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Interventional Cardiology Review Volume 12 • Issue 1 • Spring 2017

Volume 12 • Issue 1 • Spring 2017

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Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies Maurizio Taramasso, Christelle Calen, Andrea Guidotti, Shingo Kuwata, Hector Rodriguez Cetina Biefer, Fabian Nietlispach, Michel Zuber and Francesco Maisano

Managing Stroke During Transcatheter Aortic Valve Replacement Florian Hecker, Mani Arsalan and Thomas Walther

Aortic Dissection: Novel Surgical Hybrid Procedures Alessandro Cannavale, Mariangela Santoni, Fabrizio Fanelli and Gerard O’Sullivan

Use of Intravascular Ultrasound Imaging in Percutaneous Coronary Intervention to Treat Left Main Coronary Artery Disease Giovanni Luigi De Maria and Adrian P Banning

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Volume 12 • Issue 1 • Spring 2017

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

Section Editor – Structural

Section Editor – Coronary

Darren Mylotte

Angela Hoye

Galway University Hospitals, Galway

Castle Hill Hospital, Hull

Fernando Alfonso

A Pieter Kappetein

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Sergio Baptista

Tim Kinnaird

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

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

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

Ferrarotto Hospital, Catania

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

Azeem Latib

Lutz Buellesfeld

Didier Locca

San Raffaele Hospital, Milan

University Hospital, Bern

Jonathan Byrne King’s College Hospital, London

Antonio Colombo San Raffaele Hospital, Milan

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

Sameer Gafoor CardioVascular Center, Frankfurt

Gennaro Sardella Sapienza University of Rome, Rome

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

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

Mount Sinai Hospital, New York

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Thomas Modine

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

Marko Noc

Eric Eeckhout

Beth Israel Deaconess Medical Center, Boston

Lars Søndergaard

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

Carlo Di Mario

Jeffrey Popma

Roxana Mehran

Jeffrey Moses

Imperial College NHS Trust, London

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

Lausanne University Hospital, Lausanne

CHRU de Lille, Lille

Justin Davies

Divaka Perera

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

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Nicolas Van Mieghem

Keith Oldroyd

Renu Virmani

Golden Jubilee National Hospital, Glasgow

Crochan J O’Sullivan

Erasmus University Medical Center, Rotterdam CVPath Institute, Maryland

Mark Westwood

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

University Hospitals Bristol, Bristol

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

Juan Granada CRF Skirball Research Center, New York

Managing Editor Lindsey Mathews • Production Jennifer Lucy • Senior Designer Tatiana Losinska Digital Commercial Manager Ben Sullivan • New Business & Partnership Director Rob Barclay Publishing Director Liam O’Neill • Managing Director David Ramsey • Commercial Director Mark Watson •

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

Cover image 3D illustration of Heart, medical concept. © yodiyim | stock.adobe.com

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2017 All rights reserved

Radcliffe Cardiology

ISSN: 1756–1477 • eISSN: 1756–1485

Established: June 2006 Frequency: Bi-annual Current issue: Spring 2017

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

Structure and Format • Interventional Cardiology Review is a bi-annual journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Interventional Cardiology Review is available in full online at www.ICRjournal.com

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

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

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

Editorial Expertise

Distribution and Readership

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

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

Peer Review

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

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

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

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Contents

Foreword

Simon Kennon Editor-in-Chief, ICR

Coronary

Use of Intravascular Ultrasound Imaging in Percutaneous Coronary Intervention to Treat Left Main Coronary Artery Disease Giovanni Luigi De Maria and Adrian P Banning

PCI in Patients with Diabetes: Role of the Cre8 Drug-eluting Stent

Transradial Coronary Artery Procedures: Tips for Success

Robert A Byrne, Eric Eeckhout, Gennaro Sardella, Pieter Stella and Stefan Verheye

Kully Sandhu, Robert Butler and James Nolan

Structural

Managing Stroke During Transcatheter Aortic Valve Replacement

Use of Embolic Protection Devices in Peripheral Interventions

Need for Embolic Protection During Transcatheter Aortic Valve Implantation: An Interventionalist’s Perspective on Histopathology Findings

Florian Hecker, Mani Arsalan and Thomas Walther

Martin G Radvany

Herbert G Kroon and Nicolas MDA Van Mieghem

Optimising the Haemodynamics of Aortic Valve-in-valve Procedures

A Glimpse into the Future: In 2020, Which Patients will Undergo TAVI or SAVR?

Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies

Aortic Dissection: Novel Surgical Hybrid Procedures

Ren Jie Yao, Matheus Simonato and Danny Dvir

Crochan J O’Sullivan and Peter Wenaweser

Maurizio Taramasso, Christelle Calen, Andrea Guidotti, Shingo Kuwata, Hector Rodriguez Cetina Biefer, Fabian Nietlispach, Michel Zuber and Francesco Maisano

Alessandro Cannavale, Mariangela Santoni, Fabrizio Fanelli and Gerard O’Sullivan

Foreword

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

ranscatheter aortic valve implantation (TAVI), a procedure often performed under local anaesthetic with a 2–3 day length of stay, has the capacity to transform lives for the better with dramatic improvements in exercise tolerance and quality of life. Complication rates are low, but stroke – particularly disabling stroke – remains a feared outcome for patients and operators alike. As such, it is a focus of ongoing research and in this issue of Interventional Cardiology Review I am pleased to present three articles addressing the available evidence on how best to minimise the risk of stroke. Articles by Herbert G Kroon and Nicolas MDA Van Mieghem, and Martin G Radvany, relate exclusively to embolic protection devices; an article from Thomas Walther’s group reviews stroke prevention in general. There are two further articles relating to TAVI in this issue of the journal: Ren Jie Yao, Matheus Simonato and Danny Dvir provide an excellent review of how haemodynamics can be optimised after valve-in-valve procedures, while Crochan J O’Sullivan and Peter Wenaweser predict which patients will be undergoing TAVI in 2020. Tricuspid valve anatomy is a challenging environment for engineers and developing transcatheter devices for tricuspid valve interventions has taken much longer than it has for the aortic valve. In the past 2–3 years, however, real progress has been made and Francesco Maisano’s group – very much in the vanguard as researchers and operators – provides a timely review of the role of transcatheter interventions in the management of tricuspid regurgitation. Developments in transcatheter interventions are always made in the context of surgical therapies. In addition, as cardiologists, it is incumbent on us to know all the treatments that are available for our patients. Thus, I would hope the final article in this issue’s Structural Section, about novel surgical techniques for treating aortic dissection, will be both informative and stimulating. Novel devices and procedures provide new and exciting ways to treat our patients and one of the aims of this journal is to keep cardiologists up to date with developments in coronary and structural intervention. It is, however, also important that common procedures are undertaken safely and that patients derive maximum benefit from them. To this end, Kully Sandhu, Robert Butler and James Nolan, and Giovanni Luigi De Maria and Adrian Paul Banning, both provide excellent reviews of transradial coronary artery procedures and intravascular ultrasound imaging of the left main stem respectively. I commend them to you. n

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Coronary

Use of Intravascular Ultrasound Imaging in Percutaneous Coronary Intervention to Treat Left Main Coronary Artery Disease Giovanni Luigi De Maria and Adrian P Banning Heart Centre, Oxford University Hospitals NHS Trust Foundation, Oxford, UK

Abstract Due to its potential prognostic implications and technical complexity, revascularisation of left main coronary artery (LMCA) disease requires careful consideration. Since publication of the results of the SYNTAX study, and more recently the EXCEL and NOBLE trials, there has been particular interest in percutaneous revascularisation of the LMCA. It is becoming clear that percutaneous revascularisation of LMCA disease requires appropriate lesion preparation and carefully optimised stenting in order to offer patients a treatment option as effective as coronary artery bypass grafting. For this reason intravascular imaging, and especially intravascular ultrasound, is becoming a key procedural step in LMCA percutaneous coronary intervention. In the current review paper we analyse the role of intravascular imaging with intravascular ultrasound in LMCA percutaneous coronary intervention, focusing on the main applications in this context from lesion assessment to stent sizing and optimisation.

Keywords Revascularisation, left main coronary artery, percutaneous coronary intervention, imaging, intravascular ultrasound Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: Medical writing support was provided to the authors by Medical Media Communications (Scientific) Ltd funded by Philips Healthcare. Received: 12 December 2016 Accepted: 10 March 2017 Citation: Interventional Cardiology Review 2017;12(1):8–12. DOI: 10.15420/icr.2017:1:3 Correspondence: Adrian P Banning, Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Trust Foundation, Headley Way, Oxford OX3 9DU, UK. E: Adrian.Banning@ouh.nhs.uk

Detection of obstructive disease of the left main coronary artery (LMCA) is relatively unusual in the catheterisation laboratory, as it accounts for approximately 4 % of all coronary angiograms, with isolated LMCA disease observed in only 5–10 % of these cases.1 Intervention to the LMCA is, however, notable compared to the treatment of coronary stenosis elsewhere in the coronary tree. First, potential complications occurring during LMCA intervention may rapidly progress towards haemodynamic instability, since the LMCA provides the blood supply to 80 % of the left ventricle in patients with right coronary dominance.2 Second, disease of the LMCA is difficult to assess angiographically because of the possible lack of a proximal reference.3 Third, atherosclerosis at the LMCA site is diffuse in many cases, frequently involving bifurcation, and often features a higher rate of fibrotic and calcific components, making LMCA lesions tougher with a consequent need for appropriate and careful lesion preparation.4,5 In the current review we analyse the role of intravascular imaging with intravascular ultrasound (IVUS) as a key step in percutaneous coronary intervention (PCI) to the LMCA in order to achieve an optimal final result.

Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting in LMCA Disease Historically, coronary artery bypass grafting (CABG) represented the treatment of choice, with a well documented prognostic benefit mainly related to the very high rate of long-term patency of the left internal mammary artery graft.6,7 Data from four large studies have highlighted the potential equivalence of stenting and CABG in the LMCA setting.8–11

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In particular, the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) study showed that when coronary anatomy complexity is low or relatively low (defined by a SYNTAX score <32), then CABG and PCI performed well have similar outcomes at 1- and 5-year follow-up, with PCI affected by a higher rate of repeated revascularisation and CABG by an higher rate of stroke.9,12,13 These conclusions led to a change in the guidelines, with PCI having a IB indication for LMCA disease when the SYNTAX score is <22 and IIaB when the SYNTAX score is >22 and <32, with no current indications for PCI in LMCA disease when the SYNTAX score is >32 (IIIB indication).14 These conclusions also prompted initiation and recruitment for the randomised Evaluation of the Xience Everolimus Eluting Stent vs Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) and Nordic–Baltic–British Left Main Revascularization (NOBLE) studies comparing CABG with PCI for the treatment of LMCA disease.15 These two large recently-completed trials investigated CABG versus ‘state of the art PCI’ (e.g. with fractional flow reserve (FFR) and IVUS guidance and with second-generation drugeluting stent adoption) in patients with LMCA disease and low and intermediate SYNTAX scores. While EXCEL confirmed non-inferiority of PCI in LMCA compared to CABG in terms of major adverse cardiovascular events at 3-year follow-up,16 the NOBLE trial did not show the same level of benefit, with CABG still being superior to PCI.17 The need for longer follow-up in EXCEL (5 years) and several limitations in study design and implementation in NOBLE, whose analysis is beyond the aim of this review, need to be taken into account before considering a change in the guidelines for LMCA disease treatment. In our opinion, there are two clear messages that are consistent across the two studies: the unquestionable role of the heart team in the revascularisation

Intravascular Ultrasound Imaging decision-making process and the need for proper lesion preparation and optimisation of the final PCI result.

Table 1: The Technical Characteristics of Intravascular Ultrasound and Optical Coherence Tomography

The potential technical complexity behind LMCA stenting and the proven efficacy of CABG in LMCA disease mean it is essential that when PCI is performed on the LMCA, every effort is made to ensure that the final outcome from revascularisation is at as good as the one potentially achievable with CABG. This requires careful patient selection, rigorous procedural planning and application of the best available technology (in terms of stent and imaging techniques). The use of intravascular imaging, and usually IVUS, is highly recommended during elective LMCA intervention; a recommendation supported by a IIaB indication in the European guidelines.14

IVUS in LMCA PCI Definition of LMCA Anatomy and Plaque Distribution Coronary angiography is the initial technique for LMCA assessment, but because of its two-dimensional nature it cannot provide an accurate evaluation of the extent of disease, especially where there is eccentric distribution of the atherosclerotic plaque or complex anatomy with tortuous overlapping segments of the coronary tree. Moreover, a coronary angiogram only provides information about the contrast dyefilled lumen, with no insight into the vessel wall characteristics.18 In ostial LMCA involvement, for example, the coronary angiogram can be difficult to interpret, requiring the operator to rely on indirect signs of LMCA ostium disease such as pressure damping during LMCA intubation or lack of contrast dye spilling back during selective injection. Conversely, IVUS is an accurate technique for assessment of both lumen and wall characteristics.19 The higher tissue penetration of ultrasound compared to infrared light means that IVUS can play a key role in LMCA assessment compared to optical coherence tomography (OCT). IVUS imaging can provide a better visualisation of the LMCA and its ostium than OCT, since it does not require contrast injection to clear the lumen of blood. More detail is available if manual pullback is used, and consequently IVUS can offer superior assessment of the LMCA ostium. For these reasons, although we recognise the value of OCT in distal LMCA assessment,20 we believe that IVUS should probably still be considered the first-line imaging method for LMCA and LMCA ostium assessment. Table 1 summarises the main technical features of these two techniques. In the pre-fractional flow reserve era, IVUS was used to define the degree of stenosis in angiographically-determined intermediate LMCA disease. Minimal lumen area (MLA) was then adopted as a parameter to determine when intervention to the LMCA could be safely deferred. After the initial cut-off of MLA ≤9.0 mm2,21 studies started to propose progressively lower thresholds for deferring intervention, until the currently-accepted value of 6 mm2 was validated against FFR by Jasti et al22 and clinically assessed in the Spanish Working Group on Interventional Cardiology (LITRO) study,23 where it showed no difference in 2-year mortality in patients with deferred PCI to the LMCA compared to revascularised ones. Smaller cut-offs (4.8 and 4.5 mm2) have recently been proposed and validated with FFR by other groups, but since they specifically refer to Asian populations, they should not be applied in other ethnic groups.24,25 For this reason, current practice is to defer PCI to the LMCA when MLA >6 mm2. The reliability of FFR in LMCA disease has been confirmed and it is usually the first-line method for assessing angiographically-determined

INTERVENTIONAL CARDIOLOGY REVIEW

Ultrasound Tomography

Catheter size (Fr)

3.2–3.5 2.4–2.7

Maximum frame rate (frames/sec)

30–60 200

Pullback speed (mm/sec)

0.5–1.0

18–36 (up to 40)

Pullback length (mm)

150 mm

54–75 (up to 150)

Type of pullback

Mechanical Mechanical or manual

Need for blood clearance

No Yes

Tissue penetration (mm)

4–8

Axial resolution (μm)

80–100 10–20

Lateral resolution (μm)

200–250 20–40

2–3.5

The main characteristics making intravascular ultrasound potentially superior to optical coherence tomography in the assessment of left main coronary artery disease are highlighted in yellow.

intermediate LMCA disease. IVUS should be used to plan the way in which PCI should be performed to the LMCA. It is important to highlight that IVUS can still be integrated with FFR in assessing the indication for revascularisation when moderate to significant LMCA disease is present in the left anterior descending (LAD) or left circumflex (LCx) branch of the LMCA bifurcation. Data from studies of animal models and patients have shown the potential to underestimate the true LMCA stenosis using FFR when significant concomitant proximal LAD or proximal LCx disease is present.26,27 In their study, Fearon et al reported a statistically significant, though small and not clinically relevant, discrepancy between FFR values in LMCA disease in the presence and absence of concomitant LAD disease. In conclusion, therefore, FFR is an easy to use and highly effective tool for isolated LMCA disease assessment, while a more critical approach is required in the presence LMCA disease and concomitant disease of the proximal LAD or LCx branch. As the same authors noted, the real challenge is to assess LMCA disease contribution to the overall the ischaemic burden when the FFR measured in the less diseased branch is in a ‘grey zone’ between 0.85 and 0.81.27 In this context, implementation with IVUS could help the operator decide on the indication for LMCA revascularisation. When angiography is ambiguous, IVUS pullback should be performed on both branches of the LMCA bifurcation, or at least on the branch with the lower degree of angiographic disease. This approach will produce information about the distribution of atherosclerosis at the site of the bifurcation, as well as at the ostium of the LMCA. LMCA disease frequently involves both branches of the bifurcation, even when angiography appears to be ‘normal’.28 Understanding the exact distribution of plaque burden at the bifurcation is clearly important when deciding whether a provisional stenting strategy can be applied to treat LMCA disease or a two-stent strategy should be considered upfront. In this regard, a MLA <3.7 mm2 or plaque burden >56 % in the LCx ostium has been shown to predict the need for a second stent after provisional stenting of the main vessel.29 It is important to highlight that although no large randomised clinical trial has been performed to assess whether intravascular imaging-guided PCI to the LMCA is associated with better long-term clinical outcomes, there are convincing data from large registries to suggest long-term mortality benefit in patients undergoing IVUS-guided

Coronary Figure 1: The Use of Intravascular Ultrasound in Ostial Left Main Disease A

follow-up described by Sheiban et al in an international registry with a IVUS adoption of only 14 %.32 This particular aspect is relevant when considering the cost-effectiveness of IVUS imaging. Notably, the costeffectiveness analysis derived from SYNTAX I confirmed the clinical and economic benefits of LMCA PCI over CABG specifically in the subgroup of patients with low (<22) SYNTAX scores.33

Qualitative Characterisation of LMCA Disease C

Its ability to image the deeper layers of the arterial wall make IVUS the best technique for the qualitative assessment of plaque composition at the site of the LMCA. As a general rule, lesion preparation is pivotal in LMCA PCI. Calcium is expected and a low threshold for considering rotational atherectomy34 is encouraged to prepare the LMCA lesion. In this context IVUS defines the extension of calcium35 by the high backscattering signal with posterior shadowing.36

Aorta

Stent area = 12.5mm2

Stent area = 10.1mm2

Stent area = 9.7mm2

Panels A to D summarise the main procedural steps in the implantation of stenting and flaring. The final result was checked with intravascular ultrasound to confirm good stent expansion, apposition the stent, and coverage of the ostium (blue), mid body (red) and distal shaft (orange). LAD = left anterior descending; LCx = left circumflex; LMS = left main stem.

Figure 2: The Use of Intravascular Ultrasound in Bifurcation Left Main Disease A LAD

Stent Sizing

C LCx

LMS Aorta

LMS Lumen Area = 2.5mm2

POC

Lumen Area = 2.4mm2

LAD

LMS

Stent Area = 11.6mm2

LCx

Lumen Area = 4.5mm2

B POC

D Stent area = 11.2mm2

LCx

LAD

Stent area = 6.1mm2

Stent area = 7.6mm2

(A) Critical left main disease involving all three branches of the left main bifurcation, with plaque distribution assessed by intravascular ultrasound before dilation. (B) The main procedural steps of left main stenting, with the Culotte technique completed by final kissing balloon inflation. (C) The final result is checked on both the LAD and LCx with intravascular ultrasound, confirming good achievement of target stent areas in the LAD, LCx, POC and LMS according to Kang’s criteria, as summarised in (D). LAD = left anterior descending; LCx = left circumflex; LMCA = left main coronary artery; LMS = left main stem; POC = polygon of confluence.

compared to angio-guided PCI to the LMCA.30,31 Careful analysis of IVUS data from both the EXCEL and NOBLE trials will be pivotal in confirming the value of intravascular imaging in assisting LMCA PCI. Currently, it is only possible speculate that systematic IVUS could corroborate and improve on the promising results of PCI on the LMCA at 10-year

Visualisation of extension of the calcific arch is attainable with IVUS; a calcific arch >180° is a strong indication for rotational atherectomy. Pre-stenting IVUS can help differentiate cases in whom rotational atherectomy is mandatory from those in whom predilation with noncompliant balloons at high pressure could be a possible alternative, especially in those catheter laboratories with no operators trained in rotational atherectomy. Besides identifying its circular and longitudinal extension, IVUS can also help identify the depth of the calcific component.37 This is relevant, as deep and thick calcium might be associated with a higher risk of coronary perforation during balloon inflation and thus mandate rotational atherectomy.38

Having clarified plaque burden, distribution and composition, IVUS can provide information about true vessel dimensions in order to facilitate stent sizing. Due to its large calibre and the mismatch in diameter between the LMCA and LMCA-bifurcation branches, stent sizing in LMCA PCI can be tricky using angiography alone; the operator is called on to make a decision according to the information provided by a two-dimensional technique. Conversely, IVUS-defined lumen area can provide a more detailed definition of the lumen, with stent-sizing that takes into account not just one single diameter (as in angiography), but three diameters, namely the maximum, minimum and mean diameter. By more accurately detecting atherosclerosis, IVUS can assure a better definition of the proximal and distal references for stent diameter-sizing and better identification of proximal and distal landing zones that are free from disease, thus minimising the risk of longitudinal miss during stent deployment. Consequently, we believe IVUS should be applied before stenting in order to aid proper planning of PCI to the LMCA as it can define LMCA anatomy and plaque burden distribution, characterise disease, especially the extent of calcification, and aid accurate stent sizing. The use of IVUS post-stenting is mainly to check that the stent application is optimal and plaque is covered.

Stent Optimisation Stent optimisation is the main indication for IVUS in LMCA PCI, and in our opinion post-stenting IVUS should always be performed when it is safe to do so. Although there are no large randomised clinical trials to assess ad hoc whether intravascular imaging-guided PCI to the LMCA is associated with a better long-term clinical outcome, convincing data from large registries suggest a long-term mortality benefit in patients undergoing IVUS-guided compared to angio-guided PCI to the LMCA.30,31

INTERVENTIONAL CARDIOLOGY REVIEW

Intravascular Ultrasound Imaging Figure 3A: Intended Treatment Regimen for an Ostial Left Main Lesion

Figure 4: Intended Treatment Regimen for a 1,1,0 Left Main Bifurcation

1,1,0

True 1,1,0

Ostium Disease True ostium disease

Provisional MB & POT

IVUS LAD & LCx

IVUS LAD or LCx

LMS stent & flaring

no FFR <0.80 on LCx Double stent + FKI

Good Angiographic result on LCx ? yes

FFR on LCx >0.80

FKI

yes

Final LMS IVUS

Final IVUS Target MLA as in 1,1,1

After wiring either the LAD or LCx, IVUS examination confirms the extent of the disease and the correct anatomical categorisation of plaque. IVUS = intravascular ultrasound; LAD = left anterior descending; LCx = left circumflex; LMS = left main stem; POC = polygon of confluence.

Figure 3B: Intravascular Ultrasound Information Required to Treat an Ostial Left Main Lesion LAD

IVUS PRE PCI LMS

Minimal Diameter Length of disease Distal lumen area stenosis (mm) reference norm >6 mm2 (%) diameter (mm)

LCx Ostium

Legend Minimal lumen area Distal reference

IVUS POST PCI

LAD

Minimal Diameter Distal lumen area stenosis reference target >8 mm2 (%) diameter (mm)

LMS LCx

Ostium LMS

Measurement of the distal reference diameter before treatment allows the stent diameter to be calculated, and measurement of the length of the diseased segment allows the stent length to be calculated. The minimal lumen area and percentage diameter stenosis in the bottom table must be met to ensure stent expansion. IVUS POST PCI = Intravascular ultrasound post percutaneous coronary intervention; IVUS PRE PCI = Intravascular ultrasound pre percutaneous coronary intervention; LAD = left anterior descending; LCx = left circumflex; LMS = left main stem; MLA = minimal lumen area.

Stent malapposition, stent under-expansion, geographical miss and large uncovered stent-edge dissection are all possible stent-related complications detectable by IVUS.39 Stent under-expansion is the main predictor of stent failure and, as recently reported by Nerlekar et al, IVUS-assisted LMCA PCI can be associated with a lower rate of target lesion revascularisation and stent thrombosis.40 For this reason Kang et al have proposed a minimum area that should be covered in each segment of the LMCA bifurcation after stenting (>5 mm2 at the ostium of the LCx; >6 mm2 at the ostium of the LAD; >7 mm2 at the polygon of confluence; and >8 mm2 at the LMCA).41 The decision to intervene in a case of stent malapposition or edge dissection is more complex as no proven thresholds have been proposed and prospectively validated. When treating LMCA bifurcation, IVUS can be used to identify the mechanism of side-branch compromise after main-branch stenting.

INTERVENTIONAL CARDIOLOGY REVIEW

FFR >0.80 on LCx

Final IVUS Target: Kangâ&#x20AC;&#x2122;s criteria

IVUS should be performed to both the LAD and LCx to confirm the extent of disease and correct anatomical categorisation of plaque. Thereafter, single stent treatment with POT should be performed of the left main into LAD. A second stent should only be considered when there is a suboptimal LCx angiographic result and LCx FFR <0.8. Under these circumstances, a second stent should be placed, kissing balloon expansion performed and repeat IVUS of the result with target MLA, as per the Kang criteria. FKI = final kissing inflation; FFR = fractional flow reserve; IVUS = intravascular ultrasound; LAD = left anterior descending; LCx = left circumflex; LMS = left main stem; MB = main branch; MLA = minimal lumen area; POT = proximal optimization technique.

It is important to recognise whether intervention on the side branch can be avoided if safe and efficacious; IVUS has a role in defining how the operator should eventually intervene. If carina shift is identified as the underlying mechanism, then kissing balloon inflation could be enough to reshape the carina and restore normal flow down both limbs of the bifurcation. Conversely, if plaque shift is detected then the operator may switch from the provisional single-stent strategy to a two-stent procedure.

Case Studies Figures 1 and 2 illustrate the employment of IVUS guidance. Figure 1 shows a case of ostial left main disease in which IVUS was used to confirm stent expansion, stent apposition and coverage of the ostium, mid body and distal shaft. Figure 2 shows left main disease involving all three branches of the left main bifurcation. The use of IVUS enabled the assessment of plaque distribution and confirmed the achievement of Kangâ&#x20AC;&#x2122;s criteria for minimum stent areas in the LAD, LCx, polygon of confluence and left main stem.41

The Workflow Algorithm Since IVUS is configured to be a mandatory step in an already complex and potentially risky procedure such as PCI to the LMCA, it is desirable that its application is easy and user-friendly. For this reason it is extremely helpful having a workflow algorithm to guide the operator at each step of the intervention, particularly in the collection of IVUSderived data considered necessary for the decision-making process and procedure planning. Here, we propose a workflow algorithm to facilitate IVUS applications during LMCA. After having defined LMCA disease according to angiographic appearance, this algorithm encourages the operator to perform an IVUS pullback. Ideally IVUS pullback should be performed in both branches of the LMCA bifurcation, however where this is not possible it should be performed in the least diseased one. If angiographic

Coronary intermediate disease is observed, FFR is advised in addition to IVUS pullback. The algorithm helps the operator collect only the data strictly necessary for planning the procedure, making IVUS interpretation quicker and more straightforward. Nine possible scenarios are identified according to the presence of MLA <6.0 mm2 in the LMCA, or MLA <4.0 mm2 or plaque burden >70 % in one or both bifurcation limbs. These nine scenarios are: • no LMCA disease; • LMCA disease with no bifurcation involvement; • LMCA disease with Medina classification 1,0,0 bifurcation involvement; • LMCA disease with Medina 1,1,0 bifurcation involvement; • LMCA disease with Medina 0,1,0; bifurcation involvement; • LMCA disease with Medina 1,0,1 bifurcation involvement; • LMCA disease with Medina 0,0,1 bifurcation involvement; • LMCA disease with Medina 0,1,1 bifurcation involvement; • LMCA disease with Medina 1,1,1 bifurcation involvement.

