.5 %; p=0.039), as well as stent thrombosis, in the subgroup of more than 17,000 patients undergoing PCI.22 This result is achieved at the price of more CURRENT-defined major bleedings (1.6 % versus 1.1 %; p=0.009), but without significant excess of intracranial or surgical bleedings. Due to relevant inter-individual absorption and metabolisation differences, the degree of platelet inhibition is not uniform among clopidogreltreated patients, leading to the need for more potent and reliable P2Y12 blockers.23 The current recommendations by the ESC suggest a loading dose of 300 (Class:I; LOE:A) or 600 mg of clopidogrel (Class I; LOE:B) followed by a maintenance of 75 mg daily (or 150 mg until day 8) in both STEMI and NSTEMI patients when it is not possible to administer newer molecules (prasugrel, ticagrelor).4,5

Prasugrel The third-generation thienopyridine prasugrel guarantees more rapid and predictable platelet inhibition than clopidogrel even sharing an almost identical mechanism of action based on irreversible disulphide bridging on the P2Y12 receptor.24 Unlike clopidogrel, cytochromial and uptake molecules polimorphisms do not have a great effect on the prasugrel metabolism, while an estherase-mediated intestinal reaction forms thyolactones that are then rapidly converted to the active form by the P450 cytochrome system, leading to a greater bioavailability of

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the active compound.25 Standard oral loading dosages of 60 mg produce peak plasmatic concentration after just 30 minutes, while 60–70 % of platelet activity is inhibited in 2–4 hours.26 In the PRINCIPLE-TIMI (‘Thrombolysis In Myocardial Infarction’) 44 phase II trial, 60 mg loading dose and 10 mg maintenance dose of prasugrel achieved superior results in terms of platelet inhibition compared with a 600 mg loading dose and a 150 mg maintenance dose of clopidogrel.27 In the setting of STEMI or NSTEMI treated with PCI, the TRITON-TIMI 38 study compared a 60 mg loading dose followed by 10 mg daily maintenance of prasugrel with a 300 mg loading dose and 75 mg daily maintenance of clopidogrel, with the loading dose administered after coronary angiography.28 The trial demonstrated a significant reduction of the composite endpoint of cardiovascular death, non-fatal AMI and non-fatal stroke in the prasugrel group (9.9 % versus 12.1 %; p<0.001), with early survival advantages after only 3 days persisting at a mean follow-up of 14.5 months. Although this result was mainly driven by AMI reduction (7.3 % versus 9.5 %; p<0.001), the prasugrel-treated group also had less need for target vessel revascularisation (TVR) or definite or probable stent thrombosis. Patients with diabetes had the greatest reduction of the primary endpoint (12.2 % versus 17.0 %; p<0.001) with a relative risk (RR) reduction of 34 % compared with 13 % in the cohort without diabetes. This powerful antiplatelet action has the cost of increased major non-coronary artery bypass graft (CABG)-related TIMI bleedings (2.4 % versus 1.8 %; p=0.03) determining a net clinical harm in patients with previous stroke or transient ischaemic attack and no benefits in patients older than 75 or weghing less than 60 kg. In the overall study population the net balance between primary endpoint reduction and major non-CABG bleedings still favoured prasugrel treatment (12.2 % versus 13.9 %; p=0.004). The TRILOGY ACS trial investigated prasugrel in ACS patients not planned for PCI, failing to demonstrate reductions in a composite of cardiovascular death, non-fatal AMI and non-fatal stroke at 30 months.29 Therefore ESC recommends a 60 mg loading dose and 10 mg daily maintenance of prasugrel in P2Y12 naive patients undergoing PCI (Class:I; LOE:B) after visualisation of the coronary arteries.5,6 Ticlopidine or clopidogrel pre-treated patients may also receive prasugrel before PCI (Class:IIa; LOE:B).4

Ticagrelor Ticagrelor is the first representative of a new class of ADP blockers, triazolopyrimidines, which act as ADP analogues directly binding to P2Y12 causing allosteric reversible blockage of the receptor. This compound has a more powerful, rapid and predictable effect on platelet inibition than clopidogrel. Being an ADP-mimicking molecule, the drug could bind bronchial A1 receptors, possibly accounting for a unique side effect, dyspnoea, which may also be provoked by ADP accumulation and reversible P2Y12 inhibition on sensory neurons.30 Although ticagrelor is active itself, its main metabolite, produced by de-hydroxyethylation via CYP3A4, accounts for part of the effect.31 The drug peaks at 1–3 hours post loading dose, with an half-life of 6–13 hours that justifies its bi-daily administration. After 2–4 hours from an oral loading dose of 180 mg, ticagrelor inhibits platelets aggregation by 50–60 %, an effect that can be maintained with b.i.d. doses of 90 mg.32 Further increases of maintenance dosages over 90 mg produce a relatively small increment of platelet inhibition.

Clinical use in intermediate to high-risk NSTE-ACS (either treated invasively or conservatively) or STEMI patients planned for primary PCI was evaluated in the PLATO trial, comparing a standard 300–600 mg loading dose and 75 mg daily maintenance dosages of clopidogrel with a 180 mg loading dose and 90 mg b.i.d. maintenance of ticagrelor.33 The ADP blocker drug was continued for 6–12 months (mean 9 months). In

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the overall population, the study demonstrated a significant reduction in the composite primary endpoint of cardiovascular deaths, AMI and non-fatal strokes (9.8 % ticagrelor group versus 11.7 % clopidogrel group; p<0.001), mainly driven by a reduction of deaths (4.0 % versus 5.1 %) and AMI (5.8 % versus 6.9 %). In PLATO overall major bleedings were similar in both groups (11.6 % versus 11.2 %; p=0.43), treatment with ticagrelor was associated with significantly higer rates of nonCABG related bleedings (4.5 % versus 3.8 %; p=0.03) or spontaneous bleedings (3.1 % versus 2.3 %; p=0.01).34 Rare fatal intracranial bleedings were also more frequent in the ticagrelor group (0.21 % versus 0.03 %; p=0.02), as were non-procedure-elated bleedings after 30 days. Like for prasugrel, the overall clinical benefit analysis in PLATO was in favour of the ticagrelor group (7.9 % versus 9.0 %; p=0.026). In CABG-treated patients, ticagrelor versus clopidogrel reduced total mortality (4.7 % versus 9.7 %; p<0.001) by decreasing both cardiovascular and noncardiovascular deaths, while CABG-related bleedings were similar in the two treatment arms. As expected, dyspnoea was more frequent in ticagrelor-treated patients (13.8 % versus 7.8 %; p<0.001), even if this was not a significant cause of treatment dyscontinuation. Benign, early phase (transient) ventricular pauses were also more frequent in the ticagrelor group.

ESC guidelines recommend a ticagrelor 180 mg loading dose followed by 90 mg b.i.d. in all intermediate to high-risk ACS patients (Class I; LOE:B), regardless of the initial treatment strategy and including clopidogrel pre-treated patients, suspending clopidogrel at drug shift.4–6

Cangrelor and Elinogrel Potential advantages of intravenous non-GPIIbIIIa blockers antiplatelet drugs may be appreciated in patients vomiting during the acute phase of ACS – patients unable to take oral therapy, need for rapid-onset or quick revesal of the drug action e.g. for bridge therapy to CABG interventions. Cangrelor is a new intravenous direct-acting P2Y12 blocker characterised by almost immediate antiplatelet effect, a plasmatic half-life of 3–5 minutes and rapid restoration of platelet function just 1 hour after infusion cessation.35 In the BRIDGE trial, 210 ACS or PCI patients planned for CABG were randomised to either Cangrelor or Placebo infusion after stopping ongoing P2Y12 inhibitors. Cangrelor administration until 1–6 hours before CABG did not produce an excess in surgical bleeding compared with placebo (11.8 % versus 10.4 %; p=0.76), while maintaining effective antiplatelet action during the infusion.36 In the CHAMPIONS-PHOENIX trial more than 11,000 patients scheduled for urgent or elective PCI were randomised to receive a 300–600 mg loading dose of clopidogrel or cangrelor infusion.37 The primary endpoint, a composite of death, AMI, ischaemia-driven revascularisation and stent thrombosis at 48 hours after PCI, was significantly reduced in the cangrelor group (4.7 % versus 5.9 %, p=0.005) with no significant differences in the rate of major bleeding. Elinogrel is another reversible direct P2Y12 blocking agent available for both oral and intravenous administration. In the phase II INNOVATE-PCI trial38 it was compared with clopidogrel in non-urgent PCI patients without relevant increase in major bleedings, but ad hoc phase III studies are still required to clarify its potential role in the clinical setting. Current ESC guidelines do not include specific recommendations for intravenous P2Y12 blockers in ACS patients undergoing PCI.4–6

Dual Antiplatelet Therapy Although there is debate about the exact timing of administration of ADP-receptor blockers, the ESC recommends the initiation of dual antiplatelet therapy (DAPT) with ASA and a P2Y12 inhibitor (ticagrelor,

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prasugrel or clopidogrel) as early as possible for both STEMI and NSTEMI patients, as previously detailed (Class:I; LOE:A). Unless contraindicated or discouraged by excessive risk of bleeding, DAPT should be maintained for 12 months.4–6

Glycoprotein IIbIIIa inhibitors As previously discussed, GP IIbIIIa binding to several adhesive molecules, such as fibrinogen, fibronectin, vitronectin and vWF, is a crucial step in aggregation and further platelet activation. Therefore, GPIIbIIIa was ‘destined’ to be the target of a class of promisingly powerful antiplatelet agents. The first to be developed was, indeed, a large chimeric murine/human monoclonal antibody with moderate immunogenic properties called abciximab,39 which obtained US Food and Drug Administration (FDA) approval in 1994. Two years later a lower molecular weight cyclic-peptide drug based on extracts of snake venom (disintegrin, barbourin), acting as a competitive inhibitor for fibrinogen, was introduced with the name of eptifibatide.40 The third approved GP IIbIIIa inhibitor (GPI) is tirofiban, a non-peptidic small-molecule compound containing an Arg-Gly-Asp sequence that binds to the receptor inactivating it.41 Early clinical trials supported the benefits of abciximab (EPIC42 and EPILOG43), eptifibatide (IMPACT II44 and ESPRIT45) and tirofiban (PRISM46 and PRISM-PLUS47) for reduction of hard endpoints in urgent and elective PCI patients, at the price of an acceptable increment in bleedings. GPIs have been tested either in the context of early-revascularisation strategy or conservative approach. The PURSUIT trial48 randomised 10948 NTSE intermediate to high-risk patients to receive 180 μg/kg bolus and 1.3 or 2.0 μg/kg/min maintenance dose of eptifibatide or placebo over standard therapy with unfractioned heparin (UFH) and ASA. Around 60 % of the patients underwent invasive assessment with coronary angiography while around 40 % of the patients received mechanical revascularisation either with PCI or CABG. The composite primary endpoint of death and AMI was significantly reduced in high-dose eptifibatide patients up to 30 days (8.1 % versus 10.0 %; p=0.001), with a 31 % event reduction in patients treated with early (<72 hour) PCI (11.6 % versus 16.7 %; p=0.01). Bleeding was higher in the treatment group, with a significantly higher need for blood transfusion than in the placebo group (11.6 % versus 9.2 %), with no significant differences in stroke occurrence. The GUSTO IV-ACS trial49 enrolled 7,800 NSTE patients not scheduled for PCI to either bolus plus 24 or 48 hours Abciximab infusion or placebo over standard treatment with ASA and unfractioned or low molecular weight heparin (LMWH). The study failed to demonstrate benefits of GPI in this medically treated population, showing similar rates of the composite endpoint of death or AMI at 30 days in the placebo, 24- or 48-hour abciximab infusion groups (8.0 % versus 8.2 % versus 9.1 %), and slightly increased bleeding risk. Conversely, in a meta-analysis of more than 31,000 patients with NSTE-ACS not routinely scheduled for early PCI, GPIs performed better than placebo in reducing death or AMI at 30 days (10.8 % versus 11.8 %; p=0.015).50 Another meta-analysis of 6,458 patients with diabetes enrolled in the major GPI trials suggested potential survival benefits in this subgroup that, in contrast with the without diabetes cohort, showed a significant mortality reduction at 30 days in GPI-treated subjects (6.2 % versus 4.6 %; p=0.007).51 An important point regarding the management of GPIs was to clarify whether these drugs should be initiated as early as possible prior to PCI (upstream treatment) or in the cath lab after the visualisation of the coronary tree (downstream treatment). To answer this question two major trials were conducted: ACUITY-timing52 and EARLY-ACS.53 In ACUITY-timing, 9,207 patients with NSTE-ACS were randomised

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Coronary to upstream or downstream strategy with any GPI, being 64 % of the overall population under thienopyridines prior to PCI. Despite non-significantly different rates of a composite of death, AMI or unplanned revascularisation at 30 days (7.9 % downstream versus 7.1 % upstream) the downstream strategy did not meet the noninferiority goal, but major bleedings were more common in upstreamstrategy patients (4.9 % versus 6.1 %; p<0.001). Similarily, in the EARLYACS trial, upstream use of eptifibatide was not different from deferred treatment in terms of death, AMI, recurrent ischaemia or thrombotic complications during PCI (9.3 % versus 10.0 %; p=0.23). Again, early GPI use was associated with significantly higher rates of TIMI major bleedings (2.6 % versus 1.8 %; p=0.015).

As many of the older studies on GPIs were conducted without the use of P2Y12 blockers, there are limited data on the usefulness of GPIIbIIIa inhibitors in addition to ASA and ADP receptor blocker drugs.

In the ISAR-REACT II trial,54 2,022 patients with high-risk NSTE-ACS pre-treated with ASA and a 600 mg loading dose of clopidogrel were randomised to receive either downstream abciximab or placebo. The primary composite endpoint of death, AMI or urgent TVR at 30 days was lower in abciximab-treated patients than in the placebo group (8.9 % versus 11.9 %; p=0.03), with the benefit concentrated in the higher-risk troponine-positive subgroup. The use of GPIs before primary PCI in STEMI patients, also known as ‘facilitated’ primary PCI, was not associated with a convincing improvement in outcomes, while relevant increments in bleedings were observed in the FINESSE trial.55 Furthermore, in 800 STEMI patients pre-treated with clopidogrel 600 mg enrolled in the BRAVE-3 trial, there was no significant decrease of infarct size at single-photon emission computed tomography or 30-day hard endpoints with the addition of upstream abciximab therapy.56 Overall, in ESC recommendations, usage of GPIIbIIIa inhibitors in ACS patients undergoing PCI and treated with a P2Y12 blocker, may be considered in selected populations with low bleeding risk and elevated periprocedural AMI risk (Class:I; LOE:B). Eptifibatide or tirofiban may be considered in high-risk patients undergoing PCI, pretreated with ASA alone (Class:IIa; LOE:B). Pre-treatment with tirofiban or eptifibatide may be considered in selected, high-risk patients in DAPT before PCI if there is evidence of ongoing ischaemia and the bleeding risk is low (Class:IIb; LOE:C). In STEMI patients, ESC guidelines recommend GPIs as bailout therapy in highly thrombotic lesions or no-reflow situations (Class:IIa; LOE:C). There is modest recommendation also in patients treated with UFH and in case of patient transferral to an hub centre for primary PCI (Class:IIb; LOE:B). ESC guidelines do not currently recommend routine use of GPIs upstream before invasive treatment or in ACS patients treated with DAPT not scheduled for PCI (Class:III; LOE:A).4–6

Inhibiting Coagulation Rapid inhibition of the coagulative cascade by an injectable agent is recommended by ESC in all settings of PCI.4 Anticoagulants should be used in ACS patients undergoing PCI to reduce thrombus-related complications and minimise periprocedural thrombotic risks. Metaanalytic data suggest advantages of combination antithrombotic therapy with both antiplatelet and anticoagulant agents in ACS patients.57 Anticoagulation may be achieved indirectly or directly.

Indirect anticoagulation typically requires antithrombin activation that acts as a suppressor of thrombin (UFH, LMWHs) or factor Xa (fondaparinux and partially LMWHs). Similarily, direct anticoagulation is obtained by direct inhibiton of thrombin (bivalirudin, dabigatran) or factor Xa (apixaban, rivaroxaban, otamixaban).

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UFH, LMWH, fondaparinux and bivalirudin are currently used in ACS (see below) and, as a general rule, switching anticoagulants in ACS patients undergoing PCI is not recommended (ESC class:III; LOE:B) except in specific cases.5,6

Unfractioned Heparin UFH is a sulphate-polysaccharide with a mean molecular weight of 15 kDa, which is also naturally secreted by several cells such as basophils and mast cells. Almost one-third of the heparin molecules contain a pentasaccharide with high affinity for antithrombin III (AT) that binds to this molecule causing more efficient exposure of the active site, thus increasing by up to 1,000-fold the AT ability to inactivate thrombin and factor Xa.58 This anticoagulant activity may be pharmacologically reverted: in fact, protamine sulphate, originally isolated by salmon sperm, is a cationic polypeptide that forms stable ion-pair with heparin, inactivating it.59 The use of UFH for the treatment of ACS has been validated in several dated randomised trials. In the ATACS trial,60 214 ACS patients were randomised to receive either ASA 160 mg daily alone or in combination with anticoagulant therapy (i.v. UFH in the acute phase followed by a warfarin maintenance). The combination strategy significantly reduced ischaemic events (electrocardiogram [ECG] changes, MI and/or death) at 14 days (10.5 % versus 27 %; p=0.004). A meta-analysis considering six studies of NSTE-ACS patients treated with ASA plus UFH versus ASA alone found a 33 % risk reduction of death or AMI in heparin-treated patients.61 As the anticoagulant effect of UFH is quite variable between individuals, strict monitoring of the activated partial thromboplastin time (aPTT) is required to avoid lack of efficacy or haemorragic complications (recommended aPTT 1.5–2.5 times UNL).

More recent data from the FUTURA/OASIS-8 trial suggest that in NSTEACS patients treated with PCI, low (50 IU/kg) versus standard (85 IU/kg) doses of UFH do not significantly reduce major peri-PCI bleeding and vascular access-site complications.62 The ESC recommends the use of i.v. bolus UFH in NSTEMI patients proceeding to PCI (Class:I; LOE:C) at doses of 70–100 IU/Kg (or 50–60 IU/Kg in combination with GPIs) to acheive aPTT 50–70 seconds and intra-procedural activated clotting times (ACT) of 250– 350 seconds (or 200–250 seconds in combination with GPIs).5 In STEMI patients undergoing primary PCI not pre-treated with bivalirudin or enoxaparin, Class I level C recommendation is given to UFH at the same dosages than NSTEMI.6

Low Molecular Weight Heparins LMWHs are 2–10 KDa heparin derivates with different pharmacological effects on thrombin (more marked in greater molecular weight molecules) or factor Xa (especially lighter molecules). These drugs are well-absorbed after subcutanous injections, bear a prolonged plasmatic half-life and bind much less than UFH to plasmatic proteins, therefore providing a more predictable anticoagulant effect.63 The most studied and clinically used molecule of this class is enoxaparin.

In an A to Z trial, enoxaparin met the non-inferiority criteria in respect to UFH in NSTE-ACS patients treated with ASA and tirofiban.64 The larger SYNERGY trial64 randomised 10,027 high-risk NSTE-ACS patients to either receive UFH or enoxaparin. Again, enoxaparin proved non-inferior to UFH for a composite of death and non-fatal AMI at 30 days. However, both studies demonstrated a modest but significant increment of TIMI major bleedings in the enoxaparin group. In the randomised open-label ATOLL trial,65 enoxaparin did not reduce the primary endpoint of 30-day death, complications of MI, procedural failure and major bleeding (28 % versus 34 %; p=0.063),

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but the main secondary endpoint of death, recurrent ACS, or urgent revascularisation was significantly reduced (30 % versus 52 %; p=0.015), without evidence of increase in major bleedings.

ESC guidelines recommend b.i.d. subcutaneous administration of 1 mg/kg enoxaparin for NSTEMI patients when fondaparinux is not available (Class:I; LOE:B), with no need for adjunctive anticoagulant therapy during PCI if the last dose of enoxaparin was administered less than 8 hours earlier.5 In the primary PCI for STEMI setting, the use of enoxaparin may be considered, with fewer robust evidences (Class:IIb; LOE:B).

Fondaparinux Fondaparinux is a synthetic pentasaccharide similar to that contained in other glycosaminoglycanes and heparinsulphates, causing reversible, indirect and selective inhibition of factor Xa by allosteric activation of AT.66 Unlike UFH, it does not affect thrombin and bears 100 % bioavailability after subcutaneous administration, long elimination half-life (17 hours) permitting one daily administration and predictable antithrombotic effects also due to low association with plasmatic proteins. Fondaparinux does not seem to induce heparininduced thrombocytopenia (HIT), but due to its renal elimination it is contraindicated when the glomerular filtration rate is low (<20 ml/ minute). The PENTUA study67 was a dose-finding trial that randomised ACS patients to enoxaparin or fondaparinux at different daily dosages (2.5, 4, 8 or 12 mg), reporting no dose-related differences in death, MI or recurrent ischaemia after 9 days, thus suggesting the use of the lower dose. Per-protocol analysis suggested potential reduction of the endpoint in respect to enoxaparin. In the ASPIRE trial,68 350 patients undergoing elective or urgent PCI were randomised to fondaparinux 2.5 or 5 mg or to UFH. No significant differences in terms of bleeding in fondaparinux versus the UFH group were found (6.4 % versus 7.7 %; p=0.61), while a 2.5 mg dose of fondaparinux tended to have fewer bleeding events, but the study may have been undersized for adequate statistical power. The large OASIS-5 study randomised 20,078 NSTEACS patients to either Fondaparinux 2.5mg once daily or enoxaparin 1 mg/kg b.i.d. for an average of 5 days of enrolment.69 Fondaparinux was non-inferior to enoxaparin for a composite efficacy endpoint of death, AMI or refractory ischaemia at 9 days (5.8 % versus 5.7 %) with significantly fewer major bleedings in the fondaparinux group (2.2 % versus 4.1 %; p<0.001). Bleeding was an independent predictor for mortality and, as a consequence, hard endpoints at 6 months (death, AMI, strokes) were lower in patients treated with fondaparinux (11.3 % versus 12.5 %; p=0.007). As expected, in PCI patients treated with fondaparinux there were fewer major bleeding complications at 9 days (2.4 % versus 5.1 %; p<0.001). Although more catheter-related thrombosis were seen in the fondaparinux group, this difference disappeared with the addition of an UFH bolus at the beginning of PCI. Overall, OASIS-5 demonstrated a net clinical benefit of fondaparinux over enoxaparin in the balance of death, AMI, stroke and major bleeding (8.2 % versus 10.4 %; p=0.004). Conversely, the OASIS-6 randomised trial,70 designed to evaluate fondaparinux in the setting of STEMI, was not able to provide definitive results and raised multiple criticisms, mainly due to the heterogeneity in the medical and invasive treatment of the enrolled patients. Particularily, even if the authors concluded for mortality and reinfarction reduction at 30 days in the fondaparinux group, no benefits were observed in the PCI population with significantly higher guiding catheter thrombosis and other coronary complications (abrupt closure, no-reflow, dissection, new thrombus formation).

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ESC recommendations for fondaparinux are therefore strong in NSTEMI patients and administration of a daily dose of 2.5 mg subcutaneously seems associated with the most favourable efficacy–safety profile among other anticoagulants (Class:I; LOE:A). In case of fondaparinux pre-treatment, in order to lower the risk of intraprocedural thrombosis, a single bolus of UFH (85 IU/kg adapted to ACT, or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI (Class:I; LOE:B).5 Conversely, fondaparinux is not recommended in patients with STEMI undergoing PCI (Class:III; LOE:B).6

Bivalirudin Bivalirudin is a synthetic peptide congener of the natural compound hirudine, found in the saliva of the medicinal leech Hirudo medicinalis.

The drug acts as a potent, rapid and reversible inhibitor specific for thrombin that binds both to the catalytic site and to the substraterecognition site of circulating and clot-bound thrombin, inactivating it.

Thrombin itself has the ability to slowly cleave the bond with bivalirudin, restoring its procoagulant properties. The molecule does not bind to plasmatic proteins, therefore producing predictable anticoagulant effects that may also be monitored with routine coagulative tests (aPTT, ACT).71 Furthermore, bivalirudine does not seem to induce HIT. The increasing awareness of the detrimental effects of bleeding on outcome of ACS patients represents the premise to appreciate these characteristics of bivalirudine, especially in invasively treated subjects.

