ICR 10.3 by Radcliffe Cardiology

Volume 10 • Issue 3 • Winter 2015

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Left Main Stem Percutaneous Coronary Intervention – Data and Ongoing Trials Rajiv Rampat and David Hildick-Smith

Managing the Antithrombotic Therapy After Percutaneous Coronary Intervention in Patients on Oral Anticoagulation Darshni Arishta Jhagroe and Jurriën Maria ten Berg

Review of Minimally Invasive Aortic Valve Surgery Ricardo Boix-Garibo, Mohammed Mohsin Uzzaman and Vinayak Nilkanth Bapat

Computed Tomography for Structural Heart Disease and Interventions Pascal Thériault-Lauzier, Marco Spaziano, Beatriz Vaquerizo, Jean Buithieu, Giuseppe Martucci and Nicolo Piazza

Intraoperative view of a sutureless aortic valve replacement via upper hemisternotomy

Small anatomy of the sinus of Valsalva

Pre-transcatheter aortic valve replacement analysis of the aortic root

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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27/09/2015 12:29

Volume 10 • Issue 3 • Winter 2015

www.ICRjournal.com

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

Section Editor – Structural

Section Editor – Cononary

Darren Mylotte

Position vacant

Galway University Hospitals, Galway

Expressions of interest should be sent to the Managing Editor (commeditor@radcliffecardiology.com)

Fernando Alfonso

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

A Pieter Kappetein

Thoraxcenter, Erasmus University Medical Center, Rotterdam

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

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Jeffrey Popma

Athens Euroclinic, Athens, Greece

Sergio Baptista

Tim Kinnaird

Beth Israel Deaconess Medical Center, Boston

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

University Hospital of Wales, Cardiff

Andrew SP Sharp

Ajay Kirtane

Royal Devon and Exeter Hospital and University of Exeter, Exeter

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

Ferrarotto Hospital, Catania

Olivier Bertrand

Quebec Heart-Lung Institute, Laval University, Quebec

Didier Locca

Lutz Buellesfeld

Roxana Mehran

Lausanne University Hospital, Lausanne

Elliot Smith London Chest Hospital, Barts Health NHS Trust, London

Lars Søndergaard

University Hospital, Bern

Mount Sinai Hospital, New York

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Jonathan Byrne

Thomas Modine

Gregg Stone

King’s College Hospital, London

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

CHRU de Lille, Lille

Antonio Colombo

Jeffrey Moses

Justin Davies

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

San Raffaele Hospital, Milan Imperial College NHS Trust, London

Marko Noc

Carlo Di Mario

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Royal Brompton & Harefield NHS Foundation Trust, London

Keith Oldroyd

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne

Sameer Gafoor

CardioVascular Center, Frankfurt

Juan Granada

CRF Skirball Research Center, New York

Design & Production Tatiana Losinska Publishing Director Liam O’Neill

Golden Jubilee National Hospital, Glasgow

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

Nicolas Van Mieghem Erasmus University Medical Center, Rotterdam

Renu Virmani CVPath Institute, Maryland

Mark Westwood

Crochan J O’Sullivan Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Nicolo Piazza

Nina C Wunderlich

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

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Digital Commercial Manager Ben Sullivan • Account Executive Ryan Challis Managing Director David Ramsey • Commercial Director Mark Watson •

Managing Editor Lindsey Mathews commeditor@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

Cover image Human heart for medical study © angelhell | istockphoto.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. © 2015 All rights reserved

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

Aims and Scope • Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice. • Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Interventional Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • Interventional Cardiology Review is a tri-annual journal comprising review articles, editorials, and case reports. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Interventional Cardiology Review is 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 Section Editors and 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, Section Editors 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 by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, 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: commeditor@radcliffecardiology.com. The ‘Instructions to Authors’ information is available for download at www.ICRjournal.com.

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

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

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

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

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Contents

Foreword 1 30

Simon Kennon, Editor-in-Chief, ICR

Coronary 1 32

Left Main Stem Percutaneous Coronary Intervention – Data and Ongoing Trials

Rajiv Rampat and David Hildick-Smith

1 36

Twelve Months Dual Antiplatelet Therapy after Drug-eluting Stents – Too Long, too Short or Just Right?

Mohammad Sahebjalal and Nick Curzen

1 39

Managing the Antithrombotic Therapy After Percutaneous Coronary Intervention in Patients on Oral Anticoagulation

Darshni Arishta Jhagroe and Jurriën Maria ten Berg

1 42

Spontaneous Coronary Artery Dissection

Jacqueline Saw

Structural 1 44

Review of Minimally Invasive Aortic Valve Surgery

Ricardo Boix-Garibo, Mohammed Mohsin Uzzaman and Vinayak Nilkanth Bapat

1 49

Computed Tomography for Structural Heart Disease and Interventions

1 55

Transcatheter Aortic Valve Implantation for Patients with Smaller Anatomy

Pascal Thériault-Lauzier, Marco Spaziano, Beatriz Vaquerizo, Jean Buithieu, Giuseppe Martucci and Nicolo Piazza

Yusuke Watanabe and Ken Kozuma

Supported Contributions 1 58

Patient-tailored Drug-eluting Stent Choice – A Solution for Patients with Diabetes

Katrina Mountford

1 62

Absorbable Polymer Technology – Viable Solutions for Unmet Needs in PCI

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Katrina Mountford

INTERVENTIONAL CARDIOLOGY REVIEW

01/10/2015 19:52

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16/09/2015 02:56

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.

his is the third and last issue of Interventional Cardiology Review in 2015. It has been a year of consolidation rather than breakthrough. Important trials relating to transcatheter aortic valve implantation (TAVI), bifurcations and chronic total occlusions (CTOs) are ongoing with results

having the potential to transform standard practice in both coronary and structural interventions. Various technologies for percutaneous mitral valve intervention remain under intense scrutiny; the prevalence of mitral incompetence makes this an important field, but the complexity of the interaction between the mitral valve and the left ventricle – which mitral interventions attempt to repair or replace – has made progress in this field slow. Interventional Cardiology Review aims to deliver expert commentary on all developments in the field. The world of TAVI remains dominated by the need for results of randomised trials comparing outcomes following TAVI and conventional aortic valve replacement in intermediate risk patients. In the absence of any such data, it is perhaps not surprising that articles relating to coronary, rather than structural, interventions dominate this issue – and that of the three ‘structural’ articles, one relates to (minimally invasive) aortic valve surgery. This article, contributed by Boix-Garibo et al, provides welcome evidence that advances in transcatheter interventions can stimulate developments in surgical procedures, and is a valuable update for all cardiologists who refer patients for aortic valve intervention. Excellent articles on TAVI in patients with small anatomy and the use of computed tomography assessment to guide structural interventions complete the structural section of this issue. In the coronary section Rampat and Hildick-Smith provide a timely review of existing data and ongoing trials relating to left main stem interventions. There is no consensus on how to treat spontaneous coronary artery dissections, but Saw analyses and summarises the published experience in this field. I would like to thank all contributors to the 2015 volume of Interventional Cardiology Review. I look forward with keen anticipation to 2016. n

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01/10/2015 20:07

ral Course e h p ri e p l a n o ti a rn te in t rs The fi gists for interventional cardiolo

COME AND JOIN US! The Course’s «raison d’être» In light of so many patients with untreated peripheral disease, the PCR Istanbul Peripheral Course aims to increase the proficiency of interventional teams, across the world, to solve the clinical problems of this specific population. Crafted by and for interventional cardiologists, the Course’s intent is to facilitate capability and capacity building, responding to demand for education from an interventional audience. Participant profile: interventional cardiologists, worldwide g Interventional cardiologists and other vascular specialists interested in developing and expanding their peripheral interventional programme g Allied professionals involved in peripheralinterventions

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Course objectives Attend this Course if you want to learn how to: g Review patient selection and indications for peripheral procedures g Master all the phases of peripheral procedures including: - access routes - selection and use of dedicated tools and techniques - complications prevention and management Founding Course Directors Alberto Cremonesi, Ömer Göktekin Course Co-Director Thomas Zeller Simultaneous translation into Turkish will be provided

Come to Istanbul and dialogue with your peers, from around the world www.pcristanbulperipheral.com Untitled-1 173

16/09/2015 02:59

Coronary

LE ATION.

declare.

Left Main Stem Percutaneous Coronary Intervention – Data and Ongoing Trials Rajiv Rampat and David Hildick-Smith Sussex Cardiac Centre, Brighton and Sussex University Hospitals, Brighton, UK

Abstract Left main stem (LMS) disease is associated with significant morbidity and mortality. Traditionally coronary artery bypass grafting (CABG) has been the gold standard for treatment of these lesions. However over the past decade, percutaneous coronary intervention (PCI) has assumed a more prominent role in the treatment of LMS disease. With the advent of newer drug-eluting stents (DES) with an improved risk factor profile, better intravascular imaging modalities and careful patient selection, the use of PCI in this cohort is expanding. We review the current data to support this and discuss the on-going trials that will hopefully shed more light into the management of this complex disease.

Keywords Left main stem, percutaneous intervention, coronary artery bypass graft Disclosure: The authors have no conflicts of interest to declare. Received: 6 June 2015 Accepted: 1 September 2015 Citation: Interventional Cardiology Review, 2015;10(3):132–5 Correspondence: David Hildick-Smith, Sussex Cardiac Centre, Brighton and Sussex University Hospitals, Brighton, UK, BN2 5BE. E: david.hildick-smith@bsuh.nhs.uk

Left main stem (LMS) disease is identified in up to 5 % of diagnostic angiography cases.1 It has major prognostic significance due to the proportion of myocardium at risk. Many years ago, the Coronary Artery Surgery Study (CASS) registry demonstrated the superiority of coronary artery bypass grafting (CABG) over medical therapy with a 5-year mortality reduction from 43 % to 16 % in symptomatic patients.2 Since the advent of coronary angioplasty, interventional cardiologists have sought to assess the role of percutaneous treatment of LMS disease. Advances in stent technology, implantation techniques, ancillary imaging and pharmacotherapy have increasingly made this prospect a reality.

Early Experience The third patient treated by Andreas Gruntzig back in 1979 had LMS balloon angioplasty. The technical result was satisfactory but the patient unfortunately died suddenly 4 months post-procedure.3 In the 1980s, the limitations of ‘plain old balloon angioplasty’ (POBA) in the treatment of LMS disease became apparent. O’Keefe and colleagues showed a 64 % 3-year mortality rate when LMS disease was treated with balloon angioplasty4 and the practice was almost wholly abandoned. Interest in percutaneous treatment was only revived with the introduction of bare metal stents (BMS) and the advent of newer anti-platelet therapies aimed at reducing in-stent restenosis (ISR) and thrombosis. In the 1990s, promising LMS stent results were published though most stemmed from single centres. Silvestri et al. reported a 1-year survival of 89 % in a high-risk subgroup of patients,5 while Park et al. reported a 91 % 3-year survival rate in a multicentre study.6 The Unprotected Left Main Trunk Intervention Multi-Center Assessment (ULTIMA) registry evaluated the procedural and clinical outcomes after unprotected LMS percutaneous coronary intervention (PCI) was undertaken in 25 centres.7 This showed an overall 24 % 1-year mortality with a better outcome in

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low-risk groups and only a 3.4 % mortality rate at 1 year. As drug-eluting stents (DES) entered the interventional arena, several centres began reporting their experience in LMS lesions. A systematic review of 1,278 patients by Biondi-Zoccai et al. in 2008 showed that PCI was associated with a 5.5 % risk of death on average and a major adverse cardiac event (MACE) rate of 10.6 %.8

Comparison of Percutaneous Coronary Intervention with Coronary Artery Bypass Graft Registries Evidence from the early registries comparing PCI versus CABG suggested that PCI and CABG had a similar MACE rate.9,10 The two observations that emerged were a higher risk of a peri-procedural cerebrovascular accident (CVA) in the CABG group and a higher incidence of target lesion revascularisation (TLR) in the PCI group. The Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization (MAIN-COMPARE) registry, with data on a total of 2,240 patients, showed comparable outcomes at 5 years though the need for repeat revascularisation with PCI was again highlighted.11 Given the limitations of registry data, more robust evidence was needed to confirm or refute this observation. This spurred the development of randomised controlled trials (RCTs) to gain further insight into the validity of PCI as a viable therapeutic option.

Data from Randomised Controlled Trials Four RCTs have specifically looked at the cohort of patients with LMS disease to this day. The Study of Unprotected Left Main Stenting versus Bypass Surgery (LE MANS) was the first RCT and enrolled 105 patients with significant

27/09/2015 13:03

Left Main Stem Percutaneous Coronary Intervention

LMS disease (defined as >50 % stenosis angiographically).12 The primary endpoint was the change in left ventricular ejection fraction (LVEF) at 12 months, while the secondary endpoint was a major adverse cardiac and cerebrovascular event (MACCE) at 30 days and 1 year. Surprisingly, there was a statistically significant improvment in LVEF with patients treated with PCI versus CABG (58 % versus 54 %). PCI was also associated with a lower MACE rate at 30 days (2 % versus 13 %) with a MACE being equivalent at 1 year in the two groups. The study did have a number of limitations, including a small sample size, high use of BMS and a lower than contemporary use of left internal mammary artery (LIMA) grafts.

Meta-analysis

The Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial remains to this day the largest RCT to date to compare PCI to CABG in LMS disease.13 The LMS subset consisted of 705 patients randomised to receiving either the first-generation TAXUS (Boston Scientific Corporation, US) DES or CABG. The primary endpoint of MACE at 1 year was comparable with 15.8 % for PCI versus 13.7 % for CABG. However, when the cohorts were further subdivided into categories based on lesion complexity, it became apparent that CABG was more favourable for the more complex lesions. The SYNTAX score was developed to objectively quantify lesion complexity and has been fully described elsewhere.14 Stratification into tertiles of syntax score (0–22, 23–32 and >32) revealed equivalent MACCE in the lower

Influence of Stent Type/Lesion Location and Intravascular Imaging

two tertiles, but a clear superiority of CABG in the highest tertile. The 5-year follow-up results were published in 2014.15 The results bear a similar trend to the 1-year follow-up with similar outcomes across the whole cohort (36.9 % PCI versus 31 % CABG; P=0.12) but a statistically greater benefit of CABG in the highest risk group based on lesion complexity.

compared second-generation zotarolimus-eluting stent (ZES) and everolimus-eluting stent (EES) and once again showed similar clinical and angiographic outcomes at 1 year.21 Thus, the types of DES from a similar generation do not seem to influence outcome.

While the SYNTAX trial remains the best evidence-based RCT on revascularisation strategy, it is important to bear in mind that 45 % of patients were excluded from randomisation at the outset due to the complexity of coronary disease. Out of that group, 85 % went on to have CABG. So the evidence we have is from a pre-selected population and this has to be taken into consideration when evaluating whether PCI is an appropriate therapeutic option. The Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PreCOMBAT) trial was a non-inferiority trial randomising 600 patients with LMS disease to either a first-generation Cypher (Cordis Coporation, US) DES or CABG.16 Once again the primary endpoint was MACCE at 1 year. The trial was designed to test whether PCI was non-inferior and indeed proved the non-inferiority of the percutaneous option at both 1-year and 2-years follow-up.

Athappan et al. published a meta-analysis of first-generation DES versus CABG in 2013.18 The authors included 21 observational studies and three RCTs involving a total of 14,203 patients. The MACE rates did not differ between the PCI and CABG group up to 5 years though as has been previously noted, PCI was associated with a lower rate of stroke and higher rate of target vessel revascularisation (TVR). When the cases were stratified according to the SYNTAX score, the results were consistent with those of the main SYNTAX trial with comparable results for the lower two tertiles but a clear superiority of CABG for the highest group.

Stent Type If PCI is to be undertaken in LMS disease, it is crucial to minimise ISR and thrombosis. A meta-analysis by Pandya et al. comprising 44 studies, showed that DES were associated with a better outcome than BMS.19 The Intracoronary Stenting and Angiographic Results: DrugEluting Stents for Unprotected Coronary Left Main Lesions (ISAR LEFT MAIN) trials have compared different types of DES. The ISAR LEFT MAIN study compared the two first-generation DES (Cypher sirolimus-eluting stent [SES] and Taxus paclitaxel-eluting stent [PES]) and showed similar outcomes with both types of stents.20 The ISAR-LEFT MAIN 2 study

Lesion Location In an analysis of the Drug-Eluting Stent For Left Main Coronary Artery Disease (DELTA) registry comparing ostial/mid-shaft lesion versus distal lesions, Naganuma et al. demonstrated a higher rate of TLR with distal lesions.22 This primarily drove the higher MACE rates and while there was a trend towards higher mortality and MI, this was not sustained after propensity score matched analysis. Distal bifurcation lesions present a particularly challenging anatomy to treat. Notwithstanding the increased complexity of such lesions, no technique has been standardised as the technique of choice in LMS bifurcation treatment. In an analysis of the cohort from the ISARLEFT MAIN study, the need for multiple stents was an independent predictor of adverse MACE.23 There seemed to be a better outcome with the use of the Culotte technique as opposed to the T-stent technique with an ISR rate of 21 % and 56 % and a TLR rate of 15 % and 56 %, respectively.

Intravascular Ultrasound Boudriot et al. studied a smaller sample group of 201 patients and unlike the previous studies, PCI failed to achieve non-inferiority of MACE at 1 year.17 Excess MACE was driven by target vessel revascularisation. Unusually for this type of comparison, stroke was not included as a clinical endpoint, which may well have contributed to the end result. The results from the RCTs would support PCI as a reasonable alternative in the treatment of LMS disease but the studies have been hampered by limitations. These include relatively small sample sizes, different clinical endpoints among studies and the use of earlier generation DES. This has made it difficult to precisely define where PCI stands.

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The potential catastrophic consequences of stent thrombosis or restenosis in the context of a treated LMS lesion place an even stronger emphasis on appropriate stent sizing and apposition. The use of intravascular ultrasound (IVUS)-guided PCI in this context has never been formally investigated in an RCT, but data from registries suggest improved outcomes with the use of adjunctive intravascular imaging. Park et al. compared the use of IVUS-guided treatment of LMS lesions with conventional angiography in the MAIN-COMPARE registry.24 At 3 years, there was a tendency towards improved mortality rates in the former group (6 % versus 13.6 %; P=0.063). This effect was more pronounced in patients who received DES (4.7 versus 16 %; P=0.048).

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Coronary Table 1: European Society of Cardiology Guidelines (2014) 28 Recommendation for the type of revascularisation in patients with left main stem disease CABG

PCI

Class

Level of

Class

Level of

LMS disease with SYNTAX score ≥22

LMS disease with SYNTAX score 23–32 LMS disease with SYNTAX score ≥32

IIa

III

Evidence

CABG = coronary artery bypass grafting; LMS = left main stem; PCI = percutaneous coronary intervention.

Table 2: American Heart Association Guidelines (2011) 29 Revascularisation strategies compared with medical therapy in patients with stable unprotected left main stem disease Patient Group

Class Level of

CABG

All groups

PCI

Anatomic conditions associated with a low risk

IIa

Evidence

distal LMS lesions with better survival rates despite the lower number of patients in that subset.

Guidelines While the results of the two major RCTs are still awaited, the European and American societies have both issued guidelines on revascularisation of patient with LMS disease (see Tables 1 and 2).28,29 CABG maintains a class 1 indication across all anatomical subgroups. It is interesting to note that PCI assumes a stronger position in the European Society of Cardiology (ESC) guidelines with a class 1 recommendation in patients with a low SYNTAX score and 2A for an intermediate score. By contrast, the US guidelines give only a 2A for low scores and a 2B for intermediate scores. Both societies are in agreement about the superiority of CABG for patients with a high SYNTAX score.

On-going Trials

AND

Traditionally, patients with LMS disease as well as additional severe coronary disease elsewhere tend to be referred for CABG assuming decent distal targets are available for grafting. The class 1 recommendation of CABG in high Syntax scores is unlikely to be challenged in RCTs. However, the role in less-severe disease needs to be firmly established. In that respect, we look forward to the results of

Clinical characteristics that predict a significantly

two trials that hopefully will settle the matter.

of PCI procedural complications and high likelihood of good outcome (e.g SYNTAX score ≤22, ostial or trunk left main CAD

increased risk of adverse surgical outcomes (e.g STS predicted risk of mortality ≥5 %) Anataomic conditions associated with a low

IIb

III

to intermediate risk of PCI procedural complications and intermediate to high likelihood of good long term outcome (e.g SYNTAX score <33, bifurcation left main CAD) AND Clinical characteristics that predict an increased risk of adverse surgical outcomes (moderate– severe COPD, disability from prior stroke or prior cardiac surgery, STS-predicted risk of operative mortality>2%) Unfavourable anatomy for PCI and good candidate for CABG CABG = coronary artery bypass grafting; CAD = coronary artery disease; LMS = left main stem; PCI = percutaneous coronary intervention; STS = Society of Thoracic Surgeons.

The Spanish Working Group on Interventional Cardiology (LITRO) study used a pre-specified minimum lumen area (MLA) cut-off of 6 mm2 to determine revascularisation of LMS lesions.25 This was based on Murray’s law assuming an MLA cut-off of 4 mm2 in the left anterior descending (LAD) and the left circumflex (LCX) arteries. Patients with a MLA <6 mm2 underwent revascularisation with over half of the cohort (55.2 %) being treated with CABG while those with an MLA >6 mm2 were managed medically. There was no statistical difference in outcome from the revascularised group versus the medically deferred group (cardiac death-free survival 94.5 % versus 97.7 %, respectively). A cut-off of 4.8 mm2 has been proposed by Kang et al. based on correspondence to a fractional flow reserve (FFR) of 0.8, though this has not yet been clinically validated.26 In an analysis of four Spanish registries, De la Torre et al. found better 3-year outcomes with IVUS-guided revascularisation with a statistically significant reduction in mortality, TLR and MI (88.7 % versus 83.6 %).27 This was even more relevant in a subgroup analysis of patients with

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EXCEL (NCT01205776) is a multicentre study specifically looking at the treatment of patients with a low or intermediate SYNTAX score (<32). Use of the second generation Xience (Abbott Vascular, US) DES will make the results more relevant to current practice. The primary endpoint is the composite of death, MI and stroke at a mean of 3-year follow-up. It is worth noting that TVR is not included in the primary endpoint but is included as a secondary endpoint. While the original sample size was intended to be around 3,000 patients, recruitment was stopped early for financial reasons. Despite the curtailed sample size, it will still be the largest RCT covering the management of lesscomplex LMS lesions and its findings will certainly influence the management of these patients. The use of IVUS guidance to perform PCI is strongly recommended both pre- and post-treatment. The Nordic-Baltic-British Left Main Revascularization Study (NOBLE) trial (NCT01496651) is also a multicentre trial comparing the contemporary Biomatrix (Biosensors International Group, Singapore) stent versus CABG. Though the SYNTAX score is not being used for patient selection, the inclusion criteria will yield a population not dissimilar to that of Evaluation of XIENCE PRIME Everolimus Eluting Stent System or XIENCE V or XIENCE Xpedition or XIENCE PRO Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial. In addition to the LMS lesions, there should be ≤3 additional non-complex lesions elsewhere to qualify for participation. The primary endpoint is MACE at 2 years. While the overarching aim of the two trials is to compare PCI with CABG in less ‘complex’ anatomy, it is worth pointing out the subtle differences in inclusion criteria between the two trials. In the NOBLE trial, a significant LMS lesion is defined as having either a visually estimated diameter stenosis >50 % or FFR <0.8. In the EXCEL trial, it is defined as having either a visually estimated diameter of >70 % or 50–70 % with a FFR <0.8 or MLA <6 mm2. Results from both trials are expected in 2016.