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G iannoglou GD, Antoniadis AP, Chatzizisis YS, et al. Prevalence of narrowing >or=50 % of the left main coronary artery among 17,300 patients having coronary angiography. Am J Cardiol 2006;98:1202–5. DOI: 10.1016/j.amjcard.2006.05.052; PMID: 17056328 Patel N, De Maria GL, Kassimis G, et al. Outcomes after emergency percutaneous coronary intervention in patients with unprotected left main stem occlusion: the BCIS national audit of percutaneous coronary intervention 6-year experience. JACC Cardiovasc Interv 2014;7:969–80. DOI: 10.1016/ j.jcin.2014.04.011; PMID: 25234669 L efèvre T, Girasis C, Lassen JF. Differences between the left main and other bifurcations. EuroIntervention 2015;11 Suppl V:106–10. DOI: 10.4244/EIJV11SVA24; PMID: 25983141 W ykrzykowska JJ, Mintz GS, Garcia-Garcia HM, et al. Longitudinal distribution of plaque burden and necrotic corerich plaques in nonculprit lesions of patients presenting with acute coronary syndromes. JACC Cardiovasc Imaging 2012;5: S10–8. DOI: 10.1016/j.jcmg.2012.01.006; PMID: 22421223 M ercado N, Moe TG, Pieper M, et al. Tissue characterisation of atherosclerotic plaque in the left main: an in vivo intravascular ultrasound radiofrequency data analysis. EuroIntervention 2011;7:347–52. DOI: 10.4244/EIJV7I3A59; PMID: 21729837 Shah PJ, Durairaj M, Gordon I, et al. Factors affecting patency of internal thoracic artery graft: clinical and angiographic study in 1434 symptomatic patients operated between 1982 and 2002. Eur J Cardiothorac Surg 2004;26:118–24. DOI: 10.1016/ j.ejcts.2004.02.037; PMID: 15200989 haitman BR, Fisher LD, Bourassa MG, et al. Effect of C coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS). Am J Cardiol 1981;48:765–77. PMID: 7025604 B uszman PE, Buszman PP, Kiesz RS, et al. Early and long-term results of unprotected left main coronary artery stenting: the LE MANS (Left Main Coronary Artery Stenting) registry. J Am Coll Cardiol 2009;54:1500–11. DOI: 10.1016/j.jacc.2009.07.007; PMID: 19699048 orice MC, Serruys PW, Kappetein AP, et al. Outcomes in M patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation 2010;121:2645–53. DOI: 10.1161/CIRCULATIONAHA.109.899211; PMID: 20530001 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. DOI: 10.1016/j.jacc.2010.09.038; PMID: 21272743 P ark 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. DOI: 10.1056/NEJMoa1100452; PMID: 21463149 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. DOI: 10.1161/ CIRCULATIONAHA.113.006689; PMID: 24700706 N erlekar N, Ha FJ, Verma KP, et al. Percutaneous coronary intervention using drug-eluting stents versus coronary artery bypass grafting for unprotected left main coronary artery stenosis: a meta-analysis of randomized trials. Circ Cardiovasc Interv 2016;9:pii:e004729. DOI: 10.1161/ CIRCINTERVENTIONS.116.004729; PMID: 27899408 Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS

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The presence of right or left dominance is another parameter the algorithm takes into consideration. For each specific scenario, the algorithm provides an action plan suggesting the appropriate stent technique and FFR and IVUS guidance to optimise the result of stenting. For further details about the workflow, we refer the reader to the following link http://bit.ly/2qG69nx. Currently, the clinical application and validation of this workflow algorithm is under investigation, but it has been designed as a tool to encourage IVUS adoption during LMCA PCI in agreement with European guidelines. Representative examples of the IVUS algorithm are shown in Figures 3A and B (ostial left main disease) and Figure 4 (Medina 1,1,0 left main bifurcation).

Conclusion In conclusion, IVUS has become a standard part of the PCI procedure for the treatment of LMCA disease. Improving the consistency of its application is likely to improve stenting technique and results, and consequently patient outcomes. n

Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541– 619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339 C ampos CM, Christiansen EH, Stone GW, et al. The EXCEL and NOBLE trials: similarities, contrasts and future perspectives for left main revascularisation. EuroIntervention 2015;11 Suppl V:115–9. DOI: 10.4244/EIJV11SVA26; PMID: 25983143 S tone GW, Sabik JF, Serruys PW, et al. EXCEL Trial Investigators. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med 2016;375:2223–35. DOI: 10.1056/NEJMoa1610227; PMID: 27797291 Mäkikallio T, Holm NR, Lindsay M, et al. NOBLE Study Investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet 2016;388:2743–52. DOI: 10.1016/S0140-6736(16)32052–9; PMID: 27810312 T opol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995;92:2333–42. PMID: 7554219 S t Goar FG, Pinto FJ, Alderman EL, et al. Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography. J Am Coll Cardiol 1991;18:952–8. PMID: 1894869 B urzotta F, Dato I, Trani C, et al. Frequency domain optical coherence tomography to assess non-ostial left main coronary artery. EuroIntervention 2015;10:e1–8. DOI: 10.4244/ EIJV10I9A179; PMID: 25599698 N issen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001;103:604–16. PMID: 11157729 J asti V, Ivan E, Yalamanchili V, et al. Correlations between fractional flow reserve and intravascular ultrasound in patients with an ambiguous left main coronary artery stenosis. Circulation 2004;110:2831–6. DOI: 10.1161/01. CIR.0000146338.62813.E7; PMID: 15492302 de la Torre Hernandez JM, Hernández Hernandez F, Alfonso F, et al. LITRO Study Group (Spanish Working Group on Interventional Cardiology). Prospective application of predefined 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. DOI: 10.1016/j.jacc.2011.02.064; PMID: 21757111 Kang SJ, Lee JY, Ahn JM, et al. Intravascular ultrasound-derived predictors for fractional flow reserve in intermediate left main disease. JACC Cardiovasc Interv 2011;4:1168–74. DOI: 10.1016/ j.jcin.2011.08.009; PMID: 22115656 P ark SJ, Ahn JM, Kang SJ, et al. Intravascular ultrasound-derived minimal lumen area criteria for functionally significant left main coronary artery stenosis. JACC Cardiovasc Interv 2014;7:868–74. DOI: 10.1016/j.jcin.2014.02.015; PMID: 25147031 Yong AS, Daniels D, De Bruyne B, et al. Fractional flow reserve assessment of left main stenosis in the presence of downstream coronary stenoses. Circ Cardiovasc Interv 2013;6:161–5. DOI: 10.1016/j.jcin.2014.09.027; PMID: 25790763 F earon WF, Yong AS, Lenders G, et al. The impact of downstream coronary stenosis on fractional flow reserve assessment of intermediate left main coronary artery disease: human validation. JACC Cardiovasc Interv 2015;8: 398–403. DOI: 10.1016/j.jcin.2014.09.027; PMID: 25790763 Oviedo C, Maehara A, Mintz GS, et al. Intravascular ultrasound classification of plaque distribution in left main coronary artery bifurcations: where is the plaque really

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located? Circ Cardiovasc Interv 2010;3:105–12. DOI: 10.1161/ CIRCINTERVENTIONS.109.906016; PMID: 20197513 Kang SJ, Ahn JM, Kim WJ, et al. Functional and morphological assessment of side branch after left main coronary artery bifurcation stenting with cross-over technique. Catheter Cardiovasc Interv 2014;83:545–52. DOI: 10.1002/ccd.25057; PMID: 23765939 Park SJ, Kim YH, Park DW, et al. MAIN-COMPARE Investigators. 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. DOI: 10.1161/ CIRCINTERVENTIONS.108.799494; PMID: 20031713 de la Torre Hernandez JM, Baz Alonso JA, Gómez Hospital JA, et al. IVUS-TRONCO-ICP Spanish Study. 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. DOI: 10.1016/j.jcin.2013.09.014; PMID: 24650399 Sheiban I, Moretti C, D’Ascenzo F, et al. Long-term (≥10 years) safety of percutaneous treatment of unprotected left main stenosis with drug-eluting stents. Am J Cardiol 2016;118:32–9. DOI: 10.1016/j.amjcard.2016.04.007; PMID: 27209125 Cohen DJ, Osnabrugge RL, Magnuson EA, et al. SYNTAX Trial Investigators. Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents versus bypass surgery for patients with 3-vessel or left main coronary artery disease: final results from the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation 2014;130:1146–57. DOI: 10.1161/ CIRCULATIONAHA.114.009985; PMID: 25085960 Barbato E, Carrié D, Dardas P, et al. European Association of Percutaneous Cardiovascular Interventions. European expert consensus on rotational atherectomy. EuroIntervention 2015;11:30–6. DOI: 10.4244/EIJV11I1A6; PMID: 25982648 Tuzcu EM, Berkalp B, De Franco AC, et al. The dilemma of diagnosing coronary calcification: angiography versus intravascular ultrasound. J Am Coll Cardiol 1996;27:832–8. PMID: 8613611 Lotfi A, Jeremias A, Fearon WF, et al. Society of Cardiovascular Angiography and Interventions. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the Society of Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2014;83:509–18. DOI: 10.1002/ccd.25222; PMID: 24227282 Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation 1995;91:1959–65. PMID: 7895353 Hendry C, Fraser D, Eichhofer J, et al. Coronary perforation in the drug-eluting stent era: incidence, risk factors, management and outcome: the UK experience. EuroIntervention 2012;8:79–86. DOI: 10.4244/EIJV8I1A13; PMID: 22580251 Bing R, Yong AS, Lowe HC. Percutaneous transcatheter assessment of the left main coronary artery: current status and future directions. JACC Cardiovasc Interv 2015;8:1529–39. DOI: 10.1016/j.jcin.2015.07.017; PMID: 26493245 N erlekar N, Cheshire CJ, Verma KP, et al. Intravascular ultrasound guidance improves clinical outcomes during implantation of both first- and second-generation drugeluting stents: a meta-analysis. EuroIntervention 2017;12: 1632–42. DOI: 10.4244/EIJ-D-16-00769; PMID: 27840327 Kang SJ, Ahn JM, Song H, et al. Comprehensive intravascular ultrasound assessment of stent area and its impact on restenosis and adverse cardiac events in 403 patients with unprotected left main disease. Circ Cardiovasc Interv 2011;4: 562–9. DOI: 10.1161/CIRCINTERVENTIONS.111.964643; PMID: 22045969

INTERVENTIONAL CARDIOLOGY REVIEW

Coronary

PCI in Patients with Diabetes: Role of the Cre8 Drug-eluting Stent Robert A By rne, 1 Eric Eec k hout , 2 G e n n a r o S a r d e l l a , 3 P i e t e r S t e l l a 4 a n d S t e f a n Ve r h e y e 5 1. Department of Cardiovascular Diseases, German Heart Centre, Technical University, Munich, Germany; 2. Cardiology Department, Vaud University Hospital, Lausanne, Switzerland; 3. Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy; 4. Department of Interventional Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands, and National University Singapore, Singapore; 5. Antwerp Cardiovascular Center, ZNA Middelheim, Antwerp, Belgium

Abstract Patients with diabetes have poor outcomes compared to the general patient population when undergoing percutaneous coronary intervention. The Cre8™ (Alvimedica) drug-eluting stent (DES) has unique features that may improve clinical outcomes in patients with diabetes. These include abluminal reservoir technology, a proprietary polymer-free drug-release system consisting of reservoirs on the stent’s outer surface that control and direct drug release exclusively towards the vessel wall, and the Amphilimus™ formulation, which enables enhanced drug tissue permeation, utilising fatty acid transport pathways. This is particularly advantageous in diabetic patients, since increased uptake of fatty acid occurs in diabetic cells. Furthermore, mTOR inhibitors (-limus drugs), which are utilised in DESs, are relatively ineffective in diabetic cells. Clinical efficacy and safety of the Cre8™ in patients with diabetes has been demonstrated in a number of clinical trials and real-world studies, and further studies are on-going.

Keywords Coronary artery disease, diabetes, drug-eluting stent, percutaneous coronary intervention Disclosure: The authors have no relevant disclosures to make. Acknowledgements: The authors are grateful to the technical editing support provided by Katrina Mountfort of Medical Media Communications (Scientific) Ltd, which was funded by Alvimedica. Received: 16 September 2016 Accepted: 4 October 2016 Citation: Interventional Cardiology Review, 2017;12(1):13–7. DOI: 10.15420/icr.2016:28:2 Correspondence: Katrina Mountfort, Medical Writer, Medical Media Communications (Scientific) Ltd, Unit F, First Floor, Bourne Park, Bourne End, SL8 5AS, UK. E: katrina.mountfort@medicalmediacomms.com

Percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are established strategies for revascularisation in patients with coronary artery disease. While CABG was the standard of care for patients with multivessel disease, the introduction of baremetal stents (BMSs) and, later, drug-eluting stents (DESs) has led to an increased use of PCI in these more challenging cases. The latest generation of polymeric metallic DESs has shown improved efficacy and safety compared with BMSs and first-generation DESs, facilitating the treatment of more complex lesions.1 However, certain lesions and patient subsets remain difficult to treat. Patients with diabetes represent a particular challenge as they have rapidly progressing and more diffuse coronary artery disease, with lesions of longer length. They therefore continue to have worse outcomes following PCI compared with non-diabetic patients.2 In patients with diabetes and multivessel disease, CABG remains the preferred strategy but it is associated with a higher risk of peri-procedural stroke.3,4 Diabetes has reached epidemic proportions worldwide and its prevalence is rising. In 2015, 415 million adults had diabetes; nearly half (46.5%) of these remain undiagnosed.5 By 2040 this number is projected to rise to 642 million,5 representing a major health and economic burden. There is an urgent need to enhance procedural success and long-term clinical outcomes in the coronary revascularisation of patients with diabetes. In particular, there is a need for improved stent technology tailored to the needs of the diabetic population. This article describes the Cre8™ DES, which has a novel

design that may provide particular efficacy and safety advantages in patients with diabetes.

Introduction to the Cre8™ The Cre8™ has unique features that may specifically improve clinical outcomes in patients with diabetes. These include abluminal reservoir technology, which is a proprietary polymer-free drugrelease system consisting of reservoirs on the stent’s outer surface that control and direct drug release exclusively towards the vessel wall (see Figure 1). The reservoir’s design directly impacts on the drug dosage and release kinetics, allowing peak drug tissue concentration during the first days post-implantation, 50 % drug elution in approximately 18 days, 65–70 % elution within 30 days and complete drug elution within 90 days.6 The polymer-free system overcomes a major challenge of DES design. Polymer coatings have been routinely used to control drug release and optimise DES efficacy, but have also been implicated in late inflammatory reactions and delayed arterial healing after stenting.7 The Intracoronary Stenting and Angiographic Restenosis Investigators – Test Efficacy of Rapamycin-eluting Stents with Different Polymer Coating Strategies (ISAR-TEST-3) study found that failure to retard drug release results in suboptimal antirestenotic activity.8 A second design characteristic unique to the Cre8™ is the Amphilimus™ formulation of the active antirestenotic drug. In this proprietary

Access at: www.ICRjournal.com

Coronary Figure 1: Cre8™ Abluminal Reservoir Technology

technology, sirolimus and a fatty acid are eluted together, allowing sustained drug elution, modulated drug bioavailability, a more homogeneous drug distribution and enhanced drug stability. Also important is the bioinducer surface, an integral ultra-thin (<0.3 μm) pure carbon coating that is covalently bonded to the thin CoCr platform (total thickness 70–80 μm). This is hypothesised to passivate stent–platelet interactions (since the bulk of the CoCr platform is sealed by the coating) and reduce the risk of thrombotic events. Other features of the Cre8™ include homogeneous stent design in lengths from 8 to 46 mm, excellent longitudinal stability on expansion, and two platinum markers at the stent ends.

Challenges of DES Use in Patients with Diabetes The use of second-generation DESs in patients with diabetes has been associated with suboptimal outcomes. A pooled patient analysis of data from four randomised trials – the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) II, SPIRIT III, SPIRIT IV trials, and the Second-Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice (COMPARE) trial – found that, in the non-diabetic population (n=3,911), the use of an everolimus-eluting stent (EES) significantly reduced the endpoints of cardiac death or myocardial infarction (MI) at 1 year (4.3 versus 9.5 %; HR 0.44; 95 % CI [0.35–0.55]; p<0.001) compared with a paclitaxeleluting stent (PES). However, in the diabetic population (n=1,869), there was no difference between the two DESs (8 versus 7.8 %; HR 1.01; 95 % CI [0.72–1.42]; p=0.95). In addition, the incidences of death, MI and target-lesion revascularisation were all higher in diabetic than in non-diabetic patients.9 Furthermore, in the Randomized Comparison of Everolimus-Eluting Stent versus Sirolimus-Eluting Stent Implantation for De Novo Coronary Artery Disease in Patients with Diabetes Mellitus (ESSENCE-DIABETES), 300 patients with diabetes were randomised to receive either EES or sirolimus-eluting stents (a first-generation DES) for the treatment of coronary lesions. No difference in outcomes was seen between the two groups.10 Basic research has shed additional light on the reasons for the lack of benefit second-generation DESs have shown in patients with diabetes. The mammalian target of rapamycin (mTOR) inhibitors (-limus drugs) have been found to be less active in patients with diabetes compared with the general population. One reason is the direct resistance of vascular smooth muscle cells to mTOR inhibition.11,12 Dose-response curves show that a tenfold higher concentration of mTOR inhibitor is required in the diabetic cell to achieve similar inhibition to the non-diabetic cell.12 Another reason for the relative ineffectiveness of -limus drugs in diabetic patients is the effect of other hormones. BMI strongly correlates with

diabetes riks: 90 % of patients with type 2 diabetes are overweight.13 Human obesity is associated with elevated levels of the hormone leptin, which has been found to promote vascular remodelling and neointimal growth in animal studies.14 Increased leptin levels cause a ninefold increase in the dose of sirolimus required for effective inhibition of neointimal formation.15 Moreover, leptin levels have been associated with in-stent restenosis.16,17 These data highlight the potential unmet need with regard to currentgeneration DES technology in patients with diabetes. Increasing total drug delivery to the vessel wall is one approach. This may be achieved by incorporation of an increased drug–polymer load, although this is likely to negatively impact overall vessel wall healing. Another possibility would be to use the same coating thickness with an increased drug:polymer ratio, but this would negatively affect the drug-release kinetics and make the polymer brittle. Placing the drug directly onto the bare metal would also be problematic in terms of control of drug release. An optimum approach might be to use standard drug–polymer loads combined with a formulation targeted to enhance uptake of drug at the cellular level. The Amphilimus™ formulation of Cre8™ is designed to take advantage of the key role of fatty acids in cellular metabolism in patients with diabetes. In the non-diabetic cell, fatty acid metabolism is responsible for 70 % of the generation of adenosine triphosphate, the remaining 30 % being produced by glucose oxidation. However, in the diabetic cell, membrane protein overexpression leads to higher binding and translocation of fatty acids, and as a result 100 % of adenosine triphosphate production results from fatty acid oxidation.18 In diabetic mouse models, a doubling of cardiac fatty acid uptake has been demonstrated.19 This technique of using fatty acids has been shown to enhance the transdermal delivery of other drugs.20

Clinical Evidence for Use of the Cre8™ The first clinical study of the Cre8™ was the International Randomized Comparison between DES Limus Carbostent and Taxus Drug-eluting Stents in the Treatment of de novo Coronary Lesions (NEXT) clinical study, which randomly allocated patients (n=323) to the Cre8™ or a PES (TAXUS® Liberté®, Boston Scientific).21 The primary endpoint was 6-month angiographic in-stent late lumen loss (LLL). At 6 months, the Cre8™ group had a 60 % reduction in in-stent LLL compared with the PES group (0.14 ± 0.36 mm versus 0.34 ± 0.40 mm; p<0.0001). This finding was even more pronounced in the subgroup of patients with diabetes (n=82), where a 72 % reduction in in-stent LLL was seen (0.12 ± 0.29 mm versus 0.43 ± 0.41 mm; p<0.0001). In terms of 3-year major adverse cardiac events (MACE), a 37 % reduction in target lesion revascularisation (TLR) was seen in the Cre8™ versus the PES group (6.9 versus 10.9 %; p=0.2464) in the overall population and a 68 % reduction in the subgroup with diabetes (6.8 versus 21.2 %; p=0.888).21,22 These findings led to the initiation of a study enrolling patients more representative of those seen in routine clinical practice. The Prove Abluminal Reservoir Technology clinICal benefIt in all-comer PATiEnts (pARTicip8) study recruited ‘real world’ patients with ischaemic myocardial symptoms due to de novo lesions in native coronary arteries from across 30 European sites. The objective of this study was to evaluate the safety and efficacy of Cre8™ in a group of patients comparable to the everyday clinical practice population, with a specific focus on subgroups with diabetes. The primary endpoint was a

INTERVENTIONAL CARDIOLOGY REVIEW

Role of the Cre8 Stent for Diabetic Patients

Figure 2: Incidence of Composite Endpoint, Cardiac Death, Target Vessel Myocardial Infarction (TV MI) and Clinicallyindicated Target Lesion Revascularisation (Cl. Ind. TLR) at 12 Months in the INVESTIG8 Study

Figure 3: The RESERVOIR Clinical Study Results for Late Lumen Loss at 9 Months AES = Cre8

EES = Xience family

25.0

16 Non-diabetic

% of patients

Diabetic

25.0

0.14 ± 0.24*

20.0 15.0

15.0

10.0

5.0

-0.50

0.50

p=0.4863 5.0 %

4 2

0.00

3.5 %

1.50

2.00

2.50

3.00

-0.50

0.00

0.50

1.00

*SD

p=0.5623 1.6 %

Composite

1.00

0.24 ± 0.57*

20.0

2.5 %

Cardiac death

p=0.3442 0.3 %

1.1 %

TV MI

p=1.0000 1.6 % 1.4 % CI. ind. TLR

INVESTIG8 = MultIceNtric and RetrospectiVe REgiStry in 'real world' paTients with polymerfree drug elutInG stent Cre8™. Source: Reproduced from a presentation by G Sardella at EuroPCR (19–22 May 2015, Paris).25

composite of cardiac death, target vessel MI and clinically-indicated TLR 6 months after the index procedure. Of those enrolled (n=1,186), 308 (25.8 %) had diabetes. At 1 year, the incidence of clinically-indicated TLR was 1 % in the overall population and 1.4 % in the diabetic subgroup. The LLL in the diabetic subgroup was 0.16 ± 0.13. Definite late stent thrombosis was detected in only 0.08 % of the patient population.22 By contrast, most other DESs have shown a significantly higher LLL in people with diabetes compared to those without.10,21,23,24 The next step in the Cre8™ clinical development programme was the retrospective MultIceNtric and RetrospectiVe REgiStry in 'real world' paTients with polymer-free drug elutInG stent Cre8™ (INVESTIG8) study. The primary endpoint was the incidence of a clinical composite endpoint (cardiac death/target vessel MI/clinically-driven TLR) at 12 months from the index procedure.25,26 Secondary endpoints comprised the incidence of a clinical composite endpoint (all deaths/all MI/any revascularisation) from the time of the index procedure to 12 months; and the incidence of stent thrombosis from the index procedure to 12 months, classified according to the Bleeding Academic Research Consortium definition (see http://bit.ly/2eemnyq). Twelve-month followup data were available for 589 out of the 647 patients enrolled (91 %). Of these, 47.4 % had diabetes. Chronic total occlusions were present in 3.4 %, ostial lesions in 15.5 %, bifurcation in 17.8 % and de novo lesions in 93.8 % of participants. The composite endpoint occurred in 4.2 % of patients, and clinically-indicated target vessel revascularisation in 1.5 %. In a sub-analysis of non-diabetic versus diabetic patients, only the composite endpoint was higher in patients with diabetes (5.0 versus 3.5 %; p=0.4863), and this was due to the expected higher incidence of cardiac death and MI. However, the incidence of clinically-indicated TLR was not higher in the subgroup with diabetes (1.6 versus 1.4 %; p=1.000; see Figure 2). The Randomized Comparison of Reservoir-Based Polymer-Free Amphilimus™-Eluting Stent Versus Polymer-Based Everolimus-Eluting Stent in Diabetic Patients (RESERVOIR) clinical trial enrolled only patients with diabetes receiving glucose-lowering agents.27 The 112 participants were randomised either to Cre8™ or an EES (XIENCE®, Abbott Vascular). The primary endpoint – mean neointimal hyperplasia volume obstruction – was 11.97 ± 5.94 % in the Cre8™ group and 16.11 ± 18.18 % in the EES group (noninferiority p=0.0003; superiority p=0.22). Prespecified

INTERVENTIONAL CARDIOLOGY REVIEW

MLD (mm) In-stent In-segment

1.50

2.00

2.50

3.00

AES

EES

p-value

2.38 ± 0.44 2.09 ± 0.45

2.19 ± 0.59 1.84 ± 0.61

0.07 0.02

AES = Amphilimus™-eluting stent; EES = everolimus-eluting stent; LL = lumen loss; MLD = minimal lumen diameter; RESERVOIR = Reservoir-Based Polymer-Free Amphilimus™-Eluting Stent Versus Polymer-Based Everolimus-Eluting Stent in Diabetic Patients; SD = standard deviation. Source: Adapted from Romaguera et al, 2016.27

subgroup analysis showed consistent treatment effect in favour of the Cre8™ arm across all subgroups. In terms of secondary endpoints, LLL in the Cre8™ arm was 0.14 ± 0.24 mm compared with 0.24 ± 0.57 mm in the EES arm. The difference between the standard deviations is striking, and demonstrates the consistent performance of the Cre8™ (see Figure 3). The minimal lumen diameter was also higher in the Cre8™, both in-stent (2.38 ± 0.44 mm versus 2.19 ± 0.59 mm; p=0.07) and in segment (2.09 ± 0.59 mm versus 1.84 ± 0.61 mm; p=0.02). Finally, a matched analysis has been performed in which 187 consecutive patients treated with Cre8™ between January 2011 and August 2013 in four Italian centres were propensity matched with 150 patients treated with new-generation EESs during the same period. The incidence of 1-year estimated MACE was numerically lower in Cre8™ compared to the EESs, although the difference was not statistically significant (7.4 versus 10.2 %, respectively; p=0.261). The same was true of allcause mortality (1.3 % Cre8™ versus 1.4 % EES; p=0.823), target vessel revascularisation (5.2 % Cre8™ versus 8.8 % EES; p=0.169) and TLR (3 % Cre8™ versus 7.4 % EES; p=0.108). Subgroup analysis showed that these differences were more pronounced in patients with diabetes, with a 50 % decrease in the incidence of MACE, although this was not statistically significant (10 % Cre8™ versus 20 % EES; p=0.204). Of particular note, in patients with diabetes (Cre8™, n = 42; EES, n = 41), 1-year TLR was 2.5 % in the Cre8™ group versus 14.6 % in the EES group, which represented an 83 % reduction (p=0.05; see Figure 4).28 While a growing body of clinical and real-world data has provided support for the efficacy of the Cre8™, studies have been underpowered to demonstrate statistical superiority over other DESs. To do so, a large clinical study is planned: the Clinical benefit in ‘all comers’ patients with DIABetes to prove Cre8™ DES superior efficacy (DIAB8).29 In this study, all-comer patients with diabetes undergoing PCI will be randomised in a 1:1 ratio to the Cre8™ or to an everolimus DES. The primary endpoint will be 12-month target lesion failure. Around 2,200 patients from 50 international sites will be recruited and clinical follow-up will be at 1 and 3 years.

Safety In addition to these efficacy data, the Cre8™ has demonstrated excellent safety. In the INVESTIG8 study, the incidence of definite stent thrombosis at 12 months was low in both non-diabetic and diabetic

Coronary Figure 4: Target Lesion Revascularisation at 12 Months in Patients Treated with the Cre8™ versus XIENCE ® Drugeluting Stents: a Propensity-matched Analysis

Target lesion revascularisation at 12 months (%)

p=0.051

14 12 10 8 6 4 2 0

Xience DES

Cre8

DES = drug-eluting stent. Source: Adapted from Panoulas et al, 2015.28

patients (0.3 % in each group). The ranDomizEd coMparisOn betweeN novel Cre8™ DES and BMS to assess neoinTimal coveRAge by OCT Evaluation (Demonstr8) study was designed to assess whether strut coverage 3 months after implantation of the Cre8™, once it becomes a BMS after complete drug-elution, was equivalent to a standard BMS.30 Patients (n=38) with ischaemic myocardial symptoms related to de novo lesions in native coronary arteries were randomised 1:1 to receive a Cre8™ or a BMS (VISION®, Abbott Vascular). The primary endpoint of ratio of uncovered to total stent struts per cross section (RUTTS) score <30% occurred in 99.8% of Cre8™ struts and in 99.6% of the BMS struts (p for noninferiority <0.001). The first results of a single centre registry study undertaken in Utrecht (U-Cre8) have recently been presented.31 This study involved 332 coronary lesions in 201 patients with diabetes and accrued data from 2012 to 2014. A retrospective analysis propensity-matched 99 patients receiving the Cre8™ with 102 patients receiving a zotarolimus-eluting stent (ZES). The mean duration of dual antiplatelet therapy following PCI was 4.8 ± 3.4 months in the Cre8™ group versus 5.9 ± 4.1 in the

ZES group. Target-lesion failure occurred in six (6.1 %) patients in the Cre8™ group compared to 11 (10.7 %) in the ZES group. These failures were attributable to TLR in three Cre8™ patients (3.0 %) and seven ZES patients (6.9 %). End MACE-free survival was reported in 93 (93.9 %) Cre8™ patients compared to 87 (85.2 %) of the ZES group at study end. It must be stressed, however, that these are preliminary data that still require independent adjudication.

Byrne RA, Serruys PW, Baumbach A, et al. Report of a European Society of Cardiology-European Association of Percutaneous Cardiovascular Interventions task force on the evaluation of coronary stents in Europe: executive summary. Eur Heart J 2015;36:2608–20. DOI: 10.1093/eurheartj/ehv203; PMID: 26071600 Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with diabetes: part II: recent advances in coronary revascularization. J Am Coll Cardiol 2007;49:643–56. DOI: 10.1016/j.jacc.2006.09.045; PMID: 17291929 Lim JY, Deo SV, Kim WS, et al. Drug-eluting stents versus coronary artery bypass grafting in diabetic patients with multi-vessel disease: a meta-analysis. Heart Lung Circ 2014;23:717–25. DOI: 10.1016/j.hlc.2014.02.005; PMID: 24704466 Tu B, Rich B, Labos C, et al. Coronary revascularization in diabetic patients: a systematic review and Bayesian network meta-analysis. Ann Intern Med 2014;161:724–32. DOI: 10.7326/ M14-0808; PMID: 25402514 International Diabetes Federation. IDF Diabetes Atlas. 7th ed. Brussels: International Diabetes Federation, 2015. Available at: http://www.diabetesatlas.org (accessed 5 October 2016) Moretti C, Lolli V, Perona G, et al. Cre8™ coronary stent: preclinical in vivo assessment of a new generation polymerfree DES with Amphilimus™ formulation. EuroIntervention 2012;7:1087–94. DOI: 10.4244/EIJV7I9A173; PMID: 22130128 Mehilli J, Byrne RA, Wieczorek A, et al.; Intracoronary Stenting and Angiographic Restenosis Investigators – Test Efficacy of Rapamycin-eluting Stents with Different Polymer Coating Strategies (ISAR-TEST-3). Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis. Eur Heart J 2008;29:1975–82. DOI: 10.1093/eurheartj/ehn253; PMID: 18550554 Byrne RA, Kufner S, Tiroch K, et al.; ISAR-TEST-3 Investigators. Randomised trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis: 2-year follow-up results. Heart

10.