In the REPLACE-2 trial72 bivalirudine (0.75 mg/kg followed by 1.75 mg/kg/ hour during the intervention) plus provisional GPI was compared with UFH plus planned GPI over DAPT in 6,010 patients undergoing elective or urgent PCI (45 % of the patients had unstable angina). Non-significant differences were seen in the primary composite 30-day endpoint of death, MI, urgent repeated revascularisation or in-hospital major bleeding (9.2 % bivalirudine versus 10.0 % UFH). However, bivalirudine treatment reduced both in-hospital major bleeding (2.4 % versus 4.1 %; p<0.001) and minor bleeding (13.4 % versus 25.7 %; p<0.001). In the setting of ACS, the ACUITY trial73 randomised 13,819 patients planned for invasive strategy to one of three anticoagulant regimens: unfractionated heparin or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor or bivalirudin alone. Bivalirudin was started with an i.v. bolus of 0.1 mg/kg and subsequent infusion of 0.25 mg/kg/h, followed by an additional bolus of 0.5 mg/kg and infusion of 1.75 mg/kg/h, stopping infusion after PCI. The composite main endpoint of death, MI or unplanned revascularisation for ischaemia at 30 days was not different between bivalirudine/GPI and heparin/GPI (7.7 % versus 7.3 %), as was major bleeding (5.3 % versus 5.7 %) or net clinical benefit. The therapy with bivalirudine alone proved non-inferior to heparin/GPI in terms of the composite main endpoint (7.8 % versus 7.3 %), while significantly reducing major bleeding (3.0 % versus 5.7 %; p<0.001) and improving the net clinical outcome (10.1 % versus 11.7 %; p=0.02; RR=0.86). The rate of major bleeding was mildly raised in patients with <60 ml/minute creatinine clearance, but similar for all anticoagulant regimens. One sub-study of ACUITY investigated the therapy switch from UFH/LMWH to Bivalirudin at the time of PCI, reporting similar incidence of ischaemic events (6.9 % versus 7.4 %, p=0.52), less major bleeding (2.8 % versus 5.8 %; p<0.01) and improved net clinical outcomes (9.2 % versus 11.9 %; p<0.01), thus suggesting that shifting to Bivalirudin may be favorable to improve prognosis.74 In the setting of STEMI, the HORIZON-AMI75 trial randomised 3,602 primary-PCI patients presenting within 12 hours of symptoms onset to receive either UFH+GPI or bivalirudine alone. Major bleeding was substantially reduced with bivalirudin (4.9 % versus 8.3 %; p<0.001), as were 30-day rates of cardiac (1.8 % versus 2.9 %; p=0.03) and all-cause death (2.1 % versus 3.1 %; p=0.047). Although the authors

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Coronary reported an increment of acute stent thrombosis with bivalirudine alone, this difference disappeared at 30-day analysis. Possible advantages of early therapy with bivalirudin over UFH plus optional GPIs, administered during the transportation to a HUB centre for primary PCI, were investigated in the EUROMAX randomised open-label trial76 enrolling 2,218 patients with STEMI presenting within 12 hours. This study confirmed the reduction in major bleedings in the bivalirudin arm, driving the composite primary endpoint (death and major non-CABG related bleedings at 30 days) towards significance (5.1 % versus 8.5 %; RR 0.60; p<0.001), despite the persisting increment in acute stent thrombosis (1.1 % versus 0.2 %; p=0.007). Conflicting evidence arise from the single-centre HEAT PPCI study recently presented at the 2014 American College of Cardiology congress, which randomised 1,829 patients with STEMI receiving primary angioplasty in Liverpool between 2012 and 2013 to either bivalirudin or UFH before the procedure. The primary endpoint, a composite of all-cause mortality, stroke, reinfarction and target lesion revascularisation (TLR), was higher in the bivalirudin group (8.7 % versus 5.7 %; p=0.01), with more stent thrombosis (3.4 % versus 0.9 %; p=0.001), but no difference in terms of major or minor bleedings between the two strategies. Concerns were raised about the value of these monocentric data in comparison with the discussed larger multicentric trials that may deserve more credit, but the topic is object of current interest and debate.

To date, ESC guidelines for STEMI recommend Bivalirudin with bailout GPIs over UFH plus GPIs (Class:I; LOE:B). In NSTEMI patients, bivalirudin is recommended as an alternative to UFH plus GPIs in subjects undergoing early PCI especially if at high bleeding risk (Class:I; LOE:B).5,6

Novel Anticoagulant Agents Lowering thrombotic complications of ACS and modulating the effects of thrombin on both coagulative cascade and platelets aggregation represent the rationale for potential use of oral anticoagulants in the therapy of ACS-patients. In fact, several studies and meta-analyses have been conducted in the past to test the efficacy of warfarin for the improvement of clinical outcomes of these patients. 77,78 However, although these studies almost consistently found significant reductions in death, AMI or ischaemic stroke, major bleedings were markedly increased by two to threefold in warfarin-treated subjects,

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2. Fuster V, Badimon L, Badimon JJ, Chesebro JH, The pathogenesis of coronary artery disease and the acute coronary syndromes, N Engl J Med , 1992;326:242–50.

3. DeWood MA, Spores J, Notske R, et al., Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction, N Engl J Med , 1980;303:897–902.

4. The Task Force on Myocardial Revascularization of the EuropeanSociety of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on myocardial revascularization, Eur Heart J , 2010;31:2501–5.

5. The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation, Eur Heart J , 2011;32:2999–3054.

6. 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;33:2569–2619.

7. Ndrepepa G, Kastrati A, Bleeding complications in patients undergoing percutaneous coronary interventions: current status and perspective, Coron Artery Dis , 2014;25:247–57.

8. Naghavi M, Libby P, Falk E, et al., From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I, Circulation , 2003;108:1664–72.

9. Dubois C, Panicot-Dubois L, Merrill-Skoloff G, et al., Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo, Blood, 2006;107:3902–6.

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or even more when DAPT was started.79 The relatively high incidence of cardiovascular death and AMI at 5 years after an ACS, which is approximately 25 to 30 % even in the DAPT era, pushes the research towards trying novel oral anticoagulants (NOA) in secondary prevention of ischaemic events.80 Factor Xa direct inhibitors rivaroxaban and apixaban have been challenged in ACS phase II81,82 trials, but produced inconsistent effects on hard endpoints while clearly raising the risk of major bleeding. The apixaban phase III APPRAISE-2 trial was prematurely stopped due to excess of bleeding in the treatment group. In the ATLAS ACS-2 trial, 2.5/5 mg of Rivaroxaban twice daily combined with ASA or ASA plus clopidogrel demonstrated a statistically significant reduction of death from cardiovascular causes, MI or stroke compared with placebo at 13.1 months. The authors also descibed a reduction in all-cause and cardiovascular mortality with an increase in the risk of major bleeding and intracranial haemorrhage, but no increase in the risk of fatal bleeding.83 The direct thrombin inhibitor dabigatran was also tested in the unpublished RE-DEEM phase II trial, but no further development of its ACS-indication are planned by the producing industry. Another phase III study on the i.v. factor Xa inhibitor otamixaban is currently ongoing.

Therefore, despite the consistent physiopathological rationale, the use of NOA is not routinely recommended in ACS patients by current ESC guidelines and deserves more in-depth evaluation.

Conclusions The outcome of NSTEMI and STEMI patients undergoing PCI is a delicate balance between the disease’s natural history, medical therapy, early invasive treatment and the potential risk of harm of specific interventions, especially major bleeding. In order to reduce thrombotic complications, powerful and specific drugs to inhibit both platelet aggregation and the coagulative cascade have been developed, with the patient-tailored combination being an important key to therapeutic success. In this era of DAPT and direct anticoagulant agents, ACS are still associated to relevant adverse long-term outcomes. Better patients election and ischaemic/bleeding risk classification other than future progresses in pharmacological research are urgently needed to reduce this persistent gap between therapeutic options and actual long-term event-free survival. n

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28. Wiviott S, Braunwald E, McCabe C, et al., prasugrel versus clopidogrel in patients with acute coronary syndromes, N Engl J Med , 2007;357:2001–2015.

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32. Husted S, Emanuelsson H, Heptinstall S, et al., Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin, Eur Heart J ,2006;27:1038–47.

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38. Welsh RC, Rao SV, Zeymer U and the INNOVATE-PCI Investigators, A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial, Circ Cardiovasc Interv , 2012;5:347–56.

39. Topol EJ, Byzova TV, Plow EF, Platelet GPIIb-IIIa blockers, Lancet , 1999;353:227–31.

40. Phillips DR, Scarborough RM, Clinical pharmacology of eptifibatide, Am J Cardiol , 1997;80:11B–20B. 41. Egbertson MS, Chang CT, Duggan ME,et al., Non-peptide fibrinogen receptor antagonists. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp, J Med Chem , 1994;37:2537–51.

42. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty, N Engl J Med , 1994;330:956–61.

43. The EPILOG Investigators. Platelet glycoprotein IIb/ IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization, N Engl J Med , 1997;336:1689–97.

44. The IMPACT-II Investigators, Randomised placebocontrolled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACTII, Lancet , 1997;349:1422–8.

45. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial, Lancet, 2000;356:2037–44.

46. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators, A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina, N Engl J Med , 1998;338:1498–505.

47. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–Q-wave myocardial infarction, N Engl J Med , 1998;338:1488–97.

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48. The PURSUIT Trial Investigators, Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes, N Engl J Med , 1998;339:436–43.

49. The GUSTO IV-ACS Investigators, Effect of glycoprotein IIb/ IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial, Lancet , 2001;357(9272):1915–24.

50. Boersma E, Harrington RA, Moliterno DJ, et al., Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials, Lancet , 2002;359:189–98.

51. Roffi M, Chew DP, Mukherjee D, et al., Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes, Circulation , 2001;104:2767–71.

52. Stone GW, Bertrand ME, Moses JW, et al., Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial, JAMA , 2007;297:591–602.

53. Giugliano RP, White JA, Bode C, et al., Early versus delayed, provisional eptifibatide in acute coronary syndromes, N Engl J Med , 2009;360:2176–90.

54. Kastrati A, Mehilli J, Neumann FJ, et al., Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial, JAMA , 2006;295:1531–8.

55. 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.

56. Mehilli J, Kastrati A, Schulz S, et al., Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial, Circulation , 2009;119:1933–40.

57. Eikelboom JW, Anand SS, Malmberg K, et al., Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis, Lancet , 2000;355:1936–42.

58. Björk I, Lindahl U, Mechanism of the anticoagulant action of heparin, Mol Cell Biochem , 1982;48:161–82.

59. Carr JA, Silverman N. The heparin-protamine interaction: a review, J Cardiovasc Surg, 1999;40:659–66.

60. Cohen M, Adams PC, Parry G, et al., Combination antithrombotic therapy in unstable rest angina and nonQ-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group, Circulation , 1994;89(1):81–8.

61. Oler A, Whooley MA, Oler J, Grady D, Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis, JAMA ,1996;276(10):811–5.

62. Steg PG, Jolly SS, Mehta SR, et al., Low-dose vs standarddose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial, JAMA , 2010;304(12):1339–49.

63. Harrington RA, Becker RC, Cannon CP, et al., Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition), Chest , 2008;133:670S–707S. 64. Blazing MA, de Lemos JA, White HD, et al., Safety and efficacy of enoxaparin vs unfractionated heparin in patients with nonST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial, JAMA , 2004;292(1):55–64.

64. Ferguson JJ, Califf RM, Antman EM, et al., Enoxaparin vs unfractionated heparin in high-risk patients with non-STsegment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial, JAMA , 2004;292(1):45–54.

65. Montalescot G, Zeymer U, Silvain J, et al., Intravenous

enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised openlabel ATOLL trial, Lancet , 2011;378:693–703.

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67. Simoons ML, Bobbink IW, Boland J, et al., A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: the Pentasaccharide in Unstable Angina (PENTUA) Study, J Am Coll Cardiol , 2004;43:2183–190.

68. Mehta SR, Steg PG, Granger CB, et al., Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation (ASPIRE) pilot trial, Circulation , 2005;111:1390–7.

69. 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.

70. Yusuf S, Mehta SR, Chrolavicius S, et al., Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS6 randomized trial, JAMA , 2006;295:1519–30.

71. Gladwell TD, Bivalirudin: a direct thrombin inhibitor, Clin Ther , 2002;24(1):38–58.

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73. Stone GW, McLaurin BT, Cox DA, et al., Bivalirudin for patients with acute coronary syndromes, N Engl J Med, 2006;355:2203–16.

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LE ATION.

Use of Thrombectomy Devices in Primary Percutaneous Interventions for ST-elevation Myocardial Infarction – An Update Kr i shnaraj S R a t hod, 1 , 2 , 3 St ephen M Ha m s h e r e, 1 ,3 Ta w f i q R Ch o u d h u r y, 1 ,3 D a n i e l A J o n e s 1 ,2 ,3 a n d A n t h o n y Math u r 1,2,3 1. Department of Cardiology, Barts Health NHS Trust; 2. Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University, London; 3. NIHR Cardiovascular Biomedical Research Unit, London Chest Hospital, London

:

declare.

Abstract Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion modality in patients with ST-elevation myocardial infarction (STEMI). While PPCI is highly effective in achieving epicardial coronary reperfusion, a significant proportion of patients fail to achieve adequate myocardial reperfusion. This is in part due to the distal microembolisation of thrombus and plaque debris during PCI. Recognition of this has led to the development of a number of devices with different mechanisms of action that aim to reduce such distal embolisation and therefore improve end myocardial perfusion. Study results of thrombectomy devices however have been largely inconsistent, especially about clinical outcome data, and several meta-analyses have been carried out as a result. This review aims to critically analyse the literature data on thrombectomy during PPCI, taking into account the most recent studies and the latest metaanalyses looking to see whether thrombectomy use is associated with improved outcomes.

Keywords Thrombectomy, primary PCI, stemi, ST-segment resolution, myocardial blush grade, distal embolisation Disclosure: The authors have no conflicts of interest to declare.

Received: 4 April 2014 Accepted: 23 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):102–7 Correspondence: Anthony Mathur, Department of Cardiology, London Chest Hospital, Bonner Road, Bethnal Green, London E2 9JX. E: a.mathur@qmul.ac.uk

Primary percutaneous coronary intervention (PPCI) is the optimal treatment strategy for restoring coronary blood flow in the infarct related artery (IRA) and salvaging myocardium in patients with ST elevation myocardial infarction (STEMI).1,2 Despite this, PPCI fails to restore optimal myocardial perfusion in up to 40 % of patients despite restoring epicardial artery patency as evidenced by failure of ST-segment resolution (STR) and poor myocardial blush grade (MBG).3 This failure of microvascular perfusion is associated with larger infarct size, left ventricular dysfunction and decreased survival in the long term.4–6

or stent inflation, using a thrombectomy device to reduce thrombus burden before inflation may decrease the likelihood of distal embolisation (see Figure 1). This has led to the development of a number of devices to prevent this problem occurring.11 Currently, a variety of commercially available devices are available with different mechanisms that enable them to either fragment or aspirate the thrombus (see Table 1 and 2). Thrombectomy devices are broadly divided into two groups depending on whether they are motorised (mechanical thrombectomy) or not (manual thrombectomy).

Even though different mechanisms underlie microvascular injury after PPCI, such as generation of reactive oxygen species, cardiomyocyte calcium overload, vasoconstriction, inflammation and cellular and interstitial oedema, distal embolisation appears to play a pivotal role.7,8 A number of studies have demonstrated that PCI can result in an embolisation rate of up to 15 %.8,9 Embolisation of large particles, such as plaque debris, can result in occlusion of pre-arterioles and small side branches, whereas microembolisation can result in occlusion of arterioles and capillaries that can impair perfusion of the myocardium at a microscopic level.10,11 A high thrombus burden is associated with an increased incidence of distal embolisation and itself has been associated with higher frequency of adverse outcomes (major adverse cardiac events [MACEs] and mortality).12

Mechanical Thrombectomy

Strategies, such as thrombectomy devices, to help reduce thrombus burden and prevent distal embolisation have been proposed to increase microvascular flow and improve outcomes. 13,14 As this embolisation occurs predominantly at the time of the initial balloon

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Mathur_FLversion.indd 102

Mechanical thrombectomy devices have several mechanisms: some actively fragment thrombotic material before aspiration such as the AngioJet® (MEDRAD, USA), X-Sizer® (Coviden, USA) and Rinspirator™ System (eV3 Inc., USA) whereas others carry out mechanical aspiration only e.g. the TransVascular Aspiration Catheter® (Nipro, Japan) and Rescue™ (Boston Scientific, USA) devices.

The AngioJet system has been assessed in three randomised trials with conflicting results. Initially a single-centre study of 100 patients showed a reduction in infarct size and improved STR compared with PPCI alone;15 however, the larger AngioJet Rheolytic Thrombectomy In Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction (AiMI) trial (480 patients) found no advantage of the AngioJet system in terms of ‘Thrombolysis In Myocardial Infarction’ (TIMI) 3 flow, MBG or STR compared with PPCI alone.16 In fact, final infarct size and MACE rates at 30 days were higher in the thrombectomy group.

Subsequently, the Comparison of AngioJet Rheloyic Thrombectomy

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Thrombectomy Devices in Primary Percutaneous Interventions for ST-elevation Myocardial Infarction

Before Direct Infarct Artery Stenting With Direct Stenting Alone in Patients with Acute Myocardial Infarction (JETSTENT) trial17 recruited 501 patients with STEMI who were randomised to mechanical thrombectomy before direct stenting or to direct stenting alone. Unlike the AiMI study, this study required patients to have angiographically visible thrombus before they were recruited into the study. The study demonstrated no significant differences between the two groups in STR, TIMI 3 flow, TIMI blush grade 3 or infarct size (as assessed by nuclear scanning). However, the mechanical thrombectomy group had reduced MACE at 6 months and improved 1-year event-free survival rates.17 However, the improved clinical outcomes should be interpreted with caution as with no difference in infarct size or myocardial perfusion between the groups, the mechanism behind the significant clinical benefit is unclear.

In the X-Sizer in AMI for Negligible Embolization and Optimal ST Resolution (X AMINE ST) trial, the X-Sizer System® was investigated in 201 patients with STEMI undergoing PPCI. Although the study demonstrated improved STR at 60 minutes post-PCI and demonstrated reduced distal embolisation of debris and lower no reflow rates, it did not demonstrate any significant clinical benefit at 1 and 6 months.18–20 Furthermore, the X-Sizer has been associated with increased rates of coronary artery perforation in other studies.21 In terms of mechanical thrombectomy devices that aspirate thrombus without fragmentation, only the TransVascular Aspiration Catheter has demonstrated positive results with the Rescue® system not associated with any significant improvement in infarct size, MBG or left ventricular ejection fraction in randomised trials.22,23 The VAcuuM asPIration thrombus REmoval (VAMPIRE) study24 was a randomised trial comparing the TransVascular Aspiration Catheter versus PCI alone that showed a small improvement in TIMI flow and MBG. Similar MACE rates were seen at 30 days between the groups; however, a significant reduction in MACE at 8 months in the thrombectomy group was seen, mainly driven by lower revascularisation rates in this group. Importantly no difference in mortality was seen.

Table 1 lists the manual thrombectomy devices currently available as well as the randomised clinical trials investigating their use in STEMI.

Manual Thrombectomy Manual thrombectomy devices are simpler to use in comparison to mechanical thrombectomy devices. However, due to their mechanism, manual devices cannot extract large amounts of thrombus compared with mechanical thrombectomy devices, which can result in distal embolisation of thrombotic material.25 Manual thrombectomy devices that are currently in clinical use include the Export® Catheter (Medtronic, USA), Hunter (IHT Cordynamics, Spain), Diver® (Invatec, Italy), QuickCat (Spectranetics Inc., USA), Pronto® (Vascular Solutions, USA) and Eliminate (Terumo) among others. Although these devices are similar, they differ in terms of aspiration, lumen size and configuration and there are some differences in the way the thrombus is extracted.

Clinical Trial Data Manual thrombectomy in PPCI for STEMI has been assessed in a number of clinical trials. The first randomised trial that tested a manual aspiration device was the Randomised Evaluation of the Effect of Mechanical Reduction of Distal Embolisation by Thrombus Aspiration in Primary and Rescue Angioplasty (REMEDIA) study (Diver®). This study randomised 99 patients to PCI with manual aspiration or PCI only.26

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Figure 1: Manual Thrombectomy in a Patient Presenting with an Acute Anterior Myocardial Infarction A B A

B

C

D

C

D

(A) Shows an acute occlusion of the mid left anterior descending (LAD) (white arrow).

(B) Shows the position of the radiopaque distal marker on the Export® aspiration catheter as passed down the LAD (Medtronic) (white arrow) prior to aspiration. (C) Shows the LAD post aspiration prior to percutaneous coronary intervention (PCI). (D) Shows a large quantity of aspirated red thrombus from the occluded LAD.

This study demonstrated that manual aspiration was associated with significantly better STR and MBG as well as reduced no reflow and distal embolisation. Furthermore, a subgroup analysis demonstrated that thrombus aspiration appeared to be more beneficial in patients with occluded arteries and a higher thrombus burden.26 However, no associated clinical benefit was seen, as the study was underpowered.

De Luca et al. found that using manual thrombectomy in patients with anterior STEMI (n=76), demonstrated better post-procedural MBG and better STR at 90 minutes.27 However, again, these findings were not translated into improved clinical outcomes because the study was underpowered. Similar findings were seen in larger studies: Polish-Italian-Hungarian RAndomized ThrombEctomy (PIHRATE) trial (196 patients) and Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction (DEAR-MI) (Pronto catheter, 148 patients) with again no improved clinical outcomes.28,29 However, the translation of improved procedural outcomes into better clinical outcomes was achieved with the publication of the Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS) trial.

TAPAS The majority of randomised trials have shown that manual thrombectomy is associated with improved MBG, STR and TIMI flow. However, until TAPAS, most of these studies were not powered to detect a clinical benefit. The TAPAS study was a single-centre randomised trial that randomised 1,071 patients with STEMI in a 1:1 fashion to manual aspiration using the Export catheter or PCI alone.30 Patients in the thrombectomy arm had higher MBG, improved STR and fewer pathological Q-waves. Significantly, these beneficial effects on reperfusion resulted in fewer clinical events at both 30 days (reduced mortality and re-infarction) and a significant reduction in mortality at 1 year.31 After TAPAS, other trials have corroborated the benefits of manual thrombectomy. In the Thrombectomy With export Catheter in InfarctRelated Artery During Primary Percutaneous Coronary Intervention (EXPIRA) trial, 175 patients were recruited with MBG, STR and microvascular

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Coronary Table 1: Mechanical Thrombectomy Devices Thrombectomy Mode of Action Trials Primary Endpoint Clinical Endpoint Result Device (MACE and Mortality) (Primary Endpoint (Manufacturer) Significance) TVAC (NIPRO, Japan) ≥7 Fr guide catheter compatible Yokoyama et al.53 (↑) MGB (↑) 8-month MACE <0.05 (↑) 0.001 with 0.014” guidewire. Single

Ikari et al.24 (↑ trend) Slow reflow + (–)

lumen catheter connected to an

(↑trend) 0.07 +

(↑) MGB

(↑)<0.001

aspiration pump creating a vacuum for aspiration of thrombus Rescue®

≥ 7 Fr guide catheter compatible

Kaltoft et al.54

(–) Myocardial salvage

(–) 30-day MACE

(-) 0.120

(Boston Scientific,

with 0.014” guidewire. Double

Andersen et al.22

(–) LVEF

NA

(-) NS

USA)

lumen catheter connected to an

Dudek et al.23

(–) TIMI 3 +

NA

(-) + (↑) 0.004

aspiration pump creating a vacuum

for aspiration of thrombus

Rinspiratory

≥ 6 Fr guide catheter compatible

-

(↑) ST resolution -

-

(eV3 Inc., USA) with 0.014” guidewire. Dual lumen for aspiration of thrombus and infusion of heparinised saline Angiojet® (MEDRAD, ≥ 6 Fr guide catheter compatible

Antoniucci et al.15 (↑) ST resolution

(–) 30-day MACE

(↑) 0.020

USA)

with 0.014” guidewire. Over the

Miglorini et al.17 (↑) ST resolution +

(↑) 1-year MACE 0.04

(↑) 0.043 + (-) 0.398

wire 4 Fr dual lumen one allows -

Ali et al.16

(↓) 30-day MACE 0.01

(↓) 0.01

for high-velocity saline jets through

the other allows for the aspiration

of thrombotic

X-Sizer System®

≥ 7 Fr catheter compatible with

Beran et al.18 (↑) ST resolution

(–) 30-day MACE

(↑) <0.030

(Coviden, USA) 0.014” guidewire. Over-the-wire

Lefevre et al.19 (↑) ST resolution

(–) 6-month morality

(↑) <0.033

Napodano et al.20 (↑) MBG

and MACE

(↑) 0.006

introduction of a helical cutter

(-) Infarct size (↓) Infarct size

rotated at 2,100 rpm with removal

(–) 30-day MACE

of fragmented thrombus through outer lumen via vacuum effect (↑) = improved endpoint; (↓) = worsened effect on endpoint; (–) = neutral effect on endpoint. MACE = major adverse cardiac event; MAS = maximum aspiration speed; MBG = myocardial blush grade; NA = not available = not available; SAA = smallest aspiration area; TIMI = ‘Thrombolysis In Myocardial Infarction’.

obstruction (MVO) as primary endpoints. This trial was the first study to assess thrombectomy use with MVO as a primary endpoint.32 The study demonstrated that manual thrombectomy significantly improved both MBG and STR, reduced MVO and final infarct size (as assessed by cardiac magnetic resonance [CMR]) and was associated with reduced cardiac mortality and MACE at 24-month follow-up.32

In addition, there were no significant differences in rates of stroke, heart failure, left ventricular function or stent thrombosis between the two groups.35

However, unlike TAPAS and other single-centre trials, multi-centre studies have mostly been negative. The INFUSE-AMI trial (which was a Factorial, Randomized, Multicentre, Single-Blind Evaluation of Intracoronary Abciximab Infusion and Aspiration Thrombectomy in Patients Undergoing Percutaneous Coronary Intervention for Anterior ST-Segment Elevation Myocardial Infarction) recruited 452 patients presenting early with large anterior STEMI undergoing PPCI. They were randomised in a 2 x 2 factorial design to bolus intracoronary abciximab versus no abciximab and to manual aspiration thrombectomy versus no aspiration.33 Here, manual thrombus aspiration was not effective in reducing infarct size as assessed by CMR or MACE at 30 days.34 Importantly, and most significantly, the recently published Thrombus Aspiration in Myocardial Infarction (TASTE) study is the largest study performed to date and was also negative for clinical improvement.

This was a multicentre, prospective, randomised controlled trial (RCT), which randomised 7,244 patients with STEMI undergoing PPCI to manual thrombus aspiration versus PCI alone, with the primary endpoint of 30-day mortality. Manual devices used included Eliminate, Export and Pronto. Although there was a trend towards a reduction in rates of re-infarction at 30 days in the thrombectomy group, there was no significant difference in 30-day mortality between the two groups.35

Meta-analyses

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Table 2 lists the manual thrombectomy devices currently available as well as the randomised clinical trials investigating their use in STEMI.

A number of randomised trials have investigated mechanical and manual thrombectomy; however, until recently these have been mainly small studies with short follow-up periods. Hence, there have been many meta-analyses that have investigated the use of thrombectomy in the setting of PPCI, which have produced conflicting results.