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Left Main Stem Percutaneous Coronary Intervention

The Future Park et al. recently published a temporal analysis of their experience with ULM PCI over the past two decades.30 It illustrates the achievements in percutaneous treatment of coronary disease with progressively better outcomes as stent technology and profiles evolving over the past 2 decades. There are other factors that may have contributed to the improvement in clinical outcomes. In addition to improvement in stent technology with the advent of not only DES but also better stent platforms with enhanced drug-delivery systems, the use of adjunctive intravascular imaging and increasing evidence on the efficacy of different bifurcation treatment strategies may have all helped in improving angiographic and clinical outcomes in LMS PCI. With the advent of more potent antiplatelet drugs, the incidence of stent thrombosis has improved. It is important to bear in mind that the techniques of CABG have evolved as well. There is now a greater use of off-pump CABG with associated lower complication rates compared with the traditional surgery as well as almost standard use of LIMA grafts with a better patency than vein

DeMots H, Rösch J, McAnulty JH, Rahimtoola SH. Left main coronary artery disease. Cardiovasc Clin 1977;8 :201–11. 2. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344 :563–70. 3. Grüntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61–8. 4. O’Keefe JH Jr, Rutherford BD, McConahay DR, et al. Early and late results of coronary angioplasty without antecedent thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1989;64 :1221–30. 5. Silvestri M, Barragan P, Sainsous J, et al. Unprotected left main coronary artery stenting: immediate and mediumterm outcomes of 140 elective procedures. J Am Coll Cardiol 2000;35 :1543–50. 6. Park SJ, Park SW, Hong MK, et al. Stenting of unprotected left main coronary artery stenoses: immediate and late outcomes. J Am Coll Cardiol 1998;31 :37–42. 7. Tan WA, Tamai H, Park SJ, et al. Long-term clinical outcomes after unprotected left main trunk percutaneous revascularization in 279 patients. Circulation 2001;104:1609–14. 8. Biondi-Zoccai GG, Lotrionte M, Moretti C, et al. A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease. Am Heart J 2008;155 :274–83. 9. Chieffo A, Morici N, Maisano F, et al. Percutaneous treatment with drug-eluting stent implantation versus bypass surgery for unprotected left main stenosis: a single-center experience. Circulation 2006;113 :2542–7. 10. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2006;47:864–70. 11. Seung KB, Park DW, Kim YH, et al. Stents versus coronaryartery bypass grafting for left main coronary artery disease. N Engl J Med 2008;358 :1781–92. 12. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008;51:538–45.

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grafts. All this means that trials to date are already ‘out of date’ in current real world practice. The heterogeneity of LMS disease poses a particular difficulty in extrapolating results of clinical trials to the ‘real world’. In that sense, adequately powered RCTs are needed to firmly establish the role of PCI in an era where CABG still remains the gold standard for the treatment of LMS lesions.

Conclusions While the treatment of LMS disease has historically lain in the realm of the surgery, rapid advancements in the field of percutaneous coronary intervention has provided another viable therapeutic option. Both the American and European societal guidelines have endorsed PCI in patients with less-complex coronary disease while CABG still maintains a class I recommendation across all groups. The data to firmly establish the role of percutaneous treatment are currently lacking and the two on-going EXCEL and NOBLE trials will hopefully take us a step further in clarifying the role of PCI in the treatment of LMS disease. n

13. 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. 14. Sianos G, Morel M, Kappetein AP, et al. The SYNTAX score: an angiographic tool grading the complexity of coronary artery disease. Eurointervention 2005;1 :219–27. 15. Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial. Circulation 2014;129 :2388–94. 16. Park SJ, Kim YH, Park DW, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med 2011;364 :1718–27. 17. Boudriot E, Thiele H, Walther T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol 2011;57 :538–45. 18. Athappan G, Patvardhan E, Tuzcu ME, et al. Left main coronary artery stenosis: a meta-analysis of drug-eluting stents versus coronary artery bypass grafting. JACC Cardiovasc Interv 2013;6 :1219–30. 19. Pandya SB, Kim YH, Meyers SN, et al. Drug-eluting versus bare-metal stents in unprotected left main coronary artery stenosis a meta-analysis. JACC Cardiovasc Interv 2010;3:602–11. 20. Mehilli J, Kastrati A, Byrne RA, et al. Paclitaxel- versus sirolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2009;53 :1760–8. 21. Mehilli J, Richardt G, Valgimigli M, et al. Zotarolimus- versus everolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2013;62 :2075–82. 22. Naganuma T, Chieffo A, Meliga E, et al. Long-term clinical outcomes after percutaneous coronary intervention for ostial/mid-shaft lesions versus distal bifurcation lesions in unprotected left main coronary artery: the DELTA Registry (drug-eluting stent for left main coronary artery disease): a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. JACC Cardiovasc Interv 2013;6 :1242–9.

23. Tiroch K, Mehilli J, Byrne RA, et al. Impact of coronary anatomy and stenting technique on long-term outcome after drug-eluting stent implantation for unprotected left main coronary artery disease. JACC Cardiovasc Interv 2014;7:29–36. 24. Park SJ, Kim YH, Park DW, et al. Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis. Circ Cardiovasc Interv 2009;2 :167–77. 25. de la Torre Hernandez JM, Hernández Hernandez F, Alfonso F, et al. Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study. J Am Coll Cardiol 2011;58 :351–8. 26. Kang SJ, Lee JY, Ahn JM, et al. Intravascular ultrasoundderived predictors for fractional flow reserve in intermediate left main disease. JACC Cardiovasc Interv 2011;4 :1168–74. 27. de la Torre Hernandez JM, Baz Alonso JA, Gómez Hospital JA, et al. Clinical impact of intravascular ultrasound guidance in drug-eluting stent implantation for unprotected left main coronary disease: pooled analysis at the patient-level of 4 registries. JACC Cardiovasc Interv 2014;7 :244–54. 28. Authors/Task Force members, Windecker S, Kolh P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. 29. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124 :e574–651. 30. Park SJ, Ahn JM, Kim YH, et al. Temporal trends in revascularization strategy and outcomes in left main coronary artery stenosis: data from the ASAN Medical Center-Left MAIN Revascularization registry. Circ Cardiovasc Interv 2015;8 :e001846.

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Twelve Months Dual Antiplatelet Therapy after Drug-eluting Stents – Too Long, too Short or Just Right? Moh a m m a d S a h e b j a l a l a n d N i c k Cu r z e n Wessex Cardiothoracic Unit, Southampton University Hospital, Southampton, UK

Abstract Dual Antiplatelet Therapy (DAPT) remains a cornerstone in the secondary prevention of coronary artery disease. Further, in contemporary practice, a period of DAPT is considered a mandatory requirement after intracoronary stents to prevent stent thrombosis (ST), a complication associated with heart attack and a mortality rate of up to 40 %. In current clinical practice, the default strategy in most centres is 12 months’ DAPT followed by aspirin alone for life. However, the optimal duration of DAPT, particularly given the rapid iterative turnover of drug-eluting stents (DES) is the subject of discrepant evidence and clinical uncertainty. In particular, the 12-month regimen is based upon relatively weak evidence. A series of fairly small randomised trials, not powered to look specifically at ST as an endpoint, have recently indicated that there is no apparent disadvantage to shorter versus longer duration DAPT (including several trials of >12 months versus 12 months) when looking at various composite clinical endpoints. By contrast, the 9,961 patient DAPT trial, published in the New England Journal of Medicine at the end of 2014, demonstrated clinical outcome benefit, including a significantly lower rate of ST as a predefined primary endpoint, in DES patients randomised to 30 months’ DAPT compared to stopping at 12 months. Here, the authors to assess the data, including the most recent meta-analyses, in an attempt to answer the question: DAPT after DES...12 months, longer or shorter?

Keywords Dual anti-platelet therapy, duration of anti-platelet therapy, coronary artery disease, percutaneous coronary intervention, drug-eluting stents, stent thrombosis Disclosure: M Sahebjalal: None. N Curzen: Unrestricted research grants from Haemonetics, St Jude Medical, Medtronic, Heartflow, Boston Scientific; Speaker fees/ consultancy: Haemonetics, St Jude Medical, Volcano, Heartflow; Unrestricted education grant: Volcano (Personal travel sponsorship). Abbott Vascular, Biosensors, Lilly/DS, St Jude Medical Received: 5 April 2015 Accepted: 9 July 2015 Citation: Interventional Cardiology Review, 2015;10(3):136–8 Correspondence: Professor Nick Curzon, E Level North Wing, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. E: nick.curzon@uhs.nhs.uk

Antiplatelet therapy (APT) represents a major cornerstone in the secondary prevention of coronary artery disease, along with modifying patients’ risk factors. Furthermore, it has been clear, since early unsuccessful regimens, including warfarin and dypiridamole with aspirin, that it is APT that stops coronary stents from clotting off and causing stent thrombosis.1,2 Specifically, the requirement for aspirin plus a second antiplatelet drug (thus, dual-antiplatelet therapy [DAPT]) to minimise the risk of ST was quickly established.3 Initially the second agent was ticlopidine, which despite being effective at its primary task was poorly tolerated and associated with an unwelcome incidence of blood dyscrasia. Subsequently, following randomised trial evidence of beneficial clinical outcome with fewer adverse effects, clopidogrel became the P2Y12 inhibitor of choice to accompany aspirin1. Concerns about inter-individual variations in the response to clopidogrel led to the development of apparently more potent and rapidly acting agents in the form of prasugrel and ticagrelor.4,5 Specifically, the latter agents have been shown to have clinical outcome benefit compared to clopidogrel in terms of reducing some ischaemic events in heterogeneous populations of patients with acute coronary syndromes, albeit at the expense of increased bleeding.6 The concept that DAPT is necessary to prevent ST in coronary stents has been dominant for at least two decades. However, the optimal

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duration of that DAPT therapy always has been, and remains, uncertain and recently, in particular, has attracted considerable debate. Put simply, the question frontline interventional cardiologists face is this: how much DAPT do you need, and for how long, in order to prevent ST but minimise major bleeding? In most interventional centres, the default DAPT regimen for most patients receiving stents consists of 12 months followed by aspirin monotherapy for life. A forensic assessment of the basis for this default unearths (perhaps surprisingly) shaky foundations. Studying the evolution of our APT to this default DAPT regimen is valuable to put the most recent challenging trial data into context. In particular, it becomes apparent that several factors have recurrently had an influence on the requirements for DAPT, including stable or acute coronary syndrome presentation, type of stent, and risk of bleeding.

Antiplatelet Therapy for Bare-metal (BMS) and First-generation Drug-eluting (DES 1) Stents When bare-metal stents were first studied, initial therapy consisted of aspirin and dypiridamole.2 Subsequent to this, DAPT was recommended for 1 month in stable patients with BMS. The original comparative trials of DES 1 versus BMS employed DAPT for between 2 and 6 months only, admittedly in relatively stable and low-risk populations.7–9

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However, as has been the case consistently since those early days, in patients with acute coronary syndromes (ACS) receiving stents there are competing indications for DAPT, since the evidence suggests a benefit from DAPT as a medical therapy in this setting. CURE was the first randomised trial to show that in a population of non-ST elevation ACS patients DAPT (using clopidogrel with aspirin) significantly decreased the rate of recurrent ischaemic events compared with aspirin monotherapy with placebo at a mean duration of therapy of 9 months.1,10 Importantly, 64 % of the 12,562 patients in this trial did not undergo revascularisation after randomisation. Specifically, there was a 20 % relative risk reduction in myocardial infarction, stroke or cardiovascular death with long-term DAPT use with no increase in life-threatening bleeds. In the CURE-PCI sub-study, there was a 25 % relative risk reduction in the composite of myocardial infarction or cardiovascular death with DAPT (≤12 months) compared with aspirin and placebo.10 It was largely based on this evidence that 12 months’ DAPT became the recommended default for stents post-ACS. However, given that there was a 4 % per year incidence of significant bleeding in the CURE study in the cohort on DAPT, there was clearly a balance to be struck between longer DAPT to reduce ischaemic events and shorter DAPT to minimise bleeding, which itself has been shown to be an independent risk factor for worse prognosis.1,10 That tension between ischaemic and bleeding events is indeed the driver for our current debate, just as it has been since stents were first implanted. In addition, the suspicion that patients receiving stents in elective, stable settings need DAPT for less time than patients presenting with ACS consistently remains a driver for reducing duration of DAPT therapy. Finally, the consistent iterative technologically-driven evolutions in the design of stents represent a further confounding factor in determining the optimal duration of DAPT.

DAPT in DES Patients – a Moving Target! The main limitation of BMS was an exaggerated inflammatory healing response, leading to excessive neointimal proliferation and restenosis. Clinically, this led to around 10 % of patients representing with recurrent symptoms. Randomised trials demonstrating the dramatic reduction in target vessel revascularisation, due to restenosis, with DES compared with BMS has revolutionised patient care.7-9 However, the cost of this clinical benefit was a demonstrably higher risk of ST in DES1 versus BMS, which was attritional over time.11 As a result, international guidelines were changed in 2007 to indicate that all patients receiving DES should receive DAPT for “at least 12 months”.12 The default regimen was even more strongly set, albeit still based upon very little actual evidence.12 More recently, however, the continuous iteration of DES design has yielded devices with properties likely to reduce the risk of ST: thinner struts; less, or shorter duration, polymer; more sophisticated drug and dosing profiles. As a result of observational data confirming this notion, second- and third-generation DES (DES 2) have been the focus of a series of randomised trials testing shorter duration DAPT versus longer regimens.13–20 These trials are disparate in detail regarding type of stent, mix of patient presentation, duration of the DAPT regimens being compared, type of P2Y12 inhibitor and composite primary endpoint.19 However, they share some common features. First, none were powered to look at ST as a primary isolated endpoint. Second, they generally have demonstrated no advantage of a longer DAPT duration compared with shorter. Furthermore, in many cases, they demonstrated significantly higher rates of major bleeding in the longer DAPT groups.

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It is notable that in some randomised trials, the duration of DAPT could be as short as 3 months with some types of DES 216–17 without any disadvantage in terms of ischaemic endpoint. The accumulated body of this evidence has pointed interventionalists towards shorter duration DAPT in DES 2 patients. This is, indeed, reflected in the 2014 ESC guidelines21 now recommend DAPT for only 6 months in stable patients receiving DES 2, but stick to 12 months’ DAPT after ACS. A seemingly logical and intuitive evolution in what we all thought we knew about DAPT with modern DES 2 was then challenged by the DAPT trial.

The DAPT Trial – Turning What We Thought We Knew on its Head In the DAPT study 229,661 patients with a mix of elective and ACS presentations, who had undergone PCI using DES 1 and DES 2 and who had had an uneventful period of DAPT treatment for 12 months already, were then randomised to either a further 18 months of DAPT or aspirin plus placebo. There was a significant reduction in both ST (p<0.001), a specified co-primary endpoint and major adverse CV and cerebrovascular events (p<0.001) in the prolonged duration DAPT group compared with aspirin monotherapy. However, there was a significant increase in important bleeding in the 30-month DAPT group (p=0.001). Another interesting observation was that although allcause mortality was no different between the groups, the prolonged DAPT group had a significantly higher rate of non-cardiovascular death (p=0.002). The DAPT trial investigators concluded that the prolonged DAPT regimen (30 months) reduced ischaemic events, including ST, compared with 12 months’ DAPT. The implications of this trial are not yet as clear as they first seem. There is concern about committing all DES patients to a longer regimen associated with more severe bleeding. But also, despite the temptation to put the increased incidence of non-cardiovascular death down to statistical quirk, this raises alarm bells given the large number of patients worldwide being treated in this way. The meta-analysis by Palmerini et al., which includes the DAPT trial, just published in The Lancet,23 confirms that we should indeed take a cautious approach to a universal switch to prolonged DAPT after DES. The analysis includes more than 32,000 patients and confirms that there is a 33 % lower rate of non-cardiovascular mortality in the shorter duration DAPT arm compared with longer duration, and this actually drives a hazard ratio of 0.82 for all-cause mortality in the shorter duration group. On the other side of the coin, a meta-analysis by Elmariah et al., which involved 14 studies including the DAPT study, showed that extended-duration was not associated with a difference in the risk of all-cause, cardiovascular or noncardiovascular death compared with aspirin alone or short-duration.24

DAPT after DES – What Should We Do Now? Although the evidence apparently presents a chaotic and discrepant picture, some themes regarding our DAPT strategy for DES patients are manifest. First, that if DAPT is used for longer, the risk of ischaemic events, including ST, will be reduced. Second, that this reduction will be at the expense of increased bleeding. Third, strong circumstantial evidence suggests that if DAPT is used for more than a year, non-CV mortality is higher – perhaps because of the excess in important bleeding. Taking these concepts together, it seems sensible to stick, for now, with a default of 12 months’ DAPT for most patients, pending further specific data.

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Coronary DAPT after DES – What Do We Need to Know for the Future? In order to make progress in this field, we need to address more precisely some unanswered questions. These are questions that cannot be answered in trials that recruit patients with a variety of elective and ACS presentations using different generations of stent and different DAPT constituents. We need answers to these questions via appropriately powered randomised trials: 1. Using specific DES 2 (i.e. only one type in each trial), can DAPT be safely employed for 6, 3 or 1 month(s) in elective patients? 2. Using specific DES 2, can DAPT be safely employed for 6 or even 3 months in ACS patients? 3. Do we actually need DAPT anyway? The results of trials like GLOBAL

usuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in Y addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 2. Serruys PW, de Jaegere P, Kiemeneij F. A Comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994;331 :489–95. 3. Hobson A, Curzen N. Current status of oral antiplatelet therapies. In: Redwood S, Curzen N (eds) Thomas Oxford Textbook of Interventional Cardiology. Oxford: Oxford University Press, 2010; 379–94. 4. Wiviott S, Braunwald E. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357 :2001–15. 5. Wallentin L, Becker RC. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361 :1045–57. 6. Curzen N. Antiplatelet therapy in acute coronary syndromes: beyond aspirin and clopidogrel. Heart 2012;98 :1617–9. 7. Serruys PW, Degertekin M. Intravascular ultrasound findings in the multicentre, randomised, double-blind RAVEL (RAndomised study with the sirolimus-eluting VElocityballoon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial. Circulation 2002;106:798–803. 8. Moses JW, Leon MB. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349 :1315–23. 9. Stone GW, Ellis SG. One-year clinical results with the slowrelease, polymer-based, paclitaxel-eluting TAXUS stent The TAXUS-IV Trial. Circulation 2004;109 :1942–7. 10. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358 :527–33.

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LEADERS,25 randomising DES patients to ticagrelor alone compared with DAPT after a certain period of aspirin plus ticagrelor, could revolutionise our thinking about this field completely. Finally, what shines out of a forensic assessment of the current evidence about DAPT after DES is this: the concept that we can have wholesale strategies for APT for large groups of patients is fundamentally flawed. The real challenge is to develop personalised pathways of care that take into account individual risk of ischaemic events, bleeding and, probably, also their response to APT using point-of-care tests of platelet reactivity.26-27 It is time to discard our palpably inadequate “one-sizefits-all” approach and develop patient-specific strategies. Such an individualised approach might well eliminate many of the adverse effects we currently witness. n

11. L agerqvist B, James, Stefan. Long-term outcomes with drugeluting stents versus bare-metal stents in Sweden. N Engl J Med 2007;356 :1009–19 12. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. Circulation 2007;116(7):e148–304. 13. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomised, controlled trial. Circulation 2014 21;129 :304–12. 14. Feres F, Costa RA, Abizaid A, et al. and the OPTIMIZE Trial Investigators. Three versus twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomised trial. JAMA 2013;310 :2510–22. 15. Kim BK, Hong MK, Shin DH, et al. and the RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of three-month dual antiplatelet therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60 :1340–48. 16. Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stents implantation followed by six versus 12-month dual antiplatelet therapy – the SECURITY randomised clinical trial. J Am Coll Cardiol 2014;64 :2086–97. 17. Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the efficacy of Xience/Promus versus cypher to reduce late loss after stenting (EXCELLENT) randomised, multicentre study. Circulation 2012;125 :505–13. 18. Valgimigli M, Campo G, Monti M, et al. and the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Shortversus long-term duration of dual antiplatelet therapy after coronary stenting: a randomised multicentre trial. Circulation

2012;125 :2015–26. 19. E lmariah S, Mauri L, Doros G. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015 Feb 28;385 :2332–3. 20. Zhang T, Shen L, Hu L, He B. Optimal duration of dualantiplatelet therapy following drug-eluting stent implantation: a meta-analysis. J Clin Pharmacol 2013;53 :345–51. 21. Hamm CW1, Bassand JP, Agewall S, et al. and the ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: 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). Eur Heart J 2011;32 :2999–3054. 22. Mauri L, Kereiake DJ, Yeh RW. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371 :2155–66. 23. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended-duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015;385(9985):2371–82. 24. Elmariah S, Mauri L, Doros G, et al. Extended-duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015:380 :792–8. 25. GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation (ClinicalTrials.gov Identifier: NCT01813435). Available at: https://clinicaltrials.gov/ ct2/show/NCT01813435 (accessed 24 August 2015). 26. Curzen N. Prolonged antiplatelet therapy after drug-eluting stents. Lancet 2015;385 :2332–3. 27. Jiabei L, Zhao J, Wenyun G, Guozhu C. Tailored antiplatelet therapy and clinical adverse outcomes. Heart 2014;100 :41–6.

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LE ATION.

Managing the Antithrombotic Therapy After Percutaneous Coronary Intervention in Patients on Oral Anticoagulation Da rshni A r i s h t a J h a g r o e a n d J u r r i ë n M a r i a t e n B e r g St Antonius Hospital, Nieuwegein, The Netherlands

Abstract In patients on chronic oral anticoagulation (OAC) who are undergoing a percutaneous coronary intervention (PCI), dual antiplatelet therapy (aspirin and a P2Y12 inhibitor) is required. However, combining dual antiplatelet therapy with OAC increases the risk of bleeding. Newer and stronger P2Y12 inhibitors also add more complexity to the regimen, as these antiplatelet agents are currently recommended as standard treatment in patients with acute coronary syndromes (ACS). It remains unclear whether these ACS patients on chronic OAC undergoing PCI should be treated with these new P2Y12 inhibitors as part of the antiplatelet therapy. Another issue to address is that new non-vitamin K oral anticoagulants have emerged as possible alternatives for stroke prevention in patients with AF. Thus, the anticoagulated patient undergoing PCI faces a treatment dilemma. Based on a real-life case, we will discuss the optimal anticoagulant and antiplatelet treatment with a review of the literature.

Keywords Oral anticoagulation, non-vitamin K oral anticoagulants, percutaneous coronary intervention Disclosure: The authors have no conflicts of interest to declare. Received: 1 July 2015 Accepted: 24 August 2015 Citation: Interventional Cardiology Review, 2015;10(3):139–41 Correspondence: Jurriën Maria ten Berg, St Antonius Center for Platelet Function Research, St Antonius Hospital, Koekoekslaan 1, Nieuwegein 3435 CM, The Netherlands. E: jurtenberg@gmail.com

Dual antiplatelet therapy (DAPT) is indicated in patients who need to undergo percutaneous coronary intervention (PCI) procedures.1 Compared with oral anticoagulation (OAC) and aspirin, DAPT has been shown to reduce the risk of thrombotic events and the rate of bleeding events.2 Chronic OAC is required in up to 10 % of the patients undergoing PCI, and is usually indicated for AF and mechanical heart valves.3 However, when combining OAC with DAPT, which is also known as triple therapy (TT), the risk of bleeding increases two- to threefold.4–7 In contrast, the thromboembolism risk increases when OAC is not prescribed in the antithrombotic regimen, while the risk of stent thrombosis, leading to MI, increases when DAPT is not prescribed as part of the TT.8–11 To further complicate this antithrombotic regimen, newer and stronger P2Y12 inhibitors such as prasugrel and ticagrelor are currently recommended as standard treatment in patients with acute coronary syndromes (ACS). It remains unclear whether prasugrel or ticagrelor should be included as part of antiplatelet therapy in these patients with ACS who are on chronic OAC and need to undergo PCI. Another issue to address is that several non-vitamin K oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixiban and edoxaban have been shown to be at least equal or superior to vitamin K antagonists (VKAs) in reducing the risk of stroke in patients with AF.12–15 Hence, the anticoagulated patient undergoing PCI faces a treatment dilemma. At present, evidence from randomised controlled trials (RCTs) regarding the optimal antithrombotic regimen is minimal. This article will describe a case report and discuss the optimal anticoagulant and antiplatelet treatment with an overview of the literature.