11.

12.

13.

14.

15.

16.

The Prospective, Single Center, Open Label, Randomized Controlled, Two Arm Study Evaluating Safety and Efficacy of the Permanent Polymer Zotarolimus Eluting Stent Resolute Integrity Compared to the Polymer Free Amphilimus™-Eluting Stent Cre8™ (ReCre8) is currently recruiting participants. In this all-comer study, patients (n=1,530) with ischaemic myocardial symptoms are randomised to the Cre8™ or the Resolute DES (Medtronic).32 The study is also investigating the use of dual antiplatelet therapy for 1 month in elective PCI. Clinical follow-up is at 1, 2 and 3 years, and the primary endpoint is MACE at 12 months. Excellent safety and efficacy data have been reported in support of the Cre8™, and results of the ReCre8 study are awaited.

Conclusion Poorer outcomes following PCI reflect an unmet need in stent technology for patients with diabetes. The lower efficacy of DESs in these patients is largely due to reduced responsiveness of cells to -limus drugs. The Cre8™ utilises a proprietary polymer-free drugrelease system consisting of reservoirs on the stent’s outer surface, maximising drug delivery without increasing the dose. The Amphilimus™ formulation enhances cellular drug uptake, particularly in diabetic cells. Finally, clinical trial and real-world data have demonstrated the superior performance of the Cre8™ compared with other DESs in diabetic subgroups, as well as remarkable consistency in terms of LLL. These findings suggest that the Cre8™ is a useful option in PCI in this challenging patient population. Data from on-going studies are eagerly anticipated. n

2009;95:1489–94. DOI: 10.1136/hrt.2009.172379; PMID: 19592388 Stone GW, Kedhi E, Kereiakes DJ, et al. Differential clinical responses to everolimus-eluting and paclitaxel-eluting coronary stents in patients with and without diabetes mellitus. Circulation 2011;124:893–900. DOI: 10.1161/ CIRCULATIONAHA.111.031070; PMID: 21824922 Kim WJ, Lee SW, Park SW, et al.; ESSENCE-DIABETES Study Investigators. Randomized comparison of everolimuseluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus (ESSENCE-DIABETES): results from the ESSENCE-DIABETES trial. Circulation 2011;124:886–92. DOI: 10.1161/CIRCULATIONAHA.110.015453; PMID: 21810659 Woods TC. Dysregulation of the mammalian target of rapamycin and p27Kip1 promotes intimal hyperplasia in diabetes mellitus. Pharmaceuticals (Basel) 2013;6:716–27. DOI: 10.3390/ph6060716; PMID: 24276258 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. PMID: 23532775 Obesity Society. Your Weight and Diabetes. February 2015. Available at: www.obesity.org/content/weight-diabetes (accessed 5 October 2016) Schafer K, Halle M, Goeschen C, et al. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004;24:112–7. DOI: 10.1161/01. ATV.0000105904.02142.e7; PMID: 14615386 Shan J, Nguyen TB, Totary-Jain H, et al. Leptin-enhanced neointimal hyperplasia is reduced by mTOR and PI3K inhibitors. Proc Natl Acad Sci U S A 2008;105:19006–11. DOI: 10.1073/pnas.0809743105 Piatti P, Di Mario C, Monti LD, et al. Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003;108:2074–81. DOI: 10.1161/01.

CIR.0000095272.67948.17; PMID: 14530196 17. Shoukry A, El-Sherbieny I, Swelan E. Association of insulin resistance, insulin and leptin levels with coronary in-stent restenosis. Egyptian Heart J 2012;64:35–42. 18. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 2010;90:367–417. DOI: 10.1152/ physrev.00003.2009; PMID: 20086080 19. Chabowski A, Gorski J, Glatz JF, et al. Protein-mediated fatty acid uptake in the heart. Curr Cardiol Rev 2008;4:12–21. DOI: 10.2174/157340308783565429 20. Kim MJ, Doh HJ, Choi MK, et al. Skin permeation enhancement of diclofenac by fatty acids. Drug Deliv 2008;15:373–9. DOI: 10.1080/10717540802006898; PMID: 18686081 21. Carrie D, Berland J, Verheye S, et al. A multicenter randomized trial comparing amphilimus- with paclitaxel-eluting stents in de novo native coronary artery lesions. J Am Coll Cardiol 2012;59:1371–6. DOI: 10.1016/j.jacc.2011.12.009; PMID: 22284328 22. 22. Carrie D. Polymer-free Cre8TM DES: Design, current status and future directions. Presented at: TCT 2015 – Transcatherter Cardiovascular Therapeutics, San Francisco, CA, 11–15 October 2015. 23. Park GM, Lee SW, Park SW, et al. Comparison of zotarolimuseluting stent versus sirolimus-eluting stent for de novo coronary artery disease in patients with diabetes mellitus from the ESSENCE-DIABETES II trial. Am J Cardiol 2013;112:1565–70. DOI: 10.1016/j.amjcard.2013.07.012; PMID: 24063840 24. Grube E, Chevalier B, Guagliumi G, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the XIENCE V everolimus-eluting stent vs the TAXUS Liberte paclitaxeleluting stent in diabetic patients with de novo coronary artery lesions. Am Heart J 2012;163:867–75 e1. DOI: 10.1016/j. ahj.2012.02.006; PMID: 22607866 25. Sardella G. The latest available data on polymer-free DES technology in diabetic patients. Presented at: Euro PCR, Paris, France, 19-22 May 2015. Available at:

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Role of the Cre8 Stent for Diabetic Patients

www.pcronline.com/Lectures/2015/The-latest-availabledata-on-polymer-free-DES-technology-in-diabetic-patients (accessed 25 February 2016) 26. Mountfort K. Patient-tailored drug-eluting stent choice – a solution for patients with diabetes. Interventional Cardiology Review 2015;10:158–61. DOI: 10.15420/icr.2015.10.03.158 27. Romaguera R, Gomez-Hospital JA, Gomez-Lara J, et al. A Randomized Comparison of Reservoir-Based Polymer-Free Amphilimus-Eluting Stents Versus Everolimus-Eluting Stents With Durable Polymer in Patients With Diabetes Mellitus: The RESERVOIR Clinical Trial. JACC Cardiovasc Interv 2016;9:42–50. DOI: 10.1016/j.jcin.2015.09.020; PMID: 26762910 28. Panoulas VF, Latib A, Naim C, et al. Clinical outcomes of

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real-world patients treated with an amphilimus polymerfree stent versus new generation everolimus-eluting stents. Catheter Cardiovasc Interv 2015;86:1168–76. DOI: 10.1002/ ccd.25931; PMID: 26269415 29. PCR Devices. DIAB8, 2016. Available at: www.pcrdevices.com/ Stents/Trials-FINDER/Diab8 (accessed 14 September 2016) 30. 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. DOI: 10.1016/j.ijcard.2014.08.031; PMID: 25171966 31. PCR Devices. U-Cre8, 2016. Available at: www.pcrdevices.com/

Stents/Trials-FINDER/U-Cre8 (accessed 14 September 2016) 32. PCR Devices. ReCre8 (A Prospective, Single Center, Open Label, Randomized Controlled, Two Arm Study Evaluating Safety and Efficacy of the Permanent Polymer Zotarolimus Eluting Stent Resolute Integrity Compared to the Polymer Free Amphilimus Eluting Stent Cre8), 2016. Available at: www.pcrdevices.com/Stents/Trials-FINDER/ReCre8-AProspective-Single-Center-Open-Label-RandomizedControlled-Two-Arm-Study-Evaluating-Safety-andEfficacy-of-the-Permanent-Polymer-Zotarolimus-ElutingStent-Resolute-Integrity-Compared-to-the-PolymerFree-Amphilimus-Eluting-Stent-Cre8 (accessed 14 September 2016)

Coronary

Expert Opinion Transradial Coronary Artery Procedures: Tips for Success Kully Sandhu, Robert Butler and James Nolan Cardiology Department, Royal Stoke University Hospital, Stoke-on-Trent, UK

Abstract Historically, the majority of coronary procedures have been performed via the femoral artery. However, since the inception of the transradial approach, a number of studies have confirmed that this technique is associated with a significant reduction in vascular complications, equivalent procedure times and radiation exposure to femoral procedures, the ability to perform complex coronary interventions, early ambulation and patient preference. Over the last decade, this has led to an exponential rise in the use of the transradial access site, with several potential technical challenges becoming increasingly recognised. However, with greater experience and technological advancement these potential obstacles may be overcome. The following review highlights the potential challenges and suggests several tips to assist transradial operators with recognising and overcoming these challenges.

Keywords Transradial approach, coronary intervention, radial artery anomalies, radial artery spasmolytics, balloon-assisted tracking, sheathless guide catheters, radial artery occlusion prevention Disclosure: The authors have no conflicts of interest to declare. Received: 25 October 2016 Accepted: 10 April 2017 Citation: Interventional Cardiology Review 2017;12(1):18–24. DOI: 10.15420/icr.2017:2:2 Correspondence: Kully Sandhu, Cardiology Registrar, Cardiology Department, Royal Stoke University Hospital, University Hospitals of North Midlands, Stoke-on-Trent, ST4 6QG, UK. E: ksandhu@hotmail.com

Percutaneous revascularisation has become the cornerstone of ischaemic heart disease management.1,2 Historically, coronary angiography and intervention was predominantly performed via the common femoral artery.3 However, this procedure has an associated 1.5–9.0 % risk of complications, most of which are related to bleeding at the femoral access site.4 Despite a significant reduction in the incidence of major femoral bleeding complications during 1994 to 2005 from 8.4 % to 3.5 %, respectively,5 related to technological advancement (including a reduction in size of interventional devices and, controversially, the introduction of vascular closure devices), these major complications remain important.6–9 Multiple large studies have demonstrated a two- to eightfold increase in mortality rate in patients with acute coronary syndrome (ACS) who experienced major bleeding following percutaneous coronary intervention (PCI).5,10–13 Campeau reported the first contemporary use of transradial access for diagnostic procedures in 1989;14 this was shortly followed by reports of the first transradial angioplasty.15,16 Several early studies reported a significant reduction in vascular complications for transradial procedures compared with the transfemoral approach.17–19 These early studies raised interest in the transradial access site as a viable and attractive alternative to femoral access.20–22 There followed larger, multicentre, prospective, randomised trials designed to overcome any potential bias of earlier single-centre trials and retrospective meta-analyses. The Radial Versus Femoral Access for Coronary Angiography and Intervention in Patients with Acute Coronary Syndromes (RIVAL) study set out to determine whether radial access was superior to

Access at: www.ICRjournal.com

femoral access in patients with ACS undergoing coronary angiography and angioplasty.23 This large randomised, worldwide multicentre trial of 7,021 patients demonstrated that transradial procedures were associated with a 60 % reduction in vascular complications when compared with the femoral approach, but no significance difference in rates of death, MI, stroke or major bleed. However, the RIVAL primary PCI (PPCI) in ST elevation MI (STEMI) sub-analysis found that the radial artery approach was associated with a significant reduction in the rate of 30-day all-cause mortality.24 These findings led to the Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of AngioX (MATRIX) trial, a large randomised, multicentre, superiority trial comparing transradial versus transfemoral approach in 8404 patients with ACS.27 The study found no reduction in the rate of MI, stroke, or non-coronary artery bypass graft-related major bleeding at 30 days, but a 63 % reduction in the risk of vascular-access complications was seen in the transradial group. The transradial approach was also found to reduce net adverse clinical events, and all-cause mortality and major bleeding rates. This reduction in the rates of allcause mortality and bleeding occurred in all patients with ACS and was not limited to patients with STEMI, as in the aforementioned RIVAL study. Several early studies reported a reduction in mortality rates in patients undergoing transradial access for STEMI.28–31 These studies paved the way for the Radial Verses Femoral Randomized Investigation in ST elevation Acute Coronary Syndrome (RIFLE-STEACS) trial.

Transradial Procedures

The reduction in vascular complications has also been highlighted in other potential high-risk groups including obese patients, 32 octogenarians33,34 and female patients.35 Further advantages of a transradial approach include immediate ambulation, as opposed to bed rest after femoral procedures. Reduced post-procedure nursing care, reduced hospital stay and, therefore, cost, with an overwhelming patient preference for transradial angiography are all well-described additional advantages.36–42 Findings from these studies have led to the recommendation for use of the radial artery approach in both patients with STEMI43 and non-STEMI.44 Opponents of radial access have cited an associated learning curve 45 with adopting the transradial approach resulting in longer procedural time and increased radiation exposure. 46 However, a meta-analysis found the difference in radiation exposure between transradial and transfemoral approaches to decrease by >75 % over a 20-year period, and that the clinical benefits of transradial access outweighed any small observed difference in radiation exposure. 47 In addition, higher-volume radial operators were shown to have shorter procedural and fluoroscopy times. Lower-volume operators achieve a reduction in procedural and fluoroscopy times as their procedural experience increases. 48 Similarly, a sub-analysis of the multicenter RIVAL study found no significant differences in radiation exposure between either femoral or radial access for the entire cohort. However, a modest, but significant, increase in fluoroscopy time in radial cases performed in a low- to intermediate-volume center, but not in high-volume centers. Furthermore, a sub-analysis and multivariate analysis found the highest radial volume centres and operators had the lowest radiation exposure. 49 Finally, Burzotta et al. found that the case volume required to overcome the learning curve was relatively short – 50–80 transradial procedures.50 As a result of these studies, operators in the UK are increasingly adopting radial access (see Figure 1).22

Tips for Successful Transradial Coronary Artery Procedures Know Your Patient The first tip begins outside the catheter laboratory. A full and detailed explanation of the procedure should be provided not only as a consenting exercise, but also to decrease patient anxiety. It is important to obtain details of any significant patient comorbidity, allergies, previous coronary artery bypass grafts and or PCI. In patients with previous PCI, it is important to determine which arterial access approach was used, and if any difficulties were encountered including switching access site or post-procedural bleeding. Previous angiographic images should be reviewed, if possible, to identify any pre-existing coronary artery disease or procedural difficulties encountered, and to ascertain the presence of patent grafts and any

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 1: Percentage Increase in the Use of Transradial Access Approach for Coronary Intervention by Year 90 80.5

80 Cases using radial access (%)

This prospective, randomised study evaluated transradial versus transfemoral arterial access in patients with STEMI. The study enrolled 1,001 patients across four Italian centres and found not only a 47 % reduction in the rate of access-site-related bleeding complications, but also a reduction in the rate of cardiac death and hospital stay with transradial procedure.25 These findings were verified by a meta-analysis of 12 studies including 5,055 patients recommended radial approach for patients with STEMI undergoing PPCI.26

71.2

65.2 58.6

60 51.6

34.7

26.9 21.3

20 10 0

75.3

15.7 10.2

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Year

Source: reproduced with the permission from Dr Peter Ludman (British Cardiovascular Intervention Society audit returns – adult interventional procedures; data on file).

vascular abnormalities or tortuous vasculature. Relevant blood tests including haemoglobin, renal function and troponin levels should also be reviewed. The Allen’s test, once thought to be pivotal in the assessment of patiens suitability for radial angiography, is now recognised to be of little value due to ulnar–palmer collateralisation.51 Therefore, the routine use of Allen’s test is no longer recommended within the author’s institute.

Venous Access All patients should have intravenous access, preferably in the contralateral arm to the side of transradial approach, allowing administration of medication including intravenous saline or sedatives. Radial artery spasm has become an increasingly recognisable phenomena52 seen in 10–15 % of reported cases of transradial procedures.53,54 Catecholamine release due to anxiety increases risk of radial artery spasm; therefore, the patient should be as relaxed as possible. Sedation has often been used in attempt to prevent radial artery spasm. A study of 2,013 patients who were randomised to receive fentanyl plus midazolam or no sedation found a significant reduction in spasm, and the number needed to treat to avoid one case of radial artery spasm was 18.55 The crossover rate to femoral artery was 34 % lower in the group given fentanyl and midazolam. The results of this study supported the use of pre-procedural sedation. However, the study was criticised for incomplete reporting.56 A large multicentre and worldwide study found not only a wide geographic variation in the use of sedation, but also that 58.3 % of operators did not routinely use sedation.21 At present, there are insufficient data to recommend routine use of sedation.

Left or Right Radial Artery Access Transradial angiography and PCI are predominantly performed from the right radial artery due to cardiac catheter laboratory set, operator comfort and preferences. Traditionally, there had been concerns about radiation dose and success rates of the left radial approach. However, the (Randomized Evaluation of Vascular Entry Site and Radiation Exposure) REVERE trial found no significant difference in radiation dose in 1,500 patients

Coronary Table 1: Classification and Rate of Radial Artery Anomaly and Associated Rates of Procedural Failure 65 Classification of radial

Occurrence, n (%)

artery anomaly

Procedural failure, %

High-bifurcating radial origin

108 (7.0)

4.6

Full radial loop

35 (2.3)

37.1

Extreme radial artery tortuosity

30 (2.0)

23.3

Miscellaneous anomalies such as radial atherosclerosis and accessory branches

39 (2.5)

12.9

undergoing either femoral, right or left radial artery approaches.57 The study also found a reduction in radiation dose in experienced radial and femoral operators.58,59 These studies also found no difference in contrast load, number of catheters used or success rates.58,59 Major adverse cardiac and cerebrovascular event rates have also been found to be similar.58,59 Norgaz et al. attributed shorter fluoroscopy times from left radial artery approach to a threefold higher incidence of subclavian tortuosity, as well as a higher incidence of radial loops with right radial access.59 Further advantages of using the left radial artery approach include significantly shorter learning curve and progressive reduction in fluoroscopic and arterial cannulation times when compared with right radial artery approach.60 Therefore, the left radial approach is both feasible and safe in clinical practice. The left radial artery approach may also be used post coronary artery bypass graft if patients have had a left internal mammary artery (LIMA) graft to the left anterior descending (LAD) artery. This is because cannulation of the LIMA to LAD graft has been associated with a failure in 27 % of cases if performed from the right radial artery.61 The presence of a retro-oesophageal origin may either preclude or render more complex cannulation of the coronary arteries from the right radial artery, whereas a left radial approach may prove to be easier and more successful. The patients arm may be placed on an arm board anchored under the patient either at 80° or alongside the patient depending on operator preference. A folded bed sheet or specialised arm board devices placed under the wrist allows hyperextension of the wrist. This allows not only increased support, but also exposure of the radial artery. The wrist is then cleaned, draped and infiltrated with local anaesthesia.

Radial Artery Puncture Kits and Spasmolytics A number of radial access kits are currently commercially available, including the bare-metal Micropuncture® system (Cook Medical) and a Glidesheath Slender hydrophilic-coated introducer sheath (Terumo). The choice of puncture kit is at the discretion of the operator; however, familiarity of both kits is advisable. Irrespective of the puncture system used, the radial artery should be punctured at 30–45° to the horizontal and 2 cm proximal to the radial styloid process, to minimise the risk of introducing the sheath into a smaller diameter distal radial artery. A small skin incision may be performed while the guide wire is in situ, allowing easier introduction of the sheath and further reducing any distress or pain experienced by the patient. Once the radial sheath has been introduced spasmolytics are often administered to try to prevent radial artery spasm.62 A meta-analysis found that 5 mg of verapamil

or verapamil in combination with nitroglycine had the lowest rates of radial artery spasm.54 In a survey across 75 countries, the majority (85.9 %) of operators used vasodilators prophylactically with verapamil being the most commonly used agent (75.3 %), either alone or in combination with a number of other agents.21 The use of prophylactic vasodilator anti-spasmolytic cocktails is largely operator preference based on the operator’s own common practice rather than based on rigorous placebo-based clinical trials. The rate of radial artery spasm varies widely in different trial and this may be attributed due to a lack of consensus of the definition of radial artery spasm. This, in turn, limits inter-trial comparisons and, therefore, any meta-analysis. However the use of anti-spasmolytic agents have been questioned. Technical advancements such as a reduction in the diameter and the addition of hydrophilic coating of radial introducer sheaths both reducing risk of radial artery spasm. Geographic variation of the use of anti-spasmolytics has been observed, and up to 72.2 % of Japanese operators do not use anti-spasmolytics.21 The study results indicate that the preventative use of anti-spasmolytics may not be as important as once thought. Radial artery spasm has been found to be a rare event after a learning curve (1.7 %) and use of verapamil 5 mg showed no significant difference in investigated endpoints, including access site conversion, radial artery spasm or subjective pain, compared with placebo.63 These findings led to further questioning of the use of verapamil in high-volume operators. The authors concluded that prophylactic vasodilators showed no advantage.63 The omission of vasodilators may be clinically relevant by avoiding adverse effects and not precluding radial angiography in patients with known contraindications to vasodilators.64

Radial Artery Anomalies and Tortuosity A landmark study of 1,540 consecutive patients found that radial artery anatomy anomalies are a relatively common finding occurring in 13.8 % (n=212) of patients undergoing transradial coronary procedures.65 Radial artery anomalies were associated with a significant incidence of procedural failure (14.2 versus 0.9 % in non-anomalous radial arteries; see Table 1). Despite this, the overall procedural success was found to be 96.8 %, with only 1 % (n=5) having vascular complications, all managed conservatively without any ischaemic sequelae. The authors, therefore, recommended imaging of the radial artery after introducing sheath insertion. Certain radial artery anomalies (such as large-diameter radial loops) may be difficult to overcome and an alternative vascular access may be required. However, there are several available techniques for overcoming simpler anomalies such as radial tortuosity. Balloonassisted tracking is a technique that may be used to overcome radial tortuosity, spasm or loops.66,67 A regular 0.014” hydrophilic coronary angioplasty wire is passed through the difficult area under fluoroscopy. Then a diagnostic or guide catheter is loaded with a standard non-compliant balloon positioned half protruding beyond the tip of the catheter. A 5 Fr catheter will accommodate a 2.0 mm balloon, whereas a 6 Fr guide may require a 2.5 mm diameter balloon. Once correctly positioned, the balloon is inflated to 8–10 atmospheres. The catheter–balloon delivery system is then loaded onto and passed along the 0.014” hydrophilic coronary angioplasty wire. The balloon– catheter delivery system creates a soft tapered edge straightening the radial tortuosity and facilitating catheter passage through the

INTERVENTIONAL CARDIOLOGY REVIEW

Transradial Procedures Figure 2: Balloon-Assisted Tracking A

A: A 2 mm diameter standard angioplasty balloon is passed within a 6 Fr guide catheter. B: A balloon catheter is positioned so that half protrudes outside the guide catheter and is subsequently inflated to low pressure of 8–10 atmospheres. C: The balloon-inflated guide catheter is then loaded onto a standard 0.014” hydrophilic coronary angioplasty wire that is already positioned via the radial artery to the ascending aorta. D: Radiographic image of balloon-assisted tracking of the guide catheter smoothly beyond the radial artery tortuosity.

loops or areas of spasm, limiting further radial trauma and pain. This manoeuvre is performed under fluoroscopic guidance (see Figure 2). Once the catheter has reached the ascending aorta the 0.014” hydrophilic coronary angioplasty wire and balloon catheter may be changed to a standard 0.035” guide wire, providing greater support to position the catheter into the aorta root. An exchange length J-tip (260 cm) guidewire is then used to exchange catheters to avoid loss of radial access. A simpler method is passing a regular 0.014” hydrophilic coronary angioplasty wire cautiously along the tortuosity and secured within the subclavian artery. This often straightens out the radial artery. A 5 Fr diagnostic multipurpose catheter is then loaded onto the proximately positioned wire. The multipurpose catheter decreases the risk of the radial artery wall shearing and the damage that occurs with more angulated catheters such as the Judkins or Amplatzer® catheters. Cautious advancement under fluoroscopic guidance is mandatory. First, to avoid engagement into small branches and to ensure the catheter is smoothly traversing to the head and neck vessels and, second, to prevent catheter kinking within the radial artery causing intense spasm and pain to the patient (see Figure 3A–D). Once the catheter has reached the subclavian artery just proximal to the end of the regular 0.014” hydrophilic coronary angioplasty wire, the coronary angioplasty wire is then exchanged with a standard J-tip (260 cm) exchange wire. The exchanged wire provides greater support for the catheter. The multipurpose catheter is then withdrawn ensuring the exchange length (260 cm) guidewire remains positioned within the subclavian artery. A standard diagnostic or guide catheter may then be loaded onto the J-tip exchange length (260 cm) guidewire, and both passed under fluoroscopic guidance to the aortic root in standard manner. The coronary arteries are then cannulated. All subsequent catheter changes are performed via the J-tip (260 cm) guidewire avoiding the need to re-cross areas of difficult anatomy. Similarly, the above techniques may also be applied in the presence of tortuous brachial or subclavian arteries. Deep inspiration with breath holding may allow further negotiation of subclavian artery tortuosity by modifying the angulation of the brachiocephalic trunk. The optimal view for assessing the ascending aorta is in the left anterior oblique projection at 30°. This projection limits superposition of different segments of the aorta and opens out the aortic arch. Recognition of the position of the guidewire in either ascending or descending aorta is then made possible. If the guidewire repeatedly enters the descending rather than ascending aorta a diagnostic 5 Fr or 6 Fr JR4 catheter may be advanced with great care

INTERVENTIONAL CARDIOLOGY REVIEW

Figure 3: Use of a Regular 0.014” Hydrophilic Coronary Angioplasty Wire to Straighten a Radial Loop A

A: Fluoroscopic imaging of the right radial artery identifying the presence of a loop (white circle). B: A regular 0.014” hydrophilic coronary angioplasty wire is passed within the radial artery loop under fluoroscopic guidance. C: The passing of the hydrophilic angioplasty wire ’straightens’ the radial loop allowing successful passage of the catheter. Source: Images courtesy of Dr Kari Ratib (Royal Stoke University Hospital).

not to extend beyond the guidewire. On reaching the aorto– brachiocephalic or aorto–subclavian junction for right and left radial artery access, respectively, the catheter can be angulated towards the ascending aorta facilitating wire access. An exchange length (260 cm) guidewire should be used if further catheter exchanges are required. Finally, all catheters should always be withdrawn over a 0.035” guidewire even in non-tortuous radial arteries. This manouvre avoids any forceful manipulation or catheter tip induced trauma that may cause catheter kinking and radial artery spasm or avulsion.68,69

Radial Artery Diameter Radial artery diameter may potentially limit the maximum size of radial artery introducer sheath, especially as the external diameter of the introducing sheath is 2 Fr larger than its internal diameter.70 The ideal ratio of inner diameter of radial artery to sheath outer diameter has been found to be 0.9.71 Operators should avoid using sheath diameters greater than the radial artery diameter.72 The smaller-diameter hydrophilic introducer sheaths are associated with a reduction in both incidence of radial artery spasm73,74 and pain experienced by patients.71 Therefore, radial artery access had been thought to preclude larger-bore guide catheters required for more complex lesions. There are several approaches that may overcome this potential technical challenge. The first is the use of the Glidesheath Slender® (Terumo) introducer sheath, which has a thin wall providing an inner diameter compatible with 6 Fr catheters and an outer diameter corresponding to 5 Fr sheath, allowing passage of large-bore guide catheters. These introducer sheaths have been reported to have high success rates with a significant reduction in radial artery occlusion and radial artery spasm.75,76

Coronary Sheathless guide catheters negate the use of radial introducer sheaths. This technique has been shown to be both safe and effective in both elective and primary PCI for patients with STEMI.77 However, the main advantage is the ability to allow transradial passage of the large-bore 7 or 8 Fr guide catheters that may be required for complex coronary interventions.70 The radial artery is cannulated with a standard 5 or 6 Fr radial artery sheath. Diagnostic coronary angiography may be performed in the usual maner with either 5 or 6 Fr diagnostic catheters. If diagnostic images indicate that coronary intervention is required with a large-bore guide catheter then the 5 or 6 Fr diagnostic catheter is removed over a J-tip (260 cm) guidewire positioned and secured in the ascending aorta. The introducer sheath is then also removed cautiously over the J-tip (260 cm) guidewire. Pressure is then applied onto the radial artery access site once the introducer sheath is removed. A 7 or 8 Fr standard guide catheter with a 5 Fr multipurpose catheter extending beyond the tip provides a smooth transition from wire to catheter, and is loaded on to the J-tip (260 cm) guidewire. This delivery system is then passed into the ascending aorta under fluoroscopic guidance. The inner 5 Fr multipurpose catheter is then removed leaving the 7 or 8 Fr guide within the ascending aorta ready to be manoeuvred in the standard way to cannulate the coronary artery. On completion of the intervention, the guide catheter is taken out using the standard over-the-wire technique and a haemostatic compression device is placed.78 A modified version adopts the balloon-assisted technique described above for tortuous radial artery. A regular 0.014” hydrophilic coronary angioplasty wire is passed under fluoroscopic guidance through a standard 5 or 6 Fr radial introducer sheath to the ascending aorta. The introducer sheath is removed over the hydrophilic coronary angioplasty wire. A 7 Fr introducer without the sheath is loaded and passed along the coronary angioplasty wire to ensure a passage has been made into the radial artery. The delivery system is then loaded onto and passed along the hydrophilic coronary angioplasty wire to the ascending aorta. The delivery system consists of a largebore guide catheter with a balloon catheter positioned so that it protrudes partially outside the guide catheter. The balloon is then inflated to low pressure, 6–8 atmospheres. The delivery system creates a soft tapered edge that passes within the radial artery. Once the delivery system has reached the ascending aorta the balloon is deflated and, along with the 0.014” hydrophilic coronary

L evine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/ SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2016;67:1235–50. DOI: 10.1016/j.jacc.2015.10.005; PMID: 26498666. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139–228. DOI: 10.1016/j.jacc.2014.09.017; PMID: 25260718. Moscucci M. Grossman & Baim’s Cardiac Catheterization, Angiography, and Intervention. 8th edition. Philadelphia: Lippincott Williams and Wilkins, 2013. Nasser TK, Mohler ER 3rd, Wilensky RL, et al. Peripheral vascular complications following coronary interventional procedures. Clin Cardiol 1995;18:609–14. PMID: 8590528. Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on long-term survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005. JACC Cardiovasc Interv 2008;1:202–9. DOI: 10.1016/j.

angioplasty wire, may be changed to a standard 0.035” guidewire providing greater support. The coronary artery is then cannulated the standard way.