A meta-analysis by Kumbhani et al., which included 3,936 patients comparing manual/mechanical thrombectomy versus PCI alone from 18 trials showed that manual aspiration was associated with a benefit in reducing MACE, including mortality at 6 to 12 months compared with PCI alone.36 This was supported by the Long-Term Clinical Efficacy of Thrombectomy Devices in Acute ST-Elevation Myocardial Infarction (ATTEMPT) meta-analysis, which pooled analyses on 2,686 individual patient’s data from 11 randomised trials.37 ATTEMPT demonstrated that at a median of 1-year follow-up, all-cause mortality, MACE, death and myocardial infarction were significantly lower in the thrombectomy group.37 However, interestingly, survival benefit was confined to patients treated with manual thrombectomy alone with an estimated 34 patients needed to be treated to prevent one death at 1 year.37 Further metaanalyses by Costopoulos et al., which combined 10 randomised trials,

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Thrombectomy Devices in Primary Percutaneous Interventions for ST-elevation Myocardial Infarction

Table 2: Manual Thrombectomy Devices Thrombectomy Mode of Action Trials Primary Endpoint Clinical Endpoint Result Device (MACE and Mortality) (Primary endpoint (Manufacturer) Significance) Export® Catheter ≥ 6 Fr guide catheter compatible Stone et al.34 (–) Infarct size NA (–) 0.51 (Medtronic, USA) with 0.014” guidewire. Dual lumen

Svilass et al.30 (↑) MBG

(↑) 1-year cardiac 0.02 (↑) <0.001

catheter. SAA 0.90 mm2,

Chao et al.55 (↑) TIMI flow + (↑) MBG and all-cause mortality (–) 0.014 + (↑) <0.001

MAS 1.27 cc/s

Liistro et al.56 (↑) ST resolution

0.04

(↑) 0.001

Chevalier et al.57 (↑) MBG + (–) ST

NA

(↑) 0.025 + (–) 0.218

resolution

(–) 6-month MACE (–) 30-day MACE

Diver® (Invatec,

≥ 6 Fr guide catheter compatible

Buzotta et al.26 (↑) MBG +

(–) 30-day MACE

(↑) 0.020 + (↑) 0.034

USA)

with 0.014” guidewire. Dual lumen

De Luca et al.27 (↑) ST resolution

(–) 6-month MACE

(↑) 0.030 + (↑) 0.020

catheter. SAA 0.77mm2, MAS

Dudek et al.28 (↑) MBG +

(–) 6-month mortality

(–)

1.04 cc/s

Sardella et al.58 (↑) ST resolution

(↑) 2-year cardiac death (–)

Ciszewski et al.59

(↑) 0.020

(–) ST resolution

0.001 and MACE 0.04

(↑) MBG +

(–) In-hospital morality

(↑) ST resolution

(↑) Myocardial salvage

Fetch2 (MEDRAD,

≥ 6 Fr guide catheter compatible

-

-

-

USA)

with 0.014” guidewire.

SAA 0.84 mm2, MAS 1.55 cc/s

Hunter

≥ 6 Fr guide catheter compatible

-

-

-

(IHT Cordynamics,

with 0.014” guidewire. Dual lumen

Spain)

catheter. SAA 0.77 mm2

StemiCath

≥ 6 Fr guide catheter compatible

-

-

-

(Minvasys, UK)

with 0.014” guidewire. Dual lumen

catheter. SAA 0.95 mm2,

MAS 1.60 cc/s

Pronto®

≥ 6 Fr guide catheter compatible

Silva-Orrego et al.29 (↑) MBG +

(Vascular Solutions, with 0.014” guidewire. Dual lumen USA)

catheter. SAA 0.90 mm2,

MAS 0.94 cc/s

Xtract

≥ 6 Fr guide catheter compatible

(–) In-hospital MACE

(↑) 0.030 + (↑) 0.020

(↑) ST resolution

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

(Lumen Biomedical, with 0.014” guidewire. Dual lumen UK)

catheter. SAA 0.66 mm2,

MAS 1.22 cc/s

ASAP (Merit) ≥ 6 Fr guide catheter compatible with 0.014” guidewire. Dual lumen catheter.

QuickCat

≥ 6 Fr guide catheter compatible

(Spectranetics Inc.,

with 0.014” guidewire. Dual lumen

USA)

catheter. SAA 0.46 mm2,

MAS 1.11 cc/s

Eliminate (Terumo,

≥ 6 Fr guide catheter compatible

Japan)

with 0.014” guidewire. Dual lumen

catheter. SAA 1.00 mm2

VMax

≥ 5 Fr guide catheter compatible

(Astron Medical,

with 0.014” guidewire.

Germany

Dual lumen catheter. SAA 0.54 mm2

(↑) = improved endpoint; (↓) = worsened effect on endpoint; (–) = neutral effect on endpoint. MACE = major adverse cardiac event; MAS = maximum aspiration speed; MBG = myocardial blush grade ; NA = not available; SAA = smallest aspiration area; TIMI = ‘Thrombolysis In Myocardial Infarction’.

finding that manual thrombectomy was associated with better MBG, STR and TIMI 3 flow rates as well as reduced mortality (43 %; p=0.04), which contrasted to mechanical thrombectomy, where no benefit was seen,38 and by Bavry et al., which showed a significant increase in mortality in patients treated with mechanical thrombectomy compared with PCI alone (5.3 % versus 2.8 %, respectively).39 However not all meta-analyses have been positive. A Bayesian metaanalysis by Mongeon et al., which included 21 trials totalling 4,299 patients (16 trials that used manual aspiration thrombectomy device),

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thrombectomy was shown to result in more STR and TIMI 3 flow.40 However, there were no significant reductions in death, recurrent MI or stroke at 30 days post procedure. The results were similar when analysis was confined to manual thrombectomy.40 It was felt that the overall number of endpoints were low and follow-up periods were short, which may explain why no differences were seen in clinical endpoints.41 Despite this, another more recent meta-analysis

by Tamhane et al., consisting of 3,904 patients, also did not detect a difference in 30-day mortality42 despite a trend towards improved survival rates with the use of manual thrombectomy (odds ratio, 0.57;

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Coronary p=0.05). De Luca et al., conducted the most recent meta-analysis, which included 4,514 patients from 21 RCTs undergoing manual or mechanical thrombectomy, showed that thrombectomy did not reduce 30-day mortality, or reinfarction. Manual but not mechanical thrombectomy was shown to significantly improve post-procedural TIMI 3 flow. Importantly this meta-analysis raised the question that thrombus aspiration may not be a risk-free procedure. Systemic embolisation can occur, and in this meta-analysis, thrombus aspiration was associated with a trend towards an increased rate of stroke (p=0.06)43 – this was noted with both types of thrombectomy device.

Manual versus Mechanical Evidence suggests that manual thrombectomy provides the most benefit in PPCI as demonstrated by several meta-analyses.36,37,39,43 On the other hand, mechanical thrombectomy may provide limited benefit and possibly cause harm.39 There could be a number of explanations for the discouraging results seen with mechanical thrombectomy. First, mechanical thrombectomy devices are often complex to setup and operate compared with manual thrombectomy devices resulting in a steeper learning curve. Staff familiarity with the use of these devices is probably limited, especially as most PPCIs occur out of hours44 when staff levels are reduced. Second, mechanical thrombectomy decides are larger and have a longer setup time that, in turn, results in a longer procedure time. This has been demonstrated where, in contrast to manual thrombectomy studies,33,37,45,46 all mechanical thrombectomy studies19,31,40,47 have longer

Further evidence regarding routine use should be provided by the large multi-centre trial to date investigating the role of manual aspiration thrombectomy using the Export catheter (A Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patient with STEMI Undergoing Primary PCI [TOTAL]) is aiming to recruit 4,000 patients. Primary composite endpoints are cardiovascular death, recurrent MI, cardiogenic shock, or new or worsening New York Heart Association (NYHA) Class IV heart failure up to 180 days.50 A direct comparison between manual and mechanical will be provided by the Comparison of Manual Aspiration With Rheolytic Thrombectomy in Patients Undergoing Primary PCI (SMART-PCI) trial. This is a singlecentre study that is directly comparing the role of mechanical versus manual thrombectomy in PPCI.47,51 The primary endpoint is residual thrombus burden assessed as number of coronary quadrants containing thrombus by optical coherence tomography (OCT) after thrombectomy and before infarct artery stenting. Their preliminary results suggest that mechanical thrombectomy has better STR, TIMI 3 flow and TIMI grade 3 blush compared with manual thrombectomy.51 However, this study is not powered to investigate any long-term clinical benefits of thrombectomy.

Finally, a large ongoing trial in Korea including 27 centres is comparing PPCI using thrombectomy with PPCI alone. They are aiming to recruit 1,400 patients in total with a primary endpoint of cardiac death and MI at 12 months after their procedure.52

procedural times compared with PPCI without thrombectomy use.

Current Guidelines Both the current European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend coronary artery thrombus aspiration as adjunctive therapy during primary PCI for STEMI.48,49 These recommendations are based partly on TAPAS30 together with several meta-analyses,37,39 which provided the necessary evidence to endorse thrombus aspiration as a class IIa recommendation with the level of evidence B in the ACC/AHA guideline48 and with level of evidence A in the ESC guidelines.49 Whether the recent data should change this is much debated. Thrombus aspiration clearly has a role to play but perhaps the routine use is not the answer. Instead, the use of thrombectomy should probably be limited to cases of poor pre-procedural reperfusion or in cases where there is evidence of large intracoronary thrombus burden.

The Future Due to the uncertainty of the use of thrombectomy in PPCI for STEMI, a number of large multi-centre clinical trials are currently taking place, which will hopefully provide a more definite answer to whether the use of thrombectomy is associated with a clinical benefit in this setting.

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. Zijlstra F, Hoorntje JC, de Boer MJ, et al., Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction, N Engl J Med , 1999;341(19):1413–9.

3. Rezkalla SH, Kloner RA, Coronary no-reflow phenomenon: from the experimental laboratory to the cardiac catheterization laboratory, Catheter Cardiovasc Interv, 2008;72(7):950–7.

4. Ito H, Maruyama A, Iwakura K, et al., Clinical implications of the ‘no reflow’ phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction, Circulation , 1996;93(2):223–8.

5. Stone GW, Peterson MA, Lansky AJ, et al., Impact of

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Although one cannot be certain whether these trials will provide a definitive answer regarding the use of thrombectomy in PPCI for STEMI, they will hopefully add clarity to the long-term benefits of their use.

Conclusion Theoretically, thrombectomy appears to be a valuable approach to improve outcomes after PPCI and manual devices have demonstrated benefits on surrogate markers of reperfusion and clinical outcomes in many randomised trials and meta-analyses. However the largest RCT performed to date did not demonstrate an association between manual thrombectomy use and improved clinical outcomes. Mechanical thrombectomy, on the other hand, has failed to demonstrate any clinical benefit in the majority of studies performed including metaanalyses with some suggesting a harmful effect. Of concern, one recent meta-analysis highlighted potentially higher stroke rates with both forms of thrombectomy use although this was not seen in the TASTE study. Further large clinical trials in combination with registry data will gain confidence for mandating clinical change in practice in favour of thrombectomy should they prove positive. Until then, current evidence does not fully support routine use of thrombectomy. n

normalized myocardial perfusion after successful angioplasty in acute myocardial infarction, J Am Coll Cardiol , 2002;39(4):591–7.

6. van ‘t Hof AW, Liem A, Suryapranata H, 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(23):2302–6.

7. Niccoli G, Burzotta F, Galiuto L, Crea F, Myocardial no-reflow in humans, J Am Coll Cardiol , 2009;54(4):281–92.

8. Henriques JP, Zijlstra F, Ottervanger JP, et al., Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction, Eur Heart J , 2002;23(14):1112-7.

9. Napodano M, Ramondo A, Tarantini G, et al., Predictors and time-related impact of distal embolization during primary angioplasty, Eur Heart J , 2009;30(3):305–13.

10. Skyschally A, Leineweber K, Gres P, et al., Coronary microembolization, Basic Res Cardiol , 2006;101(5):373–ß82.

11. Iwakura K, Ito H, Kawano S, et al., Assessing myocardial perfusion with the transthoracic Doppler technique in patients with reperfused anterior myocardial infarction: comparison with angiographic, enzymatic and electrocardiographic indices, Eur Heart J , 2004;25(17):1526–33.

12. Sianos G, Papafaklis MI, Daemen J, et al., Angiographic stent thrombosis after routine use of drug-eluting stents in ST-segment elevation myocardial infarction: the importance of thrombus burden, J Am Coll Cardiol , 2007;50(7):573–83.

13. Hori M, Inoue M, Kitakaze M, et al., Role of adenosine in hyperemic response of coronary blood flow in microembolization, Am J Physiol, 1986;250(3 Pt 2):H509–18.

14. Okamura A, Ito H, Iwakura K, et al., Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction:

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efficacy of distal protection device, J Am Coll Cardiol , 2005;45(2):212–5.

15. Antoniucci D, Valenti R, Migliorini A, et al., Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction, Am J Cardiol, 2004;93(8):1033–5.

16. Ali A, Cox D, Dib N, 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(2):244–52.

17. Migliorini A, Stabile A, Rodriguez AE, 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(16):1298–306.

18. Beran G, Lang I, Schreiber W, et al., Intracoronary thrombectomy with the X-sizer catheter system improves epicardial flow and accelerates ST-segment resolution in patients with acute coronary syndrome: a prospective, randomized, controlled study, Circulation, 2002;105(20):2355–60.

19. Lefevre T, Garcia E, Reimers B, et al., X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial, J Am Coll Cardiol , 2005;46(2):246–52.

20. Napodano M, Pasquetto G, Sacca S, et al., Intracoronary thrombectomy improves myocardial reperfusion in patients undergoing direct angioplasty for acute myocardial infarction, J Am Coll Cardiol , 2003;42(8):1395–402.

21. Sanmartin M, Goicolea J, Ruiz-Salmeron R, et al., Coronary perforation as a potential complication derived from coronary thrombectomy with the X-Sizer device, Catheter Cardiovasc Interv, 2002;56(3):378–82.

22. Andersen NH, Karlsen FM, Gerdes JC, et al., No beneficial effects of coronary thrombectomy on left ventricular systolic and diastolic function in patients with acute S-T elevation myocardial infarction: a randomized clinical trial, J Am Soc Echocardiogr, 2007;20(6):724–30.

23. Dudek D, Mielecki W, Legutko J, et al., Percutaneous thrombectomy with the RESCUE system in acute myocardial infarction, Kardiologia Polska , 2004;61(12):523–33.

24. Ikari Y, Sakurada M, Kozuma K, et al., Upfront thrombus aspiration in primary coronary intervention for patients with ST-segment elevation acute myocardial infarction: report of the VAMPIRE (VAcuuM asPIration thrombus REmoval) trial, JACC Cardiovasc Interv, 2008;1(4):424–31.

25. Vlaar PJ, Svilaas T, Vogelzang M, et al., A comparison of 2 thrombus aspiration devices with histopathological analysis of retrieved material in patients presenting with ST-segment elevation myocardial infarction, JACC Cardiovasc Interv, 2008;1(3):258–64.

26. Burzotta F, Trani C, Romagnoli E, et al., Manual thrombusaspiration improves myocardial reperfusion: the randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-aspiration in primary and rescue angioplasty (REMEDIA) trial, J Am Coll Cardiol , 2005;46(2):371–6.

27. De Luca L, Sardella G, Davidson CJ, et al., Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodelling in patients with anterior ST elevation myocardial infarction, Heart , 2006;92(7):951–7.

28. Dudek D, Mielecki W, Burzotta F, et al., Thrombus aspiration followed by direct stenting: a novel strategy of primary percutaneous coronary intervention in ST-segment elevation myocardial infarction. Results of the Polish-Italian-Hungarian RAndomized ThrombEctomy Trial (PIHRATE Trial), Am Heart J, 2010;160(5):966–72.

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29. Silva-Orrego P, Colombo P, Bigi R, et al., Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: the DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study, J Am Coll Cardiol , 2006;48(8):1552–9.

30. Svilaas T, Vlaar PJ, van der Horst IC, et al., Thrombus aspiration during primary percutaneous coronary intervention, N Engl J Med , 2008;358(6):557–67.

31. Vlaar PJ, Svilaas T, van der Horst IC, 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(9628):1915–20.

32. Sardella G, Mancone M, Canali E, et al., Impact of thrombectomy with EXPort Catheter in Infarct-Related Artery during Primary Percutaneous Coronary Intervention (EXPIRA Trial) on cardiac death, Am J Cardiol, 2010; 106(5):624–9.

33. Stone GW, Maehara A, Witzenbichler B, et al., Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial, JAMA, 2012;307(17):1817–26.

34. Stone GW, Maehara A, Witzenbichler B, et al., Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial, JAMA, 2012;307(17):1817–26.

35. Frobert O, Lagerqvist B, Olivecrona GK, et al., Thrombus aspiration during ST-segment elevation myocardial infarction, N Engl J Med , 2013;369(17):1587–97.

36. Kumbhani DJ, Bavry AA, Desai MY, et al., Role of aspiration and mechanical thrombectomy in patients with acute myocardial infarction undergoing primary angioplasty: an updated meta-analysis of randomized trials, J Am Coll Cardiol , 2013;62(16):1409–18.

37. Burzotta F, De Vita M, Gu YL, et al., Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials, Eur Heart J , 2009;30(18):2193–203.

38. Costopoulos C, Gorog DA, Di Mario C, Kukreja N, Use of thrombectomy devices in primary percutaneous coronary intervention: a systematic review and meta-analysis, Int J Cardiol, 2013;163(3):229–41.

39. 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(24):2989–3001.

40. Mongeon FP, Belisle P, Joseph L, et al., Adjunctive thrombectomy for acute myocardial infarction: A bayesian meta-analysis, Circ Cardiovasc Interv, 2010;3(1):6–16.

41. Rihal CS, Adjunctive thrombectomy for primary percutaneous coronary intervention: What would Dr Bayes do?, Circ Cardiovasc Interv, 2010;3(1):1-2.

42. Tamhane UU, Chetcuti S, Hameed I, et al., Safety and efficacy of thrombectomy in patients undergoing primary percutaneous coronary intervention for acute ST elevation MI: a meta-analysis of randomized controlled trials, BMC Cardiovasc Disord , 2010;10:10.

43. De Luca G, Navarese EP, Suryapranata H, A meta-analytic overview of thrombectomy during primary angioplasty, Int J Cardiol, 2013;166(3):606–12.

44. Rathod KS, Jones DA, Gallagher SM, et al., Out-of-hours primary percutaneous coronary intervention for ST-elevation myocardial infarction is not associated with excess mortality: a study of 3347 patients treated in an integrated cardiac network, BMJ Open , 2013;3(6).

45. Gibson CM, Maehara A, Lansky AJ, et al., Rationale and design of the INFUSE-AMI study: A 2 x 2 factorial, randomized, multicenter, single-blind evaluation of intracoronary abciximab infusion and aspiration thrombectomy in patients

undergoing percutaneous coronary intervention for anterior ST-segment elevation myocardial infarction, Am Heart J, 2011;161(3):478-86.e7.

46. Jolly SS, TOTAL trial: A randomized trial of routine aspiration thrombectomy with PCI versus PCI Alone in patients with STEMI undergoing primary PCI. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01149044 (accessed 25 March 2014.

47. Antoniucci D, Comparison of manual aspiration with rheolytic thrombectomy in patients undergoing primary PCI. The SMART-PCI trial 2011 Available at: http://www.clinicaltrials. gov/ct2/show/NCT01281033 (accessed 25 March 2014).

48. 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–ß140.

49. Van de Werf F, Bax J, Betriu A, et al., Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology, Eur Heart J , 2008;29(23):2909–45.

50. A trial of routine aspiration thrombectomy with percutaneous coronary intervention (PCI) versus PCI alone in patients with st-segment elevation myocardial infarction (STEMI) Undergoing Primary PCI (TOTAL). Available at: www. clinicaltrials.gov/ct2/show/NCT01149044 (accessed 25 March 2014).

51. Parodi G, Valenti R, Migliorini A, et al., TCT-60 comparison of manual aspiration with rheolytic thrombectomy in acute myocardial infarction: the final 6-month results of the SMART primary PCI trial, J Am Coll Cardiol , 2012;60:(17_S).

52. Efficacy of thrombosuction in primary percutaneous coronary intervention of acute myocardial infarction (ETAMI). Available at: www.clinicaltrials.gov/ct2/show/NCT01156662 (accessed March 25, 2014).

53. Yokoyama J, Kushibiki M, Fujiwara T, et al., Feasibility and safety of thrombectomy with TVAC aspiration catheter system for patients with acute myocardial infarction, Heart Vessels , 2006;21(1):1–7.

54. Kaltoft A, Bottcher M, Nielsen SS, et al., Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: a randomized, controlled trial, Circulation , 2006;114(1):40–7.

55. Chao CL, Hung CS, Lin YH, et al., Time-dependent benefit of initial thrombosuction on myocardial reperfusion in primary percutaneous coronary intervention, Int J Clin Pract , 2008;62(4):555–61.

56. Liistro F, Grotti S, Angioli P, et al., Impact of thrombus aspiration on myocardial tissue reperfusion and left ventricular functional recovery and remodeling after primary angioplasty, Circ Cardiovasc Interv, 2009;2(5):376–83.

57. Chevalier B, Gilard M, Lang I, et al., Systematic primary aspiration in acute myocardial percutaneous intervention: a multicentre randomised controlled trial of the export aspiration catheter, EuroIntervention , 2008;4(2):222–8.

58. Sardella G, Mancone M, Bucciarelli-Ducci C, et al., Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: the EXPIRA (thrombectomy with export catheter in infarct-related artery during primary percutaneous coronary intervention) prospective, randomized trial, J Am Coll Cardiol , 2009;53(4):309–15.

59. Ciszewski M, Pregowski J, Teresinska A, et al., Aspiration coronary thrombectomy for acute myocardial infarction increases myocardial salvage: single center randomized study, Catheter Cardiovasc Interv, 2011;78(4):523–31.

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Alcohol Septal Ablation for the Treatment of Hypertrophic Obstructive Cardiomyopathy C onst a ntinos O ’ M a h o n y, S a i d i A M o h i d d i n a n d Ch a r l e s Kn i g h t The Heart Muscle Disease Clinic, London Chest Hospital, London, UK

Abstract Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disorder characterised by left ventricular hypertrophy. A subgroup of patients develops limiting symptoms in association with left ventricular outflow tract obstruction (LVOTO). Current international guidelines recommend that symptomatic patients are initially treated by alleviating exacerbating factors and negatively inotropic medication.

Drug-refractory symptoms require a comprehensive evaluation of the mechanism of LVOTO and review by a multidisciplinary team to consider the relative merits of myectomy, alcohol septal ablation (ASA) and pacing. This article provides a brief overview of HCM and the pathophysiology of LVOTO, and reviews the use of ASA in patients with drug-refractory symptoms secondary to LVOTO.

Keywords Hypertrophic cardiomyopathy, outflow tract obstruction, left ventricular outflow tract obstruction, alcohol septal ablation, myectomy Disclosure: The authors have no conflicts of interest to declare.

Received: 6 April 2014 Accepted: 23 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):108–14 Correspondence: Charles Knight, The Heart Muscle Disease Clinic, London Chest Hospital, Bonner Road, London E2 9JX, UK. E: Charles.Knight@bartshealth.nhs.uk

Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac muscle with a heterogeneous clinical course.1 The disease is clinically characterised by left ventricular hypertrophy (LVH), which is typically asymmetric, and a subgroup of patients have left ventricular outflow tract obstruction (LVOTO) caused by systolic anterior motion (SAM) of the mitral valve leaflet(s).2,3 LVOTO is often associated with limiting cardiovascular symptoms and a worse prognosis.4–8 This article provides a brief overview of HCM and the pathophysiology of LVOTO, and reviews the use of alcohol septal ablation (ASA) for the treatment drug-refractory symptoms secondary to LVOTO.

Hypertrophic Cardiomyopathy Diagnostic Criteria HCM is defined by the presence of LVH (left ventricular wall thickness ≥15 mm in a single myocardial segment) in the absence of systemic hypertension, congenital heart disease and valve lesions of sufficient severity to explain the observed degree of hypertrophy.1,9 In first-degree relatives who have inherited a disease-causing mutation, lesser degrees of LVH are sufficient to make the diagnosis.10,11 The diagnosis is reached by integrating clinical and imaging data from echocardiography and increasingly cardiac magnetic resonance (CMR) imaging.

Epidemiology The prevalence of HCM ranges from 0.02 % to 0.23 %, depending on the characteristics of the study population and methodology used.12–20

Aetiology In adults, HCM is primarily inherited in an autosomal dominant manner and is caused by mutations in cardiac sarcomere protein genes.21–23 Mutations in these genes can be found in ~60 % of patients with HCM,21–23 and the majority involve cardiac myosin binding protein-C

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(MYBPC3) and cardiac myosin heavy chain (MYH7).24 There is a poor correlation between genotype and phenotype.25,26 Metabolic diseases (e.g. Anderson-Fabry disease), syndromes (e.g.

Noonan) and amyloid can mimic sarcomeric HCM.1,27 Phenocopies may be recognised by the presence of specific phenotypic ‘red flags’ (e.g. conduction disease in Anderson-Fabry disease), which help rational selection of diagnostic tests and ultimately disease-specific treatments (e.g. enzyme replacement therapy for Anderson-Fabry disease).27

Left Ventricular Outflow Tract Obstruction LVOTO at rest is encountered in ~30 % of patients with HCM, and is associated with limiting symptoms (dyspnoea, angina, syncope) and worse prognosis.4–8 Unlike symptom limitation from ischaemic heart disease and left ventricular systolic dysfunction, effort tolerance in obstructive HCM is often variable, and patients often describe both good and bad days; this may make assessments of functional class (for example using the New York Heart Association [NYHA] classification) challenging. Approximately a third of HCM patients report postprandial exacerbation of symptoms.28 LVOTO is caused by the SAM of the mitral valve. In systole, the anterior mitral valve leaflet moves into the left ventricular outflow tract (LVOT), which is already narrowed by the hypertrophied septum creating a physical barrier, which impedes the flow of blood from the ventricle to the aorta during systole (see Figure 1).2,3 Contact of the mitral valve leaflets to the septum is termed ‘complete’ SAM, and lesser forms of SAM where there is no contact are termed ‘incomplete’. SAM of the mitral valve leaflets is often associated with varying degrees of mitral regurgitation since the two mitral valve leaflets are pulled apart during SAM, creating an orifice through which retrograde,

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Alcohol Septal Ablation for the Treatment of Hypertrophic Obstructive Cardiomyopathy

posteriorly-directed flow in the left atrium can occur. Consequently, conditions which increase LVOTO also increase the severity of mitral regurgitation.3,29 LVOTO is also promoted by coincident abnormalities of the mitral valve leaflets. The leaflets (particularly the anterior leaflet) are frequently elongated and displaced anteriorly, with abnormal attachments to the papillary muscles and chordae.30,31 Early investigators attributed SAM of the mitral valve to suction forces (Venturi effect) caused by accelerating blood flow in LVOT during systole, drawing the mitral valve leaflets anteriorly into the outflow tract. However, SAM of the mitral valve commences in early systole when the Venturi effect is minimal, and this is therefore unlikely to be the sole explanation for LVOTO.32,33 The mechanism underlying LVOTO is probably multi-factorial, involving the interaction of abnormalities of papillary muscles, chordae, mitral leaflets and LVH, which culminate in abnormal flow forces that push and/or pull the mitral valve towards the outflow septum.33 Although LVOTO gradient is the most evident abnormality, the physiology of obstructive disease includes elevated left ventricular (LV) end-diastolic pressure, mitral regurgitation and a potential for abrupt changes in LVOTO magnitude (for example with postural change or sudden exertion); these abnormalities, as well as the increased LV afterload, may all contribute to symptoms.