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Case report An 81-year-old man was admitted to the St Antonius Hospital, Nieuwegein, The Netherlands, with typical chest pain during the night. He experienced no pain at hospitalisation despite his ECG showing ST-segment depression. He had a medical history of hypertension, diabetes mellitus and paroxysmal non-valvular AF. He was diagnosed with non-ST segment elevation MI (NSTEMI), as his ECG showed ST depression and his troponin-T test result was positive. He had been treated with an angiotensin-converting enzyme inhibitor, oral antidiabetics and an NOAC for 2 years. Prior to this treatment, he had been treated with VKA; however, his international normalised ratio (INR) levels remained unstable, which led to the switch to NOAC. A loading dose of aspirin 300 mg, then 80 mg/day, and a loading dose of clopidogrel 600 mg, then 75 mg/day were started and a coronary angiography was planned. Neither prasugrel nor ticagrelor were given due to their association with increased risk of bleeding in combination with an OAC. The lower-dose NOAC tested for AF was administered. Angiography was performed via the radial approach and low-dose unfractionated heparin (60 IE/kg) was added to prevent catheter thrombosis. A second-generation drug-eluting stent (DES) was implanted when it became clear that this diabetic patient suffered from a long lesion in the left anterior descending artery. No glycoprotein IIb/ IIIa inhibitor was added to the antithrombotic regimen, as the risk of bleeding was deemed high. On the second day after PCI, the patient was discharged with the combination of low-dose aspirin, clopidogrel, lower-dose NOAC and a proton pomp inhibitor (PPI). Unfortunately, he was readmitted to the hospital 5 weeks later presenting with shock

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Coronary due to a major bleeding in the gastrointestinal tract. At this time, all antithrombotic agents were temporarily discontinued; red blood cell and platelet transfusions, prothrombin complex concentrate and intravenous PPI were given. A gastric visible vessel was sclerosed, and after 2 days the patient returned to a stable condition. Due to a high risk of stent thrombosis and an acceptable risk of rebleeding, clopidogrel and the lower-dose NOAC were restarted. Aspirin was omitted from the regimen and clopidogrel was discontinued 3 months later.

How to Manage the Anticoagulation During Percutaneous Coronary Intervention? The current European Society of Cardiology (ESC) guidelines on patients with AF presenting with ACS and/or undergoing PCI or valve interventions recommend uninterrupted OAC with no addition of heparin in the elective setting in those patients at moderate to high risk of thromboembolism (CHA2DS2-VASc score of ≥2) if the INR is >2.5.16 As the patient in this case report had unstable INR levels, VKA was replaced with NOAC. Whether it is safe for patients treated with NOAC to undergo PCI without additional periprocedural heparin or bridging is unknown, except for dabigatran. A small randomised Phase IIa study found that in patients treated with dabigatran alone during elective PCI, the rate of thrombotic events was increased in comparison with patients treated with unfractionated heparin (UFH).17 In patients on NOAC undergoing PCI, addition of low-dose heparin (60 IU/kg) is recommended to prevent catheter thrombosis.18,19 At presenty, the X-PLORER (Exploring the Efficacy and Safety of Rivaroxaban to Support Elective Percutaneous Coronary Intervention) study is investigating whether rivaroxaban can prevent thrombosis and other adverse ischaemic events in comparison with UFH during elective PCI.20 This study will hopefully shed some more light on heparin use during PCI in NOAC-treated patients. The Stenting and Oral Anticoagulant (STENTICO) registry found a significant difference in bleeding risk between the radial and the femoral approach (3.8 % versus 10.3 %; P=0.01) in patients on OAC undergoing PCI, which resulted in the general consideration that in order to reduce periprocedural bleeding risk, the radial access should be adopted, especially in the OAC-treated patient.21 Another consideration in the prevention of bleeding during PCI, is to avoid glycoprotein IIb/IIIa inhibitors in patients on NOAC, unless they are required for the management of complications that emerge during PCI such as thrombus formation during the procedure or no-reflow.22 Stent thrombosis was a frequent consequence after implantation of early generation DES in patients undergoing PCI.23 The risk of developing stent thrombosis with newgeneration DES is comparable to that with bare-metal stents (BMS).24–26 Thus, current guidelines recommend that when considering implanting a stent during PCI, second-generation DES and BMS are preferred over first-generation DES.16

Which Antiplatelet Agents Should be Given in Patients with Acute Coronary Syndrome and AF? Elective or NSTEMI patients on (N)OAC undergoing PCI with coronary stenting require TT including an antithrombotic regimen that consists of a loading dose of aspirin 150–300 mg followed by 75–100 mg/day and a loading dose of clopidogrel 300–600 mg followed by a daily intake of 75 mg. Although there are no reports of RCTs comparing NOAC and VKA in patients with AF undergoing PCI, the ESC position paper states that in patients who require TT, NOACs could be used instead of

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VKA.16 Data supporting the current guidelines are mostly based on the post-hoc analysis from the Randomised Evaluation of Long-term Anticoagulation Therapy (RELY) trial.27 A total of 6,952 patients with AF in the RELY study were, at some point during the study, on antiplatelet therapy when comparing the different dabigatran doses (110 mg or 150 mg twice daily [BID]) and VKA. Of this subgroup, there were 812 patients who were simultaneously on aspirin, clopidogrel and VKA or dabigatran, and it was observed that the relative risk of bleeding was similar whether dabigatran or VKA was given in conjunction with DAPT. In addition, 110 mg dabigatran was associated with the lowest rates of absolute bleeding, regardless of the patient’s use of only VKA, VKA and a single antiplatelet agent or VKA with DAPT.27 When considering adding NOAC to DAPT, it is advised to use the lower tested dose for stroke prevention in AF patients (dabigatran 110 mg BID, rivaroxaban 15 mg once daily or apixaban 2.5 mg BID).16 The new P2Y12 inhibitors ticagrelor and prasugrel, which are recommended as the drugs of choice in patients presenting with ACS, are both more potent than clopidogrel. There has been only one small observational study comparing prasugrel (n=21) with clopidogrel (n=356) in patients undergoing a DES implantation, who received DAPT and had an indication for OAC.28 The patients receiving prasugrel had an increased risk of bleeding (HR 4.6; 95 % CI [1.9–11.4]; P<0.001), compared with clopidogrel. Another study investigating a P2Y12 inhibitor was a Swedish registry, in which ACS patients on ticagrelor and VKA (n=107) were compared with patients treated with aspirin, clopidogrel and VKA (n=159).29 The rates of thrombotic events (recurrent ACS, stroke/transient ischaemic attack and embolism) and major bleeding events were similar in both treated groups (4.7 % versus 3.2 % and 7.5 % versus 7.0 %, respectively). Nonetheless, the regular use of both P2Y12 inhibitors should not be recommended until further research concerning the safety and efficacy of combining prasugrel or ticagrelor with OAC has been completed.

What Should be Done After the Percutaneous Coronary Intervention? The use of PPIs is recommended to prevent gastrointestinal bleeding in all patients receiving OAC in combination with antiplatelet agents, as this type of bleeding is common among patients undergoing PCI.30 Following the PCI procedure, another consideration is whether to omit aspirin in patients who require TT. The What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) study is the only published RCT that has investigated dual therapy (VKA and clopidogrel) in comparison with TT (VKA, aspirin, clopidogrel).31 This study consisted of 573 patients on chronic OAC undergoing PCI with stent implantation between 2008 and 2011. The primary endpoint was the occurrence of any bleeding event, and secondary endpoints were major adverse cardiac/cerebrovascular events. Dual therapy reduced the rates of any bleeding complication in comparison with TT (HR 0.36; 95 % CI: 0.26–0.50; P<0.001), while not increasing the rates of stent thrombosis (HR 0.44; 95 % CI [0.14–1.44]; P=0.165) or thrombotic endpoints (HR 0.69; 95 % CI [0.29–1.60]; P=0.382). The finding that dual therapy appears to be as effective and safe as TT was supported by two other studies. A Danish registry of patients with AF reported that the risk of thrombosis and bleeding was not increased in patients treated with OAC and clopidogrel (n=548) compared with patients treated with OAC, clopidogrel and aspirin (n=1896).32 Another registry study (n=975) observed that

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VKA, clopidogrel and aspirin (TT), clopidogrel and aspirin (DAPT) and VKA and clopidogrel (dual therapy) were comparable in terms of safety and efficacy33. Overall, these studies demonstrated that omitting aspirin from the TT did not lead to an increased risk of thromboembolic events and these data may imply that dual therapy (OAC and clopidogrel) may be an alternative to TT. However, it should be taken into account that these studies were not powered to detect differences in the occurrence of thrombotic events. Omission of clopidogrel from the antithrombotic regimen is not recommended in light of findings from a study by van Werkum et al., who showed that discontinuing clopidogrel within 30 days after PCI was the strongest predictor of stent thrombosis (HR 6.5; 95 % CI [8.0–167.8]).34 In contrast, the risk of developing late stent thrombosis may be reduced, as there have been several RCTs that have shown that patients who received 3 months of DAPT after PCI with second-generation DES implantation

Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation 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). G Ital Cardiol (2006) 2012;13 :171–228. 2. Rubboli A, Milandri M, Castelvetri C, et al. Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting. Cardiology 2005;104 :101–6. 3. Schlitt A, von Bardeleben RS, Ehrlich A, et al. Clopidogrel and aspirin in the prevention of thromboembolic complications after mechanical aortic valve replacement (CAPTA). Thromb Res 2003;109 :131–5. 4. Doyle BJ, Rihal CS, Gastineau DA, Holmes DR. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice. J Am Coll Cardiol 2009;53 :2019–27. 5. Chhatriwalla AK, Amin AP, Kennedy K, et al. Association between bleeding events and in-hospital mortality after percutaneous coronary intervention. JAMA 2013;309 :1022–9. 6. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374 :1967–74. 7. Dewilde W, Breet N, Koolen JJ, ten Berg JM. ‘Ins’ and ‘outs’ of triple therapy. Neth Heart J 2010;18 :444–50. 8. Orford JL, Fasseas P, Melby S, et al. Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation. Am Heart J 2004;147 :463–7. 9. Leon MB, Baim DS., Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339 :1665–71. 10. Connolly S, Pogue J, Hart R, et al. ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367 :1903–12. 11. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014,35 :2541–619. 12. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban

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had similar rates of stent thrombosis compared with patients who received 12 months DAPT.35,36 For the reasons mentioned above, it seems unsafe to cease clopidogrel within the first 3 months after PCI, but one may consider to stop clopidogrel after 3 months of PCI in patients at high risk of bleeding.11

Conclusions The optimal antithrombotic therapy remains unknown for patients on chronic OAC following PCI with coronary stenting. (N)OAC and DAPT are currently recommended by the ESC guidelines, but are associated with increased risk of bleeding. Some studies have shown evidence that clopidogrel plus OAC may be an alternative for TT. In addition, NOACs may be as effective as VKA as part of TT or dual therapy. Currently, P2Y12 inhibitors (ticagrelor and prasugrel) are not recommended as part of TT in AF patients after PCI. Further research in RCTs are required to clarify the optimal antithrombotic regimen for patients on long-term (N)OAC following PCI. n

versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365 :981–92. 13. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361 :1139–51. 14. Connolly SJ, Eikelboom J, Joyner C et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364 :806–17. 15. O’ Donoghue ML, Ruff CT, Giugliano RP, et al. Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation. Eur Heart J 2015;36 :1470–7. 16. Lip GY, Windecker S, Huber K, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014;35 :3155–79. 17. Vranckx P, Verheugt FW, de Maat MP, et al. A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients. EuroIntervention 2013;8 :1052–60. 18. Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol 2007;50 :1742–51. 19. 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. 20. ClinicalTrials.gov. X-PLORER: Exploring the Efficacy and Safety of Rivaroxaban to Support Elective Percutaneous Coronary Intervention. Available at: https://clinicaltrials.gov/ct2/ show/ NCT01442792 [accessed 29 March 2015]. 21. Gilard M, Blanchard D, Helft G, et al. Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral antiCOagulants [STENTICO]). Am J Cardiol 2009;104:338–42. 22. Heidbuchel H, Verhamme P, Alings M, et al. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15 :625–51. 23. Daemen J, Wenaweser P, Tsuchida K, Abrecht L, et al. Early and late coronary stent thrombosis ofsirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369 :667–78. 24. Stefanini GG, Kalesan B, Serruys PW, et al. Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents

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vs. 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 :1940–48. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379 :1393–402. Bangalore S, Toklu B, Amoroso N, et al. Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: mixed treatment comparison meta-analysis. BMJ 2013;347 :f6625. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. Circulation 2013;127 :634–40. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel, and vitamin K antagonists in patients with drug-eluting stent implantation and an indication for oral anticoagulation. J Am Coll Cardiol 2013;61 :2060–6. Braun OÖ, Bico B, Chaudhry U, et al. Concomitant use of warfarin and ticagrelor as an alternative to triple antithrombotic therapy after an acute coronary syndrome. Thromb Res 2015,135 :26–30. Ho KW, Ivanov J, Freixa X, et al. Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation. Can J Cardiol 2013;29 :213–8. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381 :1107–15. Rubboli A, Schlitt A, Kiviniemi T, et al. One-Year Outcome of Patients With Atrial Fibrillation Undergoing Coronary Artery Stenting: An Analysis of the AFCAS Registry. Clin Cardiol 2014;37 357–64. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol 2013;62 :981–9. van Werkum JW, Heestermans AA, Zomer A., et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009;53 :1399–409. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012;60 :1340–8. Feres F, Costa RA, Abizaid AL et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310 :2510–22.

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Coronary

Spontaneous Coronary Artery Dissection Jacqueline Saw Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Abstract Spontaneous coronary artery dissection (SCAD) is a non-traumatic and non-iatrogenic separation of the coronary artery wall that is now recognised as an important cause of myocardial infarction, especially in younger women. SCAD can be elusive on coronary angiography and clinician familiarity with non-pathognomonic angiographic SCAD variants and the use of intracoronary imaging will improve diagnosis. Conservative management and long-term cardiovascular follow-up are typically recommended.

Keywords Myocardial infarction, non-atherosclerotic, spontaneous coronary artery dissection Disclosure: Dr. Saw has received unrestricted research funding (Canadian Institutes of Health Research, University of British Columbia Division of Cardiology, AstraZeneca, Abbott Vascular, St Jude Medical, Boston Scientific, Servier), speaker honoraria (AstraZeneca, St Jude Medical, Boston Scientific, Bayer, Sunovion), consultancy and advisory board honoraria (AstraZeneca, St Jude Medical, Boston Scientific, Abbott Vascular), and proctorship honoraria (St Jude Medical, Boston Scientific). Received: 12 August 2015 Accepted: 13 August 2015 Citation: Interventional Cardiology Review, 2013;10(3):142–3 Correspondence: Jacqueline Saw, MD, FRCPC, FACC, FSCAI, Interventional Cardiology Clinical Associate Professor, 2775 Laurel Street, Level 9, Vancouver General Hospital, Vancouver, BC, V5Z1M9, Canada. E: jsaw@mail.ubc.ca

Spontaneous coronary artery dissection (SCAD) is increasingly recognised as an important cause of myocardial infarction (MI), especially in younger women. It is defined as a non-traumatic and non-iatrogenic separation of the coronary artery wall, which creates a false lumen that may or may not be in continuity with the true lumen. Although conventionally SCAD may be atherosclerotic or non-atherosclerotic in origin, contemporary series have focused on the non-atherosclerotic variant, since the pathophysiology, management, and outcomes are distinct from atherosclerotic coronary artery disease (which causes atherosclerotic SCAD). As such, contemporary usage of the term ‘SCAD’ is typically synonymous with non-atherosclerotic SCAD. SCAD may be a result of an intimal-medial tear that can manifest as multiple radiolucent lumen on angiography, or it may result from spontaneous haemorrhage into the arterial wall that can be angiographically subtle. In fact, <30 % of SCAD have angiographic type 1 appearance (pathognomonic contrast stain of arterial wall with multiple radiolucent lumen) in the author’s large contemporary series.1 Thus, intracoronary imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) play important roles in the diagnosis of non-type 1 angiographic variant of SCAD. These type 2 and 3 variants have angiographic appearance of diffuse smooth stenosis or mimic atherosclerosis, respectively.2 The diagnosis of SCAD on OCT or IVUS requires presence of intramural haematoma and/or separation of the intimomedial membrane creating double lumen.3 In the author’s largest reported intracoronary imaging SCAD series of 22 patients, the lengths of these dissections on angiography are long, especially the type 2 forms (mean length ~58 mm).3 These angiographic variants were previously poorly recognised, resulting in missed and misdiagnosis of SCAD. Thus, there is a great emphasis on angiographers to become familiar with these non-pathognomonic angiographic SCAD variants to improve diagnosis.

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The etiology of SCAD is not fully understood, but recent large series suggest that the majority of patients have potential underlying predisposing arteriopathy, such as fibromuscular dysplasia (FMD), connective tissue disorder and systemic inflammatory conditions, or the condition may be pregnancy-related.1 Less than 20 % may be idiopathic, where no predisposing arteriopathy is identified after vascular screening or detailed questionnaires for these disorders. The most dominant association with SCAD is FMD. Since the author’s discovery of the strong association and publication of the first case series of concomitant SCAD and FMD in 2012,4 the author and others subsequently reported that non-coronary FMD was present in up to 86 % of patients with SCAD.1,5,6 On the other hand, pregnancy-related SCAD (previously thought to be a major cause of SCAD) has a much lower reported frequency (<5 %) as a predisposing cause in contemporary series.7 Additional precipitating stressors, such as intense emotional stress, physical activities, hormone therapy, sympathomimetic drugs and intense Valsalva-like activities (e.g. vaginal delivery, coughing, retching, vomiting, bowel movement) have been reported to precipitate SCAD,1 especially in patients with underlying predisposing arteriopathy. The management of SCAD remains relatively unexplored. There are no randomised trials comparing conservative treatment with revascularisation. Furthermore, standard medications administered for cardiac patients have not been studied in the SCAD population. Thus, recommendations on SCAD management remain empiric and largely based on expert opinion. The rationale and strategy of pharmaceutical therapy for SCAD was previously reviewed in detail.8 In essence, aspirin and beta-blocker are administered long-term for secondary thrombotic prevention and reduction of arterial shear-stress, respectively. ACE inhibitor is administered for patients with left ventricular dysfunction and statins for patients with underlying dyslipidemia. In terms of revascularisation, the expert consensus is conservative management

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unless patients have ongoing/recurrent ischaemia, haemodynamic instability, or left main dissection, since invasive management with coronary stenting is often challenging and can have suboptimal results (procedural success in 50–70 %).1,9 The results of long-term outcome with bypass grafting are inconclusive as they are derived from small case series of <15 patients; nevertheless, there is concern over graft patency with one study showing ~75 % of grafts occluded at follow-up.10

following the acute event, a significant proportion of patients have recurrent chest pains (often atypical in features). Subacute major adverse cardiovascular events (MACE) were reported at 10–20 % at 2-year follow-up, with recurrent SCAD event of ~15 %. At longer-term follow-up from retrospective cohorts, estimated rate of MACE can be up to 50–60 %.1,10 Therefore, SCAD survivors should be closely followed by cardiovascular specialists.

Recent series of prospectively followed SCAD patients have provided important information on acute and long-term cardiovascular outcomes. Most patients present with acute coronary syndromes with either nonST elevation or ST-elevation MI and a small proportion have ventricular arrhythmias. Acute in-hospital mortality was relatively low (<5 %) in contemporary series. Recurrent MI or need for revascularisation in initially conservatively managed patients was 5–10 %.1,10 However,

In summary, SCAD can be elusive on coronary angiography and clinicians should become more cognisant of non-pathognomonic angiographic SCAD variants and consider intracoronary imaging to improve diagnosis. Conservative management is typically recommended unless patients have ongoing ischaemia, haemodynamic instability or left main involvement. Long-term cardiovascular follow-up is important since recurrent events frequently occur post-SCAD. n

Saw J, Aymong E, Sedlak T, et al. Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. Circ Cardiovasc Interv 2014;7 :645–55. Saw J. Coronary angiogram classification of spontaneous coronary artery dissection. Catheter Cardiovasc Interv 2014;84:1115-22. Saw J, Mancini GB, Humphries K, et al. Angiographic appearance of spontaneous coronary artery dissection with intramural hematoma proven on intracoronary imaging. Catheter Cardiovasc Interv 2015:epub ahead of print.

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Saw J, Poulter R, Fung A, et al. Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series.Circ Cardiovasc Interv 2012;5 :134–7. Saw J, Ricci D, Starovoytov A, et al. Spontaneous coronary artery dissection: prevalence of predisposing conditions including fibromuscular dysplasia in a tertiary center cohort. JACC Cardiovasc Interv 2013;6 :44–52. Prasad M, Tweet MS, Hayes SN, et al. Prevalence of extracoronary vascular abnormalities and fibromuscular dysplasia in patients with spontaneous coronary artery dissection. Am J Cardiol 2015;115 :1672–7.

Vijayaraghavan R, Verma S, Gupta N, Saw J. Pregnancy-related spontaneous coronary artery dissection. Circulation 2014;130 :1915–20. 8. Saw J. Spontaneous coronary artery dissection. Can J Cardiol 2013;29 :1027-33. 9. Tweet MS, Eleid MF, Best PJ, et al. Spontaneous coronary artery dissection: revascularization versus conservative therapy. Circ Cardiovasc Interv 2014;7 :777–86. 10. Tweet MS, Hayes SN, Pitta SR, et al. Clinical Features, Management and Prognosis of Spontaneous Coronary Artery Dissection. Circulation 2012;126 :579–88.

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Structural

LE ATION.

Review of Minimally Invasive Aortic Valve Surgery Ricardo Boix-Garibo, 1 Mohammed Mohsin Uzzaman 2 and Vinayak Nilkanth Bapat 1 1. Department of Cardiothoracic Surgery, St Thomas’ Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK; 2. Birmingham Children’s Hospital, Birmingham, UK

Abstract Minimally invasive aortic valve surgery (MIAVS) has been developed for the last 20 years. The improvements in techniques have permitted cardiac surgeons to perform aortic valve replacement safely and efficiently with minimally incisions. Patients have become older and have multiple comorbidities and this is expected to grow in number. Less-invasive procedures are known to reduce the number of complications, together with smaller incisions, less pain, less blood loss and reduced length of hospital stay. Selective preoperative planning with computed tomography is key to the pre-investigation stage. Hybrid and staged procedures with interventional cardiologists are part of the armamentarium and may be appealing for the present and near future. Despite the nature of demanding procedures and longer learning curve with increased cardiopulmonary bypass times, the outcomes are comparable with same quality as conventional open surgery. Patient recovery is the ultimate purpose of these approaches.