Radial artery occlusion One of the advantages of the radial artery is its superficial location, which allows safe and effective haemostasis by compression. This has led to many haemostatic compression devices becoming available, including TR Band® (Terumo), RadiStop™ (St. Jude Medical), RADstat® (Merit Medical Systems) and Helix® band (Vascular Perspectives). The most frequent complication of radial procedures is radial artery occlusion (RAO). The technique of patent haemostasis has been shown to significantly reduce radial artery occlusion at 30 days and, in the opinion of the authors, should be standard practice.79,80 RAO is usually asymptomatic due to ulnar–palmar collateralisation vascular blood supply of the hand. However, RAO precludes the use of radial artery access in any future coronary interventions. Procedural duration, arterial diameter-to-sheath ratio, compression time and pressure all have been shown to be risk factors for RAO.80 Heparin has been shown to significantly reduce rates of RAO, with a linear relationship observed between heparin dose and rate of RAO.81 This has led to most operators administering 5,000 IU of heparin or 70 IU/kg intra-arterial via the radial sheath. Heparin may also be given intravenously, with no difference in RAO whether given intra-arterially or intravenously.82 However, there are no current recommendations on heparin dose in patients taking oral anticoagulation or receiving platelet glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) or direct thrombin inhibitor use (bivalirubin). Finally, radial artery spasm has also been identified as a potential risk factor for RAO.73 However, a meta-analysis found no data to assess any link between pharmacological prevention of RAS and prevention of RAO, further highlighting the importance of preventing RAS.54

Conclusion There has been an exponential growth in the use of transradial coronary artery procedures over the last two decades. This increased use of transradial procedures has led to a number of potential technical challenges becoming recognised. However, with increasing experience many new approaches are now becoming available to overcome these potential challenges to transradial coronary procedures. n

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PMID: 24262624. 57. J olly SS, Cairns J, Niemela K, et al. Effect of radial versus femoral access on radiation dose and the importance of procedural volume: a substudy of the multicenter randomized RIVAL trial. JACC Cardiovasc Interv 2013;6:258–66. DOI: 10.1016/ j.jcin.2012.10.016; PMID: 23517837. 58. Dominici M, Diletti R, Milici C, et al. Left radial versus right radial approach for coronary artery catheterization: a prospective comparison. J Interv Cardiol 2012;25:203–9. DOI: 10.1111/j.1540-8183.2011.00689.x; PMID: 22272568. 59. Norgaz T, Gorgulu S, Dagdelen S. Arterial anatomic variations and its influence on transradial coronary procedural outcome. J Interv Cardiol 2012;25:418–24. DOI: 10.1111/ j.1540-8183.2012.00693.x; PMID: 22860990. 60. Sciahbasi A, Romagnoli E, Burzotta F, et al. Transradial approach (left vs right) and procedural times during percutaneous coronary procedures: TALENT study. Am Heart J 2011;161:172–9. DOI: 10.1016/j.ahj.2010.10.003; PMID: 21167351. 61. Guedes A, Dangoisse V, Gabriel L, et al. Low rate of conversion to transfemoral approach when attempting both radial arteries for coronary angiography and percutaneous coronary intervention: a study of 1,826 consecutive procedures. J Invasive Cardiol 2010;22:391–7. PMID: 20814043. 62. Kiemeneij F, Vajifdar BU, Eccleshall SC, et al. Evaluation of a spasmolytic cocktail to prevent radial artery spasm during coronary procedures. Catheter Cardiovasc Interv 2003;58:281–4. DOI: 10.1002/ccd.10445; PMID: 12594687. 63. Hizoh I, Majoros Z, Major L, et al. Need for prophylactic application of verapamil in transradial coronary procedures: a randomized trial. The VITRIOL (is Verapamil In TransRadial Interventions OmittabLe?) trial. J Am Heart Assoc 2014;3:e000588. DOI: 10.1161/JAHA.113.000588; PMID: 24732918. 64. Rosencher J, Chaib A, Barbou F, et al. How to limit radial artery spasm during percutaneous coronary interventions: The spasmolytic agents to avoid spasm during transradial percutaneous coronary interventions (SPASM3) study. Catheter Cardiovasc Interv 2014;84:766–71. DOI: 10.1002/ccd.25163; PMID: 23982995. 65. Lo TS, Nolan J, Fountzopoulos E, et al. Radial artery anomaly and its influence on transradial coronary procedural outcome. Heart 2009;95:410–5. DOI: 10.1136/hrt.2008.150474; PMID: 18977799. 66. Verouden NJ, Kiemeneij F. Balloon-assisted tracking to overcome radial spasm during transradial coronary angiography: a case report. Case Rep Cardiol 2014;2014:214310. DOI: 10.1155/2014/214310; PMID: 24826306. 67. Patel T, Shah S, Pancholy S, et al. Balloon-assisted tracking: a must-know technique to overcome difficult anatomy during transradial approach. Catheter Cardiovasc Interv 2014;83:211–20. DOI: 10.1002/ccd.24959; PMID: 23592578. 68. Mouawad NJ, Capers Qt, Allen C, et al. Complete “in situ” avulsion of the radial artery complicating transradial coronary rotational atherectomy. Ann Vasc Surg 2015;29:123 e7–11. DOI: 10.1016/j.avsg.2014.07.024; PMID: 25192824. 69. Alkhouli M, Cohen HA, Bashir R. Radial artery avulsion--a rare complication of transradial catheterization. Catheter Cardiovasc Interv 2015;85:E32–4. DOI: 10.1002/ccd.25528; PMID: 24760472. 70. From AM, Gulati R, Prasad A, et al. Sheathless transradial intervention using standard guide catheters. Catheter Cardiovasc Interv 2010;76:911–6. DOI: 10.1002/ccd.22742; PMID: 20824748. 71. Gwon HC, Doh JH, Choi JH, et al. A 5Fr catheter approach reduces patient discomfort during transradial coronary intervention compared with a 6Fr approach: a prospective randomized study. J Interv Cardiol 2006;19:141–7. DOI: 10.1111/j.1540-8183.2006.00121.x; PMID: 16650242. 72. Saito S, Ikei H, Hosokawa G, et al. Influence of the ratio between radial artery inner diameter and sheath outer diameter on radial artery flow after transradial coronary intervention. Catheter Cardiovasc Interv 1999;46:173–8. DOI: 10.1002/(SICI)1522-726X(199902)46:2<173::AIDCCD12>3.0.CO;2-4; PMID: 10348538. 73. Rathore S, Stables RH, Pauriah M, et al. Impact of length and hydrophilic coating of the introducer sheath on radial artery spasm during transradial coronary intervention: a randomized study. JACC Cardiovasc Interv 2010;3:475–83. DOI: 10.1016/ j.jcin.2010.03.009; PMID: 20488402. 74. Kiemeneij F, Fraser D, Slagboom T, et al. Hydrophilic coating aids radial sheath withdrawal and reduces patient discomfort following transradial coronary intervention: a randomized double-blind comparison of coated and uncoated sheaths. Catheter Cardiovasc Interv 2003;59:161–4. DOI: 10.1002/ccd.10444; PMID: 12772232. 75. Aminian A, Dolatabadi D, Lefebvre P, et al. Initial experience with the Glidesheath Slender for transradial coronary angiography and intervention: a feasibility study with prospective radial ultrasound follow-up. Catheter Cardiovasc Interv 2014;84:436–42. DOI: 10.1002/ccd.25232; PMID: 24285594. 76. Yoshimachi F, Kiemeneij F, Masutani M, et al. Safety and feasibility of the new 5 Fr Glidesheath Slender. Cardiovasc Interv Ther 2016;31:38–41. DOI: 10.1007/s12928-015-0344-2; PMID: 26141373. 77. Miyasaka M, Tada N, Kato S, et al. Sheathless guide catheter in transradial percutaneous coronary intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2016;87:1111–7. DOI: 10.1002/ccd.26144; PMID: 26354160.

Coronary 78. L i Q, He Y, Jiang R, et al. Using sheathless standard guiding catheters for transradial percutaneous coronary intervention to treat bifurcation lesions. Exp Clin Cardiol 2013;18:73–6. PMID: 23940423. 79. Pancholy S, Coppola J, Patel T, et al. Prevention of radial artery occlusion-patent hemostasis evaluation trial (PROPHET study): a randomized comparison of traditional versus patency documented hemostasis after transradial catheterization.

Catheter Cardiovasc Interv 2008;72:335–40. DOI: 10.1002/ ccd.21639; PMID: 18726956. 80. Cubero JM, Lombardo J, Pedrosa C, et al. Radial compression guided by mean artery pressure versus standard compression with a pneumatic device (RACOMAP). Catheter Cardiovasc Interv 2009;73:467–72. DOI: 10.1002/ccd.21900; PMID: 19229978. 81. Spaulding C, Lefevre T, Funck F, et al. Left radial approach

for coronary angiography: results of a prospective study. Cathet Cardiovasc Diagn 1996;39:365–70. DOI: 10.1002/(SICI) 1097-0304(199612)39:4<365::AID-CCD8>3.0.CO;2-B; PMID: 8958424. 82. Pancholy SB. Comparison of the effect of intra-arterial versus intravenous heparin on radial artery occlusion after transradial catheterization. Am J Cardiol 2009;104:1083–5. DOI: 10.1016/j.amjcard.2009.05.057; PMID: 19801029.

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Structural

Managing Stroke During Transcatheter Aortic Valve Replacement Florian Hecker, Mani Arsalan and Thomas Walther Department of Cardiac Surgery, Kerckhoff Heart Center, Bad Nauheim, Germany

Abstract Transcatheter aortic valve replacement (TAVR) has become the default treatment option for high-risk patients with aortic stenosis and an alternative to surgical aortic valve replacement in intermediate-risk patients. There are, however, concerns regarding strokes during TAVR. Reported stroke rates vary strongly depending on the type of study, stroke definition, cohort and study period. Furthermore, stroke after TAVR occurs in three distinct phases: 1) early high-risk, directly procedure related; 2) elevated risk interval between day 2 and day 30; 3) late hazard interval. Each of these phases is caused by the different aetiologies of stroke. This review summarises the different aetiologies and potential strategies for managing stroke during TAVR.

Keywords Transcatheter aortic valve replacement, transcatheter aortic valve implantation, embolic protection device, embolisation, antithrombotic, antiplatelet, transient ischaemic attack calcification Disclosure: The authors have no conflicts to declare. Received: 3 September 2016 Accepted: 12 April 2017 Citation: Interventional Cardiology Review 2017;12(1):25–30. DOI: 10.15420/icr.2016:26:1 Correspondence: Prof Thomas Walther, Department of Cardiac Surgery, Kerckhoff-Klinik, Benekestrasse 2–8, 61231 Bad Nauheim, Germany. E: T.Walther@kerckhoff-klinik.de

Transcatheter aortic valve replacement (TAVR) has become the default treatment option for high-risk patients with aortic stenosis (AS) and, based on heart team discussion, an alternative to surgical aortic valve replacement (SAVR) in intermediate-risk patients. TAVR has led to a paradigm shift in the basic therapeutic principle to treat AS: calcifications, in some patients quite excessive, are being squeezed aside instead of carefully surgically resected before valve placement. Due to these differences, the incidence of cerebrovascular events has been one of the main concerns associated with TAVR. In the Placement of AoRTic TraNscathetER Valve (PARTNER I) trial comparing TAVR and SAVR in a high-risk but operable patient cohort, stroke rates were higher after TAVR.1,2 Further studies showed that perioperative stroke leads to a five-fold increased risk of mortality after TAVR.2,3 Any technique to minimise the incidence and the risks for stroke during TAVR is therefore of the utmost importance.

is important, as stroke may be diagnosed on clinical findings alone without confirmation by specific imaging. It is recommended the terms ‘disabling’ and ‘non-disabling’ are used for stroke classification instead of ‘major’ and ‘minor’, respectively. ‘Disabling’ is defined as an mRS score of >2 points or an increase in >1 mRS category from pre-stroke baseline; ‘non-disabling’ as <2 mRS score points or without an increase in >1 category in mRS from baseline. The mRS should be assessed by a professional neurologist experienced in clinical trials 90 days after stroke onset.5 The Neurologic Academic Research Consortium recently proposed standardized neurological endpoints for cardiocascular clinical trials and aims to differentiate between clinically meaningful and incidential findings. The recommended classification includes overt and covert central nervous system (CNS) injuries and neurological dysfunctions without CNS injury.

Incidence The present review summarises the aetiologies and potential strategies for managing stroke during TAVR.

Stroke Definition The current Valve Academic Research Consortium (VARC)-2 consensus defines stroke as: “an acute episode of a focal or global neurological deficit” (see Table 1).4 Stroke is classified as ‘undetermined’ if there is no further information available as to whether it is ischaemic or haemorrhagic. Time-wise a neurological event (NE) is called ‘stroke’ if it lasts longer than 24 hours or less than 24 hours with new equivalents in neuroimaging or if the neurological deficit results in death. A NE is otherwise classified as transient ischaemic attack. The VARC-2 consensus recommends the utilisation of the modified Rankin Scale (mRS) to measure disability after stroke (see Table 2). This

Stroke is a quite rare but major complication after SAVR and is known to occur in 1.3–1.7 % of patients.6,7 In TAVR, however, initial stroke rates are higher. The PARTNER trial reported a NE rate that was twice as high in TAVR patients compared to SAVR in the high-risk cohort (cohort A), with 5.5 % versus 2.4 % at 30 days (p=0.04) and 8.3 % versus 4.3 % at 1 year (p=0.04).8 However, recent publications from large registries show lower stroke rates. The Transcatheter Valve Therapy Registry included 7,710 patients who received TAVR using both transvascular (TV) and transapical (TA) approaches between 2011 and 2013.9 An = overall stroke rate of 2.0 % (95 % CI [1.7–2.4]) was reported during hospital stay and 2.8 % (95 % CI [2.3–3.5]) at 30 days. The European SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry showed a similar 30-day incidence of stroke of 2.5 %.10 The German Aortic Valve Registry (GARY) is the largest registry including both SAVR and TAVR patients. It has reported an overall in-hospital stroke rate of 2.3 %. Although

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Structural Table 1: Valve Academic Research Consortium-2 Definitions of Stroke and Transient Ischaemic Attack Diagnostic criteria Acute episode of a focal or global neurological deficit with at least 1 of the following: change in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss affecting 1 side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or symptoms consistent with stroke Stroke: duration of a focal or global neurological deficit ≥24 h; OR <24 h if available neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit results in death TIA: duration of a focal or global neurological deficit <24 h, any variable neuroimaging does not demonstrate a new hemorrhage or infarct No other readily identifiable nonstroke cause for the clinical presentation (eg, brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in conjunction with the designated neurologist* Confirmation of the diagnosis by at least 1 of the following: Neurologist or neurosurgical specialist Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds alone Stroke classification Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central nervous system tissue Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage A stroke may be classified as undetermined if there is insufficient information to allow categorization as ischemic or hemorrhagic Stroke definitions

†

Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least 1 mRS category from an individual’s prestroke baseline Nondisabling stroke: an mRS score of <2 at 90 days or one that does not result in an increase in at least 1 mRS category from an individual’s prestroke baseline Adapted from Kappetein et al., 2013.4 mRS, Modified Rankin Scale. *Patients with nonfocal global encephalopathy will not be reported as a stroke without unequivocal evidence of cerebral infarction-based upon neuroimaging studies (CT scan or Brain MRI). †Modified Rankin Scale assessments should be made by qualified individuals according to a certification process.24–26

Table 2: Modified Rankin Scale for Measuring the Degree of Disability or Dependence in the Daily Activities of People who experience a Stroke Level Description 0

No symptoms

1 No significant disability, despite symptoms; able to perform all usual duties and activities 2 Slight disability; unable to perform all previous activities but able to look after own affairs without assistance 3 Moderate disability; requires some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requires nursing care and attention Adapted from Rankin, 195771 and van Swieten et al., 198872

there was a trend towards higher stroke rates in TA-TAVR, there were no significant differences between SAVR, TV-TAVR and TA-TAVR.11 Other reports suggested a higher incidence of NEs (up to 6.0 %) using the TV approach.12,13 As no larger study was able confirm these data, however, whether the access impacts stroke rates remains controversial.3,10,14,15 When comparing PARTNER Ib with the PARTNER II trial, a significant decline in NEs, such as strokes, can be seen over time. The PARTNER Ib trial reported a stroke rate of 5.0 % at 30 days and 7.8 % at 1 year in 2008 compared to 3.1 % at 30 days and 5.2 % at 1 year in the PARTNER II trial in 2013.16 These findings are supported by a metaanalysis comparing early versus late data from high-volume centres, showing a decline in strokes from 4.9 % to 3.4 % at 30 days.17 Thus, the observed decrease in stroke rates over time is most likely a result of experience gained in patient selection and implantation, improved and smaller TAVR devices, and lower-risk patients. Any risk of stroke, which is fortunately down to 2 to 3 %, still is of clinical concern for patients.

Registries appear to have lower stroke rates than randomised trials when reported percentages are compared. One possible explanation for the this could be the more elaborate stroke diagnosis, including expert neurologist consultation, in large prospective trials. Registry results, in comparison, are usually based on self-reporting only.

Timeline and Aetiology Stroke after TAVR occurs in three distinct phases: • early: in high-risk patients, this is a directly procedure-related phase, with up to 50 % of all NEs happening in the first 24 hours after TAVR;18–22 • delayed: this occurs in patients with an elevated risk interval between days 2 and 30; and • late: stroke occurs in those with a late hazard interval and is mostly related to patient- and disease-related factors. These phases are caused by the different aetiologies of stroke after TAVR, see Figure 1.

Phase One: Early stroke A number of brain imaging studies using diffusion weight magnetic resonance imaging (DW-MRI) technology in patients before and during the first days after TAVR have investigated the early onset of stroke.23–27 All these trials showed similar results. DW-MRI detected new lesions in the majority (up to 84 %) of patients after TAVR. Only a small proportion of these patients (up to 6 %), however, presented with new and apparent clinical symptoms of stroke. Fairbairn et al. identified a correlation between clinical strokes and the number and volume of new lesions, but their findings were based on a small study (n=31).26 Rodés-Cabau et al. found a trend towards a lower occurrence of new lesions after TA (66 %) versus TV (71 %) TAVR in a small cohort (n=60) but the difference was not statistically significant (p=0.78).25 Due to the pattern of the multiple and dispersed lesions in both hemispheres, it has been suggested that embolic events may cause

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Managing Stroke During TAVR these lesions.23–27 Histopathological investigations have confirmed this embolic theory. Van Mieghem et al. investigated particles saved by the Montage™ Dual Filter System (Claret Medical, Inc) dual filterbased embolic protection device (EPD) during TAVR.28 Debris was found in 75 % of all cases and was specified as fibrin, calcium and connective tissue most likely originating from the calcified native aortic valve and the aortic wall. Furthermore, equipment-related debris in the form of catheter shavings were found.28 Support for the embolic theory has been provided by the results of transcranial Doppler studies quantifying high-intensity transient signals and microembolic signals during TAVR.29 Although high-intensity transient signals were seen in all procedural TAVR steps, there were peaks during valve positioning and implantation, leading to the conclusion that the main source of microembolisation is in the area of the calcified stenotic native aortic valve.30–32 Manipulation of the vessels during valve delivery and the procedure itself can cause thrombus and potential emboli formation. Endothelial integrity damage uncovers tissue factor and thrombin, especially in atherosclerotic tissue such as calcified valve leaflets. Tissue factor, as the main initiator of coagulation, leads to the activation of plasmatic coagulation cascades and cellular aggregation, resulting in inflammation and thrombogenicity.21,33,34 In addition, wires, catheters, balloons and delivery systems used during the procedure are known to be prothrombotic and are potential sources of air emboli, leading to an increased risk of stroke.35 The previously-mentioned factors are the main causes of stroke during the early procedure-related high-risk phase of TAVR. In addition to strokes with ischaemic causes, 5.0 % are haemorrhagic.36,37 The highly reduced blood flow in the watershed areas of the brain vessels during balloon aortic valvuloplasty (BAV) and rapid pacing results in decreased washout of the embolised particles, and thus to an increase in ischaemic effects from embolised debris.38,22

Phase Two: Delayed Stroke After the initial TAVR procedure is done, thrombogenicity resulting in thromboembolism extends its role. New-onset atrial fibrillation (NOAF) is a known post-procedural complication after heart surgery correlating with left atrial size, volume management, inflammation, medication and extracorporal circulation.39 By VARC-2 criteria, NOAF is defined as any episode of atrial fibrillation (AF) lasting long enough to be recorded on a 12-channel electrocardiogram or at least 30 seconds on a rhythm stripe without prior history of AF.4 In TAVR, NOAF is described in 7.2–32 % of patients and is an independent predictor of delayed stroke.40,41 Nuis et al. showed a 4.4-fold increase in the risk of stroke in the presence of NOAF compared to patients without NOAF.36 Nombela-Franco et al. reported an odds ratio of 2.76.37 Amat-Santos et al. described an accentuated stroke rate of up to 40 % in patients with NOAF without anticoagulation compared to 2.9 % in patients with immediate anticoagulation therapy (p=0.008).40 In all cases of delayed stroke in TAVR, the occurrence of NOAF could be evaluated retrospectively, with an onset between days 1 and 30 after TAVR.35–37,40 Another reason for the increased thromboembolic risk is the comparatively long period of time until the artificial nitinol surfaces of TAVR valves are endothelialised.42

Phase Three: Late Stroke With an indistinct transition from NOAF to chronic AF, the late hazard interval begins to emerge. These delayed strokes are more likely

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Figure 1: Aetiology of Embolisation Secondary to Transcatheter Aortic Valve Implantation

(A) and (B) Acute embolisation. Disruption of calcific/atheromatous plaques and valve/ vascular tissue associated with: (A) the passage of guide wires and large-bore catheters and during valvuloplasty and device delivery; and (B) device positioning and implantation with thrombus forming on the catheter. (C) Subacute embolisation. Persistent nidus of calcium on the native valve leaflets provides a source for further calcific embolisation: thrombus formation secondary to structural changes to native leaflets, the presence of a prosthetic device and altered rheology attributable to both the apposition of native leaflets to the aortic wall and atrial fibrillation. Adapted from Fanning et al., 201435 with permission from Wolters Kluwer Health, Inc, © 2014.

patient-related. Commonly reported and pre-existing diseases in patients with aortic stenosis are arterial hypertension, metabolic disorders like diabetes mellitus, dyslipidaemia. Other common factors include obesity, female sex, older age and nicotine addiction. All of these factors result in a protruded risk of atherosclerosis, resulting in a higher risk for cerebrovascular disease.43,44 In comparison, the annual stroke incidence for a healthy octogenarian is about 1.0–2.3 % and is thus comparable to stroke incidence after 30 days.45

Managing Stroke Preprocedural Strategies Fairbairn et al. showed that the severity of aortic arch atheroma, catheterisation time and age are risk factors for stroke after TAVR.26 Miller et al. also found that a smaller aortic valve area index, which contributes to a higher degree of valve calcification, may be an prediction factor for stroke.2 Furthermore, risk factors for AF, such as larger left atrial size, should be evaluated before the procedure as NOAF is associated with an increased risk of stroke after TAVR.37,36,40,46 Risk stratification and a multidisciplinary heart team are essential for preprocedural stroke management in order to select the most appropriate approach for the treatment of patients with symptomatic AS. Conventional surgery and transcatheter options should be discussed in relation to the current guidelines, as well as anaesthetics, anticoagulation therapy and the use of EPDs, depending on individual patient risk and the patient’s current state of health.47 Imaging of the aortic annulus and access site by computed tomography and echocardiography are crucial in preprocedural planning of the approach and determining the correct sizing and best valve type to minimise the probability of valve misfit, under-expansion and malposition (see Figure 2).21,48,49

Procedural Strategies Embolisation is the predominant cause of new NEs in the early postprocedural high-risk phase. The essential preventive strategy for reducing embolisation risk is to minimise manipulation in the area of the native aortic valve. Less trauma may also contribute to the size

Structural Figure 2: Echocardiography and Computed Tomography of Calcified Aortic Valves

benefit regarding washout phenomena in the watershed areas of the brain.22,38,50 Balloon-expandable valve insertion techniques without previous BAV are now routine in clinical practice.51–54 Another periprocedural strategy for managing stroke and embolism is the use of EPDs. EPDs are designed to avoid cerebral embolism by capturing or deflecting debris from the cerebral circulation.55 The Sentinel™ Cerebral Protection Device (Claret Medical Inc.) is a filtering device placed in the brachiocephalic trunk and left common carotid artery, see Figure 3A. Its ability to capture debris has been shown in histopathological studies.28,56 Although debris has been found in in up to 75 % of patients who have undergone TAVR with the use of the Sentinel™, no degree of functional brain protection was able to be evaluated from these findings. The larger single-centre randomised blinded Claret Embolic Protection and TAVI (CLEAN TAVI) trial found that the number and volume of new lesions detected in DW-MRI were significantly lower in TAVR when using EPDs.57

Mildly calcified aortic valves: (1A) echocardiograph; and (2A) computed tomography scan. Heavily calcified aortic valves: (1B) echocardiograph; and (2B) computed tomography scan.

Figure 3: Embolic Protection Devices

(A) Montage™ 2 Capture Device (Claret); (B) Embrella Embolic Deflector System (Edwards Lifesciences); and (C) TriGuard™ Cerebral Protection Device (Keystone Heart). Adapted from Fanning et al., 201435 with permission from Wolters Kluwer Health, Inc, © 2014.

and rigidity of the catheters and devices used.49 In the PARTNER trial, with the early SAPIEN™ (Edwards Lifesciences Inc.) valve the catheters used were 22–24 F sized. The current generation of TAVR systems are 18 F, such as the CoreValve® Evolut™ R (Medtronic Inc.) or the Edwards SAPIEN 3™, are 18 F.17,47 In a transcranial Doppler study it was found that valve positioning and valve implantation are the most crucial triggers of intraprocedural embolisation during TAVR.31 The aortic arch seems to play only a minor role in embolisation, which may contribute to a comparable risk of stroke in TA and TV TAVR. Kahlert et al. showed a higher risk of embolisation using the self-expandable CoreValve® compared to the balloon-expandable SAPIEN™. This might be related to the longer stent combined with the slow and stepwise release of the CoreValve® resulting in prolonged and therefore more severe scraping inside the native valve and vessels.31 Smooth passage of a catheter through the aortic arch, depending on device length and flexibility, may be additional factors that minimise embolisation risk. Thus, it might be expected that the rapid implantation of the SAPIEN™ would be associated with a reduced risk of embolisation. Studies have, however, shown similar stroke rates for both TAVR systems.17 Pre-ballooning via BAV seems to a have a relatively low risk of embolisation; however, data show that post-deployment BAV results in fewer high-intensity transient signals than pre-ballooning.31 Grube et al. showed a lower stroke incidence in a trial using the CoreValve® without BAV (5.0 %) compared to pre-dilatation (11.9 %).50 Skipping the utilisation of rapid pacing while performing CoreValve® may be of additional

The Embrella Embolic Deflector System ([EEDS], Edwards Lifesciences Inc.) is a microporous screen that deflects along the great curve of the aortic arch, see Figure 3B. It got CE mark approval in 2010 and was investigated by the Prospective Outcome study in patients undergoing TAVI to Examine Cerebral Ischemia and Bleeding Complications (PROTAVI-C) trial.58 The EEDS was proved to be feasible, safe and easy to deploy, but the PROTAVI-C trial showed an even higher rate of microemboli in the EEDS group compared to the group without EEDS in TAVR, as confirmed by transcranial Doppler. DW-MRI showed new lesions in all patients, however the lesions were potentially smaller in the EEDS group. No recommendation for systematic use was given after the trial. The TriGuard™ Cerebral Protection Device (Keystone Heart), see Figure 3C, received CE mark approval in 2013 and it consists of a nitinol mesh designed to deflect debris. The multicentre Prospective, Randomized Evaluation of the TriGuard™ HDH Embolic Deflection Device During TAVI (DEFLECT III) trial59 detected fewer new neurological defects using the National Institutes of Health Stroke Scale at discharge (15.4 % versus 3.1 %; p=0.16) and demonstrated a >2-fold increase in recovery of normal cognitive function at 30 days in those randomised to TriGuard™ protection compared to those with no protection. There was also a reduction in lesion volume and number on DW-MRI. Although the results are promising, stroke rates were not significantly lower in the TAVR group protected by TriGuard™ (4.3 % versus 5.1 %; p=0.87) EPDs seem to be a promising approach to decreasing the incidence of stroke during TAVR. A reduction in the frequency of ischaemic lesions originating from the calcified native aortic valve has been seen; however, routine clinical use has not yet been established due to preliminary data from current trials. Further investigation is needed to assess the effects of EPDs on NEs.57 The benefits of EPDs, it should be noted, are directly limited to the timeframe of the procedure itself. Antithrombotic management plays a significant role in reducing stroke risk during and after TAVR, but little is known about optimal antiplatelet and anticoagulation therapy. The joint American College of Cardiology Foundation/American Association for Thoracic Surgery/Society for Cardiovascular Angiography and Intervention/Society of Thoracic Surgeons guideline recommends intraprocedural use of heparin with

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Managing Stroke During TAVR an activated clotting time of >300 seconds.47 In the PARTNER trial, a loading dose of 5,000 IU of heparin and an activated clotting time of >250 seconds was recommended.1,8 The use of antiplatelet medication after TAVR due to the stentmediated risk of thrombosis has not been determinately defined. PARTNER recommended the use of dual antiplatelet therapy (DAPT) with 75–100 mg aspirin on daily basis plus 75 mg clopidogrel for 6 months after TAVR, with a loading dose of 300 mg directly after the TAVR procedure.60,61 These recommendations are not based on larger randomised multicentre trials and are not specifically defined in guidelines. The use of DAPT with clopidogrel particularly has been questioned in TAVR patients due to its excessive bleeding risk and an unclear beneficial effect.62,63 Durand et al. showed a significantly increased risk for major bleeding in the DAPT group without a lower risk of ischaemic events compared to monoplatelet therapy using aspirin.62 Controversially, in a more recent study Gleason et al. showed that DAPT was associated with a decline in early stroke rate in TAVR.64 The study by Linke et al. supports treatment with antiplatelet substances due to the fact that the nitinol stent surface of the TAVR is known to be thrombogenic and coverage takes up to 1 year.42 Other long-term data indicate that neointimal tissue growth and coverage of bioprosthetic valves with endothelial cells occurs about 3 months after implantation, which is about the time when the risk of stroke after TAVR adjusts to a comparable population risk.65 DAPT for 3–6 months is probably the most commonly applied approach in clinical centres at present after TAVR. These results require further investigation in larger randomised multicentre trials and the production of defined guidelines.