Figure 1: Typical Echocardiographic Findings in Left Ventricular Outflow Tract Obstruction

A characteristic feature of LVOTO is that the severity of the obstruction is dynamic and subject to prevailing haemodynamic conditions.

LVOTO is exacerbated by conditions causing reduced preload (e.g.

Valsalva, squat to stand), reduced afterload (e.g. vasodilators) or positive inotropes.3 Notably, although LVOTO is most often seen in HCM, it may also occur in other conditions or physiological states and is not pathognomonic of HCM.34,35 In a smaller subgroup of HCM patients, obstruction can develop at the mid-left ventricular cavity. Mid-cavity obstruction is caused by the systolic apposition of hypertrophied mid-ventricular segments and/or papillary muscles creating a characteristic hour-glass appearance with a distinct apical cavity.36,37 This form of obstruction is often associated with apical aneurysm formation.36,37 Mid-cavity obstruction can exist in isolation (see Figure 2) or in conjunction with LVOTO. Even though ASA has been used in the treatment of mid-cavity obstruction,38,39 this is not routine practice and further discussion is beyond the scope of this review.

Assessment of Left Ventricular Outflow Tract Obstruction All patients with HCM should undergo a detailed transthoracic echocardiogram to examine: • t he severity and distribution of hypertrophy and in particular the septal wall thickness at the point of mitral-septal contact; • intra-cavity gradients with continuous and pulsed-wave Doppler to determine the severity and level of obstruction (LVOTO, mid-cavity obstruction or both); • the mitral valve apparatus for systolic anterior movement of the mitral valve, hypertrophied papillary muscles, abnormal chordal attachments and intrinsic mitral valve disease; and • other cardiac pathology that may have an impact on treatment (e.g. aortic valve disease).

If the transthoracic echocardiogram fails to provide the necessary diagnostic information, a transoesophageal echocardiogram, CMR or an invasive haemodynamic study may be required.

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Top left: Transthoracic echocardiogram parasternal long axis view shows asymmetric septal hypertrophy with a septal wall thickness of 18 mm. This provides the substrate for left ventricular outflow tract obstruction (LVOTO), particularly when the mitral valve leaflets are long. Top right: There is systolic anterior movement of the anterior mitral valve leaflet, which makes contact with the hypertrophied septum. Once the mitral-septal contact occurs a pressure gradient develops across the left ventricular outflow tract. The septal site where the mitral valve makes contact is often fibrosed and is echogenic (impact lesion). Middle left: Colour Doppler flow examination of the left ventricular outflow tract reveals aliasing arising adjacent to the mitral-septal contact point indicating increased velocities in the outflow tract. In cases of mid-cavity obstruction, aliasing originates in the mid-ventricle. Middle right: Colour Doppler flow examination of the mitral valve shows mild posteriorly directed mitral regurgitation. Severe mitral regurgitation and/or regurgitation, which is not posteriorly directed should raise suspicion of intrinsic mitral valve disease. Bottom left: M-mode examination of the mitral valve shows that during early systole the mitral valve moves anteriorly towards the septum in mid-late systole. Severe LVOTO trends to be associated with very early systolic mitral-septal contact with a large area of mitral-septal apposition. Bottom right: To determine the severity of obstruction, the left ventricular outflow tract is examined with continuous wave Doppler in the apical views.

The Doppler envelope of LVOTO is characteristically ‘dagger’ shaped. Pulsed-wave Doppler examination can be used to confirm the level of obstruction; aliasing occurs with sampling on the aortic side of the mitral-septal contact point, whilst the flow pattern is normal apical to the mitral-septal contact.

An instantaneous Doppler LVOT gradient of ≥30 mmHg is considered significant, and such patients are classified as having the obstructive form of the disease. However, LVOTO is considered to be haemodynamically significant only when the LVOT gradient is ≥50 mmHg. 3 There are few data to support these thresholds, 3 which are largely empirically defined and reflect an understanding that when LVOTO is mild, therapeutic reduction of LVOTO is less likely to improve symptoms, and alternative causes of severe symptoms should be sought.

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Structural Figure 2: Isolated Mid-cavity Obstruction

Figure 4: Alcohol Septal Ablation

In this invasive haemodynamic study synchronous blood pressure recordings are taken from a 7 Fr femoral sheath side-port and a 6 Fr end-hole pigtail catheter placed at the left ventricular (LV) apex (top left). Contrast injections show that there is an apical cavity with obliteration of the mid-ventricle during systole. There is a resting gradient of ~40 mmHg, which disappears when the pig-tail catheter is withdrawn basal to the point where the ventricle obliterates (top right). These findings are consistent with isolated mid-cavity obstruction.

Figure 3: Treatment Algorithm for Symptomatic Left Ventricular Outflow Tract Obstruction

Symptomatic LVOTO (rest or latent)

Establish mechanism mitral valve apparatus

level of obstruction

severity of hypertrophy

Correct exacerbating factors

Pharmacological treatment ß-blocker

Verapamil

Disopyramide

** Drug-refractory symptoms ** Multidisciplinary team review and discussion with patient

Invasive therapy Myectomy

Alcohol septal ablation

LVOTO = left ventricular outflow tract obstruction.

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Dual-chamber pacing

Alcohol septal ablation in a patient with left ventricular outflow tract obstruction (LVOTO) and drug-refractory symptoms. A haemodynamic study with synchronous blood pressure recordings from a 7 Fr femoral sheath side-port and a 6 Fr end-hole pigtail catheter placed in the left ventricular (LV) confirms the presence of LVOTO. As the pigtail catheter is withdrawn from the base (top left) to the subaortic position (top right) the gradient disappears. The first septal artery is wired and an over-the-wire balloon is positioned in the proximal third of the septal perforator. The balloon is inflated to isolate the septal from the rest of the coronary circulation and echocardiographic contrast is injected via the balloon lumen. A transthoracic echocardiogram shows that the contrast localises at a favourable position, adjacent to the mitral-septal contact. Additional views (not shown) illustrated that contrast did not localise at undesirable myocardial sites outside the target area. Angiographic contrast was then injected to ensure that there is no reflux into the left anterior descending (LAD) or collaterals that would allow infarction of distant myocardial segment. Alcohol is then injected slowly with close monitoring of the rhythm and appropriate analgesia. Since the patient had a defibrillator with anti-bradycardia pacing capabilities, a temporary pacing wire was not required. After 5–10 minutes the over-the-wire balloon is deflated and an angiogram at the end of the procedure shows that the septal artery is truncated.

Since LVOTO is dynamic, obstruction may not be apparent in the supine patient under resting conditions. Exercise, the Valsalva manoeuvre, postural changes or an isoprenaline infusion help demonstrate latent LVOTO.6,40–42 These additional tests are mandatory in the evaluation of patients with symptoms suggestive of obstruction, which is not demonstrable at rest.

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Treatment of Symptomatic Left Ventricular Outflow Tract Obstruction Currently, there is no evidence that asymptomatic patients with LVOTO benefit from treatment to reduce the severity of obstruction; treatment is reserved for patients with LVOTO and drug-refractory symptoms.43,44 A contemporary treatment algorithm for symptomatic patients with LVOTO is summarised in Figure 3. The first-line treatment for symptoms associated with LVOTO is correction of exacerbating factors (e.g. vasodilating antihypertensives, anaemia) followed by pharmacological therapy with β-blockers, verapamil and disopyramide, which modulate the dynamic physiology of obstruction through their negative inotropic and chronotropic effects.43–46 In patients with drug-refractory symptoms or unacceptable side effects, invasive treatments should be considered by a multidisciplinary team following a comprehensive evaluation of the mechanism of obstruction: • S urgical myectomy involves excision of the hypertrophied septum at the point of mitral contact through an aortotomy under cardiopulmonary bypass.47 Surgical myectomy is a technically demanding operation, but with improved peri-operative care and surgical techniques the current peri-operative mortality is low in high volume centres. In addition to the general complications of open heart surgery, specific peri-operative complications of myectomy include ventricular septal defects, aortic regurgitation and complete heart block requiring pacemaker implantation.48,49 • Mitral valve repair/replacement may be required as an adjunct to myectomy.50–52 Mitral valve replacement in isolation also abolishes SAM and LVOTO, but is considered only when there are other indications for valve replacement such as intrinsic mitral valve disease.53,54 • Alcohol septal ablation aims to reproduce the effects of myectomy via a minimally invasive percutaneous approach.55,56 Ethanol is injected via the septal perforator branches of the left anterior descending artery to the hypertrophied septum to induce a myocardial infarction and necrosis. Scar formation causes remodelling of the LVOT with relief of obstruction. ASA is discussed in more detail below.

• Atrioventricular (AV) sequential pacing from the right ventricular apex using dual-chamber pacemakers with short AV delay reduces LVOTO by causing septal dysynchrony and modifying preload.57 Placebo-controlled trials showed an improvement in symptoms but with a less consistent reduction in LVOTO.58–62 ASA is currently the most frequently used invasive therapy, and while it is efficacious, relatively safe and minimally invasive, outcomes from randomised trials comparing different invasive techniques are not yet available. Several experienced opinions still regard surgical treatment as the ‘gold standard’.43,44 Currently, patients must be counselled that choices between ASA, surgery and pacing are made on the basis of considerations other than proven differences in outcome.

In general, ASA may be unsuitable in the presence of co-existing mid-cavity obstruction and/or intrinsic mitral valve disease; in such cases a surgical approach should be considered. Septal reduction either by ASA or myectomy when the septal wall thickness is <15 mm at the site of mitral contact is also challenging, and alternatives such as mitral valve repair/replacement or AV sequential pacing should be considered. AV sequential pacing can also be useful in selected patients where aggressive pharmacological treatment

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with a β-blocker, verapamil and disopyramide is contemplated, and in patients too frail to tolerate more invasive treatment. In others, pacing may be considered as an initial therapeutic trial before progression to more invasive treatment. This may include individuals with conventional indicators for device therapy (including pacing and defibrillator treatment) and patients at high risk of developing heart block following invasive treatment. Patient preference is also a key factor in decision-making.

Alcohol Septal Ablation – Procedural Aspects The essential components of this percutaneous procedure include the identification of an appropriate septal perforator artery, its isolation from the rest of the coronary circulation and the selective injection of alcohol into this artery. The first septal artery is usually selected and a short over-the-wire balloon inflated within the artery. The balloon’s lumen allows selective delivery of angiographic contrast, echo contrast and ultimately, alcohol into the septal artery. Angiographic contrast ensures that the septal artery is isolated from the left anterior descending (LAD) by the inflated balloon, and echo contrast confirms that the myocardial volume subtended by the selected septal artery is an appropriate target for ablation.63–65 The proximal septal vessels may also supply the right ventricular free wall, LV apex and papillary muscles, and several echocardiographic views are needed to ensure contrast enhancement is confined to the target area; the appropriate target lies adjacent to the point of mitral-septal contact. If echo contrast does not localise to the target area, other septal arteries should be selectively assessed. A temporary pacing wire is inserted prior to the injection of alcohol in case significant bradyarrhythmias follow conduction system damage. Right bundle branch block is observed in approximately 50 % of cases.66 Adequate analgesia is provided and the alcohol is slowly injected to chemically ablate and infarct the target myocardium.67 Approximately 0.1 ml of ethanol (concentration >95 %) per 1 mm of thickness of the target myocardium is injected slowly (1 ml/minute).64 The balloon remains inflated for 5–10 minutes postethanol injection to prevent reflux in the anterior descending and to enhance delivery at the target myocardium. LVOTO is often reduced or abolished at the end of the procedure; this acute effect reflects septal stunning, and the LVOT gradient may again increase in the days following the procedure, to fall again over a period of weeks as septal remodelling occurs and a small scar develops in place of the ablated myocardium. The femoral or radial approach can be used.68 Important procedural steps are shown in Figure 4.

Acute Complications of Alcohol Septal Ablation Since its inception in 1995,55 ASA has evolved and the routine use of echo contrast to select the target septal artery has made the procedure safer and more effective.63–65 In addition to complications arising from the injection of alcohol, ASA is also associated with the complications of percutaneous coronary intervention and temporary wire insertion: • Vascular injury and haemorrhage.

• Coronary dissection from guide catheter, wire and over-the-wire balloon manipulation.69,70 • Myocardial infarction from alcohol escaping from the septal branch into the LAD56 or via septal collaterals.71 • Cerebrovascular accidents.

• Cardiac tamponade from temporary wire insertion.72 • Sustained ventricular arrhythmias.73 • Complete heart block requiring pacemaker implantation (~11 %).74

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Structural Table 1: Meta-analyses Examining Mortality Following Septal Reduction Therapy Meta-analysis Inclusion Criteria

Number of Included Studies

Zeng et al.

Case control studies comparing ASA

3

(2006)79

with SM in adult patients

Alam et al.

Case control studies comparing ASA

(2009)80

with SM in adult patients

5

Number of Patients ASA: 86

2.3 %

SM: 91

1.1 %

ASA: 183

1.6 %

SM: 168

0.6 %

Agarwal et al.

Cohort and case control studies 9 ASA: 380 (2010)81

comparing ASA with SM in adult patients

In-hospital Mortality

p=NA p=0.2

30 Day All-cause Mortality (RD) 0.01 (0.01–0.03) p=0.35

Long-term All-cause Mortality (RD) 0.02 (-0.05–0.09) p=0.55

SM: 326

Annual Rate of

All-cause Mortality Leonardi

Reports/studies with ≥5 ASA patients or

19 ASA studies 2,207

1.8 (1.2–2.6)

et al. (2010)74

≥100 SM patients

8 SM studies

2.1 (1.7–2.7)

1,887#

p=0.36

Annual Rate of Sudden Cardiac Death 0.3 (0.2–0.6)

p=0.37

0.4 (0.3–0.6)

ASA = alcohol septal ablation; NA = not available; RD = Risk difference; SCD = sudden cardiac death; SM = septal myectomy. # SM patients had longer follow-up periods than ASA patients. SM patients were also younger (mean age 44 versus 55 years), but had similar left ventricular outflow tract obstruction, New York Heart Association class and septal maximal wall thickness (MWT).

Table 2: Meta-analyses Examining Symptoms, Gradients and Need for Pacing After Alcohol Septal Ablation and Myectomy Meta-analysis

NYHA Post-procedure Alcohol Septal Ablation

Post-procedure LVOTg, mmHg Alcohol Septal Ablation

Post-procedure Pacing Alcohol Septal Ablation Versus Septal Myectomy

Versus Septal Myectomy

Versus Septal Myectomy

Zeng et al. (2006)79

1.47 versus 1.36; p=NS

15.7 versus 9.4; p <0.05

20.9 % versus 4.4 %; p=NA

Alam et al. (2009)80

1.5 versus 1.3; p=0.20

18.2 ± 6.7 versus 10.8 ± 6.3; p<0.001

18.4 % versus 3.3 %; p=0.04

Agarwal et al. (2010)81

0.30 (95 % CI -0.03, 0.63)*; p=NS

-0.09 (95 % CI -0.3, 0.1)*; p=NS

Leonardi et al. (2010)74

1.5 (1.3, 1.7) versus 1.6 (1.5, 1.7)**; p=NS 22 (15, 23) versus 3 (2, 6)**; p<0.05

OR: 2.6 (95 % CI 1.7, 3.9); p=NS 11 (8, 15) versus 5 (3, 9)**; p<0.05

*Standardised mean differences; ** median (interquartile range [IQR]); CI = confidence interval; LVOTg = left ventricular outflow tract gradient; NA = not available; NS = not significant; OR = odds ratio.

Despite these potential complications, ASA remains a relatively safe procedure with in-hospital death rates of around 1 %.69,75

Post-operative Care Patients should have a temporary pacing wire in situ with cardiac monitoring for 24–48 hours after the procedure, as they are at risk of arrhythmias. High-grade AV block resolves in the majority of cases within three days.76 On discharge, patients should be advised to report arrhythmic symptoms as rarely new onset bradyarrhythmias develop late after the procedure.77 Cardiac biomarkers peak at 12 hours post-ASA and correlate with the size of myocardial injury.78 In the absence of new conduction abnormalities, pharmacotherapy for symptomatic LVOTO should continue until a clinical review in 3–6 months, and can then be tapered if symptoms have improved.

Long and Medium-term Outcomes – Alcohol Septal Ablation Versus Myectomy Mortality associated with ASA and surgical myectomy has been examined and compared in four meta-analyses.74,79–81 Even though the meta-analyses included individual studies with very different inclusion criteria, they have consistently shown that the two procedures have similar survival outcomes (see Table 1). Both septal reduction therapies achieve similar improvements in symptoms, which is the principal aim of invasive therapy. However, myectomy is associated with a greater reduction in gradients and reduced need for post-procedural anti-bradycardia pacing (see Table 2).74,79–81 Concerns over the long term arrhythmogenic potential of the myocardial scar induced by alcohol septal ablation67 are not supported by observational data of implantable cardioverter defibrillator (ICD) recipients undergoing the procedure82 or mortality data from the meta-analyses.74,79–81

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Procedural Failure ASA is effective at reducing symptoms in more than 85 % of patients.69 In cases of procedural failure, defined by the persistence of both symptoms and LVOTO (rest or latent), further intervention with any of the modalities may be considered following a repeat assessment of the mechanisms responsible for symptoms. As changes in LV morphology following ASA may be delayed, it is prudent to delay decisions regarding further intervention for 3–6 months.83 Significant symptoms may persist in about 10–20 % of patients despite LVOTO abolition, illustrating the importance of the complexity of the disease and appropriate patient selection. It is therefore important to counsel patients that LVOTO reduction does not cure HCM and ongoing care will be required to monitor and treat their disease.

Alternative Percutaneous Septal Reduction Therapies Alternative approaches to reduce hypertrophy at the point of mitral-septal contact by means other than alcohol have been investigated: • M icrocoils, polyvinyl alcohol foam and cyanoacrylate glue delivered in the target septal artery obstruct the vessel with infarction of the subtended myocardium.84–87 • Direct endocavitary radiofrequency or cryotherapy ventricular ablation.88,89 This approach has the advantage of overcoming unfavourable septal anatomy.

Experience with these alternatives is limited and long-term safety data are not available.

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Care Beyond Left Ventricular Outflow Tract Obstruction LVOTO should not overshadow other aspects of management; patients in whom LVOTO is successfully abolished are still subject to other HCM-related risks and outcomes. HCM should be evaluated in units with relevant expertise to address family screening and genetic testing, the risk of sudden cardiac death, atrial arrhythmias and prevention of stroke.

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Conclusion LVOTO is associated with significant morbidity and mortality. In patients with LVOTO and drug-refractory symptoms, invasive treatment should be considered following a multidisciplinary team review. The choice of invasive therapy depends not only on disease-specific characteristics but also patient preference. Contrast echocardiography-guided ASA is a safe and effective modality, which will improve symptoms in the majority of patients. n

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34. Cabrera-Bueno F, Garcia-Pinilla JM, Gómez-Doblas JJ, et al., Beta-blocker therapy for dynamic left ventricular outflow tract obstruction induced by exercise, Int J Cardiol , 2007;117:222–6.

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36. Efthimiadis GK, Pagourelias ED, Parcharidou D, et al., Clinical characteristics and natural history of hypertrophic cardiomyopathy with midventricular obstruction, Circ J , 2013;77:2366–74.

37. Minami Y, Kajimoto K, Terajima Y, et al., Clinical implications of midventricular obstruction in patients with hypertrophic cardiomyopathy, J Am Coll Cardiol , 2011;57:2346–55.

38. Seggewiss H, Faber L, Percutaneous septal ablation for hypertrophic cardiomyopathy and mid-ventricular obstruction, Eur J Echocardiogr , 2000;1:277–80.

39. Tengiz I, Ercan E, Alioglu E, et al., Percutaneous septal ablation for left mid-ventricular obstructive hypertrophic cardiomyopathy: a case report, BMC Cardiovasc Disord , 2006;6:15.

40. Dimitrow PP, Bober M, Michalowska J, Sorysz D, Left ventricular outflow tract gradient provoked by upright position or exercise in treated patients with hypertrophic cardiomyopathy without obstruction at rest, Echocardiography , 2009;26:513–20.

41. Shah JS, Esteban MT, Thaman R, et al., Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy, Heart , 2008;94:1288–94.

42. Vaglio JC Jr, Ommen SR, Nishimura RA, et al., Clinical characteristics and outcomes of patients with hypertrophic cardiomyopathy with latent obstruction, Am Heart J , 2008;156:342–7.

43. Maron BJ, McKenna WJ, Danielson GK, et al., American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines, Eur Heart J , 2003;24:1965–91.

44. Gersh BJ, Maron BJ, Bonow RO, et al., 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with

the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, J Am Coll Cardiol , 2011;58:e212–60.

45. Sherrid MV, Pearle G, Gunsburg DZ, Mechanism of benefit of negative inotropes in obstructive hypertrophic cardiomyopathy, Circulation , 1998;97:41–7.

46. Sherrid MV, Shetty A, Winson G, et al., Treatment of obstructive hypertrophic cardiomyopathy symptoms and gradient resistant to first-line therapy with beta-blockade or verapamil, Circ Heart Fail , 2013;6:694–702.

47. Morrow AG, Reitz BA, Epstein SE, et al., Operative treatment in hypertrophic subaortic stenosis. Techniques, and the results of pre and postoperative assessments in 83 patients, Circulation , 1975;52:88–102.

48. Dearani JA, Ommen SR, Gersh BJ, et al., Surgery insight: Septal myectomy for obstructive hypertrophic cardiomyopathy--the Mayo Clinic experience, Nat Clin Pract Cardiovasc Med , 2007;4:503–12.

49. Smedira NG, Lytle BW, Lever HM, et al., Current effectiveness and risks of isolated septal myectomy for hypertrophic obstructive cardiomyopathy, Ann Thorac Surg , 2008;85:127–33.

50. Kwon DH, Smedira NG, Thamilarasan M, et al., Characteristics and surgical outcomes of symptomatic patients with hypertrophic cardiomyopathy with abnormal papillary muscle morphology undergoing papillary muscle reorientation, J Thorac Cardiovasc Surg , 2010;140:317–24.

51. Kaple RK, Murphy RT, DiPaola LM, et al., Mitral valve abnormalities in hypertrophic cardiomyopathy: echocardiographic features and surgical outcomes, Ann Thorac Surg , 2008;85:1527–35, 1535.e1–2.

52. Stassano P, Di Tommaso L, Triggiani D, et al., Mitral valve replacement and limited myectomy for hypertrophic obstructive cardiomyopathy: a 25-year follow-up, Tex Heart Inst J , 2004;31:137–42.

53. Walker WS, Reid KG, Cameron EW, et al., Comparison of ventricular septal surgery and mitral valve replacement for hypertrophic obstructive cardiomyopathy, Ann Thorac Surg , 1989;48:528–34.

54. Delahaye F, Jegaden O, de Gevigney G, et al., Postoperative and long-term prognosis of myotomy-myomectomy for obstructive hypertrophic cardiomyopathy: influence of associated mitral valve replacement, Eur Heart J , 1993;14:1229–37.

55. Sigwart U, Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy, Lancet , 1995;346:211–4.

56. Knight C, Kurbaan AS, Seggewiss H, et al., Nonsurgical septal reduction for hypertrophic obstructive cardiomyopathy: outcome in the first series of patients, Circulation , 1997;95:2075–81.

57. Mohiddin SA, Page SP, Long-term benefits of pacing in obstructive hypertrophic cardiomyopathy, Heart , 2010;96:328–30.

58. Nishimura RA, Trusty JM, Hayes DL, et al., Dual-chamber pacing for hypertrophic cardiomyopathy: a randomized, double-blind, crossover trial, J Am Coll Cardiol , 1997;29:435–41.

59. Kappenberger LJ, Linde C, Jeanrenaud X, et al., Clinical progress after randomized on/off pacemaker treatment for hypertrophic obstructive cardiomyopathy. Pacing in Cardiomyopathy (PIC) Study Group, Europace , 1999;1:77–84.

60. Maron BJ, Nishimura RA, McKenna WJ, et al., Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY), Circulation , 1999;99:2927–33.

61. Mickelsen S, Bathina M, Hsu P, et al., Doppler evaluation of the descending aorta in patients with hypertrophic cardiomyopathy: potential for assessing the functional significance of outflow tract gradients and for optimizing pacemaker function, J Interv Card Electrophysiol , 2004;11:47–53.

62. Qintar M, Morad A, Alhawasli H, et al., Pacing for drugrefractory or drug-intolerant hypertrophic cardiomyopathy, Cochrane Database Syst Rev , 2012;5:CD008523.

63. Faber L, Seggewiss H, Gleichmann U, Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy: results with respect to intraprocedural myocardial contrast echocardiography, Circulation , 1998;98:2415–21.

64. Faber L, Seggewiss H, Welge D, et al., Echo-guided percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: 7 years of experience, Eur J Echocardiogr , 2004;5:347–55.