Keywords Minimally invasive cardiac surgery, aortic valve replacement, hybrid procedure, right anterior thoracotomy, upper hemisternotomy, preoperative planning Disclosure: The authors declare that there are no conflicts of interest. Received: 31 July 2015 Accepted: 4 September 2015 Citation: Interventional Cardiology Review, 2015;10(3):144–8 Correspondence: Vinayak Nilkanth Bapat, Department of Cardiac Surgery, East Wing, 6th Floor, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. E: vnbapat@yahoo.com

Aortic valve replacement via full sternotomy is the gold standard surgical therapy for patients with severe aortic stenosis (AS) and insufficiency.1 This procedure has proved to be reliable, reproducible, relieves symptoms and improves prognosis of the patients. Degenerative AS is the most frequently acquired valve disease in the elderly population. In the current era, aortic valve surgery is the most common cardiac valve intervention in a cardiac surgery department.2 Improvements in anaesthesia, surgical techniques, post-operative care and in methods of myocardial protection has allowed surgeons to treat patients with increased age and or comorbidity safely with a low rate of morbidity and mortality. Data reported from the Society of Thoracic Surgeon (STS) database have shown a dramatic in-hospital mortality reduction from 3.4 % in 1997 to 2.6 % in 2006 for isolated AVR.3 The number of patients requiring aortic valve evaluation and intervention are increasing as the population grows and becomes older.4,5 However, physicians remain reluctant to recommend AVR for elderly patients more than 80 years of age or those considered very high risk.6 Instead, many patients are continued on medical management or undergo a balloon aortic valvuloplasty.6 Unfortunately, these conservative therapies provide minimal or short-lasting symptomatic relief to the patient, eventually leading to restenosis of the aortic valve or sudden death. As a result, new techniques and technologies have been developed to enhance these outcomes, particularly in high-risk complex patients. As in other fields of medicine, a trend towards minimally invasive

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surgery has swept into cardiac surgery to achieve better results for the patients with the same quality as conventional median sternotomy. The STS database defines minimally invasive cardiac surgery as “any procedure not performed with a Full Sternotomy and cardiopulmonary bypass (CPB) support”.7,8 The only aortic valve procedure precisely represented by this definition is transcatheter aortic valve implantation (TAVI). In this setting, TAVI offers an alternative treatment option in high-risk patients, having demonstrated to be superior to medical therapy in non-operable patients and non-inferior to surgical aortic valve procedure. However, controversies still exist regarding its effect on post-operative outcomes compared with conventional surgery. A meta-analysis of randomised, controlled trials that included 3,465 patients with severe AS found no significant differences between TAVI and conventional AVR in terms of myocardial infarction, stroke and mortality.9 Conversely, a sub-group analysis showed a higher incidence of vascular complications, neurological events, aortic regurgitation and need for permanent pacemaker implantation in patients undergoing TAVI.9 In 2008, a scientific statement from the American Heart Association defined minimally invasive cardiac surgery as “a small chest wall incision that does not include the conventional Full Sternotomy”; however, CPB is still utilised.10 The first description of aortic valve replacement (AVR) through right thoracotomy was published in 1993.11 Minimally invasive approaches through mini-sternotomy was popularised by Cleveland Clinic in 1996 and progressively spread in the surgical community around the world.12,13

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Historically different approaches has been described, and many types of classification, one as step wise approach for reduction of the trauma, from full incision sternotomy to non-incision sternotomy like right anterior mini thoracotomy (RAT) (see Figure 1). The most common techniques used today for minimal invasive aortic valve surgery (MIAVS) are RAT and upper hemisternotomy (UHS) incisions and hence those will be part of later discussion. Also, other approaches have been described, such as parasternal, transverse sternotomy and lower hemisternotomy.14–18 Different types of valves can be used, including standard mechanical and tissue valves. Stentless valve and sutureless valves can also be used in these minimally invasive approaches. Concomitant procedures, such as replacement of the ascending aorta and other valve interventions, have been described with these approaches as well.

Figure 1: Step Wise Reduction of Sternal Trauma A

B 1 2 3

D 1 2 3

Approaches Minimally invasive aortic valve replacement (MIAVR) requires a coordinated effort by the surgeon, perfusionist, anaesthesiologist, cardiologists and nurses to achieve the best clinical outcomes. Intraoperative transesophageal echocardiography (TEE) is used routinely. A pulmonary artery catheter is employed based on patient risk and the specific operation. For both UHS and RAT, a single lumen endotracheal tube is standard. To achieve optimal exposure during RAT, the right lung can be mechanically retracted posteriorly without the need to resort to single-lung ventilation. However, right lung isolation can be useful during the learning curve and in difficult cases using double lumen endotracheal tube or bronchial blocker. To improve emptying of the heart during CPB, vacuum-assisted or kinetic venous drainage is commonly used. The patient is positioned supine and surgically prepped from the neck to mid-thigh for both procedures. External defibrillator pads are placed similarly to redo surgery. The mandatory use and routine interpretation of the intraoperative TEE for de-airing process is a critical step at the end of cardiopulmonary bypass in any MIAVS procedure. The echocardiogram images are visualised and evaluated at the actual time of the operation – this is performed in the same manner as in the conventional full sternotomy approach. Complete de-aired heart will allow weaning of cardiopulmonary bypass and transition to the end of the procedure reducing the microemboli phenomenon.

A: Full sternotomy incision; B: Hemi upper sternotomy with ‘T’ incision; C: Upper hemisternotomy with ‘J’ incision; D: Non-sternal incision – right anterior mini-thoracotomy. 1,2,3 intercostal spaces.

Figure 2: Intraoperative View of Sutureless Aortic Valve Replacement via Upper Hemisternotomy

Upper Hemisternotomy This is the most common incision used for surgeons for MIAVS. UHS may be the best approach for less-experienced surgeons. This approach implies to split the sternum, the sternotomy incision begins at the sternal notch and is carried down by 5–8 cm to the third or fourth intercostal space on the right. A sternal saw is used and the right internal thoracic artery is spared. A rigid retractor with narrow blades is inserted. Central aortic cannulation is straightforward but should be aimed as distal as possible to provide an unencumbered working space. Venous cannulation can either be peripheral or through the right atrial appendage. Myocardial protection is accomplished to the root or directly to the coronary ostia if antegrade is planned. Retrograde cardioplegia can be either directly or peripherally via internal jugular vein if required.18 The left ventricle can be vented directly through the aortic valve using cardiotomy suction or indirectly with a percutaneously placed pulmonary artery vent placed directly in to the pulmonary artery. A transverse aortotomy is placed slightly higher to facilitate its closure and visualisation at the end of operation (see Figure 2). Retraction sutures are placed on the edges of the aortotomy, and at the peak

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of each commissure to elevate the aortic valve into the centre of the operative field. The remaining steps of the procedure is similar to conventional valve replacement. We find that placement of the aortic valve sutures is facilitated by instruments with long handles and also using a knotting device such as CoreKnot® reduces valve implant time. As the surface of the heart is not readily accessible, de-airing demands meticulous attention to detail and is monitored using TEE, being as described above a critical step in the operation.

Right Anterior Mini Thoracotomy RAT avoids sternotomy and is associated with a limited skin incision. However, the operative field is smaller and the aortic valve sits deeper within the wound. Exposure is enhanced by minimising cannula traffic within the incision via peripheral access, coupled with strategic placement of pericardial sutures. This approach is typically performed with a 4–6 cm incision through the second or third intercostal space.

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Structural Figure 3: Intraoperative View of Aortic Valve Replacement via Right Anterior Thoracotomy with Continuous Suture Technique

published a meta-analysis of MIAVS versus conventional AVR studies. They included over 20 studies consisting of more than 4,000 patients.22 MIAVR was associated with a significant reduction in mortality, shorter intensive care unit (ICU) and hospital lengths of stay and decreased ventilation times and transfusion rates.22 However, MIAVR was also associated with longer myocardial ischaemic, cardiopulmonary bypass and operative times compared with open procedures as a result of the steep learning curve involved, especially at the earliest stages of training.22 Since MIAVR procedures are usually technically more demanding, some surgeons argue that no compromises in quality should be allowed for the purpose of a smaller incision. It was also argued that de-airing at the end of such procedure could be incomplete.

Upon entering the pleural space, the right mammary vessels are usually ligated and divided. The third or fourth rib can be dislocated from the sternum to enhance exposure with the goal of visualising the tip of the right atrial appendage. A soft tissue retractor is inserted into the wound followed by a rigid retractor with narrow blades (see Figure 3). Cannulation for cardiopulmonary bypass can be central but usually peripheral. The crossclamp is applied directly through the incision or from an alternative port; however, it can also be performed peripherally with an endoclamp. Myocardial protection with antegrade cardioplegia is delivered through the root or directly to the coronary ostia. Retrograde cardioplegia could be also delivered peripherally through percutaneous jugular vein catheter into the coronary sinus. Technical details of aortotomy, prosthetic valve implantation and aortotomy closure are identical to UHS. The aortic valve is excised in the usual fashion; however, the right coronary cusp sutures are placed first and retracted to facilitate exposure. At the end of the procedure, a small chest drainage tube (e.g. Blake) is inserted in the right pleural space through a separate intercostal space. Pericardium is left open. The disarticulated rib is reattached to the sternum using non-absorbable, braided suture. To avoid lung herniation, the ribs are then reapproximated using further non-absorbable braided sutures. Importantly, if exposure with either UHS or RAT is inadequate, then conversion to full sternotomy should be considered. This ensures that valve replacement can be completed safely using an approach familiar to the surgeon.

An important fact to emphasise is that the outcome and quality of the procedure are comparable or superior to the conventional open or full sternotomy procedures, including the risks of cerebrovascular events. The recent introduction in the market of balloon expandable sutureless valves has enable a reducion of these times. Another potential disadvantage of MIAVR is the morbidity associated with peripheral cannulation, which may cause wound infection, pseudoaneurysms and neurological events. Nevertheless the improvements in technique over time has decreased the morbidity of the procedure and allows surgeons to perform the procedure in high risk and elderly patients as more familiar approach and even better-than-predicted survival in this population.5 However, despite these procedures being potentially more expensive compared with full sternotomy procedures, the benefit is proven and it leads to a reduction in post-operative complications, shorter hospital stay and faster recovery, which should result in lower costs in the long term.

Preoperative Planning Multidisciplinary preoperative and detailed planning allows better outcomes for patients. Essential and reproducible plannification is primordial for an efficient treatment.18 Effective preoperative planning is essential to identify any further complications prior to surgery that could delay patient recovery. Preoperative conditions such as chronic lung diseases, cerebrovascular disease, peripheral artery disease and chest wall abnormalities, lung irradiation and previous cardiac/lung surgery are specially emphasised within these minimally invasive approaches.

Advantages and Disadvantages Randomised trials comparing conventional sternotomy to MIAVR face formidable challenges because of patient preference, surgeon bias and, importantly, the lack of a standardised surgical approach. Postoperative complications associated with a full sternotomy are practically possible with minimal invasive approach16 In theory, avoiding full sternotomy should contribute to better post-operative stability of the sternum and thereby prevent deep infection and preserve respiratory function and mobility in the immediate post-operative period. A smaller area of exposed sternal bone marrow and periosteum may also minimise bleeding. Several retrospective studies have shown that MIAVS reduces exposure of surgical trauma to the patient, post-operative pain, blood transfusion, risk of renal failure, times for mechanical ventilation and, therefore, reduces intensive care length of stay. The hospital postoperative length of stay is also diminished.19 Patient satisfaction and recovery to normal physical activity is also improved.5,20â&#x20AC;&#x201C;22 Murtuza et al.

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Routine preoperative evaluation test such as electrocardiogram, chest X-Ray, complete bloods laboratory tests, echocardiogram and angiogram are performed in the usual manner for full sternotomy counterparts. However preoperative investigations could differ slightly from the routine investigations for standard AVR. Computed tomography (CT) has an important role in the preoperative study for these minimally invasive procedures. CT allows better understanding of the anatomy and the safer delivery of either procedure. The CT gives us information about the lungs, airway, chest wall and mediastinum, including heart and great vessels. Different entities will preclude a challenging but not impossible procedure, such as lung adhesions, diaphragm paralysis and chest wall abnormalities with kyposcolisosis, pectus carinatum or pectus excavatum. Those pathologies might change the initial planned approach. In patients with

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previous cardiac surgery or chest wall irradiation, a chest CT conveys the distance between the posterior sternal table and right ventricle. The presence of patent coronary bypass grafts crossing the midline is particularly hazardous. For the UHS approach, CT scan confirms to which intercostal space to extend the J.

Figure 4: Non-contrast Computed Tomography Chest Showing the Rightward Aorta and the Short Distance from the Second Space

For the RAT approach, the CT scan also facilitates important information regarding the aorta and the relationship with the sternum. By noting which intercostal space is closest to the tip of the right atrial appendage, the preferred intercostal space is identified during the RAT approach. In essence, the RAT procedure is more favourable if: • the aorta lies more than one-half to the right of a vertical line drawn from the right sternal border to the ascending aorta in the axial CT view; and23 • the distance is less than 10 cm from the skin to the ascending aorta where the pulmonary artery bifurcates (see Figure 4).23 Peripheral vascular and cerebrovascular disease increases the risk of stroke and embolisation. Careful assessment of the vascular system is carried out. CT angiogram is performed if suspicious or elevated risk of stroke or embolisation due to retrograde perfusion through peripheral cannulation is anticipated. Arteriosclerosis and calcium plaques in the aorta help us to choose different strategies for cannulation sites. Smooth, calcified plaque is less hazardous than soft or irregular plaque. In addition, the relative size and tortuosity of the iliofemoral vessels on angiogram are important factors in selecting the appropriate arterial cannula. Sealant devices such as angio-seal® are not recommended after preoperative angiogram because it will be difficult to perform femoral cut-down and subsequent cannulation in the procedure. In a patient with a history of stroke or transient ischaemic attack, duplex scanning of the carotid and vertebral arteries is obtained.

Hybrid Procedures As growing expertise and number of procedures performed minimally invasive, the hybrid procedures are being explored. Pre-existing coronary disease does not contraindicate minimally invasive approaches as hybrid or staged procedures can be performed with good and comparable results. Different studies have evaluated the safety and benefit of these procedures. However, further prospective randomised controlled trials needs to be addressed to clarify which is the better approach whether staged/hybrid percutaneous coronary intervention (PCI) and AVR via minimal invasive or full sternotomy combined procedure AVR and coronary artery bypass graft.24

Discussion With an increased population and, in turn, life expectancy, it could be anticipated the older generation will continue to grow. The elderly patient inevitably will have multiple pathologies. Nowadays complex cases and high-risk patients need to be approached with the most recent available techniques. Over the past 2 decades minimally invasive aortic valve surgery has been gradually introduced into clinical practice. The increasing popularity for less-invasive procedures allow surgeons to perform complex cardiac interventions with the same quality even with smaller incisions. Overall, minimally invasive surgery and combined procedures or staged/hybrid procedures permits good outcomes, even in high-risk populations.25 In today’s society of patient care is expectated to be at an increasingly high standard. Moreover, patients’ requests include minimally invasive

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procedures. Patient choice is more contemplated, evaluated in the current practice and high on the agenda in the healthcare setting. Consultation with the patients should thus include the option of a minimally invasive approach as routine. Cardiac surgeons and cardiologists must provide the most effective treatment for their patients – as physicians we need to learn to adapt to the new changing techniques. Nevertheless, safety and quality of life of patients must never be compromised and should be the first priority above any marketing concerns. It is necessary to adopt and learn these techniques in the armamentarium of treatment of heart valve disease.26 Essential endovascular skills are necessary for cardiac surgeons, therefore close communication with an interventional cardiologist is mandatory. The drawback for MIAVS is increased cardiopulmonary bypass and crossclamp times and is therefore technically more demanding for surgeons. The longer learning curve also can be detrimental for the adoption of these newer techniques. Despite these factors, the benefits shown in different retrospective studies are greater, such as improved cosmesis, reduced post-operative pain, reduced blood transfusion, reduced ventilator times and hospital length of stay.26 In order to reduce intraoperative times, three different sutureless or rapid deployment aortic valves have been recently introduced in Europe for use in both conventional AVR and MIAVR operations – the Enable™ Valve System (Medtronic, Minneapolis, MN, USA), the Perceval S™ Valve System (Sorin Biomedica Cardio Srl, Sallugia, Italy) and the Edwards Intuity™ Valve System (Edwards Lifesciences, Irvine, CA, US). In a recent study of patients undergoing MIAVR approach and sutureless devices, Santarpino et al. showed better outcomes in the sutureless group, suggesting that the combination of a MIAVR associated with a sutureless valve may be the first-line treatment for high-risk patients considered to be in the grey zone between TAVI and conventional surgery.27 Gilmanov et al. published a series of 515 patients undergoing RAT AVR, 269 with conventional prostheses and 246 using sutureless prostheses.28 They showed that CPB and crossclamp time was significantly shorter in the sutureless group, while peri-operative strokes, pacemaker implantations and in-hospital mortality were comparable.28 At median follow-up of 21 months, there was a twofold higher actual survival in the octogenarian patients with sutureless compared with sutured valves (100 % versus 50 %; P=0.02).28 We believe that sutureless valves and transcatheter procedures will

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Structural be become more prevalent as part of everyday practice in the present and in the future. We have already mentioned studies comparing outcomes of MIAVR with conventional AVR. However, there is little evidence comparing the outcomes of the UHS versus the RAT approach. Miceli et al. retrospectively examined AVR in 406 patients by either RAT or mini-sternotomy and found that patients who received RAT experienced reduced ventilation time (median 7 hours, interquartile range [IQR] 5–9 hours versus median 8 hours; IQR 6–12 hours; P=0.003), a lower incidence of new-onset postoperative atrial fibrillation (AF) (19.5 % versus 34.2 %; P=0.01), shorter ICU stays (median 1 day, IQR 1 day versus median 1 day, IQR 1–2 days; P=0.001) and overall hospital stays (median 5 days, IQR 5–6 days versus median 6 days, IQR 5–8 days; P=0.0001) compared with mini-sternotomy patients.29 In addition, survival at 1 year and 5 years was higher for RAT patients relative to mini-sternotomy patients (97 % and 86 % versus 94 % and 80 %; P=0.1), although the difference was not statistically significant.29 Similiarly, in a propensity score matched analysis, Hiraoka et al.29 found that RAT patients experienced fewer blood transfusions (42 % versus 67 %; P=0.025), a shorter operative time (235 ± 35 minute versus 272 ± 73 minute; P=0.009), shorter ICU stays (1.4 ± 0.8 days versus 2.2 ± 1.1 days; P=0.001) and shorter hospital stays (13.3 ± 6.5 days versus 21.5 ± 10.3 days; P=0.001, respectively) compared with partial and full sternotomy patients.30 Furthermore, patients who undergo RAT have little to no post-operative physical restrictions because the sternum is left intact and stable during surgery. This is in contrast to

Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33 :2451–96. 2. Tjang YS, van Hees Y, Körfer R, et al. Predictors of mortality after aortic valve replacement. Eur J Cardiothorac Surg 2007;32 :469–74. 3. Brown JM, O’Brien SM, Wu C, et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database. J Thorac Cardiovasc Surg 2009;137 :82–90. 4. Thourani VH, Ailawadi G, Szeto WY, et al. Outcomes of surgical aortic valve replacement in high-risk patients: A multi-institutional study. Ann Thorac Surg 2011;91 :49–56. 5. Tabata M, Umakanthan R, Cohn LH, et al. Early and late outcomes of 1000 minimally invasive aortic valve operations. Eur J Cardiothorac Surg 2008;33 :537–41. 6. Bouma BJ, van den Brink RB, Zwinderman K, et al. Which elderly patients with severe aortic stenosis benefit from surgical treatment? An aid to clinical decision making. J Heart Valve Dis 2004;13 :374–81. 7. STS National Database Spring 2003, Executive Summary. Duke Clinical Research Institute, Durham, NC (2003). 8. Schmitto JD, Mokashi SA, Cohn LH. Minimally-invasive valve surgery. J Am Coll Cardiol 2010;56 :455–62. 9. Cao C, Ang SC, Indraratna P, et al. Systematic review and meta-analysis of transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis. Ann Cardiothorac Surg 2013;2 :10–23. 10. Rosengart TK, Feldman T, Borger MA, et al. Percutaneous and minimally invasive valve procedures: a scientific statement from the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on

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14. 15.

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patients undergoing a UHS who are required to take sternal precautions after surgery. Larger, randomised controlled studies are needed to compare the efficacy and benefits of the two methods in detail. Future techniques as robotic and video-assisted surgeries are not as distant and inaccessible techniques were in the past decades. In order for this to be achievable, more education, funding and training needs to be provided routinely. Furthermore, as clinical trials continue with transcatheter valves, if MIAVS continues to demonstrate superior outcomes compared with full sternotomy, then it should be assumed that MIAVS should be the golden standard used to compare these emerging technologies against.

Conclusions To summarise, minimally invasive aortic valve surgery is safe and reproducible. Fewer complications are likely with a detailed and selective as appropriate plan of preoperative investigations. There is significant evidence to suggest that a shorter post-operative stay and reduced number of complications, such a blood loss and post-operative pain, are associated with minimally invasive procedures. Despite a longer learning curve and challenging procedures the improved outcome gives to the patient the optimum chance of faster recovery with the return to normal activity. Minimally invasive aortic valve procedures should be offered to any patients deemed appropriate to benefit to this approach. Ultimately, adoption of minimally invasive cardiac surgery will enhance professional careers of cardiac surgeons as well as the lives of their patients. n

Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplinary Working Group, and Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2008;117 :1750–67. Rao PN, Kumar AS. Aortic valve replacement through right thoracotomy. Tex Heart Inst J 1993;20 :307–8. Cosgrove DM III, Sabik JF. Minimally invasive approach for aortic valve operations. Ann Thorac Surg 1996;62 :596–7. Svensson LG. Minimal-access “j” or “j” sternotomy for valvular, aortic, and coronary operations or reoperations. Ann Thorac Surg 1997;64 :1501–3. Cohn LH (ed.) Cardiac Surgery in the Adult. 3rd ed. New York: The McGraw-Hill Companies, 2008. Lazzara RR, Kidwell FE. Right parasternal incision: a uniform minimally invasive approach for valve operations. Ann Thorac Surg 1998;65 :271–272. Bridgewater B, Steyn RS, Ray S, et al. Minimally invasive aortic valve replacement through a transverse sternotomy: a word of caution. Heart 1998;79 :605–7. Doty DB, Flores JH, Doty JR. Cardiac valve operations using a partial sternotomy (lower half) technique. J Card Surg 2000;15 :35–42. Malaisrie SC, Barnhart GR, Farivar RS, et al. Current era minimally invasive aortic valve replacement: techniques and practice. J Thorac Cardiovasc Surg 2014;147 :6–14. Brown ML, McKellar SH, Sundt TM, et al. Ministernotomy verses conventional sternotomy for aortic valve replacement: a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2009;137 :670–9. Brown JM, O’Brien SM, Wu C, et al. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the society of thoracic surgeons national database. J Thorac Cardiovasc Surg 2009;137 :82–90. Glauber M, Miceli A, Gilmanov D, et al. Right anterior minithoracotomy versus conventional aortic valve

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replacement: a propensity score matched study. J Thorac Cardiovasc Surg 2013;145 :1222–6. Murtuza B, Pepper JR, Stanbridge DR, et al. Minimal access aortic valve replacement: is it worth it? Ann Thorac Surg 2008;85 :1121–31. Glauber M, Miceli A, Bevilacqua S, et al. Minimally invasive aortic valve replacement via right anterior minithoracotomy: early outcomes and midterm follow-up. J Thorac Cardiovasc Surg 2011;142 :1577–9. Santana O, Funk M, Zamora C, et al. Staged percutaneous coronary intervention and minimally invasive valve surgery: Results of a hybrid approach to concomitant coronary and valvular disease. J Thorac Cardiovasc Surg 2012;144 :634–9. Miceli A, Gilmanov D, Murzi M, et al. Minimally invasive aortic valve replacement with a sutureless valve through a right anterior mini-thoracotomy versus transcatheter aortic valve implantation in high-risk patients. Eur J Cardiothorac Surg 2015 [Epub ahead of print]. Lamelas J, Nguyen TC. Minimally invasive valve surgery: When less is more. Semin Thorac Cardiovasc Surg 2015;27:49–56. Santarpino G, Pfeiffer S, Jessl J, et al. Sutureless replacement versus transcatheter valve implantation in aortic valve stenosis: a propensity-matched analysis of 2 strategies in high-risk patients. J Thorac Cardiovasc Surg 2014;147 :561–7. Gilmanov D, Miceli A, Ferrarini M, et al. Aortic valve replacement through right anterior minithoracotomy: can sutureless technology improve clinical outcomes? Ann Thorac Surg 2014;98 :1585–92. Miceli A, Murzi M, Gilmanov D, et al. Minimally invasive aortic valve replacement using right minithoracotomy is associated with better outcomes than ministernotomy. J Thorac Cardiovasc Surg 2014;148 :133–7. Hiraoka A, Totsugawa T, Kuinose M, et al. Propensity score-matched analysis of minimally invasive aortic valve replacement. Circ J 2014;78 :287.