Post-procedural Strategies After discharge, thromboembolic risk is still imminent. Individual antithrombotic and antiplatelet management may be the key to a safe and event-free long-term outcome after TAVR. NOAF is a predominant

mith CR, Leon MB, Mack MJ, et al. PARTNER Trial S Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364: 2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 Miller DC, Blackstone EH, Mack MJ, et al. PARTNER Trial Investigators and Patients; PARTNER Stroke Substudy Writing Group and Executive Committee. Transcatheter (TAVR) versus surgical (AVR) aortic valve replacement: occurrence, hazard, risk factors, and consequences of neurologic events in the PARTNER trial. J Thorac Cardiovasc Surg 2012;143:832–43. DOI: 10.1016/j.jtcvs.2012.01.055; PMID: 22424519 Werner N, Zeymer U, Schneider S, et al. German Transcatheter Aortic Valve Interventions-Registry Investigators. Incidence and clinical impact of stroke complicating transcatheter aortic valve implantation: results from the German TAVI registry. Catheter Cardiovasc Interv 2016;88:644–53. DOI: 10.1002/ccd.26612; PMID: 27258944 Kappetein AP, Head SJ, Généreux P, et al. Valve Academic Research Consortium-2. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg 2013;145:6–23. DOI: 10.1016/j.jtcvs.2012.09.002; PMID: 23084102 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. Eur Heart J 2011;32:205–217. Hamm CW, Möllmann H, Holzhey D, et al. GARY-Executive Board. The German Aortic Valve Registry (GARY): in-hospital outcome. Eur Heart J 2014;35:1588–98. DOI: 10.1093/eurheartj/ eht381; PMID: 24022003 Daneault B, Kirtane AJ, Kodali SK, et al. Stroke associated with surgical and transcatheter treatment of aortic stenosis: a comprehensive review. J Am Coll Cardiol 2011;58:2143–50. DOI: 10.1016/j.jacc.2011.08.024; PMID: 22078419 Leon MB, Smith CR, Mack M, et al. PARTNER Trial Investigators. Transcatheter aortic-valve implantation for

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risk factor for thromboembolism after TAVR and occurs in up to one-third of all patients.35–37,40 Despite this, no defined guidelines are proposed for antithrombotic management after short episodes of NOAF following TAVR.40,66 Nuis et al. and Amat-Santos et al. gave a preoperative median congestive heart failure, hypertension, age, diabetes, prior stroke or transient ischaemic attack or thromboembolism (CHADS2) score of 3 (interquartile range 2–4), which supports the theory that TAVR patients are at high risk of thromboembolism when NOAF occurs and anticoagulation therapy should be implemented immediately after NOAF onset.36,40 In the case of AF, anticoagulation with a vitamin k antagonist such as phenprocoumon or warfarin is recommended, combined with one antiplatelet substance such as aspirin or clopidogrel. The target of anticoagulation is an international normalised ratio of between 2 and 3.66–68 NOAF is a risk factor for stroke, especially between days 1 and 30. Later on other factors and diseases are responsible for an increased risk of stroke. These factors and diseases should be treated to avoid progression of arteriosclerosis as a distinct part of cerebrovascular events.21

Conclusion It is essential to identify patients who are at high risk of stroke during procedural planning. Preventive strategies such as anticoagulation and antiplatelet therapy, less traumatic devices, the avoidance of extensive manipulation while performing TAVR and the use of EPDs in special cases are key to significantly reducing NEs.69 Experience in imaging, anaesthesia, valve choice and medical treatment is required; a heart team approach is thus needed to ensure the best possible therapy and clinical outcome for each patient.47 Prediction algorithms focusing on TAVR-specific stroke risks are in development and might further ease decision-making.70 Patient characteristics and technical possibilities will change the risk of stroke in the future.49 Larger multicentre randomised trials are needed to gain further insight into the specific mechanisms and possible prevention of stroke after TAVR. n

aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/NEJMoa1008232; PMID: 20961243 Mack MJ, Brennan J, Brindis R, et al. STS/ACC TVT Registry. Outcomes following transcatheter aortic valve replacement in the united states. JAMA 2013;310:2069–77. DOI: 10.1001/ jama.2013.282043; PMID: 24240934 Thomas M, Schymik G, Walther T, et al. One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SPIEN valve. Circulation 2011;124:425–33. DOI: 10.1161/ CIRCULATIONAHA.110.001545; PMID: 21747054 Möllmann H, Bestehorn K, Bestehorn M, et al. In-hospital outcome of transcatheter vs. surgical aortic valve replacement in patients with aortic valve stenosis: complete dataset of patients treated in 2013 in Germany. Clin Res Cardiol 2016; 105:553–9. DOI: 10.1007/s00392–016–0962–4; PMID: 26830097 Himbert D, Descoutures F, Al-Attar N, et al. Results of transfemoral or transapical aortic valve implantation following a uniform assessment in high-risk patients with aortic stenosis. J Am Coll Cardiol 2009;54:303–11. DOI: 10.1016/j. jacc.2009.04.032; PMID: 19608027 Walther T, Simon P, Dewey T, et al. Transapical minimally invasive aortic valve implantation. Circulation 2007;116: I240–5. DOI: 10.1161/CIRCULATIONAHA.106.677237; PMID: 17846311 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. DOI: 10.1016/j.jacc. 2011.08.050; PMID: 22019110 Gilard M, Eltchaninoff H, Iung B, et al. FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in highrisk patients. N Engl J Med 2012;366:1705–15. DOI: 10.1056/ NEJMoa1114705; PMID: 22551129

16. W ebb JG, Doshi D, Mack MJ, et al. A randomized evaluation of the SAPIEN XT transcatheter heart valve system in patients with aortic stenosis who are not candidates for surgery. JACC Cardiovasc Interv 2015;8:1797–806. DOI: 10.1016/j. jcin.2015.08.017; PMID: 26718510 17. Athappan G, Gajulapalli RD, Sengodan P, et al. Influence of transcatheter aortic valve replacement strategy and valve design on stroke after transcatheter aortic valve replacement: a meta-analysis and systematic review of literature. J Am Coll Cardiol 2014;63:2101–10. DOI: 10.1016/j.jacc.2014.02.540; PMID: 24632286 18. Tay ELW, Gurvitch R, Wijesinghe N, et al. A high-risk period for cerebrovascular events exists after transcatheter aortic valve implantation. JACC Cardiovasc Interv 2011;4:1290–7. DOI: 10.1016/j.jcin.2011.08.012; PMID: 22192370 19. Stortecky S, Windecker S. Stroke: an infrequent but devastating complication in cardiovascular interventions. Circulation 2012;126:2921–4. DOI: 10.1161/ CIRCULATIONAHA.112.149492; PMID: 23248061 20. Bosmans J, Bleiziffer S, Gerckens U, et al. ADVANCE Study Investigators. The incidence and predictors of early- and mid-term clinically relevant neurological events after transcatheter aortic valve replacement in real-world patients. J Am Coll Cardiol 2015;66:209–17. DOI: 10.1016/j. jacc.2015.05.025; PMID: 26184612 21. Mastoris I, Schoos MM, Dangas GD, et al. Stroke after transcatheter aortic valve replacement: incidence, risk factors, prognosis, and preventive strategies. Clin Cardiol 2014;37:756–64. DOI: 10.1002/clc.22328; PMID: 25403514 22. Hynes BG, Rodés-Cabau J. Transcatheter aortic valve implantation and cerebrovascular events: the current state of the art. Ann N Y Acad Sci 2012;1254:151–63. DOI: 10.1111/j.1749–6632.2012.06477.x; PMID: 22548581 23. Kahlert P, Knipp SC, Schlamann M, et al. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation. Circulation 2010;121:870–8. DOI: 10.1161/ CIRCULATIONAHA.109.855866; PMID: 20177005

Structural 24. G hanem A, Müller A, Nähle CP, et al. Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging. J Am Coll Cardiol 2010;55:1427–32. DOI: 10.1016/j.jacc.2009.12.026; PMID: 20188503 25. Rodés-Cabau J, Dumont E, Boone RH, et al. Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches. J Am Coll Cardiol 2011;57:18–28. DOI: 10.1016/j.jacc.2010.07.036; PMID: 21185496 26. Fairbairn TA, Mather AN, Bijsterveld P, et al. Diffusionweighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation: assessment of predictive risk factors and the relationship to subsequent health status. Heart 2012;98:18–23. DOI: 10.1136/ heartjnl-2011–300065; PMID: 21737581 27. Astarci P, Glineur D, Kefer J, et al. Magnetic resonance imaging evaluation of cerebral embolization during percutaneous aortic valve implantation: comparison of transfemoral and trans-apical approaches using Edwards Sapiens valve. Eur J Cardiothorac Surg 2011;40:475–9. DOI: 10.1016/j. ejcts.2010.11.070; PMID: 21256045 28. Mieghem NMV, Schipper MEI, Ladich E, et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement: clinical perspective. Circulation 2013;127: 2194–201. DOI: 10.1161/CIRCULATIONAHA.112.001091; PMID: 23652860 29. Ringelstein EB, Droste DW, Babikian VL, et al. Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection. Stroke 1998;29:725–9. PMID: 9506619 30. Drews T, Pasic M, Buz S, et al. Transcranial Doppler sound detection of cerebral microembolism during transapical aortic valve implantation. Thorac Cardiovasc Surg 2011;59:237–42. DOI: 10.1055/s-0030–1250495; PMID: 21442580 31. Kahlert P, Al-Rashid F, Döttger P, et al. Cerebral embolization during transcatheter aortic valve implantation. Circulation 2012;126:1245–55. DOI: 10.1161/CIRCULATIONAHA.112.092544 32. Erdoes G, Basciani R, Huber C, et al. Transcranial Dopplerdetected cerebral embolic load during transcatheter aortic valve implantation. Eur J Cardiothorac Surg 2012;41:778–84. DOI: 10.1093/ejcts/ezr068; PMID: 22423058 33. Tremoli E, Camera M, Toschi V, et al. Tissue factor in atherosclerosis. Atherosclerosis 1999;144:273–83. PMID: 10407489 34. Marechaux S, Corseaux D, Vincentelli A, et al. Identification of tissue factor in experimental aortic valve sclerosis. Cardiovasc Pathol 2009;18:67–76. DOI: 10.1016/j.carpath.2007.12.014; PMID: 18402835 35. Fanning JP, Walters DL, Platts DG, et al. Characterization of neurological injury in transcatheter aortic valve implantation. Circulation 2014;129:504–15. DOI: 10.1161/ CIRCULATIONAHA.113.004103; PMID: 24470472 36. Nuis R-J, Mieghem NM Van, Schultz CJ, et al. Frequency and causes of stroke during or after transcatheter aortic valve implantation. Am J Cardiol 2012;109:1637–43. DOI: 10.1016/j. amjcard.2012.01.389; PMID: 22424581 37. Nombela-Franco L, Webb JG, de Jaegere PP, et al. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation. Circulation 2012;126:3041–53. DOI: 10.1016/j.amjcard.2012.01.389 38. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998;55: 1475–82. PMID: 9823834 39. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–73. PMID: 11747385 40. Amat-Santos IJ, Rodés-Cabau J, Urena M, et al. Incidence, predictive factors, and prognostic value of new-onset atrial fibrillation following transcatheter aortic valve Implantation. J Am Coll Cardiol 2012;59:178–88. DOI: 10.1016/j.jacc. 2011.09.061; PMID: 22177537 41. Tarantini G, Mojoli M, Windecker S, et al. Prevalence and impact of atrial fibrillation in patients with severe aortic

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1146–55. DOI: 10.1016/j.jcin.2014.04.019; PMID: 25341709 59. L ansky AJ, Schofer J, Tchetche D, et al. A prospective randomized evaluation of the TriGuard™ HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070–8. DOI: 10.1093/eurheartj/ehv191; PMID: 25990342 60. Kodali SK, Williams MR, Smith CR, et al. PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366: 1686–95. DOI: 10.1056/NEJMoa1200384; PMID: 22443479 61. Makkar RR, Fontana GP, Jilaihawi H, et al. PARTNER Trial Investigators. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366: 1696–704. DOI: 10.1056/NEJMoa1202277; PMID: 22443478 62. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014;113: 355–60. DOI: 10.1016/j.amjcard.2013.09.033; PMID: 24169016 63. Hassell MECJ, Hildick-Smith D, Durand E, et al. Antiplatelet therapy following transcatheter aortic valve implantation. Heart 2015;101:1118–25. DOI: 10.1136/heartjnl-2014–307053; PMID: 25948421 64. Gleason TG, Schindler JT, Adams DH, et al. The risk and extent of neurologic events are equivalent for high-risk patients treated with transcatheter or surgical aortic valve replacement. J Thorac Cardiovasc Surg 2016;152:85–96. DOI: 10.1016/j.jtcvs.2016.02.073; PMID: 27085389 65. Mérie C, Køber L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA 2012;308:2118–25. DOI: 10.1001/ jama.2012.54506; PMID: 23188028 66. Wann LS, Curtis AB, January CT, et al. ACCF/AHA Task Force Members. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;57:223–42. DOI: 10.1161/CIR.0b013e3181fa3cf4; PMID: 21173346 67. Fuster V, Rydén LE, Cannom DS, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation—Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2006;48:854–906. DOI: 10.1016/j.jacc.2006.07.009; PMID: 16904574 68. Macle L, Cairns JA, Andrade JG, et al. CCS Atrial Fibrillation Guidelines Committee. The 2014 atrial fibrillation guidelines companion: a practical approach to the use of the Canadian Cardiovascular Society Guidelines. Can J Cardiol 2015;31: 1207–18. DOI: 10.1016/j.cjca.2015.06.005; PMID: 26429352 69. Conrotto F, D’Ascenzo F, D’Onofrio A, et al. Predictive ability of the CHADS2 and CHA2DS2–VASc scores for stroke after transcatheter aortic balloon-expandable valve implantation: an Italian Transcatheter Balloon-Expandable Valve Implantation Registry (ITER) sub-analysis. Eur J Cardiothorac Surg 2016;50:867–73. DOI: 10.1093/ejcts/ezw199; PMID: 27354254 70. Holmes Jr. DR, Nishimura RA, Grover FL, et al. STS/ACC TVT Registry Annual outcomes with transcatheter valve therapy: from the STS/ACC TVT Registry. J Am Coll Cardiol 2015;66: 2813–23. PMID: 27175453 71. Rankin J. Cerebral vascular accidents in patients over the age of 60. I. General considerations. Scott Med J 1957;2:127–36. DOI: 10.1177/003693305700200401; PMID: 13432825 72. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988;19:604–7. PMID: 3363593

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Use of Embolic Protection Devices in Peripheral Interventions M a r t i n G Ra d v a n y Chief of Interventional Neuroradiology, WellSpan Radiology and Neurosciences, York, PA, USA

Abstract The use of embolic protection devices (EPDs) when treating coronary saphenous vein bypass grafts, performing carotid arterial stenting and treating acute coronary syndromes is well accepted. We will review currently available devices and approaches to reduce distal embolisation, first discussing their uses in carotid interventions and then in vertebral and peripheral vascular interventions.

Keywords Embolic protection devices, carotid intervention, vertebral intervention, peripheral vascular intervention, distal embolisation Disclosure: MGR has sat on a medical advisory board for Globus Medical. Received: 20 July 2016 Accepted: 7 December 2016 Citation: Interventional Cardiology Review 2017;12(1):31–5. DOI: 10.15420/icr.2016:23:2 Correspondence: Martin G Radvany, WellSpan Radiology and Neurosciences, 35 Monument Road, Suite 300, York, PA 17402, USA. E: mradvany@wellspan.org

Catheter-based vascular interventions continue to evolve as new devices continue to expand the capabilities of interventionalists and improve patient safety. The importance of athero-embolisation during vascular intervention has long been recognised.1 Embolic protection devices (EPDs) were developed to help prevent embolisation during endovascular procedures. The risk of distal embolisation is considered significant in the carotid arteries (see Figure 1), saphenous vein grafts and thrombotic lesions affecting patients with acute coronary syndromes.2 While EPDs have been designed and clinically tested for these procedures, their use during procedures in the other vascular territories has been questioned because of the increased cost, potential risk of complications and perceived lack of significance of distal embolisation in these vascular beds.3

Embolic Protection Devices Different approaches have been used in attempts to reduce distal embolisation during vascular interventions (see Figure 2). Current technologies for embolic protection employ three basic strategies: • temporary flow arrest using an occlusion balloon distal to the lesion being treated; • placement of a temporary filter distal to the lesion being treated while maintaining antegrade flow; and • proximal occlusion of the vessel, with and without flow reversal. Each technique has its advantages and disadvantages. The concept of flow arrest for distal protection during carotid artery stenting was first described by Theron and colleagues.4 Distal occlusion temporarily arrests antegrade blood flow while the intervention is performed. The PercuSurge Guardwire® (Medtronic; see Figure 3) is a commercially available device with a balloon mounted on a wire that is advanced distal to the lesion and inflated. An aspiration catheter is placed over the wire after the intervention and any debris aspirated. The advantage to this strategy is that debris trapped in the stagnant column of blood can be aspirated before the occlusion balloon is deflated. Known complications include vasospasm and

vessel dissection. Disadvantages of distal protection with occlusion balloons include: ischaemia within the territory of the occluded artery, the complete occlusion of flow making it difficult to see the lesion, the possible formation of thrombus distal to the balloon due to the low flow state, and the potential for allowing embolic debris along the edge of the balloon to go downstream once the balloon is deflated or vessel expansion occurs due to dilation from angioplasty or stenting. In the cerebrovascular system, approximately 5 % of patients do not tolerate balloon occlusion.5 Devices that maintain antegrade flow consist of a filter basket attached to a guidewire that captures embolic debris while maintaining antegrade flow – a filterwire. There are many filter-based EPDs currently available (see Table 1). These devices consist of a membrane with 80–130 um pores. These devices do not offer the same protection as an occlusion balloon, as smaller particles can still pass through the filter. The filter is attached to 0.014” guidewire, which is used as the guidewire during the procedure. The filter is constrained in a catheter and advanced and opened distal to the lesion. After the procedure, a retrieval catheter is advanced over the wire closing the filter and trapping the debris. The SpiderFX™ (Medtronic; see Figure 4) is unique in that it is loaded into a delivery catheter that is advanced distal to the stenosis over a second 0.014” guidewire of the operators choosing, with subsequent deployment of the filterwire. The Abbott Vascular Emboshield® NAV6 filter is not fixed to the wire and allows for limited wire movement independent of the filter. Filter devices have a larger crossing profile than the PercuSurge Guardwire. Disadvantages include the passage of small particles and complications related to advancement, deployment and recovery of the filters. Proximal occlusion devices work by stopping or reversing the antegrade flow of blood. These devices have the advantage of protecting the distal circulation prior to crossing the lesion; the distal protection devices must be advanced across the lesion prior to deployment, thus risking dislodgment of debris prior to deployment of the EPD. Devices designed specifically for the cerebrovascular

Access at: www.ICRjournal.com

Structural Figure 1: Carotid Stenting for Symptomatic Carotid Stenosis A

A 67-year-old man presented with transient left arm weakness. CT angiography demonstrated occlusion of the left Internal Carotid artery with 70 % stenosis of the right Internal Carotid artery. A) Baseline angiogram confirming stenosis of the right internal carotid artery. B) Angiogram post carotid stenting demonstrating no residual stenosis.

Figure 2: Approaches Used to Reduce Distal Embolisation During Carotid Stenting

persistent antegrade flow in the internal carotid artery (ICA) after the CCA balloon is inflated. The Mo.Ma® Ultra Proximal Cerebral Protection Device (Medtronic; see Figure 5) is the only currently available device in the US designed for percutaneous use. Debris can be aspirated from the guiding catheter in the CCA during the intervention. The theoretical advantage of proximal protection is the ability to arrest or reverse flow prior to crossing a carotid stenosis. This should provide a maximal means of protection. Unfortunately, these devices are large, requiring a 9-french (Fr) sheath. As such, they can be difficult to navigate around a difficult arch. As with distal occlusion devices, at least 5 % of patients will not tolerate proximal occlusion. For the sake of completeness we will briefly discuss the Enroute® Transcarotid Neuroprotection System (Silk Road Medical). This device consists of a sheath that is placed into the common carotid artery from a surgical cut-down. A vessel loop occludes the vessel proximal to the sheath. Flow is then reversed by creating a circuit between the carotid sheath and the common femoral vein. There is a filter in the circuit that traps debris. The advantages are similar to use of a proximal occlusion device. One disadvantage of this device is that it requires a surgical incision in the neck, it is not a truly percutaneous device.

Embolic Protection in Clinical Practice Distal Occlusion

Proximal Occlusion

Distal Filtration

Retractable filter

Occlusion ballon

Stent

Reversed blood flow

Figure 3: The PercuSurge Guardwire

The concept of trapping debris and preventing distal embolisation is appealing to endovascular specialists because it has been shown to improve patient outcomes in several vascular territories, and it intuitively makes sense that it would be of benefit in arterial vascular interventions. As previously discussed, the benefits of EPD use in coronary and carotid interventions is well accepted due to the significant clinical consequences of distal embolisation in these procedures. Due to their size and the lack of significant collateral circulation in most other vascular territories, the flow reversal devices do not have a role outside the cerebrovascular domain.

Vertebral Artery Vertebrobasilar circulation strokes compromise approximately 20–25 % of all ischaemic strokes.6 Strokes affecting the posterior circulation carry a higher risk of recurrent stroke and death as compared with anterior circulation strokes, especially during the first seven days following a stroke or transient ischaemic attack (TIA).7 The five-year risk of subsequent stroke, after a vertebrobasilar stroke or TIA, has been reported to be 22 %.8 Surgical treatment of vertebral artery origin stenosis can be technically challenging due to access to the vessel origin. Operative mortality rates of 0.5–3.0 % have been reported and there is at least 5 % risk of post-operative occlusion.9,10 Complications include transient phrenic nerve paralysis and a mild Horner’s syndrome.

circulation consist of a balloon guiding catheter for occlusion of the proximal common carotid artery (CCA). A second balloon catheter is incorporated into the guiding catheter to occlude the external carotid artery (ECA). The ECA balloon is inflated first to prevent retrograde flow in the ECA from providing collateral flow and allowing

Several studies have shown the feasibility of vertebral artery stenting for treatment of stenosis at the origin and proximal, V1, segment of the vertebral artery.11–13 The use of EPDs during vertebral artery stenting has also been studied in non-randomised studies.14,15 The use of flow reversal during vertebral artery stenting has also been described.16 There are two randomised trials comparing endovascular treatment of ostial vertebral artery stenosis with medical management. In the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)17 the outcomes were the same in both treatment arms; however, there were only eight patients in each treatment arm

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Embolic Protection Devices

and therefore it is difficult to make any definitive conclusions. The Vertebral Artery Stenting Trial (VAST)18 is a randomised phase II trial that compared best medical therapy to best medical therapy and stent placement. In this study, there was a 5 % risk of major periprocedural vascular complication. The paper did not specify which of the complications were intra-procedural and did not state that EPDs were used. Other studies have reported intra-procedural stroke rates of 1 % or less without the use of EPDs when treating ostial vertebral artery lesions.19,20 The primary weakness of vertebral artery stenting is the high rate of in-stent restenosis ranging from 10 to 43 %.21–23 Lesion length does appear to play a significant role in restenosis rates in vertebral artery origin stenting.23 When restenosis rates were correlated with lesion length, restenosis occurred at a much lower rate in lesions <5 mm (21 %) versus lesions >10 mm in length (50 %). The study does not specify which stents were used, but from the discussion it may be assumed that these were bare metal stents. In a more recent metaanalysis,24 the restenosis rates for drug-eluting stents was found to be significantly lower than for bare metal stents (11 versus 30 %) in the setting of vertebral origin stenosis. Distal protection devices or flow reversal devices may provide a benefit during stenting of ostial vertebral artery lesion when plaque morphology suggests an increased risk for artery-to-artery embolism.19

Table 1: Summary of Embolic Protection Devises Manufacturer

Product Name

Mechanism of Action

Medtronic

PercuSurge

Distal occlusion

Guardwire®

Cordis/Cardinal Health

Angioguard® RX/XP Accunet®

Embolic

Abbott Vascular

Protection system

Boston Scientific

Filterwire EZ™ Embolic

Protection System

W.L. Gore & Associates

Gore® Embolic Filter

Medtronic SpiderFX™ Embolic

Distal filter Distal filter Distal filter Distal filter

Protection Device

Medtronic FiberNet® Embolic

Distal filter

Protection System

Medtronic Mo.Ma® Ultra

Proximal Cerebral

Protection Device

Silk Road Medical

Enroute® Transcarotid

Neuroprotection System

Proximal occlusion

Figure 4: The SpiderFX (Medtronic)

Lower Extremity The incidence of embolisation during lower extremity interventions ranges from 2 to 100 %.25–28 This wide variation in embolisation rates can be explained by differences in lesion type, lesion length, treatment modality and diagnostic criteria. When continuous Doppler ultrasound was used for monitoring interventions, distal embolisation was demonstrated during wire recanalisation, angioplasty, stent dilation and atherectomy.25 In studies evaluating the presence of macroscopic debris in the filter baskets, distal embolisation has been documented in 55–100 % of cases.28–34 Distal embolisation is most commonly encountered with the use of atherectomy devices.26 This same study documented higher rates of distal embolisation when recanalising vascular occlusions, treating in-stent restenosis and in TransAtlantic Inter-Society Consensus (TASC) C and D lesions. Patients with subacute occlusion, those <6 months in duration, may also be at higher risk for distal embolisation due to the presence of thrombus.29 The clinical significance of distal embolisation during lower extremity revascularisation is unknown. Although distal embolisation is known to require invasive treatment and even result in limb loss, many believe that clinically significant distal embolisation happens infrequently, and in most cases, it is insignificant.25 Based on the available literature, the use of EPDs should be considered in patients with TASC C and TASC D lesions undergoing angioplasty, with or without stenting, and in patients undergoing atherectomy.