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Structural 65. Nagueh SF, Lakkis NM, He ZX, et al., Role of myocardial contrast echocardiography during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy, J Am Coll Cardiol , 1998;32:225–9.

66. Coakley E, Steinberg DH, Tibrewala A, et al., Effect of alcohol septal ablation in patients with hypertrophic cardiomyopathy on the electrocardiographic pattern, Am J Cardiol , 2008;102:621–4.

67. Baggish AL, Smith RN, Palacios I, et al., Pathological effects of alcohol septal ablation for hypertrophic obstructive cardiomyopathy, Heart , 2006;92:1773–8.

68. Cuisset T, Franceschi F, Prevot S, et al., Transradial approach and subclavian wired temporary pacemaker to increase safety of alcohol septal ablation for treatment of obstructive hypertrophic cardiomyopathy: the TRASA trial, Arch Cardiovasc Dis , 2011;104:444–9.

69. Fernandes VL, Nielsen C, Nagueh SF, et al., Follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy the Baylor and Medical University of South Carolina experience 1996 to 2007, JACC Cardiovasc Interv , 2008;1:561–70.

70. Sorajja P, Nishimura RA, Ommen SR, et al., Effect of septal ablation on myocardial relaxation and left atrial pressure in hypertrophic cardiomyopathy an invasive hemodynamic study, JACC Cardiovasc Interv , 2008;1:552–60.

71. Agarwal SC, Purcell IF, Furniss SS, Apical myocardial injury caused by collateralisation of a septal artery during ethanol septal ablation, Heart , 2005;91:e2.

72. Sorajja P, Valeti U, Nishimura RA, et al., Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy, Circulation , 2008;118:131–9.

73. Ten Cate FJ, Soliman OI, Michels M, et al., Long-term outcome of alcohol septal ablation in patients with obstructive

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hypertrophic cardiomyopathy: a word of caution, Circ Heart Fail , 2010;3:362–9.

74. Leonardi RA, Kransdorf EP, Simel DL, Wang A, Meta-analyses of septal reduction therapies for obstructive hypertrophic cardiomyopathy: comparative rates of overall mortality and sudden cardiac death after treatment, Circ Cardiovasc Interv , 2010;3:97–104.

75. Kuhn H, Lawrenz T, Lieder F, et al., Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience, Clin Res Cardiol , 2008;97:234–43.

76. Reinhard W, Ten Cate FJ, Scholten M, et al., Permanent pacing for complete atrioventricular block after nonsurgical (alcohol) septal reduction in patients with obstructive hypertrophic cardiomyopathy, Am J Cardiol , 2004;93:1064–6.

77. Kern MJ, Holmes DG, Simpson C, et al., Delayed occurrence of complete heart block without warning after alcohol septal ablation for hypertrophic obstructive cardiomyopathy, Catheter Cardiovasc Interv , 2002;56:503–7.

78. Hage FG, Aqel R, Aljaroudi W, et al., Correlation between serum cardiac markers and myocardial infarct size quantified by myocardial perfusion imaging in patients with hypertrophic cardiomyopathy after alcohol septal ablation, Am J Cardiol , 2010;105:261–6.

79. Zeng Z, Wang F, Dou X, et al., Comparison of percutaneous transluminal septal myocardial ablation versus septal myectomy for the treatment of patients with hypertrophic obstructive cardiomyopathy--a meta analysis, Int J Cardiol , 2006;112:80–4.

80. Alam M, Dokainish H, Lakkis NM, Hypertrophic obstructive cardiomyopathy-alcohol septal ablation vs. myectomy: a meta-analysis, Eur Heart J , 2009;30:1080–7.

81. Agarwal S, Tuzcu EM, Desai MY, et al., Updated meta-analysis

of septal alcohol ablation versus myectomy for hypertrophic cardiomyopathy, J Am Coll Cardiol , 2010;55:823–34.

82. Cuoco FA, Spencer WH 3rd, Fernandes VL, et al., Implantable cardioverter-defibrillator therapy for primary prevention of sudden death after alcohol septal ablation of hypertrophic cardiomyopathy, J Am Coll Cardiol , 2008;52:1718–23.

83. Qin JX, Shiota T, Lever HM, et al., Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery, J Am Coll Cardiol , 2001;38:1994–2000.

84. Iacob M, Pinte F, Tintoiu I, et al., Microcoil embolisation for ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy, Kardiol Pol , 2004;61:350–5.

85. Durand E, Mousseaux E, Coste P, et al., Non-surgical septal myocardial reduction by coil embolization for hypertrophic obstructive cardiomyopathy: early and 6 months follow-up, Eur Heart J , 2008;29:348–55.

86. Gross CM, Schulz-Menger J, Krämer J, et al., Percutaneous transluminal septal artery ablation using polyvinyl alcohol foam particles for septal hypertrophy in patients with hypertrophic obstructive cardiomyopathy: acute and 3-year outcomes, J Endovasc Ther , 2004;11:705–11.

87. Oto A, Aytemir K, Okutucu S, et al., Cyanoacrylate for septal ablation in hypertrophic cardiomyopathy, J Interv Cardiol , 2011;24:77–84.

88. Lawrenz T, Borchert B, Leuner C, et al., Endocardial radiofrequency ablation for hypertrophic obstructive cardiomyopathy: acute results and 6 months’ follow-up in 19 patients, J Am Coll Cardiol , 2011;57:572–6.

89. Keane D, Hynes B, King G, et al., Feasibility study of percutaneous transvalvular endomyocardial cryoablation for the treatment of hypertrophic obstructive cardiomyopathy, J Invasive Cardiol , 2007;19:247–51.

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Structural

Review of Data and Discussion – Who Should Undergo Patent Foramen Ovale Closure in 2014?

A m i t B h a n a n d B r i a n Cl a p p Department of Cardiology, Guy’s and St Thomas’ Hospital, London, UK

Abstract A patent foramen ovale is a relatively common finding in the general population and is associated with a number of conditions, including cryptogenic stroke. In 2014, percutaneous patent foramen ovale (PFO) closure is a frequently performed procedure; the bulk of these procedures being carried out for secondary prevention of cryptogenic stroke, along with other indications, such as prevention of decompression illness, platypnoea-orthodeoxia syndrome and migraine. Of these conditions the largest body of evidence available is for cryptogenic stroke and there is ongoing debate of the benefit of PFO closure over medical therapy. This article will review the available evidence of PFO closure in each of these contexts, with a particular focus on randomised controlled trials, and endeavour to outline in whom the evidence suggests closure should be considered.

Keywords Stroke, cryptogenic embolism, patent foramen ovale, migraine, decompression illness, platypnoea-orthodeoxia syndrome Disclosure: Brian Clapp has received consulting/speaking fees from St. Jude Medical, Boston Scientific, Medtronic and Abbott Medical.

Amit Bhan has no conflicts of interest to declare.

Received: 4 April 2014 Accepted: 26 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):115–120 Correspondence: Brian Clapp, Department of Cardiology, Guy’s and St Thomas’ Hospital, London SE1 7EH, UK. E: brian.clapp@gstt.nhs.uk

The foramen ovale is an integral component of the fetal circulation, responsible for facilitating the flow of placental pre-oxygenated venous blood from the right atrium to the left, thereby circumventing the quiescent developing lungs. Physiological closure is usually achieved after birth when pulmonary vascular resistance and right heart pressures reduce, resulting in the left atrial pressure exceeding that of the right. The ‘flap valve’ is pressed up to the secundum septum and seals over; often in the early postnatal period, and this is usually completed within the first year of life. However, it has long been known that patency of the foramen ovale frequently persists into adulthood. Although not always shunting at rest, increases in right atrial pressure (as occurs during sneezing or a Valsalva manoeuvre) can cause short periods of significant passage of deoxygenated blood at the atrial level.

A patent foramen ovale (PFO) is usually asymptomatic; however, its presence has been implicated in a number of conditions including, but not limited to, paradoxical embolism (causing a stroke, peripheral arterial occlusion or myocardial infarction with normal coronary arteries), migraine (particularly those occurring with aura), decompression illness and the more rare and underdiagnosed platypnoea-orthodeoxia syndrome (POS). In addition, it may increase risk in large-scale orthopaedic surgery and neurosurgery performed in the seated position.

It is hypothesised that bloodborne material from the venous circulation, normally excluded from the systemic side during passage through lung vasculature, bypasses this through the PFO. Such materials could

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include thrombus, air, vasoactive substances or even fragments of bone and fat in the context of fractures and surgery.

As a result, ever since the first report in 19881 of temporary closure of a PFO with a Swan-Ganz catheter to facilitate surgery, abolishing this shunt when found in specific circumstances has been attractive, particularly with modern day low-risk transcatheter techniques.

Prevalence of Patent Foramen Ovale in the General Population A number of observational studies, both in vivo and pathological, have indicated a variable prevalence. In 1984 Hagen et al.2 demonstrated from 965 autopsy specimens an overall prevalence of 27.3 %, which decreased with age; 34.3 % in the first three decades, 25.4 % during the 4th to 8th decades and 20.2 % during the 9th and 10th decades.

The size ranged from 1 mm to 19 mm and was inversely related to age. Fifteen years later Meissner et al.3 found a similar rate of PFO in vivo. Using transoesophageal echocardiography (TOE) without contrast in 585 subjects over 45, they demonstrated a prevalence of 26 % of PFO. Furthermore, increased numbers within families has suggested a genetic basis for the failure of closure.4

Patent Foramen Ovale in Cryptogenic Stroke A cryptogenic stroke (CS) occurs when no apparent cause can be found despite extensive investigation. The concept was initially developed for the stroke Data Bank by the US National Institute of Neurological and Communicative Disorders and Stroke5 and has been shown to account for up to 40 % of all strokes .6

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Structural Paradoxical embolism (PE) through a PFO has been implicated in such strokes since the 19th century, when the distinguished pathologist Julius Cohnheim performed an autopsy on a young lady who had succumbed to a large stroke. 7 He noted venous thrombus and a large PFO, and hypothesised that a clot had formed in the lower limb veins and then traversed the PFO and onwards to the cerebral circulation.

In the 1950s case reports appeared in the medical literature of thrombus trapped in PFOs.8–10 However, it was not until the 1980s, with the advent of wider spread echocardiography, that researchers began searching for evidence to support a link between ischaemic strokes or transient ischaemic attacks and PFOs.

or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale (CLOSURE I),21 the Randomized clinical trial comparing percutaneous closure of patent foramen ovale using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism (PC-Trial)22 and the Randomised Evaluation of recurrent Stroke comparing PFO closure to Established current standard of Care Treatment (RESPECT) trial23 – with a further one currently recruiting (GORE HELEX™ Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients With Patent Foramen Ovale [REDUCE]), designed to determine the effectiveness of PFO closure as secondary prevention in cryptogenic stroke (see Table 1).

CLOSURE I In 1988 two observational studies were published suggesting an association between PFO and cryptogenic stroke.11,12 At first, Lechat et al. demonstrated that those under 55 with CS had a 54 % prevalence of PFO, while Webster et al. found 50 % prevalence in their patients with ischaemic stroke or transient ischaemic attack (TIA). Both studies utilised contrast echocardiography to detect PFOs. A number of other studies have corroborated the link, even extrapolating to older patients with CS.13,14 An associated atrial septal aneurysm (ASA), when the septum moves more than 1 cm during the cardiac cycle, has been shown to have a synergistic effect to increase risk.15 Mas et al.16 investigated the role of PFO and ASA in recurrent stroke. They followed 581 patients (under the age of 55) with a history of CS treated with aspirin – a TOE demonstrated an atrial septal abnormality in 48 %. After four years the rate of recurrent stroke was 6.2 % in those without an atrial septal abnormality, 5.6 % in the group with PFO alone and 19.2 % in the group with both PFO and ASA. A further meta-analysis of 15 case control studies17 revealed that stroke under the age of 55 was associated with either PFO or ASA alone or PFO and ASA together.

A multicentre, randomised, open-label trial of device closure with a STARFlex occluder (NMT Medical Inc., Boston, Massachusetts, US) versus medical therapy (aspirin and/or warfarin). The primary endpoint was a composite of stroke or TIA during two years of followup, death from any cause during the first 30 days, or death from neurological causes between 31 days and two years. The cumulative incidence (Kaplan–Meier estimate) of the primary endpoint was 5.5 % in the closure group (447 patients) as compared with 6.8 % in the medical therapy group (462 patients) (adjusted hazard ratio [HR], 0.78 95 % confidence interval [CI] 0.45–1.35 p=0.37). The respective rates were 2.9 % and 3.1 % for stroke (p=0.79), and 3.1 % and 4.1 % for TIA (p=0.44). Of concern, in the device arm there was a greater incidence of atrial fibrillation (5.7 versus 0.7 % p<0.001) and 1.1 % of patients had gross thrombus visible on the device by TOE at six months. Rates of successful device implantation were surprisingly low at only 89 % with a large number of residual shunts – effects that may be device attributable. In addition, a cause, other than paradoxical embolism, was usually apparent in patients with recurrent neurological events.

PC-Trial Not all studies found such a clear association. In the Patent Foramen Ovale in Cryptogenic Stroke study (PICCS),18 which was a TOE substudy of the Warfarin-Aspirin Recurrent Stroke study (WARSS), there was no relationship between recurrent stroke and PFO, regardless of size.

The first case series of catheter-based permanent PFO closure was published in 1992.19 Bridges et al. used a double umbrella device on 36 patients with presumed complications of PE (31 ischaemic strokes, 25 TIAs, four systemic arterial emboli and two brain abscesses). As well as a high rate of shunt closure and a very low rate of complication, they did not see any post-procedural events during a follow-up of 8.4 months.

Numerous small non-randomised series followed, brought together in a pooled analysis of 16 studies20 (10 of transcatheter closure and six of medical therapy) that showed the one-year rate of recurrent stroke in medically treated patients was 3.8–12.0 % compared with 0.0–4.9 % in those who underwent device closure. On the basis of these observations it was predicted that a randomised trial would prove that PFO closure was preferable to medical therapy to prevent recurrent cryptogenic stroke.

Recently there have been three published randomised trials – Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/

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A European study of 414 patients randomised to closure with the Amplatzer PFO occluder (St. Jude Medical, Saint Paul, MN, US) or to receive medical therapy (antiplatelet or anticoagulation at the discretion of the treating physician). The primary endpoint was a composite of death, non-fatal stroke, TIA or peripheral embolism.

The primary endpoint occurred in 3.4 % (7) of the 204 device treated patients and 5.2 % (11) of the 210 medically treated group (HR 0.63 95 % CI 0.24–1.62 p=0.34). The power of the study was further reduced by a large number of patients (65) being lost to follow-up and 28 patients crossing from the medical to the device arm.

RESPECT Trial This trial enrolled 980 patients in the US and Canada, and randomised in a 1:1 manner to receive either medical therapy (75 % with antiplatelet therapy and warfarin in the remainder) or the Amplatzer PFO occluder in addition to antiplatelet therapy. They were followed up for a maximum of seven years over a mean of 2.6 years. Raw data analysis was not possible due to a greater rate of drop-out in the medical arm producing a statistically lower total patient-years of follow-up. In the intention-to-treat analysis there was a very low rate of recurrent stroke with no statistical difference between the groups: 6 % (16) in the medical arm versus 2 % (9) in the device arm (p=0.08 HR 0.49 95 % CI 0.22–1.11). However, a number of events occurred prior to closure and analysis as treated found device treatment to be better than medicine with five and 16 events, respectively

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Review of Data and Discussion – Who Should Undergo Patent Foramen Ovale Closure in 2014?

Table 1: Summary of Randomised Controlled Trials Regarding Patent Foramen Ovale Closure in the Secondary Prevention of Cryptogenic Stroke Trial Design

CLOSURE I Randomised

Study Best Medical Device Population Therapy 18–60 with recent Aspirin +/or STARFlex

Primary Endpoint Composite of stroke

Outcomes

Comments

5.5 % in closure group

High rates of

(2012)

multicentre

stroke 909 in total

or TIA during 2 year

versus 6.8 % (adjusted

residual shunts

(87 sites in US

(447 in device arm

follow-up, death

HR 0.78 95 % CI

and complications

and Canada)

and 462 in

from any cause during

0.45–1.35 p=0.37).

attributed to

medical arm)

the first 30 days, or

The respective rates

device design

death from neurological

were 2.9 % and 3.1 %

causes between

for stroke (p=0.79),

31 days and 2 years

and 3.1 % and 4.1 %

warfarin

(NMT)

for TIA (p=0.44)

PC-Trial

Randomised

<60 with recent

Antiplatelet

Amplatzer

Composite of death

3.4 % in the closure

Probably

(2013)

multicentre (29

stroke or TIA

therapy or oral

PFO

from any cause,

group versus 5.2 % (HR

underpowered

sites in Europe,

414 patients

anticoagulation

occluder

non-fatal stroke,

0.63 95 % CI 0.24–1.62

as low number

Australia, Brazil

(204 in device

(at discretion

(St. Jude)

TIA and peripheral

p=0.34). Non-fatal stroke

of recurrent

and Canada)

arm and 210

of treating

embolism

0.5 % in the closure

events

in medical arm)

physician)

group versus 2.4 % (HR

0.20 95 % CI 0.02–1.72

p=0.14) and TIA occurred

in 2.5 % and 3.3 %,

respectively (HR 0.71

95 % CI 0.23–2.24

p=0.56)

RESPECT

Randomised

Age 18–60 with

Aspirin or

Amplatzer

All-cause mortality

6 % in the closure group Subanalyses

(2013)

multicentre

recent stroke or TIA

warfarin or

PFO

recurrence of fatal or

versus 2 % in the device

demonstrated

(69 sites in

980 patients (499

clopidogrel or

occluder

non-fatal ischaemic stroke

arm (HR 0.49 95 %

greater risk

US and

in closure arm and

aspirin +

(St. Jude)

Canada)

481 in medical arm

dipyridamole

CI 0.22–1.11 p=0.08)

reduction with

Intention-to-treat

closure in context

or aspirin +

of ASA or

clopidogrel

substantial shunt

REDUCE

Randomised

Age 18–60 with

Antiplatelet

Gore Septal

Freedom from recurrent

Estimated

(2018)

multicentre

recent presumed

therapy

Occluder

ischaemic stroke or

primary

(~80 sites in US,

cryptogenic stroke

only

(Gore)

imaging-confirmed TIA

completion

Canada and

or embolism.

at least 24 months

date 2015

Europe)

Estimated

post-randomisation

Pending

recruitment 664

ASA = atrial septal aneurysm; CI = confidence interval; HR = hazard ratio; PFO = patent foramen ovale; TIA = transient ischaemic attack.

(HR 0.27 95 % CI 0.00–0.75 p=0.007). Analysis of the pre-specified per-protocol groups, which included the patients who received and adhered to the allotted therapy and had no major violation of inclusion or exclusion criteria, also showed a significant difference: six events in closure group versus 14 (HR 0.37 95 % CI 0.14–0.96 p=0.03). Furthermore, trends from subgroup analyses suggested that those with a substantial shunt (defined as patients with over 20 microbubbles on TOE) and those with associated ASAs had more benefit, and that recurrent events were anatomically more likely to be non-PFO related in the closure group.

The REDUCE trial (ClinicalTrials.gov identifier: NCT00738894) is ongoing and currently enrolling. The aim is to enrol just under 700 patients in around 80 sites in the US, Canada and Europe, and compare the Gore® Septal Occluder (Gore) with antiplatelet medication only in those with recent presumed CS or embolism.

Estimated primary completion date is 2015 and publication will probably be in 2018.

low number of events in all the trials (vastly less than predicted when the trials were designed24) meant that insufficient power is probable.

Specifically in the PC-Trial, an intended power of 80 % was reduced to 40 % due to the overall lack of events.25 This was compounded by slow recruitment, which in CLOSURE I trial led the investigators to reduce the target sample size by over 600 patients. Such recruitment problems may have indicated that clinicians excluded the patients perceived at highest risk, preferring to go directly to device closure, thus biasing the studies in favour of medical therapy – which itself was non-standardised. Additionally, the RESPECT trial suffered with a large number of dropouts from the medical arm, a significant proportion of who underwent off-label device closure. There was also variation in rigour with which PFO-probable strokes were enrolled between studies – a particular problem in the CLOSURE 1 study as the inclusion of TIAs increases uncertainty. A further criticism of the trials was length of follow-up. The relatively young population are clearly at risk for many decades, but importantly, along with ageing usually comes other risks for stroke, not related to PE – making simply extending the follow-up of current studies potentially flawed.

None of the published trials met their primary endpoints, although issues have been raised about them and their design. The relatively

None of the trials incorporated any form of risk stratification within the device closure groups, meaning those with lower risk anatomy

REDUCE Trial

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Structural Table 2: Summary of Randomised Trials Regarding Patent Foramen Ovale Closure in Migraine Trial Design

MIST Randomised

Study Device Primary Population Endpoint 18–60 years old STARFlex Migraine

Outcomes

Comments

No significant

Short follow-up,

(2008)

multicentre

with failed medical

difference between

potentially high rates

sham

therapy for migraine

the two groups at 6

of residual shunt

controlled

147 patients (74 in

months, 3 patients in

(no echo core lab to

device arm and 73

each arm (p=0.51)

assess shunts)

in sham arm)

PREMIUM

Randomised

18–65 years of age

Amplatzer

Reduction in

Pending

Estimated primary

multicentre

migraine attacks (with

PFO occluder

number of

completion date

(30 sites in US)

and without aura).

(St. Jude)

migraine attacks

March 2014

Device closure versus

sham procedure.

Estimated enrolment 230

(NMT)

cessation

PFO = patent foramen ovale.

may have obscured the benefit to those with higher risk anatomy (for example with concomitant ASA). There was an attempt to address this in the RESPECT trial with a subgroup analysis, and also in a recent meta-analysis performed on the three trials. A study by Rengifo-Moreno et al.26 included 2,303 patients (1,150 undergoing device closure and 1,153 receiving medical therapy) with a mean follow-up of 3.5 years.

There was a significant reduction in stroke and TIA in the device group compared with medical therapy (HR 0.59 95 % CI 0.36–0.97 p=0.04) and a suggestion, although not statistically significant, that patients with a substantial shunt benefitted the most (HR 0.35 95 % CI 0.12–1.03 p=0.06). A further paper by Khan et al.27 also suggested a beneficial effect from device closure with hazard ratios of 0.67 (95 % CI 0.44–1.00) in the intention-to-treat cohort, 0.62 (95 % CI 0.40–0.95) in the per-protocol group and 0.61 (95 % CI 0.40–0.95) in the as-treated group.

These results must be interpreted with caution due to the heterogeneity in the trials; particularly concerning medical therapy and device employed. However, Khan et al. attempted to address this by also pooling only the results from the RESPECT trial and PC-Trial, as they both employed the Amplatzer device. This appeared to enhance the robustness of their findings with hazard ratios of 0.54 (95 % CI 0.29–1.01), 0.48 (95 % CI 0.24–0.94) and 0.42 (95 % CI 0.21–0.84) in the intention-to-treat, per-protocol and as-treated populations, respectively. In addition, a further meta-analysis published last year

by Ntaios et al.28 showed that risk of recurrent stroke was reduced in those closed with the Amplatzer device but not in those who had a STARFlex device.

The Risk of Paradoxical Embolism (RoPE) study,29 has been used to develop and test risk models for application in selecting patients in the future most likely to benefit clinically and in designing ongoing trials of PFO closure for CS.

retrospective analyses up to 80 % of patients who underwent PFO closure for alternative indications reported an improvement or even cessation of migraine. Wilmshurst et al.34 contacted 37 patients who had undergone closure of a right to left shunt of whom 21 (57 %) had a history of migraine before the procedure (with aura in 16, without in five). During long-term follow-up, ten patients reported no further migraine symptoms with a further eight others reporting improvement in frequency and severity of migraines. A single-centre, non-randomised trial of PFO closure in the context of migraine in patients with high-risk (for PE) anatomy found a significant reduction in migraine in the device closed patients.35

MIST Trial The Migraine Intervention with STARFlex Technology (MIST) trial36 is the only published randomised trial addressing the question of PFO closure in the context of migraine, and did not meet its primary endpoint (complete freedom from headache) or significantly reduce headache burden. Follow-up was short (six months) and the inclusion criteria may have selected refractory headache patients.

The lack of an independent core echocardiography laboratory has led to controversy about the effectiveness of closure, and procedural complications were high at 6.8 %, which may have influenced the outcome of the study.

The Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the Amplatzer PFO Occluder to Medical Management (PREMIUM) trial with a primary endpoint of reduced migraine attacks has finished recruiting and expects to release results in the next 12 months, and although now terminated, data may be available from the international Percutaneous Closure of Patent Foramen Ovale In Migraine With Aura (PRIMA) trial in due course. Studies summarised in Table 2.

Platypnoea-orthodeoxia Syndrome Overall these studies indicate that patients are at a lower risk of recurrent stroke than initially expected, PFO closure can be performed very safely with the Amplatzer device and that there is likely to be additional benefit of device closure above medical treatment in carefully selected patients, and in particular those with large shunts, ASAs or both.30

In patients with POS, significant right to left shunting occurs dependent upon position leading to desaturation on sitting or standing. In the context of PFO this can occur in any situation where atrial septal geometry is modified or heart-lung relationships are altered.

Examples of such situations are kyphoscoliosis, post-pneumonectomy, diaphragm paralysis and dilatation of the ascending aorta.