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Structural

LE ATION.

Computed Tomography for Structural Heart Disease and Interventions Pascal Thériault-Lauzier, 1 Marco Spaziano, 1 Beatriz Vaquerizo, 1 Jean Buithieu, 1 Giuseppe Martucci 1 and Nicolo Piazza 1,2 1. McGill University Health Centre, Montreal, Quebec, Canada; 2. German Heart Centre Munich, Munich, Germany

Abstract Transcatheter cardiac interventions are a fast evolving field. The past decade has seen the development of transcatheter aortic valve replacement, transcatheter mitral valve repair and replacement, septal defect closure devices and left atrial appendage closure devices for thromboprophylaxis. More than ever, medical imaging is taking a central role in the care of patients with structural heart disease. In this review article we outline the use of MSCT as a tool for diagnosis of structural heart interventions, as well as patient selection, preprocedural planning, device sizing and post-procedural assessment. We focus on procedures targeting the aortic valve, the mitral valve, the inter-atrial septum and the left atrial appendage.

Keywords Computed tomography, interventional imaging, structural heart interventions, aortic stenosis, mitral regurgitation, atrial septal defect, thromboembolism prophylaxis, transcatheter aortic valve replacement, transcatheter mitral valve replacement, transcatheter mitral valve repair, left atrial appendage occlusion Disclosure: P Thériault-Lauzier is co-founder of FluoroCT Software; Marco Spaziano is a consultant for FluoroCT Software; G Martucci is a proctor for Medtronic and a consultant FluoroCT Software; N Piazza is a proctor and consultant for Medtronic and co-founder of FluoroCT Software; B Vaquerizo and J Buithieu have no conflicts of interest to declare. Received: 1 July 2015 Accepted: 24 August 2015 Citation: Interventional Cardiology Review, 2015;10(3):149–54 Correspondence: Nicolo Piazza, Associate Professor, Cardiology Division, McGill University Health Centre, 1001, Decarie Boulevard, Montreal, QC, H4A 3J1, Canada . E: nicolopiazza@me.com

Valvular Disease Aortic valve Severe symptomatic aortic stenosis (AS) bears a dismal prognosis. The mean survival is 2.0 to 4.7 years after the onset of angina, 0.8 to 3.8 years after the onset of syncope and 0.5 to 2.8 years after the onset of congestive heart failure.1 Surgical aortic valve replacement (SAVR) is the mainstay of treatment for these patients.2 In the last decade transcatheter aortic valve replacement (TAVR) has become an accepted alternative in patients for whom surgery would impart a high or prohibitive risk of mortality or morbidity. TAVR does not require openheart surgery. Instead, bovine or porcine pericardial prosthetic leaflets are mounted on a metal frame, which is delivered using a catheter via an endovascular or transapical route. The CoreValve US Pivotal Trial showed absolute mortality benefit of TAVR over SAVR of 4.9 % in high-risk patients (P<0.001 for non-inferiority, P=0.04 for superiority) at one year follow up.3 In the Placement of Aortic Transcatheter Valves 1 trial (PARTNER 1 trial), the absolute mortality benefit in TAVR versus SAVR was of 5.4 % at five years (P=0.76).4 The dimensions of the aortic valve complex are critical for sizing of device (see Table 1 and Figure 1). The aortic annulus, sinuses of Valsalva, ascending aorta, coronary arteries ostia and any bypass grafts should be assessed in all patients considered for TAVR.5 While 2D echocardiography provides valuable haemodynamic information and is readily available, a MSCT-based analysis of the aortic root and vascular access sites has become a sine qua non step in the pre-operative evaluation of patients for TAVR.6 Device sizing using multi-slice computer tomography (MSCT) has been shown to offer more precise

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measurements of the aortic root than echocardiography and thus reduces rates of paravalvular leak (PVL),7–10 an independent predictor of post-operative mortality from 30 days to 2 years.11–20 MSCT provides a precise method of evaluating aortic valve calcification (see Figure 2). Calcification is particularly important because it correlates with rates of post-intervention PVL9,21–24 It was recently demonstrated that rates of at least moderate PVL increase with left ventricular outflow tract (LVOT) calcification (OR 2.8, [95 % CI 1.2–7.0], P=0.022), and a leaflet calcium volume greater than 235 mm3 for a threshold of 850 HU (OR 2.8 [95 % CI 1.2–6.7], P=0.023).24 One of the most common complications of TAVR is a new left bundle branch (LBBB) or complete atrioventricular (AV) block requiring the implantation of a permanent pacemaker. The pathophysiology of these iatrogenic conduction abnormalities is the mechanical compression of the left bundle branch in the uppermost aspect of the muscular interventricular septum by the TAVR implant (see Figure 3). An increased depth of implantation is the most frequently identified predictor of LBBB with both balloon- and self-expandable prostheses.25–30 In order to obtain an optimal implantation depth, the operator must minimise parallax inherent to 2D fluoroscopy used during the implantation.31 MSCT can be used to plan optimal C-arm angulations,32–41 i.e. angulations that present the axis of the aortic root parallel to the fluoroscopic detector (see Figure 4). In a recent study,41 such optimised angulations were associated with a significant decrease in implantation time (P=0.0001), radiation exposure (P=0.02), amount of contrast (P=0.001), and risk of acute kidney injury (P=0.03).

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Structural Table 1: Transcatheter Aortic Valve Replacement Manufacturer Recommendations for Pre-procedural Anatomic Evaluation Aortic Annulus Ascending Aorta Sinus of Valsalva Sinus of Valsalva Diameter, mm Diameter, mm Width, mm Height, mm Medtronic CoreValve

Distance Aortic Annulus to Left Main Ostium, mm

Minimal Illiofemoral Diameter, mm

Evolut 23 mm

18—20†

≤34

≥25

≥15

—

≥6.0

26 mm

20—23†

≤40

≥27

≥15

—

≥6.0

29 mm

23—27†

≤43

≥29

≥15

—

≥6.0

31 mm

26—29†

≤43

≥29

≥15

—

≥6.0

23 mm

20—23*

—

≥10

≥6.0

26 mm

23—26*

—

≥10

≥6.5

29 mm

26—29*

—

≥10

≥7.0

23 mm

20.7—23.4*

—

≥10

≥5.5

26 mm

23.4—26.4*

—

≥10

≥5.5

29 mm

26.2—29.5*

—

≥10

≥6.0

Edwards SAPIEN XT

Edwards SAPIEN 3

†: CT perimeter-derived diameter (perimeter/π) *: CT area-derived diameter (2√(Area/π).62,86

Figure 1: Pre-Transcatheter Aortic Valve Replacement Analysis for the Aortic Root

Figure 2: Calcifications of the Aortic Leaflets A

A: A double oblique multiplanar reconstruction of the aortic root demonstrating the calcification burden. B: A volume rendered view of aortic valve calcifications. C: A maximum intensity projection of the aortic root showing in red the image voxels that are above a threshold attenuation. The images were generated using the FluoroCT imaging software.

Figure 3: Relationship of the Left Bundle Branch with the Aortic Root

A: A CT image of the aortic root showing the location of the aortic annulus formed by joining the basal attachment of the aortic leaflets (green), the crown-like leaflet attachment line (red), the outline sinus of Valsalva (yellow), the sinutubular junction (blue) and the outline of the ascending aorta at 40 mm above the aortic valve annulus. B: A volume rendering generated from the CT scan. C: A double oblique multiplanar reconstruction showing the aortic valve annulus en face. D: The distance from the aortic annulus to the ostium of a coronary vessel (magenta). E: A multiplanar reconstruction showing the outline of the sinuses of Valsalva with corresponding width measurements. Note that the height of the sinus of Valsalva is measured between the aortic annulus (green) and the sinutubular junction (blue). The images were generated using the FluoroCT imaging software.

MSCT also plays a role in determining the suitability of access vessels in patients evaluated for TAVR. The majority of TAVR performed today is via the retrograde trans-femoral approach. This technique is the least invasive when compared with trans-apical, trans-aortic, trans-subclavian or trans-carotid TAVR.42-–44 While less invasive, transfemoral TAVR can result in vessel dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, haematoma or nerve injury.45 The main risk factors of vascular injury secondary to the insertion of the catheter sheath include the vessel diameter, calcification, and tortuosity,46,47 (see Figure 5). Contrast-enhanced MSCT provides information about these three aspects within the same imaging study. The sheath-to-vessel diameter ≥1.05–1.12 is

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The left bundle branch (LBB) is in the uppermost aspect of the muscular inter-ventricular septum (MusS) at its junction with the membranous septum (MemS). Ao: aorta; LV: left ventricle; NCS: non-coronary sinus of Valsalva; LCS: left coronary sinus of Valsalva; RA: right atrium; RV: right ventricle.

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Figure 4: Optimal Fluoroscopic Angulations of the Aortic Root A

Figure 5: Evaluation of the Iliofemoral Arteries for Transfemoral Transcatheter Aortic Valve Replacement

C A

(A) and (C) each are simulated fluoroscopic view generated from a MSCT scan where the aortic annulus is drawn in yellow. (B) is a plot of fluoroscopic angulations demonstrating in yellow the optimal fluoroscopic angulation, i.e. the combinations of craniocaudal (CRA/CAU) and right-/ left- anterior oblique (RAO/LAO) angles that show the aortic annulus in profile. This configuration minimises parallax errors and maximises accuracy of depth perception during the delivery of the TAVR device. The images were generated using the FluoroCT imaging software.

Figure 6: Mitral Valve Annulus

A: A curved multiplanar reconstruction of the right iliofemoral artery showing the centreline of the vessel in yellow. B: A multiplanar reconstruction of the vessel in cross-section to enable analysis of the width. C: Coronal multiplanar reconstruction of the CT scan. D: A volume rendering demonstrating the relationship of the iliofemoral arteries with the pelvis.

Figure 7: Optimal Fluoroscopic Angulations of the Mitral Valve Annulus A

(A–C) show three views of the D-shaped mitral annulus, which cuts across from the right to the left fibrous trigones thus neglecting the portion of the anterior mitral leaftlet which is part of the aorto-mitral curtain. (D–F) show three views of the saddle-shaped mitral annulus. The asterisk (*) indicates the aortomitral curtain.

a predictor of vascular injury when measured with CT.47,48 The use MSCT correlates with a decrease in vascular complications.46 MSCT also yields a greater predictive value for vascular complications than plain angiography.48

Mitral valve Motivated by the success of TAVR, transcatheter mitral valve procedures are seen as the next frontier of structural cardiac interventions for patients at high surgical risk. These procedures consist in the implantation of a device that repairs or replaces the native mitral valve leaflets with the goal of reducing mitral valve regurgitation. The therapies fall into four categories49; edge-to-edge repair (MitraClip), annuloplasty rings (Carillon, Mitralign, Accucinch, Cardioband), chordal implants (NeoChord, V-Chordal) and transcatheter mitral valve replacement (CardiAQ mitral valve, Fortis mitral valve, TIARA mitral valve, Tendyne mitral valve, HighLife mitral valve). These therapies are at various stages of development, from pre-clinical research to commercial availability.

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(A) and (C) each are simulated fluoroscopic view generated from a MSCT scan where the saddle-shaped mitral annulus is drawn in yellow. A: A three-chamber view which distinguished the anterior from the posterior mitral leaflets. C: A two-chamber view where the anterior and posterior leaflets are overlapping but segments can be distinguished. B: A plot of fluoroscopic angulations demonstrating in yellow the optimal fluoroscopic angulation, as previously described in Figure 4. The images were generated using the FluoroCT imaging software. CRA: cranial; CAU: caudal; RAO: right-anterior oblique; LAO: left-anterior oblique.

MSCT will likely play a crucial goal in the assessment of the mitral valvular complex with these new therapies. MSCT has been investigated to assess the function and anatomy of the mitral valve. In the context of mitral regurgitation, MSCT can be used to determine the disease etiology,50,51 to quantify the severity,52,53 to describe changes in the geometry of the valvular complex54,55 and to diagnose mitral valve prolapse.56–58 In the context of transcatheter mitral valve replacement (TMVR), MSCT has been proposed to quantify the mitral valve annulus. The mitral valve annulus is often described as either saddle-shaped or as D-shaped (see Figure 6). It has been argued that for some of the devices, in particular those that are not axially symmetrical, the D-shaped annulus may be more appropriate for sizing purposes.59,60 This question remains to be studied, but in the interim we suggest that both techniques be employed. MSCT also plays a role in the optimisation of fluoroscopic viewing angles for mitral valve therapies.31,61 In particular, MSCT allows one to determine the optimal projection curve of the mitral valve annulus (see Figure 7). One may also preselect a fluoroscopic viewing angle corresponding to two-chamber view, which distinguishes mitral valve segments A1P1 from A2P2 and from A3P3 but overlaps the anterior and posterior leaflets such that A1 overlaps P1, A2 overlaps P2, and A3 overlaps P3. Conversely, one may preselect a fluoroscopic viewing angle corresponding to a three-chamber view that distinguishes the anterior from the posterior leaflets but overlaps segments A1,2,3 and separately P1,2,3.

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Structural Figure 8: Mitral Valve Leaflets

As new mitral valve devices undergo clinical trials, MSCT will likely play a critical role in determining patient eligibility. Further research is necessary to determine if MSCT has an impact on procedural success and clinical outcomes of these interventions.

Atrial Septal Defect and Patent Foramen Ovale The prevalence of a patent foramen ovale (PFO) reaches 25 to 30 % of the general population. In patients having suffered a cryptogenic stroke, the incidence reaches 45.9 %,64 which suggests that PFO may play a significant role in the pathogenesis of cryptogenic stroke.65 Atrial septal defects (ASD) are the most common congenital heart defect found in adult patients. The indications for defect closure include right ventricular volume overload with a pulmonary-to-systemic flow ratio >2:1, paradoxical embolisation and platypnea-orthodeoxia syndrome. The transcatheter treatment of PFOs and ASDs was first performed in 1975.66 Subsequent studies demonstrated that percutaneous closure has a similar rate of success when compared to surgical closure but offered reduced rates of complications and duration of hospital stay.67–69

CD represents the coaptation depth, also called tenting height. CL is the coaptation length. In edge-to-edge repair, CD should be <11 mm and CL ≥2 mm. ALL: anterior leaflet length; PLL: posterior leaflet length.

Figure 9: Left Atrial Appendage A

Contrast-enhanced MSCT using a saline-chaser can be used to detect and differentiate inter-atrial shunts.70,71 and can also be used to assess disease severity.72 Ostium secundum ASDs, which represent 70 % of cases, are the only type amenable to percutaneous closure. In this context, MSCT can be useful to establish the diagnosis of sinusvenosus type ASD with partial anomalous pulmonary venous return, a condition better treated surgically.73,74 MSCT is also comparable to but less invasive than trans-esophageal echocardiography in the assessment of ASD prior to percutaneous septal occluder implantation.75

Thromboembolic Prophylaxis by Left Atrial Appendage Closure

A: A double oblique multiplanar reconstruction showing the left atrial appendage ostium en face. B: An endovascular volume rendering showing the left atrial appendage from the left atrium. C: A double oblique multiplanar reconstruction showing a profile of the left atrial appendage. D: A vascular volume rendering showing a cast of the lumen of the left atrial appendage. (C) and (D) show the anchoring planes of the left atrial appendage occluder (blue and red) and the waist length of the ostium (yellow). The images were generated using the FluoroCT imaging software.

In the context of percutaneous edge-to-edge repair such as the MitraClip procedure, MSCT has been proposed for patient selection. Anatomical criteria essential for this procedure include:62,63 (1) central regurgitant jet located in the A2 and P2 mitral leaflets; (2) in functional mitral regurgitation, a coaptation length ≥2 mm and coaptation depth <11 mm (see Figure 8) and (3) in degenerative mitral regurgitation, a flail gap <10 mm and flail width <15 mm.

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Atrial fibrillation (AF) is the most common arrhythmia in the general population76 and is an important factor in the pathophysiology of atrial thrombus formation. Chronic anticoagulation is generally indicated in patients with AF and deemed at risk for stroke. A significant number of patients for whom thromboprophylaxis would be indicated are not eligible due to a high bleeding risk. Interestingly, studies suggest that 90 % of thrombus causing strokes in patients with AF originate from the left atrial appendage (LAA).77 This is thought to result from the presence of pectinate muscles within the LAA thus creating an appropriate milieu for blood stasis and thrombus formation. This prompted the development of surgical LAA ligation and eventually, of minimally invasive procedures. Percutaneous transcatheter LAA closure was first described in 2002 and has since been studied in clinical trials. The Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation trial (PROTECT AF trial) demonstrated that the procedure is non-inferior to warfarin therapy but resulted in higher rates of complications such as pericardial effusion.78 Four devices are currently available or under investigation: the WATCHMAN device, the Amplatzer Cardiac Plug, the WaveCrest device and the Lariat epicardial suturesnare delivery device. MSCT allows the anatomy of the LAA to be evaluated, which is valuable for device selection,79 assessment of procedural success and longer-term outcomes.80 It has been suggested that the perimeter-

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derived diameter of the LAA ostium is the most appropriate for device sizing.79 Other important parameters include the minimum and maximum diameters, as well as the waist length of the LAA ostium81 (see Figure 9). MSCT can also be used to determine optimal fluoroscopic angulation for the deployment of the LAA closure device.31 The information provided by MSCT regarding outcomes is complementary to that obtained from transoesophageal echocardiography (TEE). MSCT has a higher rate of detection than TEE for device leaks, which are defined as flow of blood within the LAA past the device.82 The localisation of leaks is also easier with MSCT

1. Turina J, Hess O, Sepulcri F and Krayenbuehl HP. Spontaneous course of aortic valve disease. Eur Heart J 1987;8:471–83. 2. Nishimura RA, Otto CM, Bonow RO, et al. and Members AATF. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:e521–643. 3. Adams DH, Popma JJ, Reardon MJ, et al. and Investigators USCC. Transcatheter aortic-valve replacement with a selfexpanding prosthesis. N Engl J Med 2014;370:1790–8. 4. Mack MJ, Leon MB, Smith CR, et al. and investigators Pt. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015;385:2477–84. 5. Piazza N, de Jaegere P, Schultz C, et al. Anatomy of the aortic valvar complex and its implications for transcatheter implantation of the aortic valve. Circ Cardiovasc Interv 2008;1:74–81. 6. Achenbach S, Delgado V, Hausleiter J, et al. SCCT expert consensus document on computed tomography imaging before transcatheter aortic valve implantation (TAVI)/ transcatheter aortic valve replacement (TAVR). J Cardiovasc Comput Tomogr 2012;6:366–80. 7. Willson AB, Webb JG, Labounty TM, et al. 3-dimensional aortic annular assessment by multidetector computed tomography predicts moderate or severe paravalvular regurgitation after transcatheter aortic valve replacement: a multicenter retrospective analysis. J Am Coll Cardiol 2012;59:1287–94. 8. Jilaihawi H, Kashif M, Fontana G, et al. Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation. J Am Coll Cardiol 2012;59:1275–86. 9. Schultz C, Rossi A, van Mieghem N, et al. Aortic annulus dimensions and leaflet calcification from contrast MSCT predict the need for balloon post-dilatation after TAVI with the Medtronic CoreValve prosthesis. EuroIntervention: EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2011;7:564–72. 10. Jabbour A, Ismail TF, Moat N, et al. Multimodality imaging in transcatheter aortic valve implantation and post-procedural aortic regurgitation: comparison among cardiovascular magnetic resonance, cardiac computed tomography, and echocardiography. J Am Coll Cardiol 2011;58:2165–73. 11. Abdel-Wahab M, Zahn R, Horack M, et al. and German transcatheter aortic valve interventions registry i. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 2011;97:899–906. 12. Gotzmann M, Pljakic A, Bojara W, et al. Transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis-predictors of mortality and poor treatment response. Am Heart J 2011;162:238–45 e1. 13. Hayashida K, Morice MC, Chevalier B, et al. Sex-related differences in clinical presentation and outcome of transcatheter aortic valve implantation for severe aortic stenosis. J Am Coll Cardiol 2012;59:566–71. 14. Kodali SK, Williams MR, Smith CR, et al. and Investigators PT. Two-year outcomes after transcatheter or surgical aorticvalve replacement. N Engl J Med 2012;366:1686–95. 15. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 2011;58:2130–8. 16. Sinning JM, Hammerstingl C, Vasa-Nicotera M, et al. Aortic regurgitation index defines severity of peri-prosthetic regurgitation and predicts outcome in patients after transcatheter aortic valve implantation. J Am Coll Cardiol 2012;59:1134–41. 17. Sinning JM, Scheer AC, Adenauer V, et al. Systemic inflammatory response syndrome predicts increased mortality in patients after transcatheter aortic valve implantation. Eur Heart J 2012;33:1459–68.

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than with TEE.82 Contrast-enhanced MSCT also enables the evaluation of device thrombus,83 embolisation and pericardial effusion.84,85 Further studies are necessary to provide evidence regarding the impact of MSCT imaging on outcomes of LAA closure.