Figure 5: The Mo.Ma Ultra Proximal Cerebral Protection Device (Medtronic)

Renal Artery Renal artery stenosis (RAS) secondary to atherosclerotic vascular disease is becoming increasingly common as the population ages.35 It is a progressive condition that can lead to refractory hypertension and renal insufficiency.36 Current practice guidelines suggest benefit from percutaneous revascularisation for significant RAS in the setting of severe or persistent hypertension, ischaemic nephropathy with chronic kidney disease and cardiac disturbance syndromes (i.e. flash pulmonary oedema and acute coronary syndromes).37,38

INTERVENTIONAL CARDIOLOGY REVIEW

Despite a technically successful RAS procedure, 10–20 % of patients will have continued deterioration of renal function.39,40 The aetiology behind this continued deterioration of renal function is thought to

Structural be secondary to inflammation, and microinfarction secondary to the embolisation of atheromatous debris. A review of distal protection devices for RAS ’suggested’ the use of EPDs when performing renal artery angioplasty.41 EPDs can be technically challenging to use when treating RAS due to the configuration of the renal artery. It often originates from the aorta at a right angle. RAS lesions are usually ostial and therefore the catheter system is less stable. Distal balloon and filter EPDs are designed for use in longer, narrower vessels without bifurcations. There can be poor wall apposition due to tilting of the EPD in the tortuous renal vessels and incomplete protection of the entire renal vascular bed due to early bifurcation of the renal artery. Of the available devices, the FiberNet® embolic protection system (EPS) has the smallest landing zone (1.5 cm). Its use during RAS has been described.42 When technically feasible, the use of an EPD may be beneficial. Another option for reducing cholesterol embolism is the ’No-touch’ technique.43

Mesenteric Artery Mesenteric ischaemia can be acute or chronic. Acute mesenteric ischaemia (AMI) is most often secondary to a remote embolism.44 Surgery is traditionally the treatment of choice for AMI due to the need for visual examination of the bowel to determine viability and subsequent surgical resection of infarcted segments. Chronic mesenteric ischaemia (CMI) typically results from long-standing atherosclerotic vascular disease involving two or more mesenteric vessels.45 Despite the lack of any prospective trials comparing endovascular therapy with surgical bypass, mesenteric artery stenting (MAS) has become the most frequently used method of revascularisation to treat CMI.46 Though requiring more re-interventions for restenosis and symptom recurrence,47 MAS may offer a significant reduction in patient mortality (15 % with open bypass versus 4 % with MAS).48 In a recent study using EPDs in the setting of MAS, embolic material was identified in the EPD in 66 % of patients.49 Risk factors associated with distal embolisation include vessel occlusion, severe calcification and lesion length >30 mm.50 When these lesions characteristics are present, EPD use should be considered.

Technical Notes As a result of EPDs being designed for coronary and cerebrovascular use, they are built on a 0.014” platform. These devices often lack guidewire support when intervening on ostial lesions of the renal and mesenteric vessels and when using 0.035” balloon and stent systems. In these cases a second 0.014” or 0.018” ’buddy wire’ can be

2. 3.

Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000;101 (5):570–80. PMID:10662756 Sangiorgi G, Colombo A. Embolic protection devices. Heart 2003;89 (9):990–2. PMID:12923006; PMCID:PMC1767819 Bates MC, Campbell JE. Pitfalls of embolic protection. Tech Vasc Interv Radiol 2011;14 (2):101–7. DOI:10.1053/j.tvir.2011. 01.008; PMID:21550513 Theron JG, Payelle GG, Coskun O, et al. Carotid artery stenosis: treatment with protected balloon angioplasty and stent placement. Radiology 1996;201 (3):627–36. DOI:10.1148/radiology.201.3.8939208; PMID: 8939208 Henry M, Polydorou A, Henry I, et al. Carotid angioplasty under cerebral protection with the PercuSurge GuardWire System. Catheter Cardiovasc Interv 2004;61 (3):293–305. DOI:10.1002/ccd.10776; PMID:14988883 Gesheva SI, Hastings LH, Wilson JD. The Use of Aspiration Catheter Systems for Embolic Protection during Intracranial Vertebral Artery Angioplasty and Stenting. Interv Neurol

advanced alongside the EPD. The buddy wire stabilises the catheter system while a balloon or stent is advanced into position. When using a 0.014” stenting platform and a buddy wire, it is important to keep track of the wires, advance the stent over the filterwire and remove the buddy wire prior to deployment of the stent. Failure to remove the buddy wire can result in inadvertently ’jailing’ the buddy wire.51 Worse yet, deployment of the stent on the buddy wire can result in ’jailing’ the filterwire.52 In the case of a 0.035” stent system, the stent or balloon can be advanced over both wires to provide support. In some patients the renal or mesenteric arteries can have a sharp downward angle as they branch from the aorta. This occurs most commonly with the superior mesenteric artery. In these cases a radial approach may facilitate the procedure by providing a more inline approach to the vessel thus affording greater stability to the catheter system when attempting to engage and cross lesions, especially ostial lesions. There are 6-Fr and 7-Fr expandable sheaths that are designed for use in the radial artery as well as large diameter balloon-expandable stents mounted on balloons with long shafts that will reach the abdominal vessels from a radial approach. In cases in which the stent deployment system does not reach the target, a brachial approach can be used, but with a slightly increased risk of vascular complication. When performing vertebral artery stenting, a buddy wire can be advanced distally in the subclavian artery to provide additional support for the catheter system. In cases where the angle of the vertebral artery is challenging to access from the femoral approach, the retrograde approach, either brachial or radial, should be considered. This approach can be particularly advantageous when treating a right vertebral artery stenosis with an elongated, type 3, aortic arch.

Conclusion EPDs have the potential to decrease distal embolisation during vascular procedures. Unfortunately there are few prospective studies evaluating the clinical significance of distal embolisation outside of the carotid and coronary territories. Until further prospective randomised trials are published, the limited data would seem to indicate that in lower extremity interventions and mesentric interventions, there are lesion characteristics that make some lesions at greater risk for distal embolisation. In those cases, use of EPDs may be warranted. There is even less data available for renal artery interventions. If it is technically feasible, EPDs may be useful. In the vertebral artery circulation, there is also little data to support the use of EPDs; however, as in the anterior cerebral circulation, the consequences of distal embolisation can be catastrophic and therefore the use of EPDs when treating vertebral artery lesions should be considered when feasible. n

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Structural

Need for Embolic Protection During Transcatheter Aortic Valve Implantation: An Interventionalist’s Perspective on Histopathology Findings Herbert G Kroon and Nicolas MDA Van Mieghem Department of Interventional Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands

Abstract Transcatheter aortic valve implantation (TAVI) is a less invasive aortic valve replacement technique and is indicated for patients with symptomatic severe aortic stenosis and a high operative risk. Cerebral embolisation seems inherent to TAVI, as illustrated by the consistent appearance of new brain lesions on post-procedural MRI studies. Embolic protection devices may capture or deflect embolised material en route to the brain and thus reduce TAVI-related brain injury. Histopathology studies of captured debris revealed a diverse aetiology including recent or organised thrombotic material, tissue originating from the aortic valve, atherosclerotic plaques or myocardium and foreign body components. In this overview we provide a perspective on current evidence and implications for embolic protection devices in the dynamic TAVI field.

Keywords Aortic stenosis, embolic protection device, transcatheter aortic valve implantation Conflicts of interest: NMDAvM has received research grants from Claret Medical. Received: 23 December 2016 Accepted: 12 April 2017 Citation: Interventional Cardiology Review 2017;12(1):36–9. DOI: 10.15420/icr.2016:30:2 Correspondence: Nicolas MDA van Mieghem, MD, PhD, Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Centre, Office Bd 171’s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. E: n.vanmieghem@erasmusmc.nl

Over the past decade, transcatheter aortic valve implantation (TAVI) has become the treatment of choice for elderly patients with symptomatic severe aortic stenosis at high risk for death or complications with conventional surgical aortic valve replacement.1–4 Recent studies and clinical practice confirmed TAVI feasibility in patients with a lower risk profile who are typically younger and have a longer life expectancy.5 In multiple randomised trials comparing TAVI with surgical aortic valve replacement, clinical stroke rate was similar for the two strategies.6 Still, TAVI comes with a substantial ~ 5 % post-procedural cerebrovascular event rate, which predominantly occurs in the first 48 hours after TAVI.7–9 This suggests a causative role between the procedure and cerebrovascular events and thus could indicate the need for preventive procedural measures, such as embolic protection devices (EPDs). Moreover, brain MRI studies have consistently shown signs of brain injury after TAVI.6 These new brain lesions may be clinically silent yet not trivial, as they are linked to neurocognitive decline and frank dementia.10 All these findings plead for strategies to minimise per-procedural embolisation to the brain. Various EPDs have been designed to prevent emboli from entering the cerebral circulation and should be inserted before navigating through the aortic arch.11 Embolic deflectors are deployed in the aortic arch and reroute debris away from the brain into the descending aorta; current filter-based systems are deployed in the brachiocephalic trunk and left common carotid artery to capture and remove debris travelling to brain. In this overview we discuss the safety and efficacy of EPDs and put clinical data in perspective of histopathological findings of the material that embolises to the brain during TAVI.

Clinical EPD Data The Embrella Embolic Deflector (Edwards Lifesciences Ltd) and the TriGuard (Keystone Heart Ltd) are deflecting devices that are deployed

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in the aortic arch to partially or completely cover the ostia of the brachiocephalic trunk and the left carotid and subclavian arteries (see Figure 1). The Prospective Randomised Outcome Study in Patients Undergoing TAVI to Examine Cerebral Ischemia and Bleeding Complications (PROTAVI-C) trial was a pilot study of the Embrella (see Table 1).12 Use of Embrella resulted in an overall larger new brain lesion burden according MRI, with no effects on neurological events or neurocognitive function. Furthermore, a transcranial Doppler analysis suggested more high-intensity signals as surrogate for embolisation activity during the introduction and deployment of the device.13 Safety and feasibility of the TriGuard was evaluated in the SMT Embolic Deflection CE Mark Trial DEFLECT I study.14 Complete cerebral vessel coverage was obtained in 80 % of cases, although device instability was reported in approximately one-third of the cases. TriGuard use resulted in numerically lower total lesion volume detected by MRI compared to historical data of TAVI patients without protection. DEFLECT-III was a randomised controlled trial using a second generation TriGuard (with a smaller pore size of 130 μm compared to 250 μm on the first generation).15 Patients were randomised to TriGuard versus no protection and underwent MRI 4 days post TAVI. Complete cerebral vessel coverage was obtained in 89 % of cases. New neurological deficit (i.e. worse according to the National Institutes of Health Stroke Scale) appeared in 15 % of unprotected patients but only 3 % of TriGuard-protected patients. Neurocognitive decline at discharge and 30-day follow-up was more common in unprotected patients.15 Total brain lesion volume according to diffusion-weighted (DW)-MRI was lower in TriGuard-protected patients, particularly in

Histopathology Figure 1: Overview of Commercially Available Embolic Protection Devices

A: The Embrella Embolic Deflector system consists of a polyurethane membrane containing 100-μm pores. B: The TriGuard™ Embolic Deflection device with 250-μm pores which delivers three-vessel cerebral coverage. † The stabilisers are for positioning and stability. C: The Sentinel Dual Filter contains two polyurethane mesh filters with 140-μm pores. * The proximal filter is deployed in the brachiocephalic trunk. ** The distal filter is placed in the left common carotid artery.

Table 1: Overview of Data Regarding Embolic Protection Devices in Recent Clinical Trials 12

Trial PROTAVI-C Year

DEFLECT I DEFLECT II

DEFLECT III

CLEAN TAVI MISTRAL-C SENTINEL

2014 2015 2015 2015 2016 2016 2016

Patients, n 54 37 15 85 100 65 363 EPD

EED

TriGuard EDD TriGuard EDD

TriGuard EDD

Claret Montage

Sentinel

Patients 42 37 15 46 50 32 121 (+ N=123 safety arm with EPD, n without MRI) Controls, n

Not defined

119

Clinical stroke in-hospital TA (%) vs CA (%)

2 (4.9 %) vs 0 (0 %) 2 (5.4 %) vs at 30 days unknown

0 (0 %) vs unknown

1 (2.2 %) vs 2 (5.1 %)

0 (0 %) vs 2 (7 %) at 30 days

(5.6 %) vs (9.1 %) at 30 days

12 (TA)

33 vs 26

22 vs 15

Patients diffusion weighted-MRI, n TA vs CA

217

34 vs 6

28 (TA)

MRI performed days post-TAVI

3 (2–5)

4±2 4±2

48 vs 45

Patients with new lesions, n TA (%) vs CA (%)

34 (100 %) vs 6 (100 %) p=0.999

23 (82 %) vs (78.8 %) vs 164 (76 %) (88.5 %) NS

47 (98 %) vs 44 (98 %) p=1.00

New lesions, n (average) TA vs CA

7.5 (3–13)/4 (2–8) p=0.41

3 (1.8–8) vs 2 (0.5–4.5)

8 vs 16 median, p=0.002

Total lesion volume per patient TA vs CA (mm3)

305 (130–660) vs 200 (30–400) 98.9 vs 129.4 326 vs 3378 471 vs 800 180 (75–1115) vs 300 p=0.909 median, p=0.16 Median median, p=0.024

95 (10–257) vs 197 (95–525) p=0.17

Average volume per lesion TA vs CA (mm3)

30 (20–50)/ 30 (10–60) 12.4 vs 25.1 142 vs 202.9 50 (30–70) vs 150 p=0.003 median, p=0.11 median

48 vs 75

4±2 2

5.5 vs 5.5 median, p=0.96

5±1.1

2–7

16 (73 %) vs 13 (87 %)

102.8 vs 178.0 median, p=0.33

p=0.31

Values are n or n (%), median (interquartile range), mean±SD. CA = control arm; EDD = embolic deflection device; EED = Embrella embolic deflection device; EPD = embolic protection device; NS = not significant; TA = treatment arm with embolic protection devices; TAVI = transcatheter aortic valve implantation.

patients undergoing TAVI with the SAPIEN 3 valve. Interestingly, TAVI using CoreValve (Medtronic) showed more device interference and less stability than SAPIEN 3 TAVI.16 The Cerebral Protection to Reduce Cerebral Emboli Lesions After Transcatheter Aortic Valve Implantration (REFLECT) study is currently underway and should provide further insights into Triguard. It randomises TAVI patients 2:1 into TAVI with TriGuard protection versus no protection. The primary endpoint is total volume of cerebral ischemic lesions on DW-MRI 2 to 5 days post procedure. The Sentinel dual filter system (Claret Medical Inc.) has two nitinol filters integrated in a steerable delivery system.17 The proximal filter is deployed in the brachiocephalic trunk and the distal one in the left common carotid artery, leaving the left vertebral artery unprotected. Three randomised trials evaluated subsequent generations of filter-

INTERVENTIONAL CARDIOLOGY REVIEW

based embolic protection. The Claret Embolic Protection and TAVI (CLEAN TAVI) study (NCT01833052) randomised 100 CoreValve TAVI patients to Sentinel embolic protection or no protection with brain MRI evaluation before TAVI and 2 days, 7 days and 30 days post TAVI.18 Patients with Sentinel protection had significantly fewer ischemic lesions and a smaller total lesion volume on days 2 and 7 post TAVI. The control arm also had more neurological changes, especially ataxia. The MRI Investigation in TAVI with Claret (MISTRAL-C) study (Nederlands Trial Register identifier NTR4236) enrolled 65 patients that were undergoing TAVI with either balloon-expandable or self-expanding transcatheter heart valves; patients had Sentinel protection or no protection.19 The trial suffered from a 40 % dropout rate for the follow up brain MRI study and ended up underpowered for its primary MRI endpoint. Still, patients with Sentinel protection had numerically fewer new lesions and a smaller total brain lesion volume. Effects were accentuated in the

Structural Table 2: Embolic Protection Devices Used, Successful Implantation Rate and Registered Complications in Recent Trials Naber et al., 201217

Claret CE Pro, n Claret Montage, n Sentinel, n 40

van Mieghem et al., 201321

van Mieghem et al., 201523

Successful implantation, n (%) 29 (73)

Rupture or dissection, n 2 (radial artery)

40 40 (100)

81 81 (100)

Jensen et al., 201622

217 211 (97)

–

van Mieghem et al., 201619

32 30 (94)

Total

263 368 (95)

Table 3: Reported Frequency and Sizes of Captured Debris in the Filters of Embolic Protection Devices

Figure 2: Histopathological Analysis of Captured Debris Origin of Debris (%)

study enrolled 363 patients into a safety arm with Sentinel (n=123) and a 1:1 randomised comparison arm with (n=121) and without (n=119) Sentinel protection. Patients in the randomised arm had MRI scans at baseline and 2–7 days post-TAVI. Overall, use of Sentinel did not impact new lesion volume or neurocognitive performance. However, when adjusting for pre-existing lesion volume and transcatheter heart valve type in a post hoc analysis, Sentinel protection did significantly reduce new lesion volume. Moreover, there was a correlation between lesion volume and neurocognitive decline.

Histopathology Filters deployed in the brain-supplying extracranial arteries can capture material travelling to the brain during TAVI and also offer the ability to be retrieved with the yield for histopathological analysis. Table 2 summarises published histopathology studies on this topic. The filters were safely used and retrieved in the majority of cases.17,19,21,23 Early use may have been hampered by a more challenging, less userfriendly first-generation filter design. Across the studies, macroscopic debris was visible in 54–100 % of analysed filters and microscopic debris was present in more than threequarters of patients (see Table 3).17,19,21,23 Size of captured debris varied throughout the different studies, with the biggest piece being 9 mm. Fresh or organised thrombus was detected in >80 % of cases. Acute thrombus differs from organised thrombus and consists of platelets, fibrin, acute inflammatory cells, such as neutrophils, but no interspersed spindle-shaped cells.21 Acute thrombus is more frequent, with reported rates in TAVI patients as high as 86 % (see Figure 2).22 The frequency and origin of non-thrombotic tissue found in these studies was variable. Approximately one-third of patients had valve fragments in the filters, with sizes varying between 0.2 and 5.5 mm.19, 21–23 Degenerative aortic valve leaflets show distinctive features, including

83 37

27 27

protected brain areas with up to half of the protected patients having no new lesions in these brain regions. Neurocognitive performance was also better preserved with Sentinel use. The SENTINEL Trial (NCT02214277) is the largest trial to date to address EPD with TAVI for general and filter-based protection, with the Sentinel in particular.20 The

27 30

– 43

100

99 100 –

van Mieghem et al., 201619 100

Foreign material 87

86 100 0.1–9.0

Jensen et al., 201622

Calcifications

75 100 0.15–4.0

van Mieghem et al., 201523

Myocardial tissue

Collagenous tissue

van Mieghem et al., 201321

Endothelial strands

54 0 –

Aortic valve

Either wall or valve

Naber et al., 201217

Chronic thrombus

Aortic wall

range (mm)

Acute thrombus

filters (%)

Thrombus

Size

Studied

Debris (%)

van Mieghem, 2013

van Mieghem, 2015

Jensen, 2016

van Mieghem, 2016

Data taken from van Mieghem et al. 2013, van Mieghem et al. 2015, Jensen et al. 201622 and van Mieghem et al. 2016.19 21

a central fibrous layer called lamina fibrosa, a proteoglycan-rich layer and surrounding fibroblasts (lamina spongiosa) and often contain amorphous calcified material at the base of the leaflets.23 Arterial wall fragments have be found in < 60 % of patients.22 Cardiomyocytes were identified in up to one-third of patients.19, 22, 23 Endothelial strands were responsible for the largest sized debris found in patients, with sizes varying from 0.2 to 9 mm in one-half to four-fifths of patients.19, 23 Foreign body material, derived from procedure-related fabric was found in 11–30 % of cases.19, 21–23 The Cerebral Protection in Transcatheter Aortic Valve Replacement (SENTINEL; NCT02214277) trial confirmed these findings with captured debris in 99 % of TAVI patients, most often ranging in size from 150 to 500 μm but occasionally greater than 1 mm.20

Discussion The overall success and global adoption, particularly for lower risk patients, has meant TAVI-related procedural and long-term outcomes have been scrutinised. Increasing experience of practitioners and several astute device iterations has dramatically decreased the frequency of related paravalvular leakage, bleeding and vascular complications but not clinical neurological events.24 Most strokes occur within the first 48 hours after TAVI, but the stroke rate remains substantial throughout the first 2 months.7–9 History of cerebrovascular disease and procedural factors including valve embolisation or dislodgement and the need for post-dilatation are predictors for new neurological events after TAVI.7–9, 25 Approximately 50 % of strokes after TAVI are major strokes.7–9 Indeed, the randomised Placement of Aortic Transcatheter Valves II (PARTNER-II) intermediate risk trial reported a major stroke rate of 3.2 %, which is still comparable to the major stroke rates in the Placement of Aortic Transcatheter Valves I (PARTNER-I) and US CoreValve pivotal high-risk trials (3.8 % and 4.9 %,

INTERVENTIONAL CARDIOLOGY REVIEW

Histopathology respectively).2, 3, 5 Major stroke is associated with 30-day (OR 7.43; 95 % CI [2.45–22.53]) and late (hazard ratio 1.75; 95 % CI [1.01–3.04]) mortality.7 A recent meta-analysis on the latest transcatheter heart valve designs still pointed towards a weighted 2.4 % stroke risk.26 Even more striking is the high incidence of brain injury after TAVI as demonstrated by DW-MRI. 6 The majority of these brain lesions do not seem to cause immediate clinically apparent events, but the consequence of these subclinical brain lesions is unknown and there presence is, at least, suspicious. Indeed, silent infarcts have been linked to future clinical strokes, premature neurocognitive deterioration and dementia.10 Cerebral embolisation of thrombotic and tissue-derived material undisputedly occurs with nearly every TAVI procedure.19,20,21 Patients with advanced aortic valve disease have a higher risk for extensive and more complex atherosclerotic plaques in the aortic arch, which makes them more vulnerable to neurological events in general and after cardiac procedures in particular.27 CT analyses show larger atheroma volume to be a predictor for new cerebrovascular events, specifically when located in the ascending aorta and aortic arch.25 The combination of a diseased aortic wall together with a history of cerebrovascular disease (and thus greater atheromic burden) leaves TAVI patients more vulnerable to early and late strokes.25 Indeed, TAVI pertains wire and catheter navigation through diseased aorta’s, more or less difficult (retrograde) crossing of an aortic valve that is degenerated, thickened and contains calcifications, (acute or organised) thrombus, pannus and other friable tissue. The introduction, positioning and deployment of a transcatheter heart valve will displace the native diseased aortic valve, a process that may dislodge material. The seating of stiff wires in the left ventricle may scrape the myocardium. Repeated flushing and exchanging of catheters may also create gaseous and thrombotic

1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/ NEJMoa1008232; PMID: 20961243 2. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI:10.1056/NEJMoa1103510; PMID: 21639811 3. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 2467893 4. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter Aortic Valve Replacement Using a Self-Expanding Bioprosthesis in Patients With Severe Aortic Stenosis at Extreme Risk for Surgery. J Am Col Cardiol 2014;63:1972–81. DOI: 10.1016/j. jacc.2014.02.556; PMID: 24657695 5. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324 6. Fanning JP, Walters DL, Platts DG, et al. Characterisation of neurological injury in transcatheter aortic valve implantation: how clear is the picture? Circulation 2014;129:504–15. DOI: 10.1161/CIRCULATIONAHA.113.004103; PMID: 24470472 7. Nombela-Franco L, Webb JG, de Jaegere PP, et al. Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation. Circulation 2012;126:3041–53. DOI: 10.1161/CIRCULATIONAHA.112.110981; PMID: 23149669 8. Nuis RJ, Van Mieghem NM, Schultz CJ, et al. Frequency and causes of stroke during or after transcatheter aortic valve implantation. Am J Cardiol 2012;109:1637–43. DOI:10.1016/j. amjcard.2012.01.389; PMID: 22424581 9. Tay EL, Gurvitch R, Wijesinghe N, et al. A high-risk period for cerebrovascular events exists after transcatheter aortic valve implantation. JACC Cardiovascular interventions 2011;4:1290–7. 10. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215–22. DOI: 10.1056/NEJMoa022066; PMID: 12660385 11. Van Gils L, Baumbach A, Himbert D, et al. Tools and Techniques – Clinical: Embolic protection devices in

INTERVENTIONAL CARDIOLOGY REVIEW

embolisation.21 The mechanistic concept of embolic protection is intuitive and is supported by the recent literature. Debris is prevented from reaching the brain by deflection or filtering and may result in less and smaller brain injury with consequently preserved neurocognitive performance. Yet, the data to support EPD are still not compelling. So far EPD trials have been underpowered for their primary endpoints. Because the clinical neurological event rate after TAVI is sufficiently low and sample size in clinical trials with clinical endpoints would be unreasonably high, surrogate DW-MRI endpoints have been proposed. Yet assumptions of new lesion number and volume are challenging, with relatively limited benchmark data. MRI studies may also be aggravating to elderly TAVI patients, which is underscored by high dropout rates (≤40 %) in contemporary MRI follow-up studies.15, 19 Patient and device selection may also affect the success of EPD. The DEFLECT-III and SENTINEL studies hinted towards more EPD benefit with self-expanding devices than with the balloon-expandable counterparts.15, 20 Conversely, in another study use of balloonexpandable (and not self-expanding) transcatheter heart valves was an independent predictor of tissue embolisation. A recent study-level meta-analysis of four randomised controlled EPD trials excluding SENTINEL, found significant reductions in total lesion volume and new ischemic lesions and more preserved neurocognitive performance in patients undergoing TAVI with EPD.28 The high frequency of thrombotic material in the filters after TAVI may signal suboptimal per-procedural anticoagulation and may be addressed by improved anticoagulation regimens.21 Additional pooled-patient-level analyses of existing data and larger, adequately powered randomised trials should shed further light on whether TAVI in general would benefit from EPDs. In the meantime it is fair to claim that EPDs are safe and easy to use and will capture debris in nearly every TAVI procedure. n

transcatheter aortic valve implantation. EuroIntervention 2015;11:247–8. 12. Rodes-Cabau J, Kahlert P, Neumann FJ, et al. Feasibility and exploratory efficacy evaluation of the Embrella Embolic Deflector system for the prevention of cerebral emboli in patients undergoing transcatheter aortic valve replacement: the PROTAVI-C pilot study. JACC Cardiovasc interv 2014;7:1146– 55. DOI: 10.1016/j.jcin.2014.04.019; PMID: 25341709 13. Kahlert P, Al-Rashid F, Dottger P, et al. Cerebral embolisation during transcatheter aortic valve implantation: a transcranial Doppler study. Circulation 2012;126:1245–55. DOI: 10.1161/ CIRCULATIONAHA.112.092544; PMID: 22899774 14. Baumbach A, Mullen M, Brickman AM, et al. Safety and performance of a novel embolic deflection device in patients undergoing transcatheter aortic valve replacement: results from the DEFLECT I study. EuroIntervention 2015;11:75–84. DOI: 10.4244/EIJY15M04_01; PMID: 25868876 15. Lansky AJ, Schofer J, Tchetche D, et al. A prospective randomised evaluation of the TriGuard HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070–8. DOI: 10.1093/eurheartj/ehv191; PMID: 25990342 16. Nijhoff F, Doevendans PA, Stella PR, et al. TriGuard™HD embolic deflection device for cerebral protection during transcatheter aortic valve replacement: The results of the DEFLECT II Trial. EuroIntervention May 2015. 17. Naber CK, Ghanem A, Abizaid AA, et al. First-in-man use of a novel embolic protection device for patients undergoing transcatheter aortic valve implantation. EuroIntervention 2012;8:43–50. DOI: 10.4244/EIJV8I1A8; PMID: 22403768 18. Linke A, Haussig S, Dwyer MG, et al. CLEAN-TAVI: A prospective, randomised trial of cerebral embolic protection in high-risk patients with aortic stenosis undergoing transcatheter aortic valve replacement. Presented at the Transcatheter Cardiovascular Therapeutics Conference in Washington, DC 13 September 2014. 19. van Mieghem NM, van Gils L, Ahmad H, et al. Filter-based cerebral embolic protection with transcatheter aortic valve implantation: the randomised MISTRAL-C trial. EuroIntervention 2016;12:499–507. DOI: 10.4244/EIJV12I4A84; PMID: 27436602

20. Kapadia SR, Kodali S, Makkar R, et al. Protection Against Cerebral Embolism During Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2017;69:367–7. DOI:10.1016/j .jacc.2016.10.023; PMID: 27815101 21. van Mieghem NM, Schipper ME, Ladich E, et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement. Circulation 2013;127:2194–201. DOI: 10.1161/CIRCULATIONAHA.112.001091; PMID: 23652860 22. Jensen CJ WA, Schmitz T, et al. Prevalence and etiopathology of thromboembolic debris during transcatheter interventional aortic valve replacement: results of the SENTINEL H-‐study. 2016, Presented at the EuroPCR congress. URL: http:// claretmedical.com/pdf/presentations/2016/SENTINEL-H%20 EuroPCR%202016_Jensen%20FINAL.pdf (accessed 4 November 2016). 23. van Mieghem NM, El Faquir N, Rahhab Z, et al. Incidence and predictors of debris embolising to the brain during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2015;8:718–24. DOI: 10.1016/j.jcin.2015.01.020 24. van Mieghem NM, Chieffo A, Dumonteil N, et al. Trends in outcome after transfemoral transcatheter aortic valve implantation. Am Heart J 2013;165:183–92. DOI: 10.1016/j. ahj.2012.11.002 25. Kataoka Y, Puri R, Pisaniello AD, et al. Aortic atheroma burden predicts acute cerebrovascular events after transcatheter aortic valve implantation: insights from volumetric multislice computed tomography analysis. EuroIntervention 2016;12:783–9. DOI:10.4244/EIJV12I6A127; PMID: 27542792. 26. Athappan G, Gajulapalli RD, Tuzcu ME, et al. A systematic review on the safety of second-generation transcatheter aortic valves. EuroIntervention 2016;11:1034–43. DOI:10.4244/ EIJV11I9A211; PMID: 26788706. 27. Sugioka K, Matsumura Y, Hozumi T, et al. Relation of aortic arch complex plaques to risk of cerebral infarction in patients with aortic stenosis. Am J Cardiol 2011;108:1002–7. DOI: 10.2174/157340310791658712; PMCID: PMC2994110. 28. Giustino G, Mehran R, Veltkamp R, et al. Neurological Outcomes With Embolic Protection Devices in Patients Undergoing Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. JACC Cardiovasc Interv 2016;9:2124–33. DOI: 10.1016/j.jcin.2016.07.024; PMID: 27765306.