Migraine The link between PFO and migraine, particularly with aura, was initially suggested in the late 1990s,31–33 and in non-randomised

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The first reported case of PFO closure for POS, performed surgically in 1991, was in a patient with PFO and idiopathic hemidiaphragm

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Review of Data and Discussion – Who Should Undergo Patent Foramen Ovale Closure in 2014?

paralysis.37 Subsequently device closure in similar patients has been shown to eliminate hypoxia38 and although rare, this clearly should be considered in all patients with restricting symptoms.39

Diving and Decompression Illness PFO has been associated with specific presentations of decompression illness in divers;40,41 studies have been performed to identify those at higher risk 42 and closure following neurological decompression illness has been reported.43 PFO closure in continuing divers appears to prevent symptomatic neurological events and asymptomatic ischaemic brain lesions during long-term follow-up, 44 and has been shown to reduce arterial, although not venous, bubbles in simulated dives.45 Neither recreational nor professional bodies recommend PFO screening in divers unless there has been an episode of a potentially PFO-attributable decompression illness. Given the complexity of assessing this, review by a physician with specific knowledge of diving medicine is mandatory. Recreational divers can be advised to restrict themselves to shallow depths (usually less than 15 m) and to adopt techniques to reduce nitrogen super-saturation including diving with nitrox using air tables and avoiding repetitive dives, or to consider PFO closure.46 Professional divers will require sign-off by a diving specialist and this often includes removal of a shunt if clinically relevant to avoid disabling employment restrictions.30

Surgery in the Seated Position Some neurosurgery is preferably performed in the seated position and paradoxical air embolism is a well-recognised hazard. Perkins-Pearson et al.47 demonstrated reversal of the normal inter-atrial pressure gradient making patients with an atrial communication at risk of PE, and

1. Krueger SK, Lappé DL, Right-to-left shunt through patent foramen ovale complicating right ventricular infarction.

Successful percutaneous catheter closure, Chest, 1988;94:1100–1.

2. Hagen PT, Scholz DG, Edwards WD, Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts, Mayo Clin Proc, 1984;59:17–20.

3. Meissner I, Whisnant JP, Khandheria BK, et al., Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community, Mayo Clin Proc, 1999;74:862–9.

4. Tobis J, Shenoda M, Percutaneous treatment of patent foramen ovale and atrial septal defects, J Am Coll Cardiol, 2012;60:1722–32.

5. Foulkes MA, Wolf PA, Price TR, et al., The Stroke Data Bank: design, methods, and baseline characteristics, Stroke, 1988;19:547–54.

6. Sacco RL, Ellenberg JH, Mohr JP, et al., Infarcts of undetermined cause: the NINCDS Stroke Data Bank, Ann Neurol, 1989;25:382–90.

7. Cohnheim J, Thrombose und Embolie: Vorlesung über Allgemeine Pathologie , Berlin, Germany: Hirschwald, 1877;1:134.

8. Robinson FJ, Lodging of an Embolus in a Patent Foramen Ovale, Circulation, 1950;2:304–5.

9. Elliott GB, Beamish RE, Embolic occlusion of patent foramen ovale; a syndrome occurring in pulmonary embolism, Circulation, 1953;8:394–402.

10. Soloff LA, Zatuchni J, Embolic occlusion of patent foramen ovale, AMA Arch Intern Med, 1956;98:344–7.

11. 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.

12. Webster MW, Chancellor AM, Smith HJ, et al., Patent foramen ovale in young stroke patients, Lancet, 1988;2:11–2.

13. Di Tullio M, Sacco RL, Gopal A, et al., Patent foramen ovale as a risk factor for cryptogenic stroke, Ann Intern Med, 1992;117:461–5.

14. 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.

15. Cabanes L, Mas JL, Cohen A, et al., Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography, Stroke,

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therefore the presence of a PFO is generally regarded as an absolute contraindication to surgery in the seated position. There are cases of PFO closure performed in this setting;48 however, there are no large studies and there remain questions about the timing of surgery post-intervention, with regard to endothelialisation of the device and duration of antiplatelet therapy.

Conclusion The results of data so far suggest that in patients with CS, PFO closure may be beneficial in reducing the risk of recurrent vascular events when compared with medical treatment. Furthermore, when using the Amplatzer device this can be performed with a very low-risk profile. The decision to proceed with PFO closure should be made on a case-by-case basis with the expertise of a multidisciplinary team and patient involvement. It is likely that in those with truly CS and a significant PFO device closure is appropriate; especially in those with high-risk anatomy.

In addition, closure for professional divers who have suffered an episode of PFO-attributable decompression illness, as well as amateur divers who are not willing to give up the sport and are able to accept the small risk of the procedure, is appropriate. As the data for migraine prevention is weaker it should be considered a last resort in those with severe refractory migraine.

In all these situations a combined decision should be made by expert physicians, mainly neurologists, and an experienced interventional cardiologist, alongside an open discussion with the patient. Further data is eagerly anticipated to increase clarity regarding those specific patients most likely to benefit from device closure. n

1993;24:1865–73.

16. Mas JL, Arquizan C, Lamy C, et al., Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both, N Engl J Med, 2001;345:1740–6.

17. Overell JR, Weir CJ, Walker A, Lees KR, Treatment and secondary prevention of stroke, Lancet, 2000;355:319–20; author reply 320–1.

18. Homma S, Sacco RL, Di Tullio MR, et al., Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study, Circulation, 2002;105:2625–31.

19. Bridges ND, Hellenbrand W, Latson L, et al., Transcatheter closure of patent foramen ovale after presumed paradoxical embolism, Circulation, 1992;86:1902–8.

20. Khairy P, O’Donnell CP, Landzberg MJ, Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review, Ann Intern Med, 2003;139:753–60.

21. 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.

22. 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.

23. 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.

24. Rohrhoff N, Vavalle JP, Halim S, et al., Current Status of Percutaneous PFO Closure, Curr Cardiol Rep, 2014;16:477.

25. Rhone E, Chung N, Clapp B, Current evidence for closure of a patent foramen ovale for cryptogenic stroke prevention, Int J Clin Pract, 2014;68(5):551–6.

26. Rengifo-Moreno P, Palacios IF, Junpaparp P, et al., Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials, Eur Heart J, 2013;34:3342–52.

27. 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.

28. Ntaios G, Papavasileiou V, Makaritsis K, Michel P, PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis, Int J Cardiol , 2013;169:101–5.

29. Kent DM, Thaler DE, RoPE Study Investigators, The Risk of Paradoxical Embolism (RoPE) Study: developing risk models for application to ongoing randomized trials of percutaneous patent foramen ovale closure for cryptogenic stroke, Trials, 2011;12:185.

30. Percutaneous closure of patent foramen ovale for the secondary prevention of recurrent paradoxical embolism in divers (IPG371), National Institute for Health and Care Excellence interventional procedure guidance, 2010.

Available at: http://publications.nice.org.uk/percutaneousclosure-of-patent-foramen-ovale-for-the-secondaryprevention-of-recurrent-paradoxical-ipg371 (accessed 28 April 2014).

31. Del Sette M, Angeli S, Leandri M, et al., Migraine with aura and right-to-left shunt on transcranial Doppler: a case-control study, Cerebrovasc Dis, 1998;8:327–30.

32. Anzola GP, Magoni M, Guindani M, et al., Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study, Neurology, 1999;52:1622–5.

33. Wilmshurst P, Nightingale S, Relationship between migraine and cardiac and pulmonary right-to-left shunts, Clin Sci (Lond), 2001;100:215–20.

34. Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL, Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons, Lancet, 2000;356:1648–51.

35. Rigatelli G, Dell’avvocata F, Ronco F, et al., Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism, JACC Cardiovasc Interv, 2010;3:282–7.

36. Dowson A, Mullen MJ, Peatfield R, et al., Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache, Circulation, 2008;117:1397–404.

37. Murray KD, Kalanges LK, Weiland JE, et al., Platypneaorthodeoxia: an unusual indication for surgical closure of a patent foramen ovale, J Card Surg , 1991;6:62–7.

38. Toffart AC, Bouvaist H, Feral V, et al., Hypoxemia-orthodeoxia related to patent foramen ovale without pulmonary hypertension, Heart Lung, 2008;37:385–9.

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Structural 39. Blanche C, Noble S, Roffi M, et al., Platypnea-orthodeoxia syndrome in the elderly treated by percutaneous patent foramen ovale closure: a case series and literature review, Eur J Intern Med , 2013;24:813–7.

40. Moon RE, Camporesi EM, Kisslo JA, Patent foramen ovale and decompression sickness in divers, Lancet , 1989;1:513–4.

41. Wilmshurst P, Walsh K, Morrison L, Patent foramen ovale and decompression illness in divers, Lancet, 1997;349:288.

42. Cartoni D, De Castro S, Valente G, et al., Identification of professional scuba divers with patent foramen ovale at risk

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for decompression illness, Am J Cardiol, 2004;94:270–3.

43. Walsh KP, Wilmshurst PT, Morrison WL, Transcatheter closure of patent foramen ovale using the Amplatzer septal occluder to prevent recurrence of neurological decompression illness in divers, Heart, 1999;81:257–61.

44. Billinger M, Zbinden R, Mordasini R, et al., Patent foramen ovale closure in recreational divers: effect on decompression illness and ischaemic brain lesions during long-term follow-up, Heart, 2011;97:1932–7.

45. Honèk J, Srámek M, Sefc L, et al., Effect of catheter-based patent foramen ovale closure on the occurrence of

arterial bubbles in scuba divers, JACC Cardiovasc Interv, 2014;7(4):403–8.

46. Sykes O, Clark JE, Patent foramen ovale and scuba diving: a practical guide for physicians on when to refer for screening, Extrem Physiol Med, 2013;2:10.

47. Perkins-Pearson NA, Marshall WK, Bedford RF, Atrial pressures in the seated position: implication for paradoxical air embolism, Anesthesiology, 1982;57:493–7.

48. Laban JT, Rasul FT, Brecker SJ, et al., Patent foramen ovale closure prior to surgery in the sitting position, Br J Neurosurg, 2013 [Epub ahead of print].

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Structural

Differences in Outcomes and Indications between Sapien and CoreValve Transcatheter Aortic Valve Implantation Prostheses A l i a N o o ra n i 1 a n d V i n a y a k B a p a t 2 1. Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge; 2. Department of Cardiothoracic Surgery, St. Thomas’ Hospital, London, UK

Abstract Transcatheter aortic valve implantation (TAVI) has emerged as a suitable alternative to surgical valve replacement for patients with severe, symptomatic, calcified aortic stenosis and a background of co-morbidities, which can make surgery a high-risk option. It has also evolved as an alternative for degenerative prosthetic heart valve disease. Since the inception of TAVI in 2002, the two main devices in routine clinical use are the Edwards Sapien valve (since 2006) and the Medtronic CoreValve (since 2007). The more recent Sapien XT valve and Sapien 3 have been in clinical use since 2010 and 2013, respectively. In addition to registry data on these devices, there are a number of completed and ongoing randomised controlled trials, including one comparing the two devices. The aim of this article is to discuss the differences in indications and outcomes between these two prostheses.

Keywords Transcatheter aortic valve Implantation, percutaneous access, aortic valve replacement Disclosure: Vinayak Bapat is a consultant for Edwards Lifesciences, Medtronic Inc and St. Jude Medical. Alia Noorani has no conflicts of interest to declare.

Received: 3 April 2014 Accepted: 27 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):121–5 Correspondence: Vinayak Bapat, Consultant Cardiothoracic Surgeon, Department of Cardiothoracic Surgery, St. Thomas’ Hospital, London SE1 7EH, UK. E: vnbapat@yahoo.com

Transcatheter aortic valve implantation (TAVI) is an established alternative to surgical valve replacement in the management of calcified severe aortic stenosis in those with co-morbidities or adverse features (advanced age, impaired left ventricular function), or in those where open surgery may be associated with unfavourable technical features, such as previous sternotomy with a patent internal mammary graft, porcelain aorta or previous thoracic radiation, rendering the operative field hostile.1–3 A large body of experience and evidence exists predominantly for two commonly used TAVI devices; namely the balloon-expandable Edwards Sapien Valve (ESV) (Edwards Lifesciences Ltd, Irvine, California, US) and the self-expanding Medtronic CoreValve (MCV) (Medtronic Inc, Minneapolis, Minnesota, US). Although the fundamental principle behind the two valves is similar, both involving a stent with three bioprosthetic cusps (leaflets) deployed within a calcified native aortic valve, the specific design features and potential indications are different. In this article we explore in detail the respective design features, related indications for each valve type as well as their known outcomes.

General Indications for Aortic Valve Implantation Normal aortic valve area is between 3 and 4 cm2 and a transvalvular gradient develops when the valve area decreases by half. Patients with a normal left ventricle are generally asymptomatic unless the valve area is <1 cm2, with an accompanying jet velocity of approximately 4 m/s and a mean gradient >40 mmHg (see Table 1).4 Symptoms may occur at lower gradients and with less obstruction in some patients, such as those with poor left ventricular function (low flow aortic stenosis).

Besides native aortic valve disease, it is important to consider that surgically implanted bioprosthetic valves also undergo structural

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deterioration resulting in calcification, wear and tear, thrombosis, pannus formation and endocarditis.5 This deterioration can manifest as aortic stenosis, regurgitation or mixed disease. Although in a bid to avoid redo surgery, valve-in-valve TAVI is emerging as a treatment option in this group of patients, it is beyond the scope of this article.1

Patient Selection Criteria and Contraindications for Transcatheter Aortic Valve Implantation The patient selection criteria for TAVI are essentially the same as for surgical valve replacement. The main reason for opting for TAVI is the presence of co-morbidities placing the patient in either the inoperable or the high-risk category, making the option of open surgery less favourable. Current recommended patient selection criteria for TAVI from the European Association of Cardio-Thoracic Surgery (EACTS) include one or more of the following:6 • E uropean System for Cardiac Operative Risk Evaluation (EuroSCORE) >20.

• Society of Thoracic Surgeons (STS) score >10.

• P resence of factors not covered in risk scores, such as challenging surgical cases (porcelain aorta, previous thoracic radiation, coronary artery surgery with a patent mammary artery graft) and the presence of severe co-morbidities.

Numerous exclusion criteria are present, although none are absolute.

The presence of a bicuspid, unicuspid or non-calcified aortic valve, severe aortic regurgitation (AR) and a native annulus size that is too small or too big relative to available TAVI devices (currently unsuitable annulus sizes include <18 mm or >29 mm for a MCV prosthesis

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Structural Table 1: Grading of Aortic Stenosis

Aortic Jet Velocity (m/s)

Mean Gradient Valve Area (mmHg) (cm2)

Normal ≤2.0

<5

3.0–4.0

Mild <3.0

<25

>1.5

Moderate 3.0–4.0

25–40

1.0–1.5

Severe >4.0

>40

<1.0

Figure 1: The Edwards Sapien (A), Sapien XT (B) and Medtronic CoreValve (C)

implantation the valve is crimped onto the NovaFlex delivery catheter and introduced via a sheath into the femoral artery. Transapical and transaortic delivery are also possible using the Ascendra 2 or Ascendra plus systems. Rapid pacing is required during deployment as the valve is balloon expandable. Both valves are available in 23 mm and 26 mm sizes, although more recently, the Sapien XT has been introduced in a 29 mm size, enabling treatment of annular diameters between 18 and 27 mm. The newer generation Sapien 3 valve underwent first-in-human implantation in 2012. In comparison with the Sapien and Sapien XT valve this has a lower crimp profile and an additional outer PET skirt to reduce paravalvular regurgitation. This valve is not discussed further in this article.

Medtronic CoreValve

Table 2: Comparison of Features between Edwards Sapien XT and CoreValve Features

Sapien XT

CoreValve

Frame

Cobalt chromium

Nitinol

Cusps/leaflets

Bovine pericardial

Porcine pericardial

Expandable

Balloon expandable

Self-expanding

Aortic fixation

No

Yes

Annular fixation

Yes

Yes

Reposition allowed

No

Yes

diameter

18–27 mm

18–29 mm

Pacemaker requirement

3–8 %

14–40 %

- Dilated ascending aorta

Yes

No

- Aortic regurgitation

If calcific stenosis present

If appropriate size

- Valve-in-valve

All 4 valve positions

Aortic only

Access

Transaortic, transapical,

Transaortic,

transaxillary,

transaxillary,

transfemoral

transfemoral

FDA

Yes, 2012

Yes, 2014

CE mark

Yes, 2007

Yes, 2007

Treatable annulus

The Medtronic CoreValve (MCV) consists of a nitinol self-expandable frame and porcine pericardial cusps (leaflets) mounted onto a porcine pericardium skirt (see Figure 1C). Nitinol, an alloy of nickel and titanium, exhibits martensitic transformation, which allows it to undergo a fully reversible solid-state transformation. Accordingly, at higher temperatures (e.g. body temperature) nickel exists as austenite, a strong cubic structure, whereas at lower temperatures (e.g. in an ice bath) it exists as martensite, a monoclinic crystal structure, exhibiting superelasticity, making it 10–30 times more elastic than other metals.

This property allows it to be tightly compressed into a delivery sheath for implantation via the transarterial route (aortic or femoral).10 Currently, sizes 26, 29 and 31 mm are available. The next generation CoreValve Evolut valve is now available in 23 mm, and once in routine use, the range of treatable annular diameters will be between 17 and 29 mm.

Table 2 details the differences between the ESV and MCV.

Indications for Each Valve Type There are several factors to consider when contemplating a valve type and method of delivery. These include:

Suitability

FDA = Food and Drug Administration.

and <18 mm or >27 mm for an ESV prosthesis) are some excluding factors.7–9 In addition, expected patient survival of less than one year, a dilated ascending aorta at the sinotubular junction (>45 mm for the MCV prosthesis) and the presence of apical thrombus are also considered to be contraindications.6

Differences in Transcatheter Heart Valve Design Edwards Sapien and Sapien XT Valve The Edwards Sapien valve (ESV) (see Figure 1A) has been in use since 2006. It consists of a balloon-expandable stainless steel frame and three bovine pericardium cusps (leaflets) mounted onto a polyethylene terephthalate skirt (PET). Transfemoral delivery is facilitated via the RetroFlex 3 system, and the Ascendra system is used for transapical implantation. The newer generation Sapien XT valve, introduced in 2010 (see Figure 1B) consists of a balloon-expandable cobalt chromium frame with bovine pericardium cusps (leaflets). For transfemoral

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• • • •

native annulus size; cardiac anatomy; peripheral arterial assessment; and risk of annular rupture.

Native Annulus Size Accurate assessment of the native annulus should be at the forefront when considering a TAVI procedure. It is a given that an annulus size of <18 mm or >29 mm precludes any form of TAVI at present. Since there is no current imaging gold standards for annular assessment, a combination of several methods may be employed, including transthoracic and transoesophageal echocardiography in addition to computed tomography (CT) and magnetic resonance imaging (MRI).3 Available valve sizes and their appropriate corresponding native annulus sizes are given in Table 3. It is worth mentioning that at present, until smaller sizes of MCV (Evolut 23 mm) and ESV Sapien XT (20 mm) become available for routine clinical use, a size 23 mm ESV is suitable for a native annulus size of 18–20 mm and MCV 31 for 27–29 mm annular diameters.9 Finally a degree of relative oversize (5–10 %) is required with the ESV system to minimise the risk of paravalvular regurgitation.1

Cardiac Anatomy In addition to annular diameter, a detailed assessment of cardiac anatomy is necessary as this can affect the choice of implant and method of delivery. Specifically, it is important to acknowledge specific structural variations:3

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Differences in Outcomes and Indications between Sapien and CoreValve TAVI Prostheses

• B icuspid aortic valve – the elliptical shape of the valve orifice in this condition is considered a relative contraindication to TAVI as it may result in higher rates of paravalvular regurgitation when implanting a cylindrical prosthesis. In more experienced hands, however, a slightly higher than normally positioned MCV may provide a good result.11,12 • L eft ventricular outflow size and shape is another consideration.

The presence of a sigmoid-shaped septum or an existing mitral prosthesis may make transapical delivery more suited and hence favour the ESV. • A porcelain aorta and a horizontally placed aortic root may make transfemoral delivery more challenging and risky thereby favouring a transapical or transaortic delivery of an ESV. However, with experience and improved delivery systems, transfemoral placement is becoming more feasible and predictable.

• The presence of a mitral valve prosthesis requires special consideration. Too low a placement of the transcatheter heart valve (THV) must be avoided as this can cause interference with mitral valve function.

• The height of the coronary artery ostia should be at least 10 mm from the base of the aortic valve to prevent occlusion of the coronaries following THV implantation.

• A lthough there is always some degree of valvular calcification, the presence of a large calcific nodule can cause coronary occlusion on THV implantation.

Peripheral Arterial Assessment Accurate assessment of the peripheral arterial tree is crucial when considering an ideal method of delivery and the type of implant. 3 Current methods of assessment include CT and peripheral angiography. In general, an ilio-femoral diameter <6 mm is considered unsuitable for transfemoral TAVI. The presence of ilio-femoral tortuosities, kinks in the aorta, existing stents, aneurysms or thrombi are also contraindications for transfemoral access, and alternative access via the transapical, transaortic or subclavian route have to be considered.

Risk of Annular Rupture Aggressive balloon dilatation and oversizing during TAVI using the ESV has been associated with aortic root and annulus rupture.13 In a study of 37 consecutive patients with left ventricular outflow tract (LVOT) rupture during ESV deployment, a higher degree of sub-annular LVOT calcification (Agatston score), higher frequency of oversizing (by >20 %) as well as balloon post-dilatation were all associated with a higher risk of annular rupture.14 It is possible that the introduction of the Sapien 3 valve may reduce the risk of annular rupture as relatively less oversizing is required.

Differences in Outcomes In addition to self-reported registry data, randomised data are available from the Placement of Aortic Transcatheter Valves (PARTNER) trial, which evaluated the ESV, and the CoreValve US Pivotal trial, which evaluated the MCV. The retrospective Pooled Rotterdam - Milano Collaboration (PRAGMATIC) study compared the two valves and the recent Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis (CHOICE) study is the only randomised control trial of the two devices. In summary, although device specific complications are evident, there are no differences in clinical outcomes in terms of short- or long-term survival with use of either valve.15 Details of registry data and the relevant trials are presented below.

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Table 3: Currently Available Transcatheter Heart Valve Sizes and their Corresponding Treatable Annular Diameters Manufacturer Transcatheter Size

Heart Valve model

Annulus Diameter Range in mm

Edwards Lifesciences

Sapien XT

20

16–19

23

18–21

26

22–25

29

25.0–27.7

Medtronic Inc.

CoreValve/Evolut

23 17–20

26

20–23

29

24–27

31

26–29

Red text highlights valves not currently widely used in clinical practice.

Edwards Sapien Valve PARTNER TRIAL The PARTNER trial consisted of two parallel arms. In cohort A, standard surgical aortic valve replacement (SAVR) was compared with TAVI in high-risk patients as determined by a STS score of >10 % and/or predicted operative mortality of 15 % or more. In cohort B, TAVI was compared with medical management (including balloon valvuloplasty) in inoperable patients with severe aortic stenosis. Patients enrolled into this cohort were deemed to have an operable risk of >50 %.

The one-year results from the trial demonstrated that in cohort A, TAVI and SAVR were found to be equivalent in terms of overall mortality, with all-cause mortality from TAVI at 24.2 % and 26.8 % from SAVR. Although the rate of stroke following TAVI was higher at 5.1 % compared with 2.4 % following SAVR, this result did not reach statistical significance. Results from cohort B confirmed that TAVI was superior to medical management, with the mortality rate from TAVI at 30.7 % compared with 50.7 % from medical treatment.

There was, however, a higher rate of major vascular complications and stroke in the TAVI group compared with the conservatively managed group.

Review of the two-year data showed that the rate of stroke was 11.2 % with TAVI and 6.5 % with SAVR (p=0.05), and mortality in cohort A was 33.9 % from TAVI compared with 35.0 % from SAVR. Additionally, although paravalvular regurgitation was noted to be moderate in 7.0 % and severe in 1.9 % at one-year, this had decreased to 6.9 % and 0.9 %, respectively at two years, (p<0.001 for both intervals). Nonetheless, even mild paravalvular regurgitation was associated with an increased mortality (p<0.001).

Important findings from cohort B showed that mortality from TAVI was 43.3 % in the TAVI group compared with 68.0 % in the medical group, (p<0.05).15–17

SOURCE Registry The Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) Registry is the largest series of consecutively ESV implanted TAVI patients with one-year outcomes. A total of 2,344 consecutive patients were enrolled in two cohorts to reflect trends overtime.

Cohort 1 consisted of 1,038 patients enrolled at 32 European centres between November 2007 and January 2009. Transfemoral TAVI was undertaken in 463 patients and transapical in 575 patients. The overall one-year survival was 76.1 %; 72.1 % for transapical and 81.1 % for transfemoral access. The transapical group represented a higher-risk

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Structural population, given that the logistic EuroSCORE for this group was significantly higher than that of the transfemoral TAVI patients.

Cohort 2 of the Registry consisted of a further 1,306 consecutive patients at 37 European centres enrolled between February 2009 and December 2009. Final results from the SOURCE registry indicated excellent results, with two-year survival at 67.7 % overall, similar stroke risks between the two cohorts of 2.5 % in cohort 1 and 2.8 % in cohort 2, which notably were lower than the 30 day stroke risk from transapical TAVI in cohort A of the PARTNER trial at 3.8 %.18,19

by: successful vascular access; and deployment and retrieval without the need for a second valve; and less than mild AR post-procedure.

Secondary endpoints included the need for a permanent pacemaker system, cardiovascular and all-cause mortality at 30 days.

Results from this trial showed that although cardiovascular mortality, bleeding and vascular complications were similar for both valves, there was a higher risk of pacemaker insertion following MCV implantation, a lower rate of more than mild AR following ESV implantation and better device success with the ESV valve (95.5 % versus 77.5 % p<0.001).23

Medtronic CoreValve ADVANCE Study

PRAGMATIC Study

The MCV ADVANCE Study is the largest multicentre prospective MCV study comprising of 1,015 patients treated at 44 centres in 12 countries. The stroke rate in this group of patients was lower than the PARTNER A cohort at 4.5 %, and the one-year all-cause mortality rate was better than PARTNER A; 17.9 % compared with 24.2 %. These results were an improvement on previous pre-dated registry data such as FRANCE-2 and the UK registry (see below).20

The aim of the PRAGMATIC study was to compare outcomes from transfemoral TAVI between the Medtronic CoreValve and Edwards Sapien/XT valves for patients with severe aortic stenosis. This non-randomised, retrospective study analysed pooled data from four experienced European centres, which underwent propensity score matching in view of differences in baseline characteristics. Of a total of 793 possible patients, 204 in each group were identified.