Conclusions Herein, we described the utility of MSCT in the context of structural heart interventions. With the fast development of these therapies, MSCT will likely play a role in the development of future sizing algorithms. In the future, interventional cardiologists will likely need to become imaging experts to offer their patients the most optimal outcomes from structural heart interventions. n

18. Takagi K, Latib A, Al-Lamee R, M, Chieffo A, et al. Predictors of moderate-to-severe paravalvular aortic regurgitation immediately after CoreValve implantation and the impact of postdilatation. Catheterization and cardiovascular interventions: official journal of the Society for Cardiac Angiography & Interventions. 2011;78:432–43. 19. Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299–308. 20. Unbehaun A, Pasic M, Dreysse S, et al. Transapical aortic valve implantation: incidence and predictors of paravalvular leakage and transvalvular regurgitation in a series of 358 patients. J Am Coll Cardiol 2012;59:211–21. 21. John D, Buellesfeld L, Yuecel S, Mueller R, Latsios G, Beucher H, Gerckens U and Grube E. Correlation of Device landing zone calcification and acute procedural success in patients undergoing transcatheter aortic valve implantations with the self-expanding CoreValve prosthesis. JACC Cardiovasc Interv 2010;3:233–43. 22. Colli A, Gallo M, Bernabeu E, et al. Aortic valve calcium scoring is a predictor of paravalvular aortic regurgitation after transcatheter aortic valve implantation. Ann Cardiothorac Surg 2012;1:156–9. 23. Haensig M, Lehmkuhl L, Rastan AJ, et al. Aortic valve calcium scoring is a predictor of significant paravalvular aortic insufficiency in transapical-aortic valve implantation. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 2012;41:1234–40; discussion 1240–1. 24. Jilaihawi H, Makkar RR, Kashif M, et al. A revised methodology for aortic-valvar complex calcium quantification for transcatheter aortic valve implantation. Eur Heart J Cardiovasc Imaging 2014;15:1324–32. 25. Urena M, Mok M, Serra V, et al. Predictive factors and longterm clinical consequences of persistent left bundle branch block following transcatheter aortic valve implantation with a balloon-expandable valve. J Am Coll Cardiol 2012;60:1743–52. 26. Piazza N, Onuma Y, Jesserun E, et al. Early and persistent intraventricular conduction abnormalities and requirements for pacemaking after percutaneous replacement of the aortic valve. JACC Cardiovasc Interv 2008;1:310–6. 27. Franzoni I, Latib A, Maisano F, et al. Comparison of incidence and predictors of left bundle branch block after transcatheter aortic valve implantation using the CoreValve versus the Edwards valve. J Am Coll Cardiol 2013;112:554–9. 28. Colombo A and Latib A. Left bundle branch block after transcatheter aortic valve implantation: inconsequential or a clinically important endpoint? J Am Coll Cardiol 2012;60:1753-5. 29. Calvi V, Conti S, Pruiti GP, et al. Incidence rate and predictors of permanent pacemaker implantation after transcatheter aortic valve implantation with self-expanding CoreValve prosthesis. Journal of interventional cardiac electrophysiology: an international journal of arrhythmias and pacing. 2012;34:189–95. 30. Aktug O, Dohmen G, Brehmer K, et al. Incidence and predictors of left bundle branch block after transcatheter aortic valve implantation. Int J Cardiol. 2012;160:26–30. 31. Theriault-Lauzier P, Andalib A, Martucci G, et al. Fluoroscopic anatomy of left-sided heart structures for transcatheter interventions: insight from multislice computed tomography. JACC Cardiovasc Interv 2014;7:947–57. 32. Tzikas A, Schultz C, Van Mieghem NM, et al. Optimal projection estimation for transcatheter aortic valve implantation based on contrast-aortography: validation of a Prototype Software. Catheterization and cardiovascular interventions: official journal of the Society for Cardiac Angiography & Interventions 2010;76:602–7. 33. Arnold M, Achenbach S, Pfeiffer I, et al. A method to determine suitable fluoroscopic projections for transcatheter aortic valve implantation by computed tomography. J Cardiovasc Comput Tomogr 2012;6:422–8. 34. Binder RK, Leipsic J, Wood D, et al. Prediction of optimal deployment projection for transcatheter aortic valve replacement: angiographic 3-dimensional reconstruction of

the aortic root versus multidetector computed tomography. Circ Cardiovasc Interv 2012;5:247-52. 35. Cockburn J, Trivedi U, de Belder A, Hildick-Smith D. Optimal projection for transcatheter aortic valve implantation determined from the reference projection angles. Catheter Cardiovasc Interv 2012;80:973–7. 36. Dvir D, Kornowski R. Percutaneous aortic valve implantation using novel imaging guidance. Catheter Cardiovasc Interv 2010;76:450–4. 37. Gurvitch R, Wood DA, Leipsic J, et al. Multislice computed tomography for prediction of optimal angiographic deployment projections during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010;3:1157-65. 38. Kempfert J, Falk V, Schuler G, et al. Dyna-CT during minimally invasive off-pump transapical aortic valve implantation. Ann Thorac Surg 2009;88:2041. 39. Kurra V, Kapadia SR, Tuzcu EM, et al. Pre-procedural imaging of aortic root orientation and dimensions: comparison between X-ray angiographic planar imaging and 3-dimensional multidetector row computed tomography. JACC Cardiovasc Interv 2010;3:105–13. 40. Poon KK, Crowhurst J, James C, et al. Impact of optimising fluoroscopic implant angles on paravalvular regurgitation in transcatheter aortic valve replacements -- utility of three-dimensional rotational angiography. EuroIntervention 2012;8:538–45. 41. Samim M, Stella PR, Agostoni P, et al. Automated 3D analysis of pre-procedural MDCT to predict annulus plane angulation and C-arm positioning: benefit on procedural outcome in patients referred for TAVR. JACC Cardiovasc Imaging 2013;6:238–48. 42. Thourani VH, Gunter RL, Neravetla S, et al. Use of transaortic, transapical, and transcarotid transcatheter aortic valve replacement in inoperable patients. Ann Thorac Surg 2013;96:1349–57. 43. Noble S. Transapical aortic valve implantation: a reasonable therapeutic option, but not the only alternative to transfemoral approach. J Thorac Dis 2013;5:360–1. 44. Bleiziffer S, Ruge H, Mazzitelli D, et al. Survival after transapical and transfemoral aortic valve implantation: talking about two different patient populations. J Thorac Cardiovasc Surg 2009;138:1073–80. 45. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253–69. 46. Toggweiler S, Gurvitch R, Leipsic J, et al. Percutaneous aortic valve replacement: vascular outcomes with a fully percutaneous procedure. J Am Coll Cardiol 2012;59:113–8. 47. Hayashida K, Lefevre T, Chevalier B, et al. Transfemoral aortic valve implantation new criteria to predict vascular complications. JACC Cardiovasc Interv 2011;4:851–8. 48. Okuyama K, Jilaihawi H, Kashif M, et al. Transfemoral access assessment for transcatheter aortic valve replacement: evidence-based application of computed tomography over invasive angiography. Circ Cardiovasc Imaging 2015;8:e001995 49. Ruiz CE, Kliger C, Perk G, et al. Transcatheter Therapies for the Treatment of Valvular and Paravalvular Regurgitation in Acquired and Congenital Valvular Heart Disease. J Am Coll Cardiol 2015;66:169–83. 50. Killeen RP, Arnous S, Martos R, et al. Chronic mitral regurgitation detected on cardiac MDCT: differentiation between functional and valvular aetiologies. Eur Radiol 2010;20:1886–95. 51. Kim K, Kaji S, An Y, et al. Mechanism of asymmetric leaflet tethering in ischemic mitral regurgitation: 3D analysis with multislice CT. JACC Cardiovasc Imaging 2012;5:230–2. 52. Alkadhi H, Wildermuth S, Bettex DA, et al. Mitral regurgitation: quantification with 16-detector row CT--initial experience. Radiol 2006;238:454–63. 53. Guo YK, Yang ZG, Ning G, et al. Sixty-four-slice multidetector computed tomography for preoperative evaluation of left ventricular function and mass in patients with mitral regurgitation: comparison with magnetic resonance imaging and echocardiography. Eur Radiol 2009;19:2107–16. 54. Delgado V, Tops LF, Schuijf JD, et al. Assessment of mitral

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Structural valve anatomy and geometry with multislice computed tomography. JACC Cardiovasc Imaging 2009;2:556–65. 55. Shudo Y, Matsumiya G, Sakaguchi T, et al. Assessment of changes in mitral valve configuration with multidetector computed tomography: impact of papillary muscle imbrication and ring annuloplasty. Circulation 2010;122(Suppl 11):S29–36. 56. Feuchtner GM, Alkadhi H, Karlo C, et al. Cardiac CT angiography for the diagnosis of mitral valve prolapse: comparison with echocardiography1. Radiol 2010;254:374–83. 57. Shah RG, Novaro GM, Blandon RJ, et al. Mitral valve prolapse: evaluation with ECG-gated cardiac CT angiography. AJR Am J Roentgenol 2010;194:579–84. 58. Ghosh N, Al-Shehri H, Chan K, et al. Characterization of mitral valve prolapse with cardiac computed tomography: comparison to echocardiographic and intraoperative findings. Int J Cardiovasc Imaging 2012;28:855–63. 59. Blanke P, Dvir D, Cheung A, et al. Mitral Annular Evaluation With CT in the Context of Transcatheter Mitral Valve Replacement. JACC Cardiovasc Imaging 2015;8:612–5. 60. Blanke P, Dvir D, Cheung A, et al. A simplified D-shaped model of the mitral annulus to facilitate CT-based sizing before transcatheter mitral valve implantation. J Cardiovasc Comput Tomogr 2014;8:459–67. 61. Blanke P, Dvir D, Naoum C, et al. Prediction of fluoroscopic angulation and coronary sinus location by CT in the context of transcatheter mitral valve implantation. J Cardiovasc Comput Tomogr 2015;9:183–92. 62. Ewe SH, Klautz RJ, Schalij MJ, Delgado V. Role of computed tomography imaging for transcatheter valvular repair/ insertion. Int J Cardiovasc Imaging 2011;27:1179–93. 63. Beigel R, Wunderlich NC, Kar S, Siegel RJ. The evolution of percutaneous mitral valve repair therapy: lessons learned and implications for patient selection. J Am Coll Cardiol 2014;64:2688–700. 64. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002;33:706–11. 65. Cheng TO. Mechanisms of platypnea-orthodeoxia: what causes water to flow uphill? Circulation 2002;105:e47. 66. King TD, Thompson SL, Steiner C, Mills NL. Secundum atrial septal defect. Nonoperative closure during cardiac

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catheterization. JAMA 1976;235:2506–9. 67. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation 2008;118:e714–833. 68. Silversides CK, Dore A, Poirier N, et al. Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: shunt lesions. Can J Cardiol 2010;26:e70–9. 69. Baumgartner H, Bonhoeffer P, De Groot NM, et al. Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of C, Association for European Paediatric C and Guidelines ESCCfP. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 2010;31:2915–57. 70. Kosehan D, Akin K, Koktener A, et al. Interatrial shunt: diagnosis of patent foramen ovale and atrial septal defect with 64-row coronary computed tomography angiography. Jpn J Radiol 2011;29:576–82. 71. White HD, Halpern EJ, Savage MP. Imaging of adult atrial septal defects with CT angiography. JACC Cardiovasc Imaging 2013;6:1342–5. 72. Osawa K, Miyoshi T, Morimitsu Y, et al. Comprehensive assessment of morphology and severity of atrial septal defects in adults by CT. J Cardiovasc Comput Tomogr 2015;9:354–61. 73. Hoey ET, Lewis G, Yusuf S. Multidetector CT assessment of partial anomalous pulmonary venous return in association with sinus venosus type atrial septal defect. Quant Imaging Med Surg 2014;4:433–4. 74. Kafka H and Mohiaddin RH. Cardiac MRI and pulmonary MR angiography of sinus venosus defect and partial anomalous pulmonary venous connection in cause of right undiagnosed ventricular enlargement. AJR Am J Roentgenol 2009;192:259–66. 75. Ko SF, Liang CD, Yip HK, et al. Amplatzer septal occluder closure of atrial septal defect: evaluation of transthoracic echocardiography, cardiac CT, and transesophageal echocardiography. AJR Am J Roentgenol 2009;193:1522–9. 76. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed

atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–5. 77. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. 78. Reddy VY, Doshi SK, Sievert H, et al. and Investigators PA. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720–9. 79. Wang Y, Di Biase L, Horton RP, et al. Left atrial appendage studied by computed tomography to help planning for appendage closure device placement. J Cardiovasc Electrophysiol 2010;21:973–82. 80. Ismail TF, Panikker S, Markides V, et al. CT imaging for left atrial appendage closure: a review and pictorial essay. J Cardiovasc Comput Tomogr 2015;9:89–102. 81. Vaitkus PT, Wang DD, Guerrero M, et al. Left atrial appendage closure with amplatzer septal occluder in patients with atrial fibrillation: CT-based morphologic considerations. J Invasive Cardiol 2015;27:258–62. 82. Jaguszewski M, Manes C, Puippe G, et al. Cardiac CT and echocardiographic evaluation of peri-device flow after percutaneous left atrial appendage closure using the AMPLATZER cardiac plug device. Catheter Cardiovasc Interv 2015;85:306–12. 83. Romero J, Husain SA, Kelesidis I, et al. Detection of left atrial appendage thrombus by cardiac computed tomography in patients with atrial fibrillation: a meta-analysis. Circ Cardiovasc Imaging 2013;6:185–94. 84. Saw J, Fahmy P, DeJong P, et al. Cardiac CT angiography for device surveillance after endovascular left atrial appendage closure. Eur Heart J Cardiovasc Imaging 2015: epub ahead of print. 85. Romero J, Cao JJ, Garcia MJ, Taub CC. Cardiac imaging for assessment of left atrial appendage stasis and thrombosis. Nat Rev Cardiol 2014;11:470–80. 86. de Araujo Goncalves P, Campos CA, Serruys PW, GarciaGarcia HM. Computed tomography angiography for the interventional cardiologist. Eur Heart J Cardiovasc Imaging 2014;15:842–54.

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Structural

LE ATION.

Transcatheter Aortic Valve Implantation for Patients with Smaller Anatomy Yusuke Watanabe and Ken Kozuma Department of Internal Medicine, Division of Cardiology, Teikyo University School of Medicine, Tokyo, Japan

Abstract Transcatheter aortic valve implantation (TAVI) has reached relative maturity for the treatment of severe, symptomatic aortic stenosis (AS). TAVI for patients with smaller anatomy is a challenging procedure due to specific anatomical difficulty and complications including annulus rupture and vascular complications. Prevention of these complications, and the introduction of a newer-generation and lowerprofile TAVI system, will encourage the prevalence of TAVI for patients with smaller anatomy.

Keywords Transcatheter aortic valve implantation, small body size, vascular complication, aortic valve Disclosure: The authors have no conflicts of interest to declare. Received: 30 July 2015 Accepted: 4 September 2015 Citation: Interventional Cardiology Review, 2015;10(3):155–7 Correspondence: Yusuke Watanabe, Teikyo University School of Medicine, 2–11–1 Kaga, 173–8606 Tokyo, Japan. E: yusuke0831@gmail.com

Transcatheter aortic valve implantation (TAVI) is evolving rapidly with an exponential growth in the number of procedures in worldwide.1,2 As worldwide experience with this modality increases, more and more patients are being offered this alternative to open surgery for the treatment of severe, symptomatic aortic stenosis (AS). Although this technique has reached relative maturity, further optimisation of patient selection and device implantation is essential for achieving improved prognosis. Patients of small body size (e.g. body surface area <1.4 m2) typically have a smaller annulus size and smaller vascular access. Smaller annulus (e.g. annulus area <300 cm2) may increase the risk of annulus rupture due to relative valve oversizing.3 Annulus rupture or perforation is a rare but catastrophic complication of TAVI associated with a high risk of death, and has been reported to be between 0–1.1 %.4,5 Aggressive device oversizing and large calcifications in the epicardial fat area of the annulus were reported as risk factors for annulus rupture.3,5,6 Our previous report showed a trend towards higher incidence (2.3 %) of annulus rupture in patients with small body size.7 Accurate measurement of the aortic root using multidetector CT is crucial for appropriate device sizing.8–10 A smaller valve such as a 20 mm balloon-expandable transcatheter heart valve should also contribute to the reduction of annulus rupture in patients with smaller annulus (see Figures 1–3).11 Vascular access is also an important factor in small body sized patients undergoing TAVI. Smaller vascular access increases the sheath to femoral artery ratio, resulting in a higher risk of vascular complications,12 which have been shown to be associated with a significant increase in mortality.12–14 Our previous report showed the incidence of major vascular complications was significantly higher in the small body size group compared with the normal body size group because of the smaller access (13.0 % versus 4.3 %; p<0.01).7 Care should be taken to

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avoid vascular complications in patients with smaller ilio-femoral access (see Figure 4). New emerging TAVI technologies with lower-profile sheath system, SAPIEN 3 (Edwards Lifesciences Inc., Irvine, CA, US) and Evolut R (Medtronic, Santa Rosa, California, US) have the potential to reduce the risk of vascular complications.15,16 Due to the smaller access route, a non-femoral approach is preferred in patients with smaller anatomy. In recent results of national registry, non-femoral access was one of the significant predictors of adverse outcome.17 Using the newer and lower-profile sheath TAVI system, femoral access will be used more frequently and encourage the prevalence of TAVI for patients with smaller anatomy. The distance between the coronary ostium and the aortic annulus plane is also a matter of great concern for TAVI in small body size patients. Our previous study showed the distance between the left coronary ostium and the aortic annulus plane was shorter in the small body group.7 Rebeiro et al. reported on data from a multicentre registry, which showed that a lower-lying coronary ostium and a shallow sinus of valsalva were associated with coronary obstruction after TAVI.18 Prevention of coronary occlusion using, for example, coronary protection with prior wire placement into the coronary before valve implantation may be a valuable solution.19 In the registry data, the coronary obstruction rate was more than twice as high among patients who received a balloonexpandable valve than among those who received a self-expandable valve (0.81 % versus 0.34 %).9 A self-expandable valve system will be suitable for the small body patients with the risk of coronary obstruction, however, attention should be paid to the small size of sinus of valsalva with a potential risk of coronary obstruction. Surgical aortic valve replacement carries a potential risk of abnormally high post-operative gradients especially in patients with severe AS and small aortic annulus size.20,21 One study demonstrated that the

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Structural Figure 1: Small Anatomy of Aortic Annulus

Figure 2: Small Anatomy of Sinus of Valsalva

Figure 4: Small Size of Ilio-femoral Access

Figure 3: Small Anatomy of Sino-tubler Junction

with standard surgical valves. In patients with smaller body and smaller annulus size, TAVI may have a potential benefit of avoidance of abnormally high post-operative gradients.23

mean post-procedural transprosthetic gradient was significantly lower in the balloon expandable TAVI cohort compared with surgical aortic valve replacement.22 According to the authors’ findings, distention of the aortic annulus due to systematic oversizing and the absence of a sewing ring may have been the potential mechanisms accounting for the superior haemodynamic profile associated with TAVI compared

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. Mylotte D, Osnabrugge RL, Windecker S, et al. Transcatheter aortic valve replacement in europe: Adoption trends and factors influencing device utilization. J Am Coll Cardiol 2013;62 :210–9. Blanke P, Reinohl J, Schlensak C, et al. Prosthesis oversizing in balloon-expandable transcatheter aortic valve implantation is associated with contained rupture of the aortic root. Circ Cardiovasc Interv 2012;5 :540–8. Pasic M, Unbehaun A, Dreysse S, et al. Rupture of the device landing zone during transcatheter aortic valve implantation: A life-threatening but treatable complication. Circ Cardiovasc Interv 2012;5 :424–32. Hayashida K, Bouvier E, Lefevre T, et al. Potential mechanism of annulus rupture during transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;82 :E742–6. Barbanti M, Yang TH, Rodes Cabau J, et al. Anatomical and

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TAVI for patients with smaller anatomy is challenging in terms of specific anatomical difficulty and complications. In order to avoid these serious complications, meticulous annulus measurement,8 evaluation of calcification distribution on the aortic annulus24 and pre-screening of ilio-femoral access12 are of great importance. In addition to these pre-screening efforts, the prevalence of newer-generation and lowerprofile TAVI systems will surely provide safe TAVIs for patients with smaller anatomy. n

procedural features associated with aortic root rupture during balloon-expandable transcatheter aortic valve replacement. Circulation 2013;128 :244–53. 7. Watanabe Y, Hayashida K, Lefevre T, et al. Transcatheter aortic valve implantation in patients of small body size. Catheter Cardiovasc Interv 2014;84 :272–80. 8. Hayashida K, Bouvier E, Lefevre T, et al. Impact of ct-guided valve sizing on post-procedural aortic regurgitation in transcatheter aortic valve implantation. EuroIntervention 2012;8 :546–55. 9. Jilaihawi H, Kashif M, Fontana G, et al. Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation. J Am Coll Cardiol 2012;59 :1275–86. 10. Schultz CJ, Moelker AD, Tzikas A, et al. Cardiac ct: Necessary for precise sizing for transcatheter aortic implantation. EuroIntervention 2010;6 (Suppl G):G6–G13. 11. Binder RK, Wood D, Webb JG, Cheung A. First-in-human

12.

13.

14.

15.

16.

valve-in-valve implantation of a 20mm balloon expandable transcatheter heart valve. Catheter Cardiovasc Interv 2013;82 :E929–31. Hayashida K, Lefevre T, Chevalier B, et al. Transfemoral aortic valve implantation: New criteria to predict vascular complications. J Am Coll Cardiol Intv 2011;4 :851–8. Webb JG, Chandavimol M, Thompson CR, et al. Percutaneous aortic valve implantation retrograde from the femoral artery. Circulation 2006;113 :842–50. Rodes-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. Webb J, Gerosa G, Lefevre T, et al. Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. J Am Coll Cardiol 2014;64 :2235–43. Sinning JM, Werner N, Nickenig G, Grube E. Medtronic

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Transcatheter Aortic Valve Implantation for Patients with Smaller Anatomy

corevalve evolut r with enveo r. EuroIntervention 2013;9 Suppl:S95–6. 17. Ludman PF, Moat N, de Belder MA, et al. Transcatheter aortic valve implantation in the united kingdom: Temporal trends, predictors of outcome, and 6-year follow-up: A report from the uk transcatheter aortic valve implantation (tavi) registry, 2007 to 2012. Circulation 2015;131 :1181–90. 18. Ribeiro HB, Webb JG, Makkar RR, et al. Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: Insights from a large multicenter registry. J Am Coll Cardiol

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2013;62 :1552–62. 19. Inohara T, Hayashida K, Yashima F, et al. “Dual role” guiding catheter: A new technique for patients requiring coronary protection during transcatheter aortic valve implantation. Cardiovasc Interv Ther 2015 [Epub ahead of print]. 20. Rahimtoola SH. The problem of valve prosthesis-patient mismatch. Circulation 1978;58 :20–4. 21. Pibarot P, Dumesnil JG. Prosthetic heart valves: Selection of the optimal prosthesis and long-term management. Circulation 2009;119 :1034–48. 22. Clavel MA, Webb JG, Pibarot P, et al. Comparison of the

hemodynamic performance of percutaneous and surgical bioprostheses for the treatment of severe aortic stenosis. J Am Coll Cardiol 2009;53 :1883–91. 23. Kalavrouziotis D, Rodes-Cabau J, Bagur R, et al. Transcatheter aortic valve implantation in patients with severe aortic stenosis and small aortic annulus. J Am Coll Cardiol 2011;58 :1016–24. 24. Watanabe Y, Lefevre T, Bouvier E, et al. Prognostic value of aortic root calcification volume on clinical outcomes after transcatheter balloon-expandable aortic valve implantation. Catheter Cardiovasc Interv 2015 [Epub ahead of print].

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Supported Contribution

LE ATION.

Patient-tailored Drug-eluting Stent Choice – A Solution for Patients with Diabetes Proceedings of Two Satellite Symposia Held at EuroPCR in May 2015 in Paris Katrina Mountfort, Medical Writer, Radcliffe Cardiology Reviewed for accuracy by: Roxana Mehran, 1 Antonio Colombo, 2 Pieter Stella, 3 Rafael Romaguera 4 and Gennaro Sardella 5 1. Mount Sinai School of Medicine, New York, NY, USA; 2. San Raffaele Scientific Institute, Milan, Italy; 3. University Medical Centre, Utrecht, The Netherlands; 4. Hospital de Bellvitge, Idibell, University of Barcelona, Barcelona, Spain; 5. Policlinico Umberto I “Sapienza“ University of Rome, Rome, Italy

Abstract Although second-generation drug-eluting stents (DES) have improved outcomes in percutaneous coronary interventions (PCIs), important unmet needs remain. Two symposia at EuroPCR 2015 focused on two challenging scenarios. First, patients with diabetes mellitus (DM) have generally inferior outcomes following PCI. The Cre8™ stent (manufactured by CID Spa, member of Alvimedica Group) has shown unique efficacy in subpopulations of patients with DM during clinical trials. A live case in a patient with diabetes illustrated the challenges of complex multivessel disease. Second, optimising stent selection towards devices that have demonstrated complete and early endothelialisation offers the potential to reduce the duration of dual antiplatelet therapy. The Cre8™ DES features a polymer-free platform and has been associated with low rates of in-stent thrombosis.