Structural

Optimising the Haemodynamics of Aortic Valve-in-valve Procedures R en J ie Ya o, M a t h e u s S i m o n a t o a n d D a n n y D v i r Department of Cardiology, St Paul’s Hospital, Vancouver, Canada

Abstract Bioprosthetic surgical valves are increasingly implanted during cardiac surgery, instead of mechanical valves. These tissue valves are associated with limited durability and as a result transcatheter valve-in-valve procedures are performed to treat failed bioprostheses. A relatively common adverse event of aortic valve-in-valve procedures is residual stenosis. Larger surgical valve size, supra-annular transcatheter heart valve type, as well as higher transcatheter heart valve implantation depth, have all been shown to reduce the incidence of elevated post-procedural gradients. With greater understanding of technical considerations and surgical planning, valve-invalve procedures could be more effective and eventually may become the standard of care for our increasingly ageing and comorbid population with failed surgical bioprostheses.

Keywords Valvular disease, bioprosthetic valve, transcatheter valve-in-valve implantation, prosthesis-patient mismatch, haemodynamics Disclosure: DD is a consultant to Edwards Lifesciences, Medtronic, St. Jude Medical. Received: 29 August 2016 Accepted: 9 November 2016 Citation: Interventional Cardiology Review 2017;12(1):40–3. DOI: 10.15420/icr.2016:25:2 Correspondence: Danny Dvir, Department of Cardiology, St Paul’s Hospital, 1081 Burrard St, Vancouver, Canada V6Z1Y6; E: danny.dvir@gmail.com

In the context of an ageing population, care for valvular disease is becoming an increasingly important field. A recent large-scale population-based study found the prevalence of valvular disease to be 8.5 % in the 65–74-year-old group and 13.2 % in those over 75 years.1 While mechanical surgical valves are more durable, bioprosthetic valves are often used as they are less thrombogenic and do not require life-long anticoagulation. A recent meta-analysis found that bioprosthetic valves have significantly fewer thromboembolic events and anticoagulation-related events, including major bleeding.2 A large multi-centre database study also found that from 1997 to 2006 the use of bioprosthetic valves increased from 40 % to 80 %.3 This trend illustrates the importance of managing the long-term dysfunction events of bioprosthetic valves, as they tend to degenerate within 10–20 years, requiring more re-operation than mechanical valves.2,4 Traditionally, patients with degenerated bioprosthetic valves required re-operation; however, these patients are often of advanced age and have other co-morbidities that put them at high risk for surgical complications. Transcatheter valve-in-valve (VIV) implantation has become a potential alternative procedure for high-risk patients with degenerated bioprosthetic valves, and the Valve-in-Valve International Data (VIVID) Registry has been established to collect information on these procedures. A recent meta-analysis of degenerated aortic valves found that VIV implantation achieved comparable haemodynamic outcomes to open aortic valve replacement while at a lower risk of stroke and bleeding.5 In addition, VIV achieved a comparable perioperative mortality rate to the open procedure, with reported 83 % survival after 1 year.5,6 While there have been reports of success during intermediate term follow-up,7,8 the long-term durability of VIV implants is unknown. The three main adverse events of VIV are device malpositioning (15 % of VIV patients in the VIVID Registry, mainly in stentless surgical valves), coronary obstruction (~3 %),

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and elevated (defined as >20 mmHg) residual transvalvular gradient (28.4 %).9 With greater operator experience, the rate of both malpositioning and coronary obstruction seems to decrease, while residual elevated gradients remains an issue.10 Elevated post-procedural gradients can be partially explained by the non-distensible nature of bioprosthetic valves, often resulting in an underexpansion of VIV implants.11 The underexpansion of the transcatheter heart valve (THV) has been shown in vitro to create localised high-stress regions within the leaflet commissures or within the belly of the leaflets.12 This increased mechanical stress and deformation has been hypothesised to result in accelerated degeneration of these valves. In addition, underexpansion results in a higher gradient after VIV procedure (average mean gradient of 15.8 ±8.9 mmHg reported in the VIVID Registry) as compared to regular transcatheter valve implants in native aortic valves (5–10 mmHg), therefore creating unique challenges and considerations for the VIV procedure.6,13 These haemodynamic considerations are critical because studies have shown that elevated post-procedural mean gradient is associated with worse clinical outcomes.14 In addition, an elevated post-procedural mean gradient is inherently present with prosthesis–patient mismatch (PPM), defined as having too small of an effective orifice area in relation to the patient’s body size.15 PPM has been shown to be associated with reduced recovery of ventricular hypertrophy, increased cardiac events and mortality.15 A large-scale meta-analysis of 27,000 surgical patients found that PPM is associated with both an increase in all-cause mortality and cardiacrelated mortality.16 Due to the nature of the VIV procedure, the rate of PPM post-VIV has also been reported to be higher than surgical valve replacement.17,18 Post-procedural mean gradient and its associated PPM is influenced by a combination of factors, including surgical valve

Haemodynamics of Aortic Valve-in-valve Procedures

size and its aetiology of degradation, as well as the THV device type, size and depth of implantation. This review will summarise the newest findings in this area and explore modifiable factors that could improve the haemodynamic outcomes of a VIV procedure.

Pre-surgical Considerations The VIVID Registry revealed that patients with smaller (manufacturer label size ≤21 mm) and intermediate bioprostheses (manufacturer label size >21 and <25 mm) as compared to larger bioprostheses (manufacturer label size ≥25 mm) had a worse survival rate.10 This difference in mortality may be explained by the increased restriction on THV expansion in smaller surgical valves, which can lead to an increased likelihood of developing elevated post-procedural gradients, PPM and less improvement in clinical functional status. Potentially, patients with smaller surgical valves are at a greater risk of having PPM prior to the VIV procedure, leading to a situation that will not be solved by VIV alone, without removing the small surgical valve during repeat surgery. Data from the VIVID Registry suggests that patients who already had severe PPM of their surgical valve had significantly worse outcomes after VIV. Having severe PPM of the original surgical valve was found to be a strong correlate for 1-year survival, with severe PPM of the surgical valve being associated with 71.8 % 1-year post-VIV survival as opposed to 85.8 % survival in the combined no PPM and moderate PPM group (unpublished data from the VIVID Registry). This suggests that patients with severe PPM may not be optimal candidates for an aortic VIV procedure and that this factor should be carefully evaluated in candidates for VIV procedures. In addition to the surgical valve size, the type of degeneration is also useful to consider, as a predominant surgical valve stenosis has been associated with increased mortality when compared to patients with regurgitation.10 This may also be related to the haemodynamic outcomes, as a stenotic bioprosthetic valve would impede the expansion of the THV device more than a regurgitant one. This restriction increases the likelihood of developing elevated post-procedural gradients, which could have contributed to the worse outcomes seen in the study. One important distinction to make is that, for bioprosthetic surgical valves, the manufacturer’s label size matches the outer diameter of the device; but the truly relevant measurement for VIV sizing is the internal diameter, as this is where the THV will actually be expanded. This value may vary from 1 to 4 mm from the reported label size, depending on the manufacturer.11 The true internal diameter is currently available in the “VIV Aortic” app from Mr Vinayak Bapat (UBQO Limited) and should be used by operators to enable appropriate THV valve size selection and also to predict the risk of poor post-procedural haemodynamics. As the risk of surgical valve degeneration requiring reoperation is high, new surgical valves that are appropriately designed to provide better conditions for VIV are urgently needed. Proposed features for these new surgical valves could include clear fluoroscopic markings indicating size and the region of appropriate positioning, more flexible and expandable annuli to allow for complete expansion, and larger internal diameters.19 These new features would facilitate the VIV procedure and help to reduce potential complications such as THV misplacement, while also allowing for better haemodynamics. If possible, it would be preferable to select the surgical valve with the largest effective orifice area, in order to facilitate optimal future VIV procedures. Some studies have reported that haemodynamic

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outcomes are better in supra-annular positioning compared to intraannular bioprostheses.20,21 Recently, sutureless valves have also been proposed as an alternative to aortic root enlargement; they have an acceptable safety profile while allowing for a larger valve size to be inserted.22 Another meta-analysis showed that stentless valves provide larger effective orifice areas, lower mean gradient and greater ventricular mass regression.23 In addition, techniques such as aortic root enlargement to allow for the insertion of larger bioprosthetic valves are occasionally considered for patients at risk of severe PPM. This procedure prolongs the cardiopulmonary bypass time, and concerns with the safety of this approach have been raised in the past, however several studies have shown favourable results while utilising this approach in selected cases.24 This trend of implanting larger surgical valves can already be seen in several hospitals, with one recent report showing that from 2002 to 2012, the average valve label size has increased from 22.8 to 23.9 mm, with the internal diameter increasing from 19.6 to 20.3 mm.25 While this trend is promising, further research into surgical valve size, type, positioning and techniques allowing for larger valve sizes to be implanted is needed in order to prevent PPM and to improve potential future VIV procedures.

VIV Considerations Other than the considerations of size and mechanism of failure of the original surgical valve, the type, size and deployment position of the THV are also important in optimising haemodynamic outcomes. Currently, there are two main valve designs: intra-annular valves, where the leaflets are built at the level of the annulus; and supra-annular valves, where the leaflets are above the annulus. Among the commerciallyavailable surgical THVs, the Edwards Sapien XT and Sapien 3 (Edwards Lifesciences) are intra-annular and the Medtronic CoreValve (Medtronic) is supra-annular. Due to the fact that supra-annular devices have functional areas that operate in a more elevated position, it is expected that they will attain a more complete expansion with better haemodynamic results. This expectation is supported by data from the VIVID Registry, which shows that in small surgical valves with an internal diameter <20 mm, elevated gradients were found in 59 % of Sapien valves, but only 20 % of CoreValves.9,10 This evidence is supported by an in vitro study that found that the gradient across the Sapien THV is highly dependent on surgical valve size, with a mean gradient of 9.1 mmHg in a 23-mm CarpentierEdwards Perimount (Edwards Lifesciences) surgical valve, 19.5 mmHg in a 21-mm bioprosthesis, and 46.5 mmHg in a 19-mm bioprosthesis.26 This relationship with surgical valve size is not as significant in CoreValve implants, which is likely due to the supra-annular design of the valves consequently allowing for a larger orifice and less restriction from the surgical valve. In addition to the type of THV valve, the implantation depth has been shown to be the most important independent factor for elevated mean gradient in a recent VIVID Registry study, followed by the THV valve type and mechanism of surgical valve failure.27 Other in vitro studies found that the supra-annular position was superior to the annular position in producing lower gradients for the CoreValve in the Trifecta (St. June Medical Inc.), surgical valve.28,29 Even in a 19-mm surgical valve, it has been shown in vitro that 3- or 6-mm supra-annular deployment of the THV significantly decreases the mean gradient as compared to normal position, but may increase the risk of leaflet thrombosis and valve migration.30

Structural Figure 1: Examples of the Depth of Valve-in-valve Implantation Carpentier-Edwards Perimount 23 mm CoreValve 26 mm

Depth: 6.7 mm Mean Gradient: 24 mmHg

Depth: 0 mm Mean Gradient: 6 mmHg

Carpentier-Edwards Perimount 23 mm SAPIEN XT 23 mm

Depth: 14.7 % Mean Gradient: 30 mmHg

Depth: 8.6 % Mean Gradient: 11 mmHg

Left: Two examples of CoreValve positioning, with low (6.7 mm) and high (0 mm) implantation. Right: Two examples of Sapien XT positioning, with low (14.7 %) and high (8.6 %) implantation. In both devices, higher implantation is associated with lower post-procedural gradients, likely due to improved expansion of the transcatheter device.

In a clinical study it was found that high implantation of a THV was associated with lower rates of elevated gradients compared to low implantation, with the optimal implantation depth defined as 0–5 mm for CoreValve Evolut and 0–2 mm (0–10 % of device frame) for Sapien XT.27 While a higher implantation depth would allow for better haemodynamics, it is also important for operators to be aware of the potential risks of an excessively high position, which may lead to coronary obstruction, malpositioning or embolism.31 The intricacies of optimal THV positioning demonstrate the importance of understanding the different fluoroscopic markings of the surgical valves for determining the ideal position (see Figure 1). In terms of less conventional approaches, and also considering the importance of using a large THV to improve post-operative haemodynamics, some reports of success through cracking the bioprosthesis ring with ultrahigh-pressure balloons to facilitate the expansion of THV have recently been published.32,33 While this technique may be valuable in certain contexts, it may be involved with an increased risk of root injury and should be further studied. The introduction of small THV devices such as the 20-mm Sapien XT/ Sapien 3 and 23-mm CoreValve Evolut may allow for less THV deformation when implanted in smaller surgical valves.6 The smaller THVs may also create PPM depending on patient characteristics, however, and careful pre-procedural calculations should be conducted. Additionally, an interesting in vitro report recently suggested that THV undersizing may decrease the risk of coronary obstruction in at-risk patients.34 It is still unclear, however, if the proposed effects are true in real-life situations.

Post-operatively, it is crucial for patients to receive proper assessment and follow-up, including a 30-day echocardogram assessment to allow for the early identification of issues such as elevated gradients and to assess thrombosis risk. Valve thrombosis is a potentially serious complication that is rarely reported and is potentially under-recognised. While most studies of valve thrombosis were analysed for transcatheter aortic valve implantations (TAVIs), there have also been recent reports of thrombosis in VIV procedures.37 A dramatic increase in mean gradient within 30 days of VIV is a warning for potential thrombotic complications, and these patients should be monitored carefully. In a systematic review and a large-scale clinical study on valve thrombosis in TAVI, it was found that while the thrombus could not always be visualised with echocardiography, these patients had common features of progressive exertional dyspnoea (65 %), a rapid dramatic increase in mean gradient from 10 to 40 mmHg within months of the procedure, and leaflet thickening (77 %).38,39 In these two analyses, 81–88 % of the patients were able to restore the mean gradient to baseline within 2 months after treatment with warfarin, while the remaining patients had to receive either percutaneous VIV or surgical valve explantation due to this complication.34,35 This shows the reversible nature of valve thrombosis if treated promptly; since the median time for valve thrombosis diagnosis is 6 months, it raises the question of whether early detection from proper followup assessments and 30-day echocardiography would be able to prevent additional invasive procedures due to valve thrombosis.38 Future anticoagulation trials would also help guide future postoperative coagulation protocols and help prevent post-procedural complications such as thrombosis.

Post-VIV Care to prevent structural valve degeneration after VIV is another important consideration in improving haemodynamics. Antimineralisation treatment has been reported to be the most significant independent predictor of structural valve degeneration.35 In addition, a large-scale THV study recently found the absence of anticoagulation therapy at discharge to be an independent predictor of THV haemodynamic deterioration, which illustrates the importance of antithrombotic therapy post-procedure.36 The standard regimen is warfarin for the first 3 months only, which can be switched to aspirin unless patients have risk factors for thromboembolism such as atrial fibrillation, left ventricular dysfunction and a hypercoagulable condition.

Conclusion The combination of surgical valve characteristics, THV characteristics and implantation depth influence haemodynamic and patient outcomes. Since an elevated gradient is seen in almost a third of VIV patients and remains an unresolved issue, further research into the optimal procedure is needed. Many recent studies have shown the benefits of using supra-annular THVs, which are larger when possible and indicated, and a higher implantation depth in order to reduce the incidence of elevated mean gradients. Other future considerations surround the characteristics and procedure of the initial surgical valve implantation, such as the implantation of larger

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Haemodynamics of Aortic Valve-in-valve Procedures

surgical valves with larger internal diameters to prevent PPM, and incorporation of standardised fluoroscopic markings to facilitate future VIV procedures. With greater understanding of the technical

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Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368 :1005–11. DOI: 10.1016/S0140-6736(06)69208-8; PMID: 16980116 Zhao DF, Seco M, Wu JJ, et al. Mechanical versus bioprosthetic aortic valve replacement in middle-aged adults: A systematic review and meta-analysis. Ann Thorac Surg 2016;102 :315–27. DOI: 10.1016/j.athoracsur.2015.10.092; PMID: 26794881 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. DOI: 10.1016/j.jtcvs.2008.08.015; PMID: 19154908 Forcillo J, Pellerin M, Perrault LP, et al. CarpentierEdwards pericardial valve in the aortic position: 25-years experience. Ann Thorac Surg 2013;96 :486–93. DOI: 10.1016/j. athoracsur.2013.03.032; PMID: 23684486 Phan K, Zhao DF, Wang N, et al. Transcatheter valve-in-valve implantation versus reoperative conventional aortic valve replacement: A systematic review. J Thorac Dis 2016;8 :E83–93. DOI: 10.3978/j.issn.2072-1439.2016.01.44; PMID: 26904259 Dvir D, Barbanti M, Tan J, et al. Transcatheter aortic valve-invalve implantation for patients with degenerative surgical bioprosthetic valves. Curr Probl Cardiol 2014;39 :7–27. DOI: 10.1016/j.cpcardiol.2013.10.001; PMID: 24331437 Cheung A, Webb JG, Barbanti M, et al. 5-Year experience with transcatheter transapical mitral valve-in-valve implantation for bioprosthetic valve dysfunction. J Am Coll Cardiol 2013;61 :1759–66. DOI: 10.1016/j.jacc.2013.01.058; PMID: 23500301 Ye J, Cheung A, Yamashita M, et al. Transcatheter aortic and mitral valve-in-valve implantation for failed surgical bioprosthetic valves an 8-year single-center experience. JACC Cardiovasc Interv 2015;8 :1735–44. DOI: 10.1016/j. jcin.2015.08.012; PMID: 26476608 Dvir D, Webb J, Brecker S, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: Results from the global valve-in-valve registry. Circulation 2012;126 :2335–44. DOI: 10.1161/ CIRCULATIONAHA.112.104505; PMID: 23052028 Dvir D, Webb JG, Bleiziffer S, et al.; Valve-in-Valve International Data Registry Investigators. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA 2014;312 :162–70. DOI: 10.1001/jama.2014.7246; PMID: 25005653 Webb JG, Dvir D. Transcatheter aortic valve replacement for bioprosthetic aortic valve failure: The valve-in-valve procedure. Circulation 2013;127 :2542–50. DOI: 10.1161/ CIRCULATIONAHA.113.000631; PMID: 23797741 Abbasi M, Azadani AN. Leaflet stress and strain distributions following incomplete transcatheter aortic valve expansion. J Biomech 2015;48 :3672–80. DOI: 10.1016/j. jbiomech.2015.08.012; PMID: 26338100 Kodali SK, Williams MR, Smith CR, et al.; PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366 :1686–95. DOI: 10.1056/NEJMoa1200384; PMID: 22443479 Chan KL, Chen SY, Chan V, et al. Functional significance of elevated mitral gradients after repair for degenerative mitral

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considerations and surgical planning, VIV procedures could be more effective for our increasingly ageing and comorbid population with failed surgical bioprostheses. n

regurgitation. Circ Cardiovasc Imaging 2013;6 :1041–7. DOI: 10.1161/CIRCIMAGING.112.000688; PMID: 24014825 15. Pibarot P, Dumesnil JG. Prosthetic heart valves: Selection of the optimal prosthesis and long-term management. Circulation 2009;119 :1034–48. DOI: 10.1161/ CIRCULATIONAHA.108.778886; PMID: 19237674 16. Head SJ, Mokhles MM, Osnabrugge RLJ, et al. The impact of prosthesis patient mismatch on long-term survival after aortic valve replacement: A systematic review and meta-analysis of 34 observational studies comprising 27 186 patients with 133 141 patient-years. Eur Heart J 2012;33 :1518–29. DOI: 10.1093/eurheartj/ehs003; PMID: 22408037 17. Ewe SH, Muratori M, Delgado V, et al. Hemodynamic and clinical impact of prosthesis-patient mismatch after transcatheter aortic valve implantation. J Am Coll Cardiol 2011;58:1910–8. DOI: 10.1016/j.jacc.2011.08.027; PMID: 21982276 18. Seiffert M, Conradi L, Baldus S, et al. Impact of patientprosthesis mismatch after transcatheter aortic valve-in-valve implantation in degenerated bioprostheses. J Thorac Cardiovasc Surg 2012;143 :617–24. DOI: 10.1016/j.jtcvs.2011.11.004; PMID: 22169448 19. Noorani A, Radia R, Bapat V. Challenges in valve-in-valve therapy. J Thorac Dis 2015;7 :1501–8. DOI: 10.3978/j.issn.20721439.2015.06.16; PMID: 26543595 20. Botzenhardt F, Eichinger WB, Bleiziffer S, et al. Hemodynamic comparison of bioprostheses for complete supra-annular position in patients with small aortic annulus. J Am Coll Cardiol 2005;45 :2054–60. DOI: 10.1016/j.jacc.2005.03.039; PMID: 15963409 21. Badano LP, Pavoni D, Musumeci S, et al. Stented bioprosthetic valve hemodynamics: is the supra-annular implant better than the intra-annular? J Heart Valve Dis 2006;15 :238–46. PMID: 16607907 22. Beckmann E, Martens A, Alhadi F, et al. Aortic valve replacement with sutureless prosthesis: better than root enlargement to avoid patient-prosthesis mismatch? Interact Cardiovasc Thorac Surg 2016;22 :1–6. DOI: 10.1093/icvts/ivw041; PMID: 26920726 23. Kunadian B, Vijayalakshmi K, Thornley AR, et al. Meta-analysis of valve hemodynamics and left ventricular mass regression for stentless versus stented aortic valves. Ann Thorac Surg 2007;84 :73–8. DOI: 10.1016/j.athoracsur.2007.02.057; PMID: 17588387 24. Peterson MD, Borger MA, Feindel CM, et al. Aortic annular enlargement during aortic valve replacement: Improving results with time. Ann Thorac Surg 2007;83 :2044–9. DOI: 10.1016/j.athoracsur.2007.01.059; PMID: 17532393 25. Silaschi M, Conradi L, Treede H, et al. Trends in surgical aortic valve replacement in more than 3,000 consecutive cases in the era of transcatheter aortic valve implantations. Thoracic and Cardiovascular Surgeon 2016;64 :382–391. DOI: 10.1055/ s-0035-1564615 26. Azadani AN, Jaussaud N, Matthews PB, et al. Transcatheter aortic valves inadequately relieve stenosis in small degenerated bioprostheses. Interact Cardiovasc Thorac Surg 2010;11 :70–7. DOI: 10.1510/icvts.2009.225144; PMID: 20395249 27. Simonato M, Webb J, Kornowski R, et al. Transcatheter replacement of failed bioprosthetic valves: Large multicenter assessment of the effect of implantation depth on hemodynamics after aortic valve-in-valve. Circ Cardiovasc Interv

2016;9 :1–12. DOI: 10.1161/CIRCINTERVENTIONS.115.003651; PMID: 27301396 28. Simonato M, Azadani AN, Webb J, et al. In vitro evaluation of implantation depth in valve-in-valve using different transcatheter heart valves. EuroIntervention 2016;12 :909–18. DOI: 10.4244/EIJV12I7A149; PMID: 27639744 29. Zenses AS, Mitchell J, Evin M, et al. In vitro study of valve-in-valve performance with the CoreValve selfexpandable prosthesis implanted in different positions and sizes within the Trifecta surgical heart valve. Comput Methods Biomech Biomed Engin 2015;5842 :1–2. DOI: 10.1080/10255842.2015.1069634; PMID: 26260517 30. Midha PA, Raghav V, Condado JF, et al. How can we help a patient with a small failing bioprosthesis? An in vitro case study. JACC Cardiovasc Interv 2015;8 :2026–33. DOI: 10.1016/j. jcin.2015.08.028; PMID: 26627992 31. Bapat VN, Attia RQ, Condemi F, et al. Fluoroscopic guide to an ideal implant position for Sapien XT and CoreValve during a valve-in-valve procedure. JACC Cardiovasc Interv 2013;6 :1186– 94. DOI: 10.1016/j.jcin.2013.05.020; PMID: 24139931 32. Tanase D, Grohmann J, Schubert S, et al. Cracking the ring of Edwards Perimount bioprosthesis with ultrahigh pressure balloons prior to transcatheter valve in valve implantation. Int J Cardiol 2014;176 :1048–9. DOI: 10.1016/j.ijcard.2014.07.175; PMID: 25156860 33. Brown SC, Cools B, Gewillig M. Cracking a tricuspid Perimount bioprosthesis to optimize a second transcatheter Sapien valve-in-valve placement. Catheter Cardiovasc Interv 2016;88 :456–9. DOI: 10.1002/ccd.26507; PMID: 27015096 34. Stock S, Scharfschwerdt M, Meyer-Saraei R, et al. Does undersizing of transcatheter aortic valve bioprostheses during valve-in-valve implantation avoid coronary obstruction? An in vitro study. Thorac Cardiovasc Surg 2016; DOI: 10.1055/s-0036-1584356; PMID: 27304222: epub ahead of press 35. Flameng W, Rega F, Vercalsteren M, et al. Antimineralization treatment and patient-prosthesis mismatch are major determinants of the onset and incidence of structural valve degeneration in bioprosthetic heart valves. J Thorac Cardiovasc Surg 2014;147 :1219–24. DOI: 10.1016/j.jtcvs.2013.03.025; PMID: 23623617 36. Del Trigo M, Muñoz-Garcia AJ, Wijeysundera HC, et al. Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement multicenter registry. J Am Coll Cardiol 2016;67 :644–55. DOI: 10.1016/j.jacc.2015.10.097; PMID: 26868689 37. Goleski PJ, Reisman M, Don CW. Reversible thrombotic aortic valve restenosis after valve-in-valve transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2016; DOI: 10.1002/ccd.26522; PMID: 27198960: epub ahead of print 38. Córdoba-Soriano J, Puri R, Amat-Santos I, et al. Valve thrombosis following transcatheter aortic valve implantation: a systematic review. Rev Esp Cardiol (Engl Ed) 2015;68 :198–204. DOI: 10.1016/j.rec.2014.10.003; PMID: 25667117 39. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8 :e001779. DOI: 10.1161/ CIRCINTERVENTIONS.114.001779; PMID: 25873727

Structural

A Glimpse into the Future: In 2020, Which Patients will Undergo TAVI or SAVR? Crochan J O’Sullivan 1 and Peter Wenaweser 2,3 1. Department of Cardiology, Stadtspital Triemli, Zurich, Switzerland; 2. Department of Cardiology, University Hospital Bern, Inselspital, Switzerland; 3. Cardiovascular Center Zurich, Hirslanden Clinic im Park, Zurich, Switzerland

Abstract Transcatheter aortic valve implantation (TAVI) has evolved into a safe and effective procedure to treat symptomatic patients with severe aortic stenosis (AS), with predictable and reproducible results. Rates of important complications such as vascular complications, strokes and paravalvular leaks are lower than ever, because of improved patient selection, systematic use of multidector computer tomography, increasing operator experience and device iteration. Accumulating data suggest that transfemoral TAVI with newer generation transcatheter heart valves and delivery systems is superior to conventional surgical aortic valve replacement among intermediate- and high-risk patients with severe symptomatic AS with regard to all-cause mortality and stroke. One can anticipate that by 2020, the majority of patients with severe symptomatic AS will undergo TAVI as first line therapy, regardless of surgical risk.

Keywords Aortic stenosis, aortic valve replacement, transcatheter aortic valve implantation Disclosure: PW has received institutional grants from Medtronic, and proctoring and lecture fees from Medtronic, Edwards Lifesciences and Boston Scientific. CJO’S has no conflicts of interest to declare. Received: 26 July 2016 Accepted: 15 October 2016 Citation: Interventional Cardiology Review 2017;12(1):44–50. DOI: 10.15420/icr.2016:24:2 Correspondence: Peter Wenaweser, MD, Department of Cardiology, Bern University Hospital, Inselspital, 3010 Bern, Switzerland. E: peter.wenaweser@insel.ch

Since the first ‘proof-of-concept’ case of transcatheter aortic valve implantation (TAVI) was reported by Cribier and colleagues in 2002, more than 200,000 patients have undergone the procedure in approximately 65 countries.1,2 Since its inception, the majority of patients undergoing TAVI have been considered inoperable or high risk for conventional surgical aortic valve replacement (SAVR) as recommended by guidelines.3 However, with increasing operator experience, technical advancements in delivery systems and transcatheter heart valves (THVs) and the systematic use of multi detector computed tomography (MDCT) for vascular access and annulus sizing, rates of important complications such as stroke, paravalvular aortic regurgitation and major vascular complications have significantly declined, resulting in lower mortality rates. This has led to a paradigm shift whereby TAVI is being increasingly performed in lower-risk patients.4–7 Therefore, surgical risk will play less of a role in patient selection in 2020 and greater emphasis will be placed on clinical and anatomical characteristics as well as patient preference. However, because all current THVs are bioprostheses, questions remain regarding the long-term durability of THVs, particularly in a younger patient population. Since the publication of the 2012 European Society of Cardiology (ESC) guidelines in which TAVI was recommended exclusively among inoperable or high-risk patients, two major randomized controlled trials – Placement of Aortic Transcatheter Valves (PARTNER) 2a and the Nordic Aortic Valve Intervention Trial (NOTION) trial – have demonstrated the safety and efficacy of TAVI among non-high-risk patients.7,8 The purpose of the present review is to provide an update on the rapidly changing field of TAVI and to provide a glimpse into the future regarding which patients will undergo SAVR and which patients will undergo TAVI in 2020.