There was no difference in 30-day all-cause mortality (MCV 8.8 % versus ESV 6.4 %, p=0.3520), major vascular complications (MCV 9.3 % versus ESV 12.3 %, p=0.340), or one-year all-cause or cardiovascular mortality between the two valves. There was a higher

CoreValve US Pivotal Trial This prospective, randomised controlled multicentre trial of 795 patients in 45 centres in the US compared the MCV with SAVR in high-risk patients. The primary endpoint was the risk of death from any cause at one-year.

All-cause mortality at one-year was 14.2 % in the MCV group versus 19.1 % in the SAVR group. In addition, lower rates of cardiovascular and cerebrovascular events were noted in the TAVI group. In contrast to PARTNER A, this study did not show a higher rate of stroke post-TAVI when compared with rates post-SAVR. The incidence of moderate to severe AR post-TAVI at one-year was 6.1 %, although this did not have an adverse effect on survival.

In the majority of patients (76.2 %) discharged with moderate to severe AR, this had reduced to mild or none on one-year follow-up.

Possible explanations given were the properties of nitinol, a higher placement and more accurate pre-TAVI assessment of the annulus with CT.21

Weighted Meta-analysis of Early and Late Clinical Outcomes after CoreValve Transcatheter Aortic Valve Implantation in Seven National Registries This meta-analysis included 2,156 patients treated with the MCV prosthesis between 2007 and 2010 in seven countries. Reported results included early (30-day) outcomes including procedural success, stroke and pacemaker rates as well as one-year survival rates. Pooled procedural success was 97.8 %, the stroke rate was 2.8 % and the pacemaker implantation rate was 28.7 %. Early survival was 93.4 % and one-year mortality was 17.1 %. Limitations of this meta-analysis by virtue of its design included the variability in patient selection criteria, the non-standardised definitions of adverse events and the under reporting of clinical events.22

CoreValve Versus Sapien Valve CHOICE Randomised Clinical Trial The CHOICE study is the only randomised controlled trial (RCT) comparing a self-expandable valve (MCV) to a balloon-expandable valve (ESV). In this trial the primary endpoint was device success as measured

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incidence of permanent pacemakers in the MCV group at 22.5 % versus 5.0 % in the ESV group (p≤0.001), which is likely a result of valve design. In addition, this study found that although there was no difference observed in the incidence of AR of any grade between the two valves types, residual moderate to severe AR was associated with an increased one-year mortality.24

UK Registry Data from the UK TAVI registry evaluated outcomes according to valve type and method of delivery. In essence, there was no significant difference in mortality between the ESV and MCV groups at any timepoints, and no difference in mortality between the two valves types for transfemoral delivery. There was a higher incidence of permanent pacemaker implantation as well as paravalvular regurgitation with the MCV prosthesis. Transapical delivery of the ESV valve was associated with higher mortality at 30 days as well as one-year when compared with transfemoral delivery of the same valve type. Trans-subclavian delivery of the MCV was associated with higher mortality, although this did not reach statistical significance. Cumulative survival for transapically implanted ESV was found to be associated with a lower survival than with transfemoral delivery. Survival rates for subclavian delivery of the MCV cohort initially tracked that of both valves when delivered via the transfemoral route, but at six months this fell dramatically, meeting the poorer survival rates for transapically delivered ESV.2

FRANCE 2 Registry This study was a prospective multicentre study of the French national TAVI registry. The primary endpoint was death from any cause. A total of 3,195 patients were included, having undergone TAVI using the ESV and the MCV between January 2010 and October 2011, at 34 centres.

Results from this study were comparable with the PARTNER trial in terms of mortality at 30 days (9.7 %) and one-year (24 %). MCV use as associated with a higher rate of permanent pacemaker (PPM) as well as periprosthetic regurgitation. Multivariate analysis indicated that a higher logistic EuroSCORE and transapical approach as well as residual paravalvular regurgitation was associated with an increased mortality.25

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Differences in Outcomes and Indications between Sapien and CoreValve TAVI Prostheses

Meta-analysis of Impact, Incidence and Predictors of Aortic Regurgitation after Transcatheter Aortic Valve Implantation This meta-analysis of 45 studies included a total of 12,926 patients.

Results indicated that AR was common post-TAVI and was an adverse prognostic indicator of short and long-term survival. AR was also more prevalent in the MCV group at 16.1 % versus 9.1 % in the ESV group (p=0.005).26

Conclusions TAVI is a suitable alternative to surgical valve replacement in inoperable and a select group of high-risk patients with severe symptomatic aortic stenosis. Significant technological and device design advances have occurred since the first TAVI was performed. Two devices in current use

1.

Bapat V, Attia R, Redwood S, et al., Use of transcatheter heart valves for a valve-in-valve implantation in patients with degenerated aortic bioprosthesis: technical considerations and results, J Thorac Cardiovasc Surg , 2012;144(6):1372–9.

2. Blackman DJ, Baxter PD, Gale CP, et al., Do Outcomes from transcatheter aortic valve implantation vary according to access route and valve type? The UK TAVI Registry, J Interv Cardiol, 2014;27(1):86–95.

3. Al-Lamee R, Godino C, Colombo A, Transcatheter aortic valve implantation: current principles of patient and technique selection and future perspectives, Circ Cardiovasc Interv, 2011;4(4):387–95.

4. 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, Circulation , 2014 [Epub ahead of print].

5. Piazza N, Bleiziffer S, Brockmann G, et al., Transcatheter aortic valve implantation for failing surgical aortic bioprosthetic valve: from concept to clinical application and evaluation (part 1), JACC Cardiovasc Interv, 2011;4(7):721–32.

6. 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.

7. Medtronic Inc, CoreValve, 2014. Available at: www.corevalve. com (accessed 1 May 2014).

8. Edwards Lifesciences Corporation, 2014. Available at: www. edwards.com (accessed 1 May 2014).

9. Mylotte D, Martucci G, Piazza N, Patient selection for transcatheter valve implantation: an interventional cardiology perspective, Ann Cardiothorac Surg , 2012;1(2):206–15.

10. Forrest JK, Transcatheter aortic valve replacement: design,

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are the MCV and the ESV. Although device design features may vary and individual device complications may be present, studies have not shown a difference in mortality between the two valve types. At present, device choice is dictated by physician preference, annular diameter and, in a small percentage of patients, by availability of transapical access route for ESV. It is unclear at present which of the two devices is better with respect to degree of AR, as it may be dictated by local anatomy rather than device choice; although due to its specific design features, the MCV was found in some studies to be associated with a higher rate of AR, which did decline overtime, perhaps explaining the lack of difference in outcome data between the two valves. The MCV was also found to be associated with a higher rate of permanent pacemaker implantation, and along with AR, these factors may well become more important if TAVI is introduced into a lower risk population. n

clinical application, and future challenges, Yale J Biol Med , 2012;85(2):239–47.

11. Wijesinghe N, Ye J, Rodés-Cabau J, Transcather valve implantation in patients with bicuspid aortic valve stenosis, JACC Cardiovac Int , 2010;3(11):1122–5.

12. Himbert D, Pontnau F, Messika-Zeitoun D, et al. Feasibility and outcomes of transcatheter aortic valve implantation in high risk patients with stenotic biscupid aortic valves, Am J Cardiol , 2012;110(6):877–83.

13. Hayashida K, Bouvier E, Lefèvre T, Successful managemnt of annulus rupture in transcather aortic valve implantation, JACC Cardiovasc Interv, 2013;6(1):90–1.

14. Barbanti M, Yang T, Rodès Cabau J, et al., Anatomical and procedural features associated with aortic root rupture during balloon expandable transvatheter aortic valve replacement, Circulation , 2013;128(3):244–53.

15. Iqbal J, Serruys PW, Comparison of Medtronic CoreValve and Edwards Sapien XT for Transcatheter Aortic Valve Implantation: The Need for an Imaging-Based Personalized Approach in Device Selection, JACC Cardiovasc Interv , I7(3):293–5.

16. Svensson LG, Tuzcu M, Kapadia S, et al., A comprehensive review of the PARTNER trial, J Thorac Cardiovasc Surg , 2013;145(3 Suppl), S11–6.

17. Kodali SK, Williams MR, Smith CR, et al., Two-year outcomes after transcatheter or surgical aortic-valve replacement, N Engl J Med , 2012;366(18):1686–95.

18. Thomas M, Schymik G, Walther T, et al., One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve, Circulation , 2011;124(4):425–33.

19. W endler O, Walther T, Schroefel H, et al., Transapical aortic valve implantation: mid-term outcome from the SOURCE registry, Eur J Cardiothoracic Surg , 2013;43(3)505–11.

20. 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 Hear J , 2014 [Epub ahead of print].

21. Adams DH, Popma JJ, Reardon MJ, et al., Transcatheter AorticValve Replacemnt with a Self-Expanding Prosthesis, N Engl J Med [Epub ahead of print].

22. Ruiz C, Grube E, Laborde JC, et al., Weighted Meta-analysis of early and late clinical outcomes after CoreValve – TAVI seven National Registries. Presented at EuroPCR , Paris, France, 17–20 May 2011.

23. Abdel-Wahab M, Mehilli J, Frerker C, et al., Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial, JAMA, 2014;311(15):1503–14.

24. Chieffo A, Buchanan GL, Van Mieghem NM, et al., Transcatheter aortic valve implantation with the Edwards SAPIEN versus the Medtronic CoreValve Revalving system devices: a multicenter collaborative study: the PRAGMATIC Plus Initiative (Pooled-RotterdAm-Milano-Toulouse In Collaboration), J Am Coll Cardiol , 2013;61(8):830–6.

25. Gilard M, Eltchaninoff H, Iung B, et al., Registry of transcatheter aortic-valve implantation in high-risk patients, N Engl J Med , 2012;366(18):1705–15.

26. Athappan G, Patvardhan E, Tuzcu EM, et al., Incidence, predictors, and outcomes of aortic regurgitation after transcatheter aortic valve replacement: meta-analysis and systematic review of literature, J Am Coll Cardiol , 2013;61(15):1585–95.

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Structural

Transcatheter Aortic Valve Replacement and Left Atrial Appendage Occlusion – A Stitch in Time?

Sam eer Ga foor, 1 Luisa Heuer, 1 J en n i f e r F r a n k e , 1,2 S t e f a n B e r t o g , 1,3 L a u r a V a s k e l y t e , 1 I l o n a H of man n 1 and Horst Sievert1 1. CardioVascular Center, Frankfurt, Germany; 2. University of Heidelberg, Heidelberg, Germany; 3. Department of Veterans Affairs, Minnesota, US

Abstract Many patients have now been able to receive transcatheter aortic valve replacement (TAVR) therapy for severe aortic stenosis. These patients have atrial fibrillation and are placed on warfarin for stroke prophylaxis. The opportunity for treatment with left atrial appendage occlusion (LAAO) in place of warfarin for this population exists, especially for those with increased bleeding risk. This paper discusses the prevalence and aetiology of stroke in patients presenting for TAVR (with a focus on the risk from chronic and acute atrial fibrillation) and also the benefit of LAAO closure in this population.

Keywords Aortic stenosis, atrial fibrillation, left atrial appendage, aortic valve replacement, transcatheter aortic valve replacement, transcatheter aortic valve implantation, left atrial appendage closure, left atrial appendage occlusion Disclosure: Dr. Sievert’s institution has ownership interest in or has received consulting fees, travel expenses or study honoraries from the following companies: Abbott, Access Closure, AGA, Angiomed, Arstasis, Atritech, Atrium, Avinger, Bard, Boston Scientific, Bridgepoint, Cardiac Dimensions, CardioKinetix, CardioMEMS, Coherex, Contego, CSI, EndoCross, EndoTex, Epitek, Evalve, ev3, FlowCardia, Gore, Guidant, Guided Delivery Systems, Inc., InSeal Medical, Lumen Biomedical, HLT, Kensey Nash, Kyoto Medical, Lifetech, Lutonix, Medinol, Medtronic, NDC, NMT, OAS, Occlutech, Osprey, Ovalis, Pathway, PendraCare, Percardia, pfm Medical, Rox Medical, Sadra, SJM, Sorin, Spectranetics, SquareOne, Trireme, Trivascular, Velocimed, Veryan. All other authors have no disclosures.

Received: 2 April 2014 Accepted: 12 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):126–9 Correspondence: Horst Sievert, CardioVascular Center, Seckbacher Landstrasse 65, 60389 Frankfurt, Germany. E: info@cvcfrankfurt.de

Many patients with aortic stenosis have now been able to receive transcatheter aortic valve replacement (TAVR). In addition, patients with atrial fibrillation have also been able to receive left atrial appendage (LAA) occlusion for prevention of stroke. According to current studies and guidelines, LAA closure is indicated in patients with non-valvular atrial fibrillation. However, what happens if the valvular disease is treated and the atrial fibrillation persists? Can LAA closure help modify the risk of stroke in patients with aortic stenosis that receive TAVR? This query brings up issues of prevalence, indication, procedural safety and long-term outcomes.

The patients under discussion are those with aortic stenosis who are at risk for stroke due to atrial fibrillation. The Placement of Aortic Transcatheter Valves (PARTNER) trial reported one-year stroke data as 8.3 % in cohort A (high-risk operable) patients1 and 10.6 % in cohort B (non-operable) patients.2 Other registry data show that 30-day stroke risk was present in multiple registries (periprocedural stroke risk of 1.5 %, 30-day stroke rate of 4.0 %, with 30-day major stroke risk of 3.2 % and 30-day minor stroke risk of 1.0 %).3,4 Yet other studies indicate that roughly half of strokes within the first 30 days will be periprocedural, and half will be after the procedure.5–7

Why Does Stroke Happen After Transcatheter Aortic Valve Replacement?

There are many theories addressing this question, as captured in Table 1. These include procedural risk factors and post-procedural risk factors. Some procedural risk factors are known from experience

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with balloon valvuloplasty, but some are specific to valves. Serial transcranial Doppler examinations identify high-intensity transient signals (HITS) during transcatheter aortic valve implantation (TAVI), which may serve as a surrogate for microembolization. 8–10 For example, duration of valve manipulation may be longer and lead to more HITS with self-expanding CoreValve than balloon-expandable Edwards. Of note, atrial fibrillation – both new onset and chronic – are risk factors for stroke in patients with TAVR. These theories and risk factors give rise to additional questions.

How Often is Atrial Fibrillation Present in Patients Undergoing Transcatheter Aortic Valve Replacement?

Chronic atrial fibrillation was present at a high rate in both the PARTNER cohort A: high-risk TAVR arm (40.8 %) and cohort B: inoperable TAVR arm (32.9 %). Further analysis of TAVR patients found that atrial fibrillation is a predictor of mortality regardless of type (paroxysmal, persistent or permanent). Atrial fibrillation also predicts mortality regardless of subclass (age, gender, diabetes, renal function, coronary artery disease or left ventricular ejection fraction).15 Further, pre-existing chronic atrial fibrillation was found in one study to predict stroke even after 30 days, with a hazard ratio of 2.84 and a cumulative transient ischaemic attack (TIA)/CVA hazard ratio of 1.91.5 However, this was not the case in other papers, namely by Stortecky et al.,15 likely due to two reasons.

Firstly, these studies do not differentiate strokes at >24 hours to later strokes. Secondly, they do not differentiate strokes from 30 days to one-year as a different subgroup. Timing of the cerebrovascular event may be relevant to the cause.

© RADCLIFFE CARDIOLOGY 2014

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Transcatheter Aortic Valve Replacement and Left Atrial Appendage Occlusion – A Stitch in Time?

How Often Does New Onset Atrial Fibrillation Occur After Transcatheter Aortic Valve Replacement?

The literature reports a rate between 7.5 and 31.9 %.1,2,5,14,16 Predictive factors for new onset atrial fibrillation include transapical access and large left atrial size.16 The timing of new onset atrial fibrillation is variable.

About a third (36.3 %) of new onset atrial fibrillation start during the procedure, but over 50 % of cases start at over a 24 hour time period.

Further, the duration of new onset atrial fibrillation is also variable, with >50 % of new onset atrial fibrillation lasting <24 hours. New onset atrial fibrillation in the first 30 days increased the odds of having atrial fibrillation again in the first year.16

Does New Onset Atrial Fibrillation After Transcatheter Aortic Valve Replacement Lead to Stroke?

There is evidence of a significant correlation. In 2012, NombelaFranco et al.5 showed how new onset atrial fibrillation with onset of <24 hours, 0–30 days and 1–30 days after TAVR has an odds ratio for stroke of 2.46, 2.27 and 2.76, respectively. According to another paper, new onset atrial fibrillation in the first year after procedure has an odds ratio for stroke of 4.3.16 In total, chronic atrial fibrillation is already present in 30 % of patients undergoing TAVR; this number increases to 40–50 % when new atrial fibrillation is included.17

Preventing Stroke in Transcatheter Aortic Valve Replacement Patients with Atrial Fibrillation – Chronic and Acute Chronic Atrial Fibrillation The optimal strategy for stroke prevention in TAVR patients with preexisting atrial fibrillation is unknown. Patients without pre-existing atrial fibrillation in the PARTNER trial received aspirin 81 mg indefinitely with clopidogrel for three months. The American Association for Thoracic Surgery (AATS)/American College of Cardiology Foundation (ACCF)/Society for Cardiovascular Angiography and Interventions (SCAI)/Society of Thoracic Surgeons (STS) guidelines18 mention that clopidogrel can be continued for 3–6 months. The Canadian Cardiovascular Society (CCS) position statement19 recommends thienopyridine for 1–3 months. For patients with chronic atrial fibrillation, warfarin is substituted for clopidogrel.

Rodés-Cabau et al.17 analysed the evidence behind anticoagulation for patients with atrial fibrillation undergoing TAVR. They found that there was a “lack of uniformity regarding the choice of postprocedural antithrombotic treatment”. This was reflected in a German registry paper of 1,450 patients showing that 7 % of patients received aspirin and clopidogrel monotherapy, 11 % received aspirin or clopidogrel with an oral anticoagulant, 66 % of patients received dual antiplatelet therapy, and 16 % received triple therapy with aspirin, clopidogrel and an oral anticoagulant. The triple therapy was associated with an increased risk of composite of death, stroke, embolism or major bleeding (adjusted odds ratio 1.78, 95 % confidence interval [CI] 1.1– 2.9).20 It therefore seems that for patients with chronic atrial fibrillation who have received TAVR, the use of warfarin with dual antiplatelet therapy is associated with increased risk of bleeding.

New Onset Atrial Fibrillation What can be done for stroke prevention in new onset atrial fibrillation?

What is the necessary duration of atrial fibrillation that will mandate

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Table 1: Potential Risk Factors For Stroke Procedural Risk Factors Wire in atheromatous aorta

Post-procedural Risk Factors Age

Balloon valvuloplasty

Higher atherosclerotic burden

Valve positioning

Prior stroke

Duration of valve manipulation

Severe aortic insufficiency

Valve expansion

COPD

Post-dilation

Low BMI

Valve dislodgement

Diabetes

Smaller annulus valves (more calcium)

New onset atrial fibrillation

Air emboli

Chronic atrial fibrillation

Learning curve Information on potential risk factors for stroke collected from various studies.7–9,11–14 COPD = chronic obstructive pulmonary disease; BMI = body mass index.

anticoagulation? Should anticoagulation be started at one-hour of new onset atrial fibrillation or one-day of new onset atrial fibrillation?

The answer is unknown. This uncertainty in diagnosing burden of disease leads to uncertainty in prescribing appropriate stroke prophylaxis regimens.

Warfarin and Newer Anticoagulants As mentioned earlier, warfarin has been used for TAVR patients in the setting of atrial fibrillation. However, this comes with multiple issues. The first is a high risk of bleeding complications, 21 both major and minor. In addition, there are issues of compliance. Some studies have shown that only a third of all patients are eligible for warfarin, are taking warfarin in the community non-trial setting. 22 Finally, the amount of time that patients taking warfarin in clinical trials with therapeutic international normalised ratio (INR) has been less than ideal, up to 38.7 % of the time. In a real-life study, patients had non-therapeutic INR up to 50 % of the time.23,24 New anticoagulants, such as dabigatran, rivaroxaban and apixaban, provide great promise for stroke prophylaxis in patients with atrial fibrillation. These medications operate through mechanisms other than vitamin K antagonism, including oral direct thrombin inhibitor (dabigatran) and oral direct factor Xa inhibitor (rivaroxaban and apixaban). While the new medications were likely to decrease haemorrhagic stroke in published studies, they all are associated with an increase in major bleeding. In addition, they all have discontinuation rates of more than 20 % in a heavily controlled clinical trial setting.25–27 Causes for discontinuation include interactions with drugs, interactions with diet, polypharmacy, side effects, cost, nuisance bleeding or need for an invasive procedure. There has been no data looking at newer anticoagulants for chronic atrial fibrillation in patients after TAVR; however, the increased risk of bleeding and high non-compliance rate would be issues also applicable to this population.

Left Atrial Appendage Closure There have been multiple studies showing the benefit of LAA closure. The Watchman™ device (Boston Scientific, Natick MA, US) has significant positive data. Early issues of safety and treatment failures were addressed with continued access registry, late versus early analysis with Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT-AF), and the second randomised controlled Randomized Trial of LAA Closure vs Warfarin for Stroke/ Thromboembolic Prevention in Patients with Non-valvular Atrial Fibrillation (PREVAIL) trial, which all showed increasing rates of implant success with decreasing rates of vascular complications and

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Structural pericardial effusions needing intervention.28 In addition, the four-year analysis of the PROTECT-AF trial showed that LAA closure was superior to warfarin, specifically in the area of all-cause mortality.29 Finally, LAA occlusion was found to be effective in patients with contraindication to warfarin,30 tolerant of small peri-device leaks,31 cost-effective32 and correlated with an improvement in quality of life.33 The Amplatzer™ Cardiac Plug (ACP) system (St. Jude Medical, St. Paul, Minnesota, US) also has significant long-term safety and efficacy data.34–37 However, all of these patients enrolled in these trials had ‘non-valvular atrial fibrillation’. This definition is often, unfortunately, unclear. What exactly is valvular atrial fibrillation?

According to the European Society of Cardiology (ESC) 2012 Valvular Heart Disease Guidelines, “It is conventional to divide AF into cases which are described as ‘valvular’ or ‘non-valvular’. No satisfactory or uniform definition of these terms exists. In this guideline, the term valvular AF is used to imply that AF is related to rheumatic valvular disease (pre-dominantly mitral stenosis) or prosthetic heart valves”.

• • • •

TAVR procedural risk; risk of clot in the LAA; risk of clot on the valve; and risk of clot elsewhere.

LAA closure only affects the risk of clot in the LAA. As soon as the valve has been replaced in aortic stenosis, the risk of clot in the LAA should be similar to patients with ‘non-valvular’ atrial fibrillation. The atrium is not excessively dilated, such as in mitral stenosis or mitral regurgitation.

This would be the area where LAA occlusion may have an impact.

For the TAVR procedural risk, LAA closure does not have a significant impact. This may account to 50 % of strokes that happen in the first 30 days, as these occur in the first 24 hours. All steps of the procedure add to the risk, especially valve advancement and positioning.8 The key to success here may be smaller sheaths, better delivery systems and easier to position valves. Carotid protection systems may also provide a reduction in risk, but this has not yet been proven. In fact, placement of the carotid protection system can lead to an embolic risk or interference with the TAVI valve delivery system.7

Atrial Fibrillation and Valvular Heart Disease Do patients with degenerative aortic stenosis treated with TAVR still count as patients with ’valvular heart disease’? There is evidence to say that this may not be the case.

Firstly, the pathophysiological mechanism of atrial fibrillation in aortic stenosis is different than in other valvular lesions. For example, mitral regurgitation is associated with left atrial volume overload, and the left atrium is often enlarged. In aortic stenosis, there is left ventricular pressure overload, which leads to left atrial pressure overload; consequently, left atrial size is not the important outcome measure in aortic stenosis. Different valvular disorders affect the left atrium differently.38 Secondly, the original papers on the presence of clot in the LAA focused on the different presence of clots based on rheumatic and non-rheumatic valve disease; however, patients with rheumatic valve disease were more likely to have mitral stenosis as opposed to aortic valve disease. Blackshear et al.39 analysed the results of 23 studies, comparing a total of 3,504 patients with rheumatic valve disease and 1,288 patients without rheumatic valve disease. In this paper, there were found to be more LAA clots in the patients with non-rheumatic valve disease than in patients with rheumatic valve disease. Based on these findings, the idea arose that LAA obliteration may be an answer for atrial fibrillation without valvular heart disease. However, the vast majority of these valvular heart disease patients were patients with rheumatic mitral valve disease. It is a significant jump from patients with untreated rheumatic valvular heart disease to patients after TAVR. Finally, not all prosthetic valves are alike. Compared with mechanical valves, bioprosthetic valves have a lower risk of stroke, as low as 1.3 ± 0.3 %.40 With a different stroke rate, there is even more evidence that the valve replacement type plays a significant role in the overall anticoagulation strategy.

How Will Left Atrial Appendage Closure Decrease the Stroke Risk in Transcatheter Aortic Valve Replacement?

There are four main areas where there is risk of stroke in patients undergoing TAVR. These include:

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The risk of thrombus on the valve is difficult to estimate. The guidelines therefore point to aspirin (indefinitely) and clopidogrel (1–6 months), as listed in the ACCF/AATS/SCAI/STS guidelines41 and the CCS guidelines.19 Use of LAA closure to replace warfarin is not likely to change this risk, and dual antiplatelet strategy should be continued.

Finally, there can be clots in other areas. These include left atrium (outside of the LAA), left ventricle, aorta and carotids. TAVR may increase left-sided outflow and decrease stasis, which may decrease the risk of stroke from thrombus in the left atrium or left ventricle.

Use of smaller delivery systems or a transaortic/transapical strategy may also decrease risk of stroke from an atherosclerotic aorta. Risk of stroke from carotid artery disease would be similar.

LAA closure is therefore only likely to help decrease part of the overall stroke risk for these patients, but may help in patients with atrial fibrillation, where the risk of stroke from the LAA is increased.

Among Patients Receiving Transcatheter Aortic Valve Replacement, Who Are the Best Candidates for Left Atrial Appendage Occlusion?