Keywords Percutaneous coronary intervention, diabetes mellitus, polymer-free drug-eluting stent, reducing dual antiplatelet therapy Disclosures: R Mehran is a consultant for Abbott Laboratories, AstraZeneca, Boston Scientific, Bristol-Myers Squibb, CSL Behring, Covidien, Janssen Pharmaceuticals, Merck and The Medicines Company; is on the scientific advisory boards of Covidien, Janssen Pharmaceuticals and Sanofi Aventis; and has other activities that include, but are not limited to, committee participation and data safety monitoring board membership for Maya Medical, a Covidien company. A Colombo reports a financial relationship with Direct Flow Medical. P Stella has received grant/research support from Edwards Lifesciences and Medtronic, is a consultant for DEKRA and has received honorarium from Alvimedica. R Romaguera has no disclosures. G Sardella has received honoraria from Abbott, Alvimedica, Astra Zeneca, Biosensors and Boston Scientific and institutional grant/research support from Biosensors and Volcano. Received: 24 August 2015 Accepted: 10 September 2015 Citation: Interventional Cardiology Review, 2015;10(3):158–61 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berkshire, SL6 9PN, UK. E: katsmountfort@virginmedia.com

Support: The publication of this article was supported by Alvimedica.

The use of second-generation polymeric metallic drug-eluting stents (DES) in percutaneous coronary intervention (PCI) is now routine practice and has demonstrated excellent safety and efficacy compared with first-generation DES. These stents have enhanced PCI procedures, enabling the treatment of more complex lesions and clinical cases. However, specific patient subsets still require procedural and/or technological refinement to further enhance success rates and longterm patient-centred clinical outcomes. Two symposia at EuroPCR in May 2015 in Paris focused on how polymer-free DES may increase safety in PCI requiring short duration of dual antiplatelet therapy (DAPT) and are more efficacious in the setting of patients with diabetes

mellitus (DM). Patients with diabetes are particularly challenging in terms of PCI, as they tend to have worse outcomes compared with patients without diabetes. In order to meet these clinical challenges, a novel DES was discussed: the Cre8TM (manufactured by CID Spa, member of Alvimedica Group), which features controlled polymer-free amphilimus formula elution from abluminal reservoirs on the surface of the stent. These unique and innovative features may enhance clinical outcomes in patient subsets, such as those with DM, and may represent a step forwards in treating these patients. n

The Latest Available Data on Polymer-Free Drug-eluting Stent Technology in Patients with Diabetes Gennaro Sardella of Rome, Italy, introduced his presentation by outlining the causes of DES failure in patients with DM (see Figure 1). These include a prothrombotic state and resistance to antiplatelet drugs, for which prasugrel and ticagrelor may be indicated. Other

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causes include diffuse coronary artery disease (CAD), negative remodelling and smaller minimal lumen area (MLA) post procedure, as well as extensive CAD with more complex lesions and CAD progression in the non-stented segment. The latter may be managed by the

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Patient-tailored Drug-eluting Stent Choice – A Solution for Patients with Diabetes

use of a coronary artery bypass graft (CABG) and statins. Persistent polymer-related arterial inflammation may be overcome by the use of a polymer-free or absorbable polymer DES. However, these patients typically present with neointimal hyperplasia and impaired rapamycinanalogue inhibition, suggesting the need for a more efficacious DES – ideally a DES designed for patients with DM. The clinical efficacy of the Cre8™ DES was evaluated in the International Randomized Comparison Between DES Limus Carbostent and Taxus Drug-Eluting Stents in the Treatment of De Novo Coronary Lesions (NEXT) clinical study, with a primary endpoint of 6-month angiographic in-stent late lumen loss (LLL). The study achieved its primary endpoint of non-inferiority compared with a permanent polymer DES Taxus (Liberté, Boston Scientific, US). However, the most striking finding of this study was that the LLL in the subgroup with diabetes was comparable to that in the general study population, a finding that had not been seen with other DES.1 At 3 years in the clinical follow-up a 37 % decrease in target lesion revascularisation (TLR) was reported in the Cre8™ group versus the Taxus group and a reduction of 68 % was seen in the population with diabetes. These findings led to further investigation of the Cre8™ DES in the population with diabetes. Another clinical study, ranDomizEd coMparisOn betweeN novel Cre8™ DES and BMS to assess neoinTimal coveRAge by OCT Evaluation (DEMONSTR8), assessed the Ratio of Uncovered to Total Stent Struts Per Cross Section (RUTTS) score, determined by optical coherence tomography (OCT) at 1 and 3 months for Cre8™ and a bare metal stent (BMS), and found that the Cre8™ DES at 3 months has comparable strut coverage to the BMS at 1 month, while preserving a greater efficacy in neointimal formation reduction.2 A propensity matched study (San Raffaele Scientific Institute, Milan, Italy) compared clinical outcomes of 187 real-world patients treated with the amphilimus polymer-free Cre8™ stent versus 150 patients receiving new-generation everolimus-eluting stents (EES) during the same period. It found superior clinical outcomes with Cre8™ compared with an EES in patients with diabetes.3 The MultIceNtric and RetrospectiVe REgiStry in ‘real world’ paTients with polymer-free drug elutInG stent Cre8™ (INVESTIG8) study has as its primary endpoint the incidence of clinical composite endpoint from baseline procedure to 12 months (cardiac death/ target vessel MI/clinically driven TLR). Secondary endpoints include the incidence of a clinical composite endpoint from the baseline procedure to 12 months (all deaths/all MI/any revascularisation); and the incidence of stent thrombosis from baseline procedure to 12 months, classified according to the Academic Research Consortium (ARC) definition. A recent subanalysis indicates that at

Figure 1: Causes of Drug-eluting Stent Failure in Patients with Diabetes Mellitus

Worse acute results Smaller post-procedural MLD Longer and more complex lesions

↑Thrombotic risk

Polymer-related inflammation

Hypercoagulable state Resistance to antiplatelet drugs

↑Risk of restenosis

mTOR resistance Growth factors overexpression

Endothelial dysfunction

Aggresive CAD progression CAD = coronary artery disease; MLD = minimal lumen diameter; mTOT = mammalian target of rapamycin.

1 year, the composite endpoint was seen in 3.5 % of the population without diabetes and 5 % of those with diabetes. Clinically driven TLR was reported in 1.6 % of the population without diabetes versus 1.4 % of the population with diabetes. Freedom from events was seen in 97.8 % of the population without diabetes study and 95.6 % of those with diabetes. Definite and probable stent thrombosis occurred in only 0.6 % of the population without diabetes and 1.4 % of the population with diabetes. In the Randomized Trial Comparing Reservoir-Based Polymer-Free Amphilimus‐Eluting Stents (AES) versus Everolimus-eluting Stents with Durable Polymer in Patients with Diabetes Mellitus (RESERVOIR) study, 112 patients with diabetes receiving glucose-lowering agents, were randomised to an amphilimus-eluting stent (AES) (Cre8™) stent or an EES with non-erodible polymer. The primary endpoint was neointimal volume obstruction at 9 months, evaluated by OCT. Secondary endpoints included strut coverage, angiographic in-stent late lumen loss and clinical endpoints such as target vessel revascularisation and probably/definite stent thrombosis.4,5 Results show that the Cre8™ was non-inferior to the EES and demonstrated non-significant superiority in the primary endpoint. In addition, the Cre8™ resulted in a lower LLL with a lower standard deviation, though without achieving statistical significance. In conclusion, the ideal DES should combine safety with an increased DES efficacy. The Cre8™ DES has unique safety features (polymerfree structure, abluminal reservoir technology) and unique efficacy features (polymer-free structure and the amphilimus formulation), and is currently being tested in a large clinical programme. Data obtained so far suggest that the best application of Cre8™ seems to be the subset of patients with diabetes. n

Live Case of a Patient with Diabetes Mellitus This was a case of multivessel disease in a patient with DM. The patient had a prior history of atrial fibrillation (AF) and was taking oral anticoagulants. He was also suffering from hypertension, hyperlipidaemia and angina. An electrocardiogram (ECG) showed AF with ventricular response. Blood tests showed high glucose and glycated haemoglobin (HbA1c) levels and slightly abnormal cholesterol levels. The patient presented with angina (Canadian Cardiovascular

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Society [CCS] class 2). Angiography showed calcified stenosis of the proximal left anterior descending (LAD) artery and a double bifurcation stenosis of the marginal artery. The primary aim of the intervention was to treat the long lesion of the LAD. The lesion was wired using regular wire then dilated using a 2.0 balloon. A long stent was used (Cre8™ 46 mm), which crossed the

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Supported Contribution lesion easily. There were two bifurcation lesions: one proximal LCX and one distal. The marginal branch lesion was dilated with a 2.5 balloon and a single stent was used with good result. The aim was to put a stent on the main branch and the use of two stents was considered an alternative possible solution. A 2.5 mm x 20 mm Cre8™ stent was used for the proximal lesion; a 2.75 mm x 8 mm stent was used for the distal lesion. The artery was successfully opened. A 3.25 mm stent was used

for the distal circumflex lesion. A radial approach was selected because the patient was in AF taking oral anticoagulation. The use of the Cre8™ stent should allow cessation of DAPT at 3 months and to continue with a single antiplatelet agent as well as oral anticoagulation. Closure of the left atrial appendage (LAA) was discussed as an option if an issue arises with triple therapy. n

Polymer-free Technology in Patients with Diabetes Mellitus – Procedure and Clinical Outcome Rafael Romaguera of Barcelona, Spain, presented the case of a 62-yearold man with angina and DM, for which he was receiving insulin therapy. The patient was admitted with acute coronary syndrome (ACS) and 50–60 % stenosis in the LAD. The physician advised the patient that if a DES was used, he would do better than with BMS; that a secondgeneration DES is better than a first; that an EES has the most robust evidence of safety; and that he would be prescribed new antiplatelet drugs and statins. However, despite these interventions, he would remain at high risk of restenosis and adverse cardiovascular events. A 3.0 mm x 15 mm second-generation DES (zotarolimus-eluting stent [ZES]) was implanted. At 6-month follow up, the patient had stable angina. A 3.5 mm x 15 mm paclitaxel-eluting balloon was utilised to treat the restenotic lesion and the patient was discharged after experiencing no further events. However, 3 months later, the patient was readmitted due to an ACS and he was treated with crush stenting with a DES. The patient mentioned at the beginning of the presentation returned 3 months later with restenosis and received a stent of the left main. This patient was enrolled into the RESERVOIR clinical trial and received an AES. Dr Romaguera considered the causes of DES failure. Polymer-related inflammation is an important cause (see Figure 2). In addition, resistance to mammalian target of rapamycin (mTOR) inhibition is seen in patients with DM: a tenfold higher concentration of an mTOR inhibitor is needed in the diabetic cell to achieve similar inhibition to that seen in a non-diabetic one.6 The Cre8™ AES has unique features, making it well suited to patients with diabetes (see Figure 2). Among these, the amphiphilic carrier, which is a fatty acid, is a major component. Fatty acids play a main role in DM; cardiac cells cannot use glucose for energy generation as they are forced to utilise fatty acids. There is therefore an

Figure 2: Design of the Cre8™ Stent

Polymer-free platform

Abluminal reservoir technology

Amphilimus™ formulation: BIS – Bio induced surface sirolimus + organic acid

overexpression of cell membrane transporters and increased fatty acid uptake.7 The amphiphilic carrier utilises this mechanism to enhance drug delivery: more than 99 % of the drug is eluted to the vessel wall. Dr Romaguera concluded by describing DM as the Achilles heel of interventional cardiology. Around 30 % of patients present with DM, and these patients need different DES characteristics, leading to the concept of a DES for patients with diabetes. The Cre8™ stent may fulfill this need as it has demonstrated unique efficacy in this population. However, it is important to remember that patients with DM will remain at high risk of adverse events due to disease progression in non-stented segments. n

Percutaneous Coronary Intervention in a Patient with Dual Antiplatelet Therapy Constraints – Procedure and Clinical Outcome Pieter Stella of Utrecht, The Netherlands, began by discussing PCI in the subsets of patients who have DAPT constraints: these include patients receiving oral anticoagulants (OACs), aged over 80 years, with previous bleeding events, with scheduled and urgent surgery and those non-compliant to medication.

presence of: congestive heart failure, hypertension, age ≥75 years, DM [CHADS2] score), whether or not the patient presents with ACS and the choice between BMS and DES. Age is also an important consideration; in octogenarians, the use of DES is associated with a lower cumulative death or MI rate (15.1 %) than with BMS (17.7 %).8

The first factor associated with patients taking OACs is peri-procedural management during PCI. The choice of vascular access site is important, as is anticoagulant and antiplatelet management. The second factor is long-term management, where the risk of bleeding must be balanced against the risk of stent thrombosis. Factors that should be taken into consideration include bleeding risk, stroke risk (assessed by the

The duration of DAPT has been the subject of considerable recent debate. A recent meta-analysis of 10 randomised controlled trials (RCTs) and 31,666 patients investigated mortality with extended duration DAPT. Although treatment with DAPT beyond 1 year after DES implantation reduces MI and stent thrombosis, it was associated with increased mortality because of a 49 % increased risk of non-

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cardiovascular mortality, which is not offset by a reduction in cardiac mortality. It is worth mentioning that this could have been chance finding. In addition, prolonged DAPT has been associated with a 72 % risk of major bleeding.9 Therefore extended duration DAPT is not routinely recommended following PCI with stent implantation, but without DAPT, the risk of stent thrombosis increases.

Figure 3: Principal Causes of Drug-eluting Stent Thrombosis 5% 11 % 28 % 14 %

The principal causative factors of DES stent thrombosis are summarised in Figure 3.10 Of these, around 25 % are procedural-related issues, 36 % are DES safety-related issues and 34 % are DES efficacy-related issues. In a case-controlled study of 54 cases and 35 controls, the presence of uncovered stent struts was associated with stent thrombosis after DES: with a RUTTS score exceeding 30, stent thrombosis was seen in 21.6 % of cases versus none in cases with a RUTTS score less than 30.11 In terms of DES efficacy issues related to stent restenosis, a RCT showed that EES were comparable to sirolimus-eluting stents (SES) in terms of overall clinical efficacy and safety.12 Therefore, optimising the choice of DES can reduce stent thrombosis by approximately 70 %. The Cre8™ DES features a polymer-free platform to reduce the risk of inflammation associated with durable polymers and the breakdown products of absorbable biopolymers (see Figure 2). A drug-delivery system, abluminal reservoir technology, utilises a formulation of sirolimus and a fatty acid, amphiphilic carrier. Sirolimus, an mTor inhibitor, is an immunosuppressant with antiproliferative and antimicrobial activity. In addition, it inhibits inflammatory cell activities and has high potency. The organic acid maintains sustained drug delivery; fatty acids are used to improve the transdermal delivery of numerous drugs.13 The fatty acid also enhances drug stability, as well as increasing the bioavailability of the drug; cardiac fatty acid uptake is doubled in diabetic mouse models.14 This results in an increased homogeneous drug distribution in diabetic cardiac cells. In addition, the bio inducer surface, a second-generation integral pure carbon coating, is designed to accelerate stent endothelialisation and strut coverage, thus reducing the risk of thrombosis. The Cre8™ DES is polymer-free, eliminating the disadvantages associated with durable polymers or their breakdown products. To end the presentation, Professor Stella discussed his experience with implantation of the Cre8™ stent in the University Medical Centre, Utrecht. To date, 786 implantations have been performed, 372 with

Neoatherosclerosis Restenosis Uncovered struts Underexpansion Malapposition Other

36 % Source: Byrne, 2014.10

ACS and 414 with stable disease. All stable elective cases were treated with life-long aspirin and clopidogrel for 3 months; all ACS cases were treated with 12 months of DAPT. Outcomes to date have been excellent. In patients presenting with stable disease: at 6 months, stent thrombosis was seen in only 0.2 % of patients and TLR in 1.2 %. These findings have led to a new study design; an investigator-initiated randomised two-centre study, RECre8, which is currently enrolling, aims to recruit around 1,530 patients and is designed to compare the Resolute Integrity DES (Medtronic) versus Cre8™. Participants will be given 1 month DAPT in elective PCI and 12 months DAPT in ACS. Clinical follow up will be at 12 months and 3 years and will assess all MACE. To end the presentation, Professor Stella presented a case of a 78-year-old man admitted for colon cancer, who suffered an ACS; an ECG showed inferolateral MI. Potential strategies included plain old balloon angioplasty (POBA), drug-eluting balloon (DEB) and implantation of a BMS or DES. The patient was treated with Cre8™ DES implantation and 4 weeks DAPT. At 4 weeks, OCT showed that all the struts were covered; therefore, the patient was referred for surgery and DAPT therapy was stopped. Six weeks later, an untreated residual stenosis was stented. The patient was doing well at clinical follow-up. In conclusion, the Cre8™ polymer-free DES combines excellent efficacy with the safety associated with BMS, and offers the potential for reduced duration of DAPT. The ReCre8 study will further study the efficacy and safety of the Cre8™ stent with further reduced DAPT. n

Summary and Concluding Remarks Patients with DM often present with multivessel disease and complex lesions. The polymer-free technology of the Cre8™ stent makes it a good choice in patients with diabetes. Clinical studies to date have demonstrated excellent outcomes in this 1.

Carrie D, Berland J, Verheye S, et al. A multicenter randomized trial comparing amphilimus- with paclitaxeleluting stents in de novo native coronary artery lesions. J Am Coll Cardiol 2012;59 :1371–6. Prati F, Romagnoli E, Valgimigli M, et al. Randomized comparison between 3–month Cre8 DES vs. 1–month Vision/Multilink8 BMS neointimal coverage assessed by OCT evaluation: the DEMONSTRATE study. Int J Cardiol 2014;176 :904–9. Panoulas VF, Latib A, Naim C, et al. Clinical outcomes of realworld patients treated with an amphilimus polymer-free stent versus new generation everolimus-eluting stents. Catheter Cardiovasc Interv 2015: Epub ahead of print. Romaguera R, Brugaletta S, Gomez-Lara J, et al. Rationale and study design of the RESERVOIR trial: A randomized trial comparing reservoir-based polymer-free amphilimus-eluting stents versus everolimus-eluting stents with durable polymer in patients with diabetes mellitus. Catheter Cardiovasc Interv 2015;85 :E116–E22.

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important patient subgroup. The live case demonstrated the advantages of the Cre8™, which include minimising time taking DAPT, an important consideration for patients who are also receiving oral anticoagulation. n

Abbate A, Kontos MC, Biondi-Zoccai GG, No-reflow: the next challenge in treatment of ST-elevation acute myocardial infarction. Eur Heart J 2008;29 :1795–7. 6. Lightell DJ Jr, Woods TC, Relative resistance to Mammalian target of rapamycin inhibition in vascular smooth muscle cells of diabetic donors. Ochsner J 2013;13 :56–60. 7. Glatz JF, Luiken JJ, Bonen A, Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 2010;90 :367–417. 8. Bainey KR, Selzer F, Cohen HA, et al. Comparison of three age groups regarding safety and efficacy of drug–eluting stents (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am J Cardiol 2012;109 :195–201. 9. Palmerini T, Benedetto U, Bacchi–Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015;385 :2371–82. 10. Byrne RA, Stent thrombosis after drug-eluting stenting, insights

11.

12.

13. 14.

from the European–wide PRESTIGE registry. Presented at Cardiovascular Research Technologies Conference, 22–25 February 2014, Washington DC, US. Guagliumi G, Sirbu V, Musumeci G, et al. Examination of the in vivo mechanisms of late drug-eluting stent thrombosis: findings from optical coherence tomography and intravascular ultrasound imaging. JACC Cardiovasc Interv 2012;5 :12–20. Byrne RA, Kastrati A, Massberg S, et al. Biodegradable polymer versus permanent polymer drug-eluting stents and everolimus- versus sirolimus-eluting stents in patients with coronary artery disease: 3–year outcomes from a randomized clinical trial. J Am Coll Cardiol 2011;58 :1325–31. Kim MJ, Doh HJ, Choi MK, et al. Skin permeation enhancement of diclofenac by fatty acids. Drug Deliv 2008;15 :373–9. Chabowski A, Gorski J, Glatz JF, et al. Protein-mediated fatty acid uptake in the heart. Curr Cardiol Rev 2008;4 :12–21.

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Absorbable Polymer Technology – Viable Solutions for Unmet Needs in PCI Proceedings of two satellite symposia held at EuroPCR, Paris in May 2015 K a trina Mou n t f o r t , M e d i c a l Wr i t e r, Ra d c l i f f e Ca r d i o l o g y Reviewed for accuracy by: Ahmed Khashaba, 1 Roberto Garbo, 2 Kurstat Tigen, 3 Helge Moellmann 4 and Marie-Claude Morice 5 1. Ain Shams University and the Al Dorrah Heart Care Hospital Cairo, Egypt; 2. San Giovanni Bosco Hospital Turin, Italy; 3. Marmara University, Istanbul, Turkey; 4. Kerckhoff-Klinik, Bad Nauheim, Germany; 5. Institut Cardiovasculaire Paris Sud, Massy, France

Abstract The use of drug-eluting stents (DES) has improved clinical outcomes in percutaneous coronary intervention procedures, but many challenges remain. In two symposia at EuroPCR 2015, the factors necessary to ensure successful chronic total occlusion (CTO) intervention were presented. Good preparation, sufficient operator experience and the correct approach are key to the success of CTO interventions. A live case demonstrated the challenges of these complex cases. Stent choice in CTO interventions is crucial; second-generation DES are associated with lower rates of restenosis and re-occlusion compared with first-generation DES. The Coracto™ DES features unique structural properties and rapidly absorbable polymer, resulting in excellent conformability, efficacy and safety.

Keywords Percutaneous coronary interventions, drug-eluting stent, chronic total occlusions Disclosure: R Garbo has received consultancy fees from Alvimedica Medical Technologies, Terumo, and Volcano; and honorarium from Abbot Vascular. The others authors have made no disclosures. Received: 27 July 2015 Accepted: 3 August 2015 Citation: Interventional Cardiology Review, 2015;10(3):162–6 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN, UK. E: katsmountfort@virginmedia.com Support: The publication of this article was supported by Alvimedica.

Although the latest polymeric drug-eluting stents (DES) have enhanced percutaneous coronary intervention (PCI) procedures, a substantial proportion of patients requiring percutaneous transluminal coronary angiography (PTCA) is elderly with numerous different comorbidities. This population requires use of effective DES that can minimise the risk of bleeding and/or thrombosis. Two symposia were held at EuroPCR, the official congress of the European Association of Percutaneous Cardiovascular Interventions, in Paris

on 19–22 May 2015, with the objectives of sharing clinical experiences in the use of absorbable polymer stents and to understand why an absorbable polymer DES may be specifically indicated in PCI subsets such as chronic total occlusions (CTOs) or tortuous coronary anatomies. To meet these clinical challenges, a novel DES was discussed: Coracto™ (Alvimedica) is a DES with a unique design that elutes sirolimus from an absorbable poly(lactic-co-glycolic acid) (PLGA) polymer. n

How to Ensure Procedural Safety and Good Long-term Results in Complex Coronary CTO Procedures Professor Ahmed Khashaba of Cairo, Egypt presented the factors that should be considered before performing a CTO procedure. First, it is essential to select the right patient, keeping in mind that the expected benefit of a CTO procedure must exceed the negative consequences. It is also important to take the age of the patient into account, as well to assess the level of anti-ischaemic medical therapy received, the symptom status and the ischaemic burden. According to current guidelines, percutaneous recanalization of CTOs should be considered in patients with expected ischaemia reduction in a corresponding myocardial territory and/or angina relief.1 In addition, retrograde recanalisation of CTOs may be considered after a failed antegrade approach or as the primary approach in selected patients. In a meta-analysis comparing successful and failed PCI for CTO, successful PCI recanalisation of a CTO was associated with improved long-term clinical outcomes.2 In

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another meta-analysis, successful recanalisation was associated with a significant reduction in the rate of residual/recurrent angina.3 Good preparation is essential for performing CTO procedures. Preprocedural imaging should include myocardial perfusion imaging to assess ischaemia and myocardial viability, and multiple detector computed tomography to determine the 3D vessel course in the occluded segment, the length and composition of the CTO, and the distal vessel size and remodelling. Pre-procedural medications should comprise standard dual antiplatelet (DAPT) and anti-ischaemic therapy. Strategies to prevent contrast-induced nephropathy should also be considered; these include discontinuing any nephrotoxic drugs, intravascular volume expansion and administering a predefined maximum radiographic contrast dose (4 ml x body weight [kg]/serum creatinine [mg/dl]).