The best candidates for LAA occlusion with TAVR are those with chronic atrial fibrillation and established contraindications to anticoagulation or a high bleeding risk (i.e. for both warfarin-ineligible and warfarin-eligible patients). Many patients who are candidates for TAVR have a high bleeding risk and are often withheld warfarin, making them preferential candidates for LAA occlusion.42 Other candidates include those patients with a high risk of drug–drug interaction or warfarin non-compliance. Patients with coronary artery stenting that need dual antiplatelet therapy also benefit from being off warfarin and being treated with LAA occlusion; this removes the risk of prolonged anticoagulation and/or triple therapy.

Patients that have to take warfarin for other reasons should not be candidates for LAA occlusion (e.g. patients with pulmonary embolism, deep vein thrombosis or haematological abnormality).

When should LAA closure happen? There is evidence that this can be done in the same setting as TAVR, as reported in 10 % of patients in

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Transcatheter Aortic Valve Replacement and Left Atrial Appendage Occlusion – A Stitch in Time?

a case series published by Nietlispach et al.43 Multiple case reports have also demonstrated safety of TAVR immediately followed by LAA occlusion.44–46 This takes advantage of transoesophageal guidance (and if used, general anaesthesia) for both procedures. In addition, the patients may be able to tolerate a LAA occlusion complication (e.g. embolisation45 and tamponade) if the aortic valve obstruction has been treated prior (personal communication, Fabien Nietlispach, 10 April 2014). Other centres have performed TAVI first with LAA occlusion to follow.47

1. Smith CR, Leon MB, Mack MJ, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Engl J Med , 2011;364:2187–98.

2. 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;363:1597–607.

3. Eggebrecht H, Schmermund A, Voigtländer T, et al., Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients, EuroIntervention , 2012;8:129–38.

4. Généreux P, Head SJ, Van Mieghem NM, et al., Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies, J Am Coll Cardiol , 2012;59:2317–26.

5. Nombela-Franco L, Webb JG, de Jaegere PP, et al., Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation, Circulation , 2012;126:3041–53.

6. Tay EL, Gurvitch R, Wijesinghe N, et al., A high-risk period for cerebrovascular events exists after transcatheter aortic valve implantation, JACC Cardiovasc Interv , 2011;4:1290–7.

7. Praz F, Nietlispach F, Cerebral protection devices for transcatheter aortic valve implantation: is better the enemy of good?, EuroIntervention , 2013;9 Suppl:S124–8.

8. Kahlert P, Al-Rashid F, Döttger P, et al., Cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study, Circulation , 2012;126:1245–55.

9. Erdoes G, Basciani R, Huber C, et al., Transcranial Dopplerdetected cerebral embolic load during transcatheter aortic valve implantation, Eur J Cardiothorac Surg , 2012;41:778–83; discussion 783–4.

10. Drews T, Pasic M, Buz S, et al., Transcranial Doppler sound detection of cerebral microembolism during transapical aortic valve implantation, Thorac Cardiovasc Surg , 2011;59:237–42.

11. Rodes-Cabau J, Dumont E, Boone RH, et al., Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches, J Am Coll Cardiol , 2011;57:18–28.

12. Astarci P, Glineur D, Kefer J, et al., Magnetic resonance imaging evaluation of cerebral embolization during percutaneous aortic valve implantation: comparison of transfemoral and trans-apical approaches using Edwards Sapiens valve, Eur J Cardiothorac Surg , 2011;40:475–9.

13. Fairbairn TA, Mather AN, Bijsterveld P, et al., Diffusionweighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation: assessment of predictive risk factors and the relationship to subsequent health status, Heart , 2012;98:18–23.

14. Nuis RJ, Van Mieghem NM, Schultz CJ, et al., Frequency and causes of stroke during or after transcatheter aortic valve implantation, Am J Cardiol , 2012;109:1637–43.

15. Stortecky S, Buellesfeld L, Wenaweser P, et al., Atrial fibrillation and aortic stenosis: impact on clinical outcomes among patients undergoing transcatheter aortic valve implantation, Circ Cardiovasc Interv , 2013;6:77–84.

16. Amat-Santos IJ, Rodés-Cabau J, Urena M, et al., Incidence, predictive factors, and prognostic value of new-onset atrial

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In the case of chronic atrial fibrillation, the TAVR should be performed first as this is the more clinically important intervention. In addition, there is no evidence to show that LAA closure will change the procedural stroke rate. LAA closure may take place immediately or early within the first month after TAVR to prevent intermediate and late stroke. For centres that plan to do both in the same setting, this requires careful patient selection, planning and operator experience. In this case, the dual antiplatelet therapy that is used for TAVR may also be used for post-LAA occlusion management. n

fibrillation following transcatheter aortic valve implantation, J Am Coll Cardiol , 2012;59:178–88.

17. Rodés-Cabau J, Dauerman HL, Cohen MG, et al., Antithrombotic treatment in transcatheter aortic valve implantation: insights for cerebrovascular and bleeding events, J Am Coll Cardiol , 2013;62:2349–59.

18. Tommaso CL, Bolman RM 3rd, Feldman T, et al., Multisociety (AATS, ACCF, SCAI, and STS) expert consensus statement: operator and institutional requirements for transcatheter valve repair and replacement, part 1: transcatheter aortic valve replacement, J Am Coll Cardiol , 2012;59:2028–42.

19. Webb J, Rodés-Cabau J, Fremes S, et al., Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement, Can J Cardiol , 2012;28:520–8.

20. Zeymer U, Zahn R, Gerckens U, et al., Antithrombotic therapy after transfemoral aortic valve implantation (TAVI). Potential hazard of triple-therapy, Eur Heart J , 2011;32(Abstract Supplement):900.

21. Hynes BG, Rodés-Cabau J, Transcatheter aortic valve implantation and cerebrovascular events: the current state of the art, Ann N Y Acad Sci , 2012;1254:151–63.

22. Stafford RS, Singer DE, National patterns of warfarin use in atrial fibrillation, Arch Intern Med , 1996;156:2537–41.

23. Gottlieb LK, Salem-Schatz S, Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice?, Arch Intern Med , 1994;154:1945–53.

24. Reynolds MW, Fahrbach K, Hauch O, et al., Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis, Chest , 2004;126:1938–45.

25. Connolly SJ, Ezekowitz MD, Yusuf S, et al., Dabigatran versus warfarin in patients with atrial fibrillation, N Engl J Med , 2009;361:1139–51.

26. Patel MR, Mahaffey KW, Garg J, et al., Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, N Engl J Med , 2011;365:883–91.

27. Granger CB, Alexander JH, McMurray JJ, et al., Apixaban versus warfarin in patients with atrial fibrillation, N Engl J Med, 2011;365:981–92.

28. Reddy VY, Holmes D, Doshi SK, et al., Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry, Circulation , 2011;123:417–24.

29. Reddy VY, Long term results of PROTECT AF: The mortality effects of left atrial appendage closure versus warfarin for stroke prophylaxis in AF, Presented at: Heart Rhythm Society 34th Annual Scientific Sessions, Denver, CO, US, 9 May 2013.

30. Reddy VY, Möbius-Winkler S, Miller MA, et al., Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology), J Am Coll Cardiol, 2013;61:2551–6.

31. Viles-Gonzalez JF, Kar S, Douglas P, et al., The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke

in Patients With Atrial Fibrillation) substudy, J Am Coll Cardiol , 2012;59:923–9.

32. Singh SM, Micieli A, Wijeysundera HC, Economic evaluation of percutaneous left atrial appendage occlusion, dabigatran, and warfarin for stroke prevention in patients with nonvalvular atrial fibrillation, Circulation , 2013;127:2414–23.

33. Alli O, Doshi S, Kar S, et al., Quality of life assessment in the randomized PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial of patients at risk for stroke with nonvalvular atrial fibrillation, J Am Coll Cardiol , 2013;61:1790–8.

34. Nietlispach F, Gloekler S, Krause R, et al., Amplatzer left atrial appendage occlusion: single center 10-year experience, Catheter Cardiovasc Interv , 2013;82:283–9.

35. Wiebe J, Bertog S, Franke J, et al., Safety of percutaneous left atrial appendage closure with the amplatzer cardiac plug in patients with atrial fibrillation and contraindications to anticoagulation, Catheter Cardiovasc Interv, 2014;83:796–802.

36. Horstmann S, Zugck C, Krumsdorf U, et al., Left atrial appendage occlusion in atrial fibrillation after intracranial hemorrhage, Neurology , 2014;82:135–8.

37. Meerkin D, Butnaru A, Dratva D, et al., Early safety of the Amplatzer Cardiac Plug for left atrial appendage occlusion, Int J Cardiol , 2013;168:3920–5.

38. Widgren V, Dencker M, Juhlin T, et al., Aortic stenosis and mitral regurgitation as predictors of atrial fibrillation during 11 years of follow-up, BMC Cardiovasc Disord , 2012;12:92.

39. Blackshear JL, Odell JA, Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation, Ann Thorac Surg , 1996;61:755–9.

40. Ruel M, Masters RG, Rubens FD, et al., Late incidence and determinants of stroke after aortic and mitral valve replacement, Ann Thorac Surg , 2004;78:77–83; discussion 83–4.

41. Holmes DR Jr, Mack MJ, Kaul S, et al., 2012 ACCF/AATS/SCAI/ STS expert consensus document on transcatheter aortic valve replacement, J Am Coll Cardiol , 2012;59:1200–54.

42. Pilgrim T, Wenaweser P, Windecker S, Meier B, Comprehensive “one stop-shop” percutaneous cardiac intervention, Cardiovascular Medicine , 2010;13:171–3.

43. Nietlispach F, Glökler S, Khattab A, et al., Percutaneous left atrial appendage closure, Eur Geriatr Med , 2012;3:308–11.

44. Guérios EE, Wenaweser P, Meier B, Left ventricular guidewire pacing for transcatheter aortic valve implantation, Catheter Cardiovasc Interv, 2013;82:E919–21.

45. Attinger-Toller A, Luscher TF, Landmesser U, Nietlispach F, Catch me if you can, Eur Heart J , 2014;35:903.

46. Attinger-Toller A, Haager PK, Hans R, et al., To do or not to do? Changing paradigms: value of balloon-sizing and left atrial appendage occlusion, Cardiovascular Medicine, 2014;17:21–3.

47. Bogunovic N, Scholtz W, Prinz C, et al., Percutaneous closure of left atrial appendage after transcatheter aortic valve implantation - an interventional approach to avoid anticoagulation therapy in elderly patients: TAVI and closure of LAA to avoid warfarin therapy, EuroIntervention , 2012;7:1361–3.

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Transcatheter Aortic Valve Implantation Without General Anaesthetic S i m o n Ke n n o n a n d Z h a n L i m London Chest Hospital, Cardiology Department, London, UK

Abstract Transcatheter aortic valve implantation (TAVI) procedures are increasingly being performed under local anaesthetic, generally with sedation. Operators hope this will reduce mortality, morbidity and length of hospital stay. A general anaesthetic (GA), however, although involving intrinsic risk, permits transoesophageal echocardiogram (TOE) imaging throughout a procedure as well as eliminating patient anxiety, pain and movement. This article reviews the published literature, all single-centre experiences, comparing TAVI procedures performed with and without a GA. Procedures performed without GA are generally shorter with reduced length of stay compared with those performed under GA. There is no evidence of any difference in outcomes.

Keywords Transcatheter aortic valve implantation, local anaesthetic, sedation, transfemoral, outcomes, length of stay, contrast used, procedure length, intensive therapy unit stay Disclosure: Simon Kennon has received conference sponsorship from Edwards Lifesciences and Medtronic.

Received: 13 April 2014 Accepted: 20 April 2014 Citation: Interventional Cardiology Review, 2014;9(2):130–2 Correspondence: Dr Simon Kennon, London Chest Hospital, Cardiology Department, Bonner Road, London, E2 9JX, UK. E: simon.kennon@radcliffecardiology.com

The main advantages of transcatheter aortic valve implantation (TAVI) over conventional aortic valve replacement (cAVR) surgery are the avoidance of sternotomy, heart lung bypass and prolonged procedure times. These advantages facilitate early mobilisation and discharge – important both clinically and in terms of resource utilisation. Balanced against this, TAVI is less predictable than cAVR – evidenced by valve embolisation, the requirement for implantation of more than one prosthesis and conversion to cAVR – and there is a higher rate of significant aortic regurgitation post-procedure.1,2 While technical advances in valve and delivery system design are reducing unpredictability and residual aortic regurgitation, TAVI operators are increasingly trying to reduce the invasiveness to further reduce procedural mortality and morbidity, and length of stay. Key elements in this are the move from surgical cut down to the use of percutaneous closure devices for vascular access and from general anaesthetic (GA) to local anaesthetic (LA) with sedation.

Most centres when starting TAVI programmes perform procedures under GA. The primary advantage of GA is the ability to have a transoesophageal echocardiogram (TOE) probe in place throughout the procedure. The TOE probe is useful for allowing early recognition of complications, for positioning the prosthesis and for the assessment of residual aortic regurgitation. In addition, a GA eliminates patient discomfort, anxiety and movement during the procedure. However, a GA involves intrinsic risk in the form of haemodynamic instability and the need for intubation and ventilation.

Intuitively one would expect patients undergoing TAVI under LA to have a shorter recovery period post-procedure, to mobilise earlier and have a shorter length of stay as compared with those patients undergoing the procedure under GA. Published data comparing TAVI

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under GA and LA are few and far between, perhaps because TAVI is a relatively new procedure, but it may also be that many centres regard the superiority of LA as self-evident. However, before there is a general shift over to LA, it is important that we are sure the proposed advantages of LA are not offset by higher incidence of aortic regurgitation, prolonged screening times, higher contrast loads and procedural complications relating to patient movement.

This paper reviews the currently available literature. Key data are documented in Table 1. For the sake of brevity, procedures not performed under a GA are referred to as LA procedures. In general, however, as well as local anaesthetic agents being used at access sites, a combination of opiates (often remifentanil) and benzodiazepines are used for the purposes of sedation. Additionally, regional anaesthesia (e.g. epidural) is used in some cases.

A single meta-analysis3 including seven studies4–10 has recently been published by Fröhlich et al. They found that procedures performed under LA were significantly shorter than those performed under GA, and that length of stay was shorter. No other differences in procedures or outcomes were demonstrated, perhaps reflecting the absence of randomised studies as well as the marked heterogeneity of the included studies.

Other than this meta-analysis, published data about TAVI under LA are limited to single-centre experiences. Publications can loosely be divided into two categories. Firstly, there are registries of cases performed under LA where outcome data are compared with those from other published studies in which GA is used in all or the majority of cases. These studies are not included in the meta-analysis.

Secondly, there are papers where cases performed in the single centre under both LA and GA are compared directly.

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Transcatheter Aortic Valve Implantation Without General Anaesthetic

Table 1: Key Data for Procedures with and without General Anaesthetic Paper Cohort Size 30 Day Mortality

Contrast Used (ml)

Procedure Time (minutes)

Length of Stay** (days)

Intensive Therapy Unit Length of Stay

LA GA LA GA LA GA LA GA LA GA LA GA

Greif

461

0

5.0 %

NA

171.28 ±

NA

131.03 ±

NA

10.13 ±

NA

2.83 ±

NA

101.29 40.89 6.22 2.84 days Durand

151

0

6.6 %

NA

185.20 ±

NA

136.60 ±

NA

7.00 (5–9)

NA

78.20 ±

93.5 ±

8.10 ±

12.2 ±

3.30 ±

3.9 ±

30.90*

26.9*

6.50*

8.3*

1.5 days*

2.2 days*

80.00

120.0

8.50

15.5

3.00 (2–4)

3.0 (2–5)

96.40

47.00

Yamamoto

184.70 ±

180.7 ±

99.60

88.0

130

44

7.8 %

6.7 %

Dehédin

34

91

9.0 %

8.0 %

(67–102)* (90–140)* (7–14.5)* (10–24)* days days Motloch

41

33

12.2 %

9.1 %

112.30 ±

167.6 ±

8.80 ±

11.9 ±

0.70 ±

1.1 ±

4.90 5.2 0.90 1.9 0.20 0.3 days Ben-Dor

70

22

4.2 %

18.1 %*

Covello

42

27

0.0 %

64.50 ±

51.6 ±

91.00

155

5.00 (3–9)* 7.5

56.00 39.9 (74–150)* (120–240)*

0.0 %

8.70 ±

27 (23–70)

72 (28–108)

(4.5–14)* hours* hours* 9.2 ±

15.30 ±

31.6 ±

1.60 1.9 2.80 hours 2.7 hours Behan

9

3

0.0 %

33.3 %

105.00

135.0

3.00 (2–8)

4.0 (3–6)

0 days

1 day

(95–130) (85–205) *statistically significant **Durand, Ben-Dor, Greif are procedure to discharge. Yamamoto, Dehédin, Greif, Motloch, Covello and Behan are length of hospital stay. Blank areas = data not provided. GA = general anaesthetic; LA = local anaesthetic; NA = not applicable.

In the former group, Greif et al have published their experience of a large cohort (n=461) of patients from a single centre using both Sapien and CoreValve prostheses where LA is the default for transfemoral procedures. They have provided detailed procedural information including X-ray duration, procedure duration, volume of contrast used, inotrope requirement and rates of conversion to GA, as well as standard outcomes such as degree of aortic regurgitation, vascular complications, length of stay and mortality. They have gone on to compare their outcomes with those from other studies including Placement of aortic transcatheter valves (PARTNER) A&B,1,2 the German Aortic Valve Registry (GARY)12 and the French Aortic National CoreValve and Edwards (France 2) Registry,13 and have demonstrated similar rates of death, stroke and vascular complications. Durand et al.14 published their single-centre experience of 151 Sapien and Sapien XT cases in 2012, again documenting detailed procedural information as well as standard outcomes that are compared with those from other studies including PARTNER,1,2 the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry15 and Vancouver TF.16 This latter paper by Durand et al. confirms that both surgical cut down to the femoral artery and the use of percutaneous closure devices are compatible with the use of LA; all cases using the Sapien prosthesis involved surgical cut down whereas a Prostar closure device was used in 97 % of cases involving the Sapien XT prosthesis.

These two papers provide indirect evidence of the efficacy and safety of TAVI procedures performed under LA in a total of over 600 patients. They also document the important procedural data points that are required to make useful comparisons between the two types of anaesthesia.

In the second group of papers there is direct comparison between procedures performed under LA and GA within the same institution.

The earliest and smallest study by Behan et al.4 was published in 2008.

Twelve consecutive patients undergoing CoreValve procedures were included – nine under LA and three under GA. Not surprisingly, there were no differences between the groups characteristics or outcomes, but they documented one conversion from LA to GA and one death

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(from respiratory failure) in the GA group. Dehédin et al.5 compare their experience with TAVI under GA (n=91) and under LA (n=34) after a decision was made in March 2010 that LA should be the default for transfemoral procedures. Importantly, preoperative characteristics were similar in both groups, but LA was associated with shorter procedures, shorter length of stay and lower rates of inotrope requirement. Motloch et al.6 have presented their experience with general and LA in an institution where an individualised decision is made. As one might expect, patients undergoing TAVI under LA had higher STS scores and they were also more likely to present with pulmonary hypertension and renal impairment. Despite these adverse factors, procedures under LA were shorter, inotropes were used less commonly and patients mobilised earlier. There were no differences in outcomes or complication rates, although numbers were small (GA 33, LA 41). Intermediate between Dehédin and Motloch, Yamamoto et al.7 report their experience where initially GA (n=44) was generally used but with increasing experience the majority of transfemoral TAVI procedures were performed under LA (n=130). Procedures under LA were associated with shorter ITU and total length of stay. Conversion from local to general anaesthetic occurred in 4.6 % of cases; Durand et al. quote a figure of 3.3 % for conversion to GA, and in both cohorts conversion followed major complications such as tamponade, cardiac arrest, annular and vascular rupture. Ben-Dor et al.8 had an 11 % conversion rate in a cohort of 92 Sapien procedures, of whom 76 % were performed under LA. They noted higher logistic EuroSCORE and a higher incidence of previous stroke in those undergoing procedures under LA. Surgical cut down was less common under LA and procedure duration shorter. In the meta-analysis

by Fröhlich et al. the overall rate of conversion from LA to GA was 6.3 %.

Further information about TAVI under LA is indirectly provided by studies assessing non-femoral access routes. Azmoun et al.17 have reported promising outcomes in a small (n=19) cohort of high-risk patients undergoing TAVI via the carotid artery under LA. Petronio et al.18 have reported outcomes in a cohort of procedures performed via the subclavian artery. LA was used with increasing frequency as operators became more familiar with the procedure and this shift in practice was not associated with any change in outcomes.

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Structural In summary, the use of LA for TAVI procedures has the potential to significantly reduce resource consumption. The available data consistently supports this and there has been no suggestion that this comes at the price of unfavourable outcomes. Data, however, are few and far between, largely single-centre and all registry (nonrandomised) based, with all the problems inherent in these sorts of

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;21:363.

2. Smith CR, Leon MB, Mack MJ, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Engl J Med, 2011;9:2187–98.

3. Fröhlich GM, Lansky AJ, Webb J, et al., Local versus general anesthesia for transcatheter aortic valve implantation (TAVR) - systematic review and meta-analysis, BMC Med , 2014;12(1):41.

4. Behan M, Haworth P, Hutchinson N, et al., Percutaneous aortic valve implants under sedation: our initial experience, Catheter Cardiovasc Interv, 2008,72:1012–5.

5. Dehédin B, Guinot PG, Ibrahim H, et al., Anesthesia and perioperative management of patients who undergo transfemoral transcatheter aortic valve implantation: an observational study of general versus local/regional anesthesia in 125 consecutive patients, J Cardiothorac Vasc Anesth , 2011;25(6):1036–43.

6. Motloch LJ, Rottlaender D, Reda S, et al., Local versus general anesthesia for transfemoral aortic valve implantation, Clin Res Cardiol , 2012;101(1):45–53.

7. Yamamoto M, Meguro K, Mouillet G, et al., Effect of local

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publications. Although a dedicated randomised trial seems unlikely, data from national databases and subgroup analyses of international randomised trials should provide sufficient information for TAVI operators to decide if LA should be the default for the relevant access routes and, if this is the case, who are the exceptions where a GA is required. n

anesthetic management with conscious sedation in patients undergoing transcatheter aortic valve implantation, Am J Cardiol , 2013;111(1):94–9.

8. Ben-Dor I, Looser PM, Maluenda G, et al., Transcatheter aortic valve replacement under monitored anesthesia care versus general anesthesia with intubation, Cardiovasc Revasc Med, 2012,13:207–10.

9. Linke A, Bosmans J, Gerckens U, et al., Local vs. General Anaesthesia: Impact on the outcomes of transcatheter aortic valve implantation: insights from the multicentre ADVANCE study, Eur Heart J , 2012;33:1098.

10. Covello RD, Ruggeri L, Landoni G, et al., Transcatheter implantation of an aortic valve: anesthesiological management, Minerva Anestesiol, 2010,76:100–8.

11. Greif M, Lange P, Näbauer M, et al., Transcutaneous aortic valve replacement with the Edwards SAPIEN XT and Medtronic CoreValve prosthesis under fluoroscopic guidance and local anaesthesia only, Heart, 2014;100(9):691–5.

12. Hamm CW, Möllmann H, Holzhey D, et al., The German Aortic Valve Registry (GARY): in-hospital outcome, Eur Heart J, 2013 [Epub ahead of print].

13. Gilard M, Eltchaninoff H, Iung B, et al., Registry of transcatheter aortic-valve implantation in high-risk patients,

N Engl J Med, 2012;366:1705–15.

14. Durand E, Borz B, Godin M, et al., Transfemoral aortic valve replacement with the Edwards SAPIEN and Edwards SAPIEN XT prosthesis using exclusively local anesthesia and fluoroscopic guidance: feasibility and 30-day outcomes, JACC Cardiovasc Interv, 2012;5:461–7.

15. Thomas M, Schymik G, Walther T, et al., Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: A European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve, Circulation, 2010;122:62–9.

16. Rodés-Cabau J, Webb JG, Cheung A, et al., Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience, J Am Coll Cardiol, 2010;55:1080–90.

17. Azmoun A, Amabile N, Ramadan R, et al., Transcatheter aortic valve implantation through carotid artery access under local anaesthesia, Eur J Cardiothorac Surg , 2014 [Epub ahead of print].

18. Petronio A, De Carlo M, Bedogni F, et al., Safety and Efficacy of the Subclavian Approach for Transcatheter Aortic Valve Implantation With the CoreValve Revalving System, Circ Cardiovasc Interv , 2010;3:359–66.

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Call for Submissions Interventional Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free access to the journal, please visit: www.ICRjournal.com

Radcliffe Cardiology Interventional Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews from across the speciality, visit: www.radcliffecardiology.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Glasgow, UK

September 13-17

CIRSE 2014 The CIRSE Annual Meeting is by far the largest and most significant platform for minimally invasive, image-guided medicine, welcoming over 6,500 delegates from 94 countries in 2013.

CIRSE 2014 will offer over 250 hours of scientific and educational content transmitted through a range of formats, including special focus sessions, hands-on workshops, interactive case discussions, electronic posters, debates, a state-of-the-art technical exhibition and much more.

Main topics • • • • • •

Vascular Interventions Transcatheter Embolisation Non-Vascular Interventions Interventional Oncology Neurointerventions IR Management

Now! r e t s i Reg ird Fees Early B ilable ava For more information please visit us at: www.cirse.org Check out highlights from past congresses and the latest Society updates here: www.esir.org – the largest educational platform in the field facebook.com/CIRSEsociety youtube.com/CIRSEsociety

SE C eR a rs y

C RSE

For you’re a jolly good Fellow!

It is CIRSE Members, Fellows and Committee Members that make up our Society. To celebrate 30 years of this extraordinary community, we’re offering our Members a specially reduced registration fee of €300 for CIRSE 2014. But this is only available until June 5, so don’t miss out!

Cardiovascular and Interventional Radiological Society of Europe

Spotlight: Innovation and the Heart

Discover the Scientific Programme www.escardio.org/ESC2014programme

â&#x20AC;˘ Early Registration deadline : â&#x20AC;˘ Late Registration deadline :

31 May 31 July

5 days of scientific Sessions 150 CV Topics 30 000 healthcare professionals from 140 countries 11 400+ abstracts submitted 500 expert sessions 200 exhibiting companies & all year long on ESC Congress 365

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