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It is also important to tailor the case selection to the level of experience of the operator. A Level C operator (i.e. having undertaken <500 PCIs) should only perform PCI of simple lesions and simple bifurcations. A Level B operator (500–1000 PCIs) may perform more complex procedures including PCI of complex bifurcations, moderate calcified lesions and some cases of CTO. Only a Level A operator (>1000 PCIs, including ≥300 CTOs) should be permitted to perform PCI of difficult cases such as long and highly calcified lesions and complex CTOs, including retrograde approaches. If a Level C operator attempts a Level A task, he/she is less likely to be successful and may cause harm to the patient.4 Data from the European CTO registry shows the correlation between success rate and case load in performing PCI for CTOs (see Figure 1; http://www.ercto.org/).

Figure 1: Relationship Between Success in Performing Percutaneous Coronary Interventions in Chronic Total Occlusions and Case Load Variance analysis p<0.001 100 84

88 89

Percentage (%)

Radiation dose management is essential as radiation injury can lead to severe consequences for the patient, ranging from erythema that resolves in hours to ulceration that can take >6 weeks to heal; therefore, the patient should not undergo a repeat procedure prematurely.

86 78

89 91 80

60 40 20 0 2008

2009

2010

2011

2012

Year >150–200 procedures

>200–300 procedures

>300 procedures

Source: http://www.ercto.org/

Another essential factor in assuring success with CTO procedures is the use of the appropriate approach. A bilateral femoral approach gives a larger lumen for more equipment and better support, but has a higher rate of vascular complications. A bilateral radial approach results in a smaller lumen, less support, higher radiation exposure, but has a lower rate of vascular complications and better patient comfort. A combined femoral and radial procedure is the optimal approach, using a larger sheath/guide than when using an antegrade approach. It is essential to exert minimal disruption during the PCI procedure. A study assessing the incidence of reocclusion and identification of predictors of angiographic failure after successful CTO, found that a successful subintimal tracking and re-entry technique was associated with a 57 % reocclusion rate.5 However, the use of everolimus-eluting stents was associated with a significantly lower reocclusion rate. The immediate outcome should be optimised – a final thrombolysis in myocardial infarction flow < grade 3 (TIMI <III) is associated with lower major adverse cardiac event-free survival rate.6 A recent study found

that the use of intravascular ultrasound (IVUS)-guided intervention leads to increased post-dilation, balloon pressures and post-procedural minimum lumen diameter, and improved clinical outcomes compared with conventional angiography-guided approaches.7 Finally, stent choice for CTO interventions is crucial; second-generation DES are associated with lower rates of restenosis and re-occlusion compared with first-generation DES.5,8–10 An ideal stent for a complex CTO intervention would be a biodegradable polymer or polymer-free DES with thin struts and vessel conformability, thus resulting in good vessel coverage, low or no longitudinal stent deformation and low restenosis rates. In conclusion, appropriate pre-procedural planning is key to ensuring high success rates and avoiding unnecessary risk. Optimising the immediate outcome is essential to maintaining long-term patency. This may be facilitated by minimal vessel disruption, and the use of IVUS and second-generation DES. Currently available DES with absorbable polymer may further improve device safety and efficacy. n

Live Case Demonstration In order to illustrate the points discussed, a live case was presented from the Institut Cardiovasculaire Paris Sud, Massy, France. The patient was a 56-year-old man with hypertension and hyperlipidemia, and he was an ex-smoker, but had an active lifestyle. The patient had a history of obstructive sleep apnoea and ischaemic heart disease with inferior ST elevation in 2007, when he underwent implantation of a bare-metal stent (BMS) into the left circumflex artery (LCX). In 2012 he had a negative MRI stress test. He presented with 3 months of dyspnoea and a positive MRI stress test in April 2015. At this time his renal function was normal. An ECG showed evidence of the previous infarct. An echocardiogram showed focal hyperkinesis with normal pulmonary pressures and there was a positive MRI for ischemia in the atrial septal regions; the injection fraction was normal in the two-chamber view; and focal anteroseptal and apical ischaemia were detected in 4 of 17 segments. A delayed perfusion scan showed evidence of the previous infarct. The cranial view on angiogram showed proximal left anterior-descending artery (LAD) occlusion with a tapered proximal cap. The right coronary artery (RCA) also showed proximal stenosis.

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A biradial antegrade approach was used from the left radial artery to the RCA, with the aim of minimising the risk of bleeding complications. The occlusion was a CTO of approximately 10 mm with a J-CTO score of 0 or 1. An antegrade microcatheter approach was taken to penetrate the proximal cap using soft wire, thus minimising the use of a contrast agent. A double injection was used. Little ischaemia was evident but a proximal LAD occlusion was seen. The Gaia guidewire was rotated rather than pushed into the cap. The proximal section was relatively easy to cross but the distal section was more difficult. The wire was withdrawn and re-entry attempted but it was not possible to cross the lesion with a microcatheter. To stabilise the catheter, trapping with a balloon was considered the safest approach. At the second attempt, the wire still did not move freely but managed to cross the occlusion. However, difficulty was encountered in crossing the occlusion with a balloon. An anchoring technique was then used to support the guide. The guidewire was changed and a subsequent predilation with a 2.0 balloon proved easier. However, the lesion was so calcified that the predilation was not fully successful, therefore a 2.5 balloon was used, up to

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maximum 6 months. If the patient tolerates DAPT and is doing well, there is no need to stop early. n

PCI in a Patient with a Complex Coronary CTO: Procedure and Clinical Outcome Dr Roberto Garbo of Turin, Italy began his presentation by stating that the availability of DES has greatly improved outcomes in CTO, as the use of BMS has been associated with revascularisation and restenosis. However, a DES has specific requirements when treating CTO; these include deliverability, stent matching to the vessel and good clinical results at follow-up. In terms of delivery, the Coracto DES features optimised geometry in the ‘crimped’ state owing to its sinusoidal link position that allows flexibility (see Figure 2), thin stent struts (a total strut thickness of 88 μm, lower than other currently available DES) and an optimised delivery system. Next, Dr Garbo considered stent matching to the vessel. The Coracto DES also features optimised geometry in its expanded state, a result of its sinusoidal link shape. Another important consideration is elastic recoil, i.e. the natural reduction in diameter of the stent after deflation of the balloon due to the elasticity of the stent material. Most DES are formed of cobalt-chromium, which has an average recoil of 5–6 %. The Coracto DES is made of stainless steel, which has an average recoil of only 2–3 %.11 Stent recoil has been identified as a significant predictor of late lumen loss (LLL).12 Longitudinal stent deformation is also a crucial factor in matching a stent to a vessel. The sinusoidal shape of the links in the Coracto stent minimises longitudinal deformation. The stent has a maximum expanded cell diameter of 4.0 mm, making it ideal for side-branch crossing.11 Finally, the Coracto DES is designed to optimise clinical outcomes. Preclinical studies indicated that the polymer of the Coracto DES provides controlled release of rapamycin (sirolimus), and degradation of the polymer is completed within 8–10 weeks, leaving a BMS (see Figure 3).13

Figure 2: The Coracto™ Drug-eluting Stent Sinusoidal link position allows structures relative movement in crimped state

Platform flexibility in crimped state

In expanded state, sinusoidal links minimise longitudinal stent deformation Before

After

Figure 3: The Coracto Stent: Rapid Absorption of Polymer DES implantation

8–10 weeks*

BMS

Sirolimus H2O Sirolimus

H2O

Lactis & Glycolic Lactis & Glycolic H O Acid, Oligomers 2 Acid, Oligomers

PLGA

Dr Garbo presented a case of a 75-year-old man with effort angina and moderate antero-lateral ischaemia identified by single-photon emission computerised tomography. A basal angiogram showed LAD ostial occlusion with some collateral flow from the right. The blunt CTO segment and occlusion length of >20 mm resulted in a J-CTO score of 2, which indicates a difficult procedure with reduced success rate (<90 %).14 Treatment of the CTO was by PCI of the ostial LAD with a bilateral femoral approach using a Fielder XT-A guidewire and a Corsair 135 catheter. A contralateral injection was performed to confirm entry into the true lumen, followed by predilation with the microcatheter. IVUS was also used to evaluate the left main (LM) artery. Two stents were implanted: a Coracto 3.0 × 24 mm and a 3.5 × 17 mm on the LM artery. Proximal optimisation technique was performed in the LM artery with an NC 4.0 balloon and a triple kissing balloon 3.5–2.5–2.5 was also needed. Final IVUS confirmed the success of the procedure. At 9 months’ follow-up, angiography and optical coherence tomography (OCT) were performed. Good endothelialisation of all stents

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BMS

Hydration

PLGA hydrolysis

Mass loss

BMS

BMS = bare metal stent; DES = drug-eluting stent; PLGA = poly(lactic-co-glycolic acid) *Reifart et al.13

was seen with mild in-stent restenosis on the worst area of occlusion (LLL: 0.39 mm). In conclusion, complex CTO recanalisation is easier to achieve when using the most appropriate method (e.g. controlateral injection for the visualisation of distal vessels) and adequate materials (microcatheters and dedicated wires). The Coracto DES has unique properties that make it a useful option in treating such challenging lesions, including rapid reabsorption of polymer. It has demonstrated a good safety profile, showing complete endothelialisation of all struts at follow-up OCT evaluation. n

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PCI in a Patient with a Complex Coronary Anatomy: Procedure and Clinical Outcome Dr Kursat Tigen, of Istanbul, Turkey discussed the challenges of PCI in complex coronary anatomy, which includes unprotected LM stenosis, bifurcation lesions, CTOs, long lesions, diffuse lesions, severe calcification and tortuosity, and thrombotic and undilatable lesions. Atraumatic delivery and precise positioning of a stent across the target lesion are the most basic requirements of a successful intervention. This requires careful preparation, including selection of the access site, guiding catheter (type, size and curve), guidewire and dedicated devices for lesion crossing, as well as a planned procedure, including the decision whether to perform predilation, direct stenting and single- or double-stent strategy. The need for surgical back-up and pharmacotherapy to reduce the risk of thrombotic complications should also be considered. Stent selection is an important part of planning an intervention, with the aim of avoiding procedural failure. Unfavourable mechanical properties of stent delivery systems such as rigidity, poor deliverability and crossability can reduce the success rates in complex coronary PCI procedures. Resistance to longitudinal deformations is also important and is influenced by strut thickness, connector number and design.

III) and dyspnoea. He had arterial hypertension, diabetes and a family history of coronary artery disease, and had been a smoker for 40 years. Echocardiography showed inferior hypokinesia with preserved ejection fraction, as well as mild mitral regurgitation. The angiogram showed mild proximal LAD disease but severe stenosis in the body and the side branch of the LCX artery. The RCA also had sub-total occlusion from the proximal to the distal end of the vessel; this was a long lesion. Fractional flow reserve measurement of the proximal LAD disease revealed a haemodynamically non-significant lesion (basal: 0.89; maximum hyperaemia: 0.81). The procedure was carried out with PCI to the complex RCA lesion. Peri-procedural management included a loading dose of 300 mg clopidogrel and 100 mg aspirin, and 8000 IU heparin for anti-coagulation. A right femoral approach was selected with a 7F sheath, a JR4 AlviguideBlue+ guiding catheter used for coronary engagement and a BMW Universal 0.014 inch guidewire was used for lesion crossing. This passed the lesions easily despite marked complexity. Predilation was performed using a 1.25 x 15 mm balloon, then a 2.0 x 20 mm balloon. Stenting was performed using a full-metal jacket procedure from the proximal segment of the postero-lateral branch to the osteal RCA. A 2.5 x 28 mm Coracto DES was followed

The open-cell design is preferred to increase the flexibility of the stent at the expense of reduced radial force. The mechanical response of coronary stent systems has been described using terms such as pushability, trackability, crossability, flexibility and conformability. Each of the three delivery parameters (pushability, trackability and crossability) is based on the resisting forces that can be quantified along the delivery path.

by 2.75 x 28 mm, 3.0 x 32 mm and 3.0 x 21 mm Coracto DES, and the procedure was finalised with 3.0 x 15 mm non-compliant balloon postdilation up to 24 atmospheres. The final angiogram revealed good stent expansion and strut coverage with a TIMI-III flow. Despite severe tortuosity and calcification, the stent conformability was excellent. One year angiographic follow-up demonstrated an intact RCA with all stents open and no significant restenosis.

Pushability represents the transmission of the applied force to the catheter tip, and hence ‘feel’ of the operator. The bending stiffness of the stent system also contributes to the pushability. Bending stiffness is a measure of the structure’s resistance to bending deformation and is the reciprocal of flexibility. Trackability is the ability of stent delivery system (SDS) to track or move easily through the curved vascular pathway. The ability of the SDS to bend and twist will most likely depend on the geometry of the connections and raw material. Low tracking forces are necessary to prevent stent dislodgement or mechanical vascular injury. Crossability is the ability of SDS to pass through the target lesion. Crossability depends mainly on the profile of the crimped stent. Low-profile SDS devices appear to be essential in cases with extremely tight and complex target lesions. Flexibility is critical in preservation of the function and the integrity of the stent in complex coronary interventions. Flexible stents are easily inflated and show great adaptability to vessel shape compared with a rigid stent. The ability of a stent system to conform to the geometrical shape of the vessel after stent implantation is defined as conformability. Stent conformability is associated with efficient and homogeneous diffusion of the anti-proliferative drugs in the coronary vessels. Stents with biodegradable polymer technology are also desired devices for complex lesions as they have been associated with lower rates of late stent thrombosis.

In addition to the favourable mechanical properties increasing the success rate, such as stent design, thin struts and low polymer thickness, resulting in a DES that is easy to manipulate, several factors influenced the choice of Coracto DES in this complex coronary procedure. Its 100 % absorbable (PLGA) coating is quickly absorbed, assuring no long-term inflammation with optimised endothelialisation and reduced rates of stent restenosis. Controlled elution of sirolimus is also associated with excellent efficacy in terms of anti-proliferative properties.

To illustrate these factors, Dr Tigen presented the case of a 50-year-old man who had exercise angina (Canadian Cardiovascular Society Grade

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In challenging endovascular anatomy, usually more than one important mechanical property of SDS and the stent platform may come in to play. In practical terms, the design of the Coracto DES presents numerous advantages in complex coronary interventions. Greater pushability is useful for small vessels and diffuse atherosclerotic disease with narrow proximal access. Good trackability and flexibility are beneficial in diffuse or calcified lesions, highly tortuous proximal vessels and distal target lesions. Furthermore, a high demand on crossability is required in cases with tight and complex target lesions. Finally, stent conformability is essential in homogeneous diffusion of the anti-proliferative drugs in the coronary vessels. In conclusion, the Coracto DES is a safe and effective option in PCI of complex coronary anatomy cases with high procedural success rates and long-term beneficial effects. n

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Summary and Concluding Remarks These presentations have highlighted some important unmet needs in PCI interventions. In complex clinical cases such as CTO and full-metal

Authors/Task Force Members, Windecker S, Kolh P, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for CardioThoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. Khan MF, Wendel CS, Thai HM, et al. Effects of percutaneous revascularization of chronic total occlusions on clinical outcomes: a meta-analysis comparing successful versus failed percutaneous intervention for chronic total occlusion. Catheter Cardiovasc Interv 2013;82:95–107. Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of chronic total occlusions: a systematic review and meta-analysis. Am Heart J 2010;160:179–87. Reifart N. Antegrade approach: step by step. In: Waksman R, Saito S (eds). Chronic Total Occlusions: A Guide to Recanalization. Oxford: John Wiley & Sons, 2013;126–33. Valenti R, Vergara R, Migliorini A, et al. Predictors of reocclusion

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jacket procedures, the Coracto stent’s unique structure and rapid polymer absorption offers excellent conformability, efficacy and safety. n

after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion. J Am Coll Cardiol 2013;61:545–50. 6. Galassi AR, Boukhris M, Tomasello SD, et al. Long-term clinical and angiographic outcomes of the mini-STAR technique as a bailout strategy for percutaneous coronary intervention of chronic total occlusion. Can J Cardiol 2014;30:1400–6. 7. Cardiovascular Research Foundation. Results of IVUS-CTO Trial Reported at TCT 2014 [press release]. 2014. Available at: http:// bit.ly/1E5mJC7 (accessed 20 August 2015). 8. Moreno R, Garcia E, Teles R, et al. Randomized comparison of sirolimus-eluting and everolimus-eluting coronary stents in the treatment of total coronary occlusions: results from the chronic coronary occlusion treated by everolimus-eluting stent randomized trial. Circ Cardiovasc Interv 2013;6:21–8. 9. Wohrle J, Werner GS. Paclitaxel-coated balloon with bare-metal stenting in patients with chronic total occlusions in native coronary arteries. Catheter Cardiovasc Interv. 2013;81:793–9. 10. Van den Branden BJ, Teeuwen K, Koolen JJ, et al. Primary Stenting

11.

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of Totally Occluded Native Coronary Arteries III (PRISON III): a randomised comparison of sirolimus-eluting stent implantation with zotarolimus-eluting stent implantation for the treatment of total coronary occlusions. EuroIntervention 2013;9:841–53. Alvimedica. Coracto technical information. Available at: http:// www.alvimedica.com/wp-content/uploads/2013/02/IC-DESCORACTO-IC0701555081-REV-B.pdf (accessed 28 May 2015). Escaned J, Sandoval J, Colmenarez H, et al. Stent recoil and angiographic outcome in drug eluting stents. Results of the STEREO-DES pilot study. J Am Coll Cardiol 2011;58 (Suppl B):TCT-633. Reifart N, Hauptmann KE, Rabe A, et al. Pre-clinical and Clinical Study Results for the CoractoTM Rapamycin-eluting Stent – A New-generation Drug-eluting Stent. Interventional Cardiology 2010;5:39–42. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21.

INTERVENTIONAL CARDIOLOGY REVIEW

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LAA 2015 – HOW TO CLOSE THE LEFT ATRIAL APPENDAGE NOVEMBER 20 – 21, 2015 | FRANKFURT, GERMANY The majority of patients with atrial fibrillation cannot take anticoagulation initially or have to stop it later due to complications. Even newly invented anticoagulants are often unsuitable for these patients. Left Atrial Appendage closure for stroke prevention in atrial fibrillation has been shown to be a good alternative to anticoagulation therapy. Three devices have CE mark and many others are already in clinical trials.

This 2-day course is designed to give you an overview on all aspects of this treatment modality. Clinical studies will be covered and we will also demonstrate how to perform the procedure step by step and how to prevent and manage complications. Live case transmissions are a core aspect of this course and will allow direct attendee-operator interaction to maximize the learning experience.

NS TR AT IO NS OM LIV E CA SE DE MO – WATC H & LE AR N FR RT S FR OM LE AD IN G EX PE – FO LL OW LE CT UR ES HU B TIC E AT TH E TR AI NI NG – DE EP EN YO UR PR AC E WI TH CO LL EA GU ES – DI SC US S AN D SH AR N IN DU ST RY EX HI BIT IO – NE TW OR K AT TH E

SC AN FO R LA A PR OG RA M :

LAA 2015, NOVEMBER 20 – 21 | FRANKFURT, GERMANY FOR FURTHER INFORMATION OR TO REGISTER:

AP PR OV ED FO R CM E

www.csi-congress.org/laa

BOARD OF DIRECTORS Horst Sievert, MD | Shakeel A. Qureshi, MD | Neil Wilson, MD | Sameer Gafoor, MD | Stefan Bertog, MD

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Upcoming CRF Educational 2016 Events – Save the Dates TTT in Partnership with TCT

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Taiwan Transcatheter Therapeutics January 9-10, 2016 Taipei City, Taiwan

Chinese Interventional Therapeutics March 17-20, 2016 Beijing, China

BIT (TCT Highlights Session)

Echo

Bangla Interventional Therapeutics February 5-7, 2016 Kolkata, India

JIM in Partnership with TCT Joint Interventional Meeting February 11-13, 2016 Milan, Italy

CADECI in Partnership with TCT Sociedad Mexicana de Electrofisíologia y Estimulación Cardíaca February 17-20, 2016 Guadalajara, Mexico

CTO Chronic Total Occlusion Summit 2016: A Live Case Demonstration Course February 25-26, 2016 New York Marriott Marquis New York, NY A CRF Event

TCT@ACC-i2 March 2-4, 2016 Chicago, IL

Echocardiography Conference: State-of-the-Art 2016 March 21-23, 2016 New York, NY

Intravascular Coronary Imaging and Physiology Intravascular Coronary Imaging and Physiology 2016: A Clinical Workshop March 2016 New York, NY

Fellows Interventional Cardiology Fellows Course April 14-17, 2016 Orlando, FL A CRF Event

CardioVascular Summit – TCTAP CardioVascular Summit April 26-29, 2016 Seoul, South Korea

TCT @ AATS May 14-18, 2016 Baltimore, MD

TCT Russia June 2016

SOLACI in Partnership with TCT Sociedad Latinoamericana de Cardiología Intervencionista June 8-10, 2016 Rio de Janeiro, Brazil

Gi2 in Partnership with TCT Global Summit on Innovations in Interventions June 8-10, 2016 Rio de Janeiro, Brazil

TCT India Next August 2016 Delhi, India

Società Italiana di Cardiologia Invasiva October 2016 Genoa, Italy

CACI (TCT Highlights Session) Colegio Argentino de Cardioangiólgos Intervencionistas October 2016 Buenos Aires, Argentina

PULSE Pulse of the City Gala December 11, 2016 New York, NY A CRF Event

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Innovations in Cardiovascular Interventions December 2016 Tel Aviv, Israel

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LEADERSHIP IN LIVE CASE DEMONSTRATION

F E B R U A R Y 11-13, 2016

JOINT INTERVENTIONAL MEETING IN PARTNERSHIP WITH

, Italy

w w w . j i m - v a s c u l a r . c o m ORGANIZING SECRETARIAT Victory Project Congressi • Via C. Poma, 2 - 20129 Milan - Italy Phone +39 02 89 05 35 24 • Fax +39 02 20 13 95 • E-mail info@victoryproject.it Untitled-1 175

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Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

AN INTERACTIVE LIVE CASE COLLABORATION BETWEEN

LIVE FROM THE HAMMERSMITH

ON DEMAND – Contemporary management of Acute Coronary Syndrome (ACS) from diagnosis to therapy

Livestream organised & funded by AstraZeneca & Medtronic

ON DEMAND VIDEO AVAILABLE

AGENDA SUMMARY • Identification and confirmation of ACS diagnosis • Evidence basis for diagnostic pathway • Pre-procedural work-up and pharmacological regime based on the latest clinical evidence base • Invasive diagnostic work-up • Assessment of stenosis severity • Revascularisation • Take Home Messages

Performed by

Dr. Justin E Davies Consultant Cardiologist Imperial College NHS Trust

This live case was also streamed at the AstraZeneca booth (E100 &E150) with Professor Carlo Di Mario as special guest moderator during the ESC 2015 at the Excel Centre, London, UK

WATCH ON DEMAND VIDEO NOW For more information visit www.radcliffecardiology.com/academy/livecases August 2015 - ATLAS ID: 828.602,011 - Expiry date: August 2016

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Supporting life-long learning for interventional cardiovascular professionals Led by Editor-in-Chief Simon Kennon and underpinned by an editorial board of worldrenowned physicians, Interventional Cardiology Review is a peer-reviewed journal that publishes reviews, case reports and original research. Available in print and online, Interventional Cardiology Reviewâ&#x20AC;&#x2122;s articles are free-to-access, and aim to support continuous learning for physicians within the field.

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

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