Past Over the last 50 years, surgical aortic valve replacement (SAVR) has become the standard-of-care for the treatment of patients

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with severe symptomatic aortic stenosis (AS). Nevertheless, up to one-third of patients with severe symptomatic AS were being denied treatment because they were considered too high risk to undergo the procedure, and with a global aging population this dilemma was set to be exacerbated.9 This trend was disrupted by a less-invasive, catheter-based approach to aortic valve replacement for patients with severe AS. Following the seminal work in pigs of Andersen and colleagues,10 the first-in-man TAVI procedure was performed by Cribier and colleagues in 2002.1 Since then, TAVI has evolved to become the treatment of choice for inoperable patients with symptomatic severe AS and is a viable alternative to SAVR for patients considered to be at high surgical risk. The current ESC guidelines on valvular heart disease have given a Class I indication in patients with severe symptomatic AS and a predicted survival of >1 year who are not candidates for SAVR.3 The definition of ‘inoperable’ has been problematic because widely used surgical risk scores do not capture all comorbidities that render a patient inoperable. It became increasingly clear that other factors such as frailty and anatomical factors (e.g., porcelain aorta, ‘hostile chest’, liver disease) needed to be considered. The clinical data supporting this indication have come from several European registries and the randomised PARTNER 1B study and the CoreValve (Medtronic) extremerisk registry.11–15 The current ESC guidelines also recommend that TAVI should be an alternative to SAVR in severe AS patients who are at high risk for mortality and complications after SAVR.3 The clinical evidence for this recommendation derives from several large European registries and two important randomised controlled trials comparing TAVI versus SAVR: the PARTNER 1a trial using a balloon-expandable THV and the CoreValve High-Risk study using a self-expandable THV.16,17 The 5-year echocardiographic follow-up of THVs implanted as part of the PARTNER

Expert Opinion studies have been reassuring and demonstrated haemodynamic improvements, which were equivalent to surgery at both 1 and 5 years.18 The mean gradient across the THV was stable at 10.7 mmHg and the mean aortic valve area was 1.6 cm2, with no signs of structural valve degeneration. The CoreValve US pivotal trial compared the outcomes of patients with symptomatic severe AS at high risk for surgery who underwent TAVI with a self-expanding prosthesis versus those undergoing SAVR.17 The study showed TAVI to be superior to SAVR with regards to the primary endpoint of all-cause mortality at 1 year (absolute mortality difference 4.9 %), which persisted after 2 years follow-up (absolute mortality difference 6.4 %; p=0.004).19 Furthermore, strokes were less frequent among TAVI patients after 2 years of follow-up (10.9 % versus 16.6 %; p<0.05).19 Taken together, the evidence to date suggests that TAVI is now the preferred therapy and the standard-of-care for patients with severe symptomatic AS who are not candidates for surgery. Among operable patients with severe AS who are at high surgical risk, the above-mentioned randomised trials and registries suggest that TAVI should be elevated to a Class I recommendation, as a preferred alternative to SAVR in patients who are good candidates for TAVI, especially via the transfemoral route. There are now eight commercially available TAVI systems in Europe with several that have undergone iterative changes. The main advantages for the new TAVI systems include markedly lower-profile catheter and delivery systems compared with early systems, improved operator ease-of-use, increased range of valve sizes to accommodate smaller and larger aortic annulus dimensions, retrievable and repositionable features to insure optimal valve positioning and reduced paravalvular regurgitation. Indeed, the newest generation of THVs, including the balloon-expandable SAPIEN 3 (Edwards Lifesciences) and the selfexpanding CoreValve Evolut-R (Medtronic), incorporate most of these features and have helped transform TAVI into a low-risk procedure with predictable outcomes. Comparing mortality and stroke outcomes from the earliest PARTNER randomised trials versus the most recent results from the SAPIEN 3 studies indicates a reduction in 30-day mortality from 6.3 % to 2.2 % and a reduction in strokes from 6.7 % to 2.6 %.2 Indeed, a large meta-analysis from 25 multicentre registries and 33 single-centre studies found an important reduction in strokes after TAVI over time and these findings were associated with increased operator experience and technology advancement.20 Vascular complications after TAVI, which are associated with subsequent mortality, were 32 % at 1 year in the PARTNER 1b study,14 18 % in the PARTNER 1a study with the first generation SAPIEN THV,16 17 % in PARTNER IIb with the SAPIEN XT THV,8 compared with <10 % in a recent study with SAPIEN 3.21 Because the main procedure related predictors of early and late mortality after TAVI are strokes, major vascular complications, bleeding and moderate to severe paravalvular regurgitation,22 the reduction of these complications has helped to establish TAVI as a relatively safe procedure, with mortality rates at least as low as SAVR.

Present Whereas the first TAVI procedure performed by Cribier in 2002 was conducted under conscious sedation, location anaesthesia and without the guidance of transoesophageal echocardiography (TOE),1 procedural safety measures including general anaesthesia and intraprocedural TOE were employed thereafter in order to improve safety with large bore transcatheter delivery systems and early operator experience. However, recently the focus has shifted toward an optimised procedural approach with a simplification of the procedure.2 This strategy comprises percutaneous transfemoral vascular access, conscious sedation, reduction or elimination of intraprocedural TOE

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guidance, reduction or elimination of balloon pre-dilatation before valve implantation and pre-specified care plans to encourage rapid ambulation and early hospital discharge. Some high-volume centres are using this optimised approach as the standard-of-care for most TAVI patients.23–25 However, most centres prefer a ‘hybrid’ strategy, whereby this optimised approach is used in straightforward cases and a more conventional approach in either high-risk or ‘borderline’ cases, in which TOE guidance may be beneficial (e.g., high risk for coronary occlusion or annulus rupture, valve sizing problems, chronic kidney disease etc.).2 The selective use of TOE guidance during TAVI can also be of great value in the assessment and treatment of post-implantation paravalvular aortic regurgitation and rapid diagnosis of potentially life-threatening complications such as annulus or ventricular rupture, coronary occlusion, severe aortic or mitral regurgitation (MR), bleeding or left ventricular outflow tract obstruction. However, because significant paravalvular aortic regurgitation and the aforementioned complications have gradually reduced with new TAVI devices and increasing operator experience, the optimised strategy has become prevalent in most high-volume TAVI centres. Indeed, a recent study showed that the use of an optimised transfemoral strategy reduced hospital length of stay by 40 % and total inpatient costs by US $10,000 per case compared with a standard approach using general anaesthesia and TOE guidance, without negatively affecting clinical outcomes or increasing rates of paravalvular regurgitation.26 Many TAVI centres are also developing early discharge programs to compliment the minimalist strategy. In a retrospective study of 500 high-risk or inoperable patients who underwent transfemoral TAVI, >20 % were discharged within 72 hours and there were no differences in 30-day outcomes between the two groups.27 Valve sizing has been a particularly controversial area in the recent past. After earlier attempts to measure the aortic annulus dimensions using 2D echocardiography, the current gold standard is a MDCT scan focussing on either area or perimeter measurement of the asymmetric annulus.28,29 Optimal evaluation of valvular anatomy and dimensions are crucial in order to avoid complications (e.g., annulus rupture, valve embolisation), facilitate valve positioning and prevent paravalvular regurgitation. Numerous studies have demonstrated that optimizing valve sizing with MDCT is critical in reducing the likelihood of paravalvular aortic regurgitation.28–30 Occasionally, the CT measurements fall in a grey zone between two valve sizes requiring the use of other modalities such as virtual valve implantation (e.g., using the HeartNavigator system [Philips Healthcare]), balloon sizing or 3D TOE to make the final decision regarding valve size used.31 Valve positioning is also an important consideration. Imprecise valve positioning can result in significant paravalvular aortic regurgitation, valve embolization, coronary obstruction, or conduction system abnormalities requiring permanent pacemaker insertion. However, newer generation TAVI delivery systems have dramatically improved valve positioning accuracy due to the availability of retrievable and repositionable delivery systems with newer versions of self-expanding TAVI devices and other design enhancements. The choice of a dedicated TAVI device for the individual patient is an important consideration. It remains to be seen whether comparable clinical results can be achieved with different devices in a randomised study. This topic is of great interest as many TAVI devices differ with respect to frame geometry and composition, valve tissue properties and delivery system characteristics. Hitherto, the only THVs compared in a randomised clinical trial are the balloon expandable Edwards SAPIEN

Structural Table 1: Open Issues with Transcatheter Aortic Valve Implantation and How to Address Them Issue

How to address

Feasibility in lower-risk patients Randomized trials comparing TAVI with SAVR Device selection Randomized trials comparing different TAVI devices Bicuspid anatomy

Specific prosthesis design

Valve thrombosis Prospective trials evaluating the role of anticoagulants Durability Echocardiographic and 4D CT scan studies Avoidance of annulus rupture

Definition of maximal calcium load

Reduction of access site complications

Specific vascular closure devices

Reduction of stroke rates Evaluation of protection devices/ antithrombotic therapy SAVR = surgical aortic valve replacement; TAVI = transcatheter aortic valve implantation.

valve and the self-expanding Medtronic CoreValve bioprosthesis. The Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis (CHOICE) study was a small-randomised trial in which 241 TAVI patients were randomised to receive either the SAPIEN valve or the CoreValve and be followed up at 30-days and 1-year.32,33 Although treatment with the CoreValve was associated with a higher frequency of paravalvular regurgitation and new pacemaker insertion, there were no significant differences between the two TAVR systems in 1-year clinical outcomes (death, stroke, repeat hospitalisations, vascular or bleeding events, and acute kidney injury).33 According to the clinical data available, most patients with AS who are candidates for TAVI can be treated with either an Edwards SAPIEN or Medtronic CoreValve bioprosthesis. Some anatomical circumstances may lead to favour one over another device design. For example, horizontal aortas, a heavily calcified aortic valve with protrubing calcification into the left ventricular outflow tract, bicuspid anatomy, a high risk for permanent pacemaker according to baseline ECG and patients with concerns regarding the use of rapid pacing are frequent arguments for a selfexpanding versus a balloon-expandable system.34 Most importantly, operator learning curves and experience with each TAVI system are major considerations. TAVI expertise requires device-specific training for correct valve sizing, accurate valve placement and avoidance of complications. Therefore, it is likely in the future that even highvolume operators will restrict their TAVI device use to only a few different systems.2 The more appropriate adjunctive pharmacotherapy during and after TAVI is an important detail in clinical practice with potential high impact on clinical long-term success after procedural success. Atrial fibrillation (AF) is present in about 40 % of the elderly patient population undergoing TAVI and these patients are at high risk for both strokes and iatrogenic bleeding complications.35–36 Most studies have used a drug therapy approach consisting of intraprocedural heparin (or less commonly bivalirudin) and post-procedural dual antiplatelet therapy (aspirin and clopidogrel) for 3 or 6 months and combined with warfarin as indicated. The optimum antiplatelet and anticoagulation regimen following TAVI needs to be defined. In the phase III GALILEO trial (Global Study Comparing A Rivaroxaban-Based Antithrombotic Strategy To An Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement To Optimize Clinical Outcomes; NCT02556203), all TAVI patients (regardless of AF status) will be randomised to receive either

rivaroxaban 10 mg one daily plus aspirin 75–100 mg once daily for 3 months, followed by rivaroxaban 10 mg once daily alone, or clopidogrel 75 mg once daily plus aspirin 75–100 mg for 3 months, followed by aspirin 75–100 mg once daily alone. Table 1 provides a summary of the open issues with transcatheter aortic valve implantation and suggests how to address them.

Future It has been suggested that an optimal TAVI centre should be able to achieve the following outcomes in high-risk patients with severe AS in the future: 1) all-cause mortality of approximately 2–3 % at 30 days and <10 % at 1 year; 2) significant strokes at 30 days in <2 %; 3) major vascular complications in <5 %; 4) new permanent pacemakers in <10 %; and 5) moderate or severe paravalvular aortic regurgitation in <5 %.2 These arbitrary benchmarks provide a good starting point in order to achieve optimal clinical practices. The ideal transcatheter delivery system would be less traumatic and easier to implant to further minimise the risk of vascular complications as well as paravalvular leak. The destiny of some alternative routes for the TAVI procedure (e.g., direct aortic, transapical and carotid routes) in 2020 will be limited to patients with inadequate transfemoral access. The extension of TAVI to other patient populations, including those presently being treated with SAVR and other patient subsets, is an area of great interest for the future and a number of randomised controlled trials are already underway in several of these areas. These areas include lower-risk patients, valve-in-valve for bioprosthetic valve degeneration, bicuspid aortic valve disease and treatment of severe AS and concomitant disease (e.g., AF, MR, coronary artery disease).

TAVI in Lower-risk Patients Because TAVI was a new and unproven treatment for severe AS, the application of risk stratification to select patients for treatment was appropriate when considering the relative high frequency of periprocedural complications in the early years and the unknown durability of transcatheter bioprosthetic valves. However, after 14 years since its introduction, with over 200,000 TAVIs performed worldwide, major reductions in TAVI-related complications and reliable evidence for good medium-term valve durability, there is less justification for the imposition of strict limitations on the use of TAVI based on surgical risk stratification. In the future, as more data in lower-risk patients are accumulated, it is highly probable that TAVI will not be curtailed by risk stratification but rather will be influenced more by anatomic and clinical factors and probably patient preference. Currently, several clinical research studies have demonstrated a downward drift towards performing TAVI in lower-risk patients.4–6,37 For example, in the initial patients treated with TAVI in the Transcatheter Valve Therapy registry, the median Society of Thoracic Surgeons (STS) score for high-risk and inoperable patients was just 7 %.38 Furthermore, in the European registries and in a single-centre study, the observed 30-day mortality rate after TAVI in lower-risk patients was significantly lower than in high-risk patients.4–6,37 A recent meta-analysis of four randomised trials comparing TAVI versus SAVR (PARTNER 1A, US CoreValve, NOTION and PARTNER 2A) showed that TAVI, when compared with SAVR, was associated with a significant 13 % relative risk reduction (hazard ratio 0.87; 95 % CI [0.76–0.99]; p=0.038) for the primary outcome of all-cause mortality at 2 years.39 In subgroup analyses, TAVI showed a strong survival benefit over SAVR for patients undergoing transfemoral access and in female patients.39 Secondary outcomes of kidney injury, new-onset AF, and major bleeding favoured TAVI, while major vascular

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Expert Opinion complications, incidence of permanent pacemaker implantation, and paravalvular aortic regurgitation favoured SAVR.39 Importantly, two of the included randomised trials in this meta-analysis included patients lower than high risk (PARTNER 2a and NOTION). Furthermore, the superiority of TAVI over SAVR was observed irrespective of the THV device (i.e., balloon-expandable versus self-expandable) employed across the spectrum of intermediate- and high-risk patients with similar outcome with respect to cerebrovascular accidents, stroke, and myocardial infarction. Moreover, whereas more than mild paravalvular aortic regurgitation is less frequent among SAVR patients, the post implantation THV haemodynamics (i.e., mean gradient and aortic valve area) tend to favour TAVI patients leading to a lower incidence of patient-prosthesis mismatch.39 A major limitation of randomised controlled clinical trials to date that compare TAVI with SAVR has been the use of earlier generation TAVI devices and delivery systems. A number of studies of patients with intermediate- and high-risk/inoperable AS treated with a third-generation TAVI system (SAPIEN 3 valve) have recently been published.21,40,41 The SAPIEN 3 valve is a balloon-expandable THV and consists of bovine pericardial leaflets sutured to a cobalt chromium frame. A polyethylene terephthalate skirt covers the lower portion of the frame and is designed specifically to reduce paravalvular regurgitation. The THV system is delivered through expandable 14-F (20, 23, 26 mm THV) or 16-F (29 mm THV) transfemoral delivery sheaths that expand to accommodate the device. The SAPIEN 3 THV can also be delivered via the direct transaortic or transapical routes. A recent large non-randomised registry showed excellent 30-day outcomes among intermediate-risk patients treated with the SAPIEN 3 THV.21 Among 1078 intermediate-risk patients treated with the SAPIEN 3 valve included in the multicentre registry, the rate of 30 day all-cause mortality was 1.1 %, cardiovascular mortality 0.9 %, major/disabling stroke 1.0 %, major bleeding 10.6 %, major vascular complications 6.1 % and requirement for permanent pacemaker 10.1 %.21 Transfemoral access was used in 87 %, which is important as transfemoral access enables faster recovery and shorter hospital stay as compared with nontransfemoral access.21 Furthermore, transfemoral access is associated with improved quality of life and functional status when compared with both SAVR and non-TF TAVI. A subsequent analysis compared 1-year clinical outcomes between the 1077 intermediate-risk patients (88 % via transfemoral access) from this multicentre registry with those for intermediate-risk patients treated with SAVR in the PARTNER 2a trial, using a propensity score analysis.40 The primary endpoint was the composite of death from any cause, all strokes and incidence of moderate or severe aortic regurgitation.40 For the propensity score analysis, 963 patients treated with SAPIEN 3 TAVI and 747 patients treated with SAVR were included. For the primary composite endpoint of mortality, strokes and moderate or severe aortic regurgitation, TAVI was superior (p<0.0001) to SAVR mainly driven by significant reductions in mortality and stroke, suggesting that TAVI might be the preferred treatment alternative in intermediate-risk patients.40 As compared with SAVR, all-cause mortality rates were lower at both 30 days (1.1 % versus 4.0 %) and 1 year (7.4 % versus 13 %) among TAVI patients.40 Moreover, disabling strokes were also lower at both 30 days (1.0 % versus 4.4 %) and 1 year (2.3 % versus 5.9 %).40 However, moderate or severe aortic regurgitation was still higher in the SAPIEN 3 TAVR cohort than in the surgery cohort (3.8 % versus 0.6 %) and was associated with increased late mortality.40 Mild paravalvular leak was also more prevalent among TAVI compared with SAVR patients (45 % versus 2.8 %) but was not associated with increased late mortality.

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These data, combined with the encouraging 5-year valve durability findings, have increased the enthusiasm for accelerating efforts to extend the ruse of TAVI as an alternative to surgery for lower-risk patients. Indeed, the PARTNER 3 trial (NCT02675114) is a multicentre randomised controlled trial that will compare transfemoral TAVI with the SAPIEN 3 bioprosthesis with SAVR in low-risk patients (STS <4) requiring aortic valve replacement who have severe symptomatic AS. Inclusion criteria include patients ≥65 years of age with adequate iliofemoral access. The primary outcome is a composite of allcause mortality, stroke and rehospitalisation. Secondary endpoints will include new-onset AF and length of index hospitalisation. The Evolut R Low Risk trial (NCT02701283) is an open label, randomised controlled trial that will compare TAVI with the Evolut R or CoreValve transcatheter heart valves with SAVR in low-risk patients (STS <3 %). The primary endpoint is all-cause mortality or disabling stroke at 2-years. Preliminary data are expected in October 2018 for the PARTNER 3 trial and March 2018 for the Evolut R Low Risk trial. A major limitation that will affect the possibility to extend the indication of TAVI to younger patients is the high rate of permanent pacemaker implantation with certain THV prostheses. By 2020, we predict that clinical risk assessment will be replaced by a more practical approach that relies on the knowledge of experienced TAVI operators. The multidisciplinary heart team will be of critical importance for decision-making in borderline situations, which include potentially too frail patients and patients with formal anatomical contraindications for TAVI. In individuals with favourable anatomical characteristics, patient preference will become a determinative factor.

Valve-in-valve for Bioprosthetic Valve Degeneration The frequency of implanted surgical aortic and mitral bioprosthetic valves currently exceeds mechanical valve implantations. 42 Bioprosthetic valves are mainly preferred owing to the fact that they are less thrombogenic, hence obviating the need for long-term anticoagulation. However, structural degeneration of bioprosthetic valves can result in either stenosis, regurgitation, or both, typically within 10–15 years after implantation. Therefore, the management of patients with bioprosthetic valve degeneration who are poor candidates for repeat SAVR is problematic. Since the first description of transcatheter valve-in-valve implantation in 2007,43 this procedure has become an increasingly popular strategy to treat structural bioprosthetic valve failure in high-risk and inoperable patients.44,45 On the basis of clinical registry data, the balloon expandable SAPIEN XT valve and the self-expanding CoreValve have been approved for use in high-risk patients with aortic bioprosthetic valve failure. In the largest international registry of transcatheter aortic valve-in-valve implants, early haemodynamic findings were encouraging, with 1-year survival of 83.2 %.45 Stenotic degeneration of the surgical bioprosthesis and small valve implant size were associated with worse outcomes.45 Valve-invalve therapy results in less frequent paravalvular regurgitation and new pacemakers compared with native valve TAVI but more common coronary occlusions, especially in surgical valves, in which the leaflets are externally sutured outside the stent frame. In smaller surgical valves, the self-expanding CoreValve results in less patient-prosthesis mismatch following valve-in-valve implantation because of the supraannular valve position. It is likely that in the future, transcatheter valvein-valve implantation will become the preferred therapy for surgical bioprosthesis valve degeneration in a wide spectrum of patients. Future bioprostheses will be designed to serve as a base for a potential valve-in-valve procedure in the longer-term follow-up.

Structural Bicuspid Aortic Valve Disease Bicuspid aortic valves have a high prevalence in younger patients with AS, but even in the elderly bicuspid valves comprise approximately 20 % of surgical cases.46 Bicuspid valves tend to have a more oval annulus shape, unequal leaflet size, and heavy eccentric calcification of the leaflets. These characteristics, together with the presence of calcified raphes, may interfere with optimal THV deployment and/or lead to suboptimal haemodynamic with increased paravalvular aortic regurgitation.47 A recent analysis of CT scans revealed that, compared with tricuspid aortic valves, the annulus was more circular and less elliptical, the annulus area and perimeter were significantly larger and there was more eccentric calcification in bicuspid valves.48 Other issues relate to the durability of bioprosthetic THVs in this patient population and the management of associated aortic pathologies, including aortic aneurysms and dissections.47 To date, only a small percentage of TAVIs are performed in bicuspid valves. A recent multicentre retrospective registry involving 12 high-volume centres (139 patients) in Europe and Canada supports the early notion that TAVI is safe among patients with bicuspid aortic valves, with a 5 % 30-day and 17.5 % 1-year mortality.49 However, post-implantation moderate to severe paravalvular aortic regurgitation was found in 28.4 % of patients, although this appeared to be mitigated somewhat by CT-based THV sizing.49 Furthermore, this registry comprised patients treated with earlier generation THVs.49 It remains to be determined whether newer generation THVs and newer technologies with THVs specific for bicuspid aortic valves may prevent paravalvular aortic regurgitation. Specific clinical trials among patients with bicuspid AS and newer generation THVs are required to help determine the most appropriate clinical indications and the most appropriate transcatheter valve design.

Treatment of Severe AS and Concomitant Disease Elderly patients with severe AS frequently have significant cardiac comorbidities that may require additional treatment. These conditions include concomitant coronary artery disease, other valvular lesions (mitral and/or tricuspid regurgitation) and AF.

Coronary Artery Disease Over 50 % of patients aged >70 years with severe AS also have coronary artery disease.50 The standard approach to managing patients with severe AS and CAD undergoing SAVR has been simultaneous coronary revascularisation. However, in the TAVI era, these ideas have been challenged and now selective proximal vessel, clinically-driven revascularisation is preferred rather than complete revascularisation using percutaneous coronary intervention.50,51 A number of factors must be considered in managing patients with severe AS and concomitant CAD, including the timing of percutaneous coronary intervention (before, during, or after TAVI) and the complexity of coronary lesions.50,51 Dedicated clinical trials are ongoing and should provide more definitive evidence-based guidelines.

Mitral and Tricuspid Regurgitation MR is commonly found in patients with severe AS, and moderate or severe MR has been reported in up to 30 % of patients undergoing TAVI.52 Data from several European registries show a significant association between moderate to severe MR and 1-year mortality after TAVI.53–55 Conversely, a post-hoc analysis of the PARTNER 1A trial found that moderate to severe MR at baseline did not affect 2-year mortality among TAVI patients but did have an effect on mortality among patients undergoing SAVR.56 A recent meta-analysis by Nombela-Franco et al. revealed that 1-year mortality rates were significantly increased

among TAVI patients with moderate to severe MR and that the impact of MR on mortality did not differ between self-expandable and balloonexpandable valves.57 The management strategy of patients with severe AS and concomitant moderate or severe MR depends on a number of factors including operative risk, MR severity, MR aetiology and likelihood of improvement. Key to decision making is the evaluation of MR aetiology and severity by quantitative echocardiographic methods, with the use of TOE if necessary. In selected patients with residual haemodynamically relevant MR after TAVI and continued symptoms of heart failure, a new approach is staged or simultaneous treatment with percutaneous mitral valve repair using the MitraClip system (Abbott Laboratories).58,59 Tricuspid regurgitation is also commonly found in patients with severe AS, and the combination of severe TR with right ventricular dysfunction predicts worse outcomes after TAVI.60 In the future, several methods of transcatheter TR reduction, including ‘spacers’ and plication or ring annuloplasty devices, may be combined with TAVI in selected symptomatic patients.2

Atrial Fibrillation Pre-existing AF is present in approximately 40 % of patients with severe AS.35 New-onset AF occurs in up to 13 % after TAVI.36 AF can adversely affect cardiac physiology owing to the loss of atrioventricular synchrony and irregularity of cardiac contractility, which can result in reduced cardiac output and elevated filling pressures. AF has been associated with increased periprocedural strokes after TAVI and is associated with reduced long-term survival.35,36 The optimum anticoagulation regimen following TAVI among patients with AF needs to be defined. This can follow either a pharmacotherapy- or device-based (i.e., left atrial appendage occlusion) strategy. The latter approach in patients with AS and AF obviates the need for anticoagulation therapy and the use of combination device applications will likely become more frequent in the future.

Other Clinical Indications for TAVI Asymptomatic Severe AS Up to 50 % of patients with severe AS report no symptoms at the time of diagnosis and the optimal timing of intervention for these patients is uncertain and controversial.61 A recent meta-analysis found that patients with severe asymptomatic AS have a 3.5-fold higher rate of all-cause death with a watchful-waiting strategy compared with aortic valve replacement.61 Current guidelines recommend aortic valve replacement for asymptomatic severe AS in the following circumstances: 1) left ventricular ejection fraction <50 %, 2) undergoing other cardiac surgery, 3) symptoms on exercise test clearly related to AS, 4) very severe (aortic velocity >5.5 m/s) AS and low surgical risk, 5) rate of peak transvalvular velocity progression ≥0.3 m/s/year and low surgical risk, 6) increase of mean gradient with exercise by >20 mmHg and low surgical risk, 7) decreased exercise tolerance and/or abnormal systolic blood pressure response (drop or <20 mmHg rise), 8) severe left ventricular hypertrophy and 9) sustained B-type natriuretic peptide elevation.3,61,62 Given the uncertainty regarding the value of AVR in asymptomatic severe AS and the large number of affected patients, a randomised controlled trial comparing aortic valve replacement (either SAVR and/or TAVI) with conservative treatment is required.

Moderate AS and Clinical Heart Failure Patients with moderate AS and clinical heart failure will be evaluated in a new randomised clinical trial comparing standard medical therapy versus early TAVI. The Transcatheter Aortic Valve Replacement to Unload the Left Ventricle in Patients with Advanced Heart Failure study

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Expert Opinion (TAVR-UNLOAD; NCT02661451) will compare clinical outcomes among symptomatic patients (New York Heart Association class ≥2) in heart failure (left ventricular ejection fraction 20–50 %) and moderate AS undergoing TAVI with the SAPIEN 3 valve versus optimised heart failure therapy. The primary outcome will be all-cause death at 1 year and the hierarchical occurrence within one year of all-cause death, disabling stroke, hospitalisations related to heart failure and change in Kansas City Cardiomyopathy questionnaire relative to baseline.

Severe Aortic Regurgitation Patients with severe aortic regurgitation and clinical indications for surgical repair or SAVR, but who are at high risk for surgery, have already been treated with TAVI63 and this will soon be the subject of a feasibility study in the U.S.

TAVI in Non-cardiac Surgery Sites The 2012 ESC guidelines explicitly state that TAVI should be restricted to hospitals with both cardiology and cardiac surgery departments on-site.3 Owing to the continued evolution of TAVI to become an effective and safe treatment modality, the need for emergency cardiac surgery for complications during TAVI is currently low and about 1 %.38 A recent German multicentre registry comparing outcomes after TAVI among patients treated in centres with and without on-site cardiac surgery reported that while patients undergoing TAVI at hospitals without on-site cardiac surgery were older and at higher predicted surgical risk, major complications and in-hospital mortality were not statistically different.64 This opens the discussion about the feasibility and safety of heart-team-based TAVI at non-cardiac surgery sites.

Stroke and TAVI Stroke is among the most feared complications of TAVI because of the burden of morbidity and mortality. With increased operator experience and newer generation devices, overall rates of cerebrovascular incidents have declined to rates ranging between 1.5 % and 6 %. Disabling stroke rates amount to 1–3 % at 30 days. Nevertheless, systematic neurologic and neuroimaging follow-up in TAVI and SAVR patients has just started to become of crucial interest, and silent neurologic deficits and cerebral ischaemia is reported in up to 15–28 % of patients. Even though not always clinically apparent, these cerebral lesions have been linked in non-TAVI patient populations to cognitive decline, an increased risk of subsequent dementia, and a >3-fold increased risk of future stroke.65–67 Several cerebral protection devices, such as the Embrella Embolic Deflector system, the Triguard HDH Embolic Deflection device or the Claret device have been developed to capture freed embolic material during TAVI procedures. Neuroimaging studies have shown improvements suggesting increased cerebral perfusion with cerebral protection in early randomised clinical trials.68,69 However, it remains unclear whether these devices should be used systematically versus selectively in highrisk patients undergoing TAVI. In the SENTINEL IDE trial (NCT02214277), 356 patients have been randomised to embolic protection or no embolic protection, with the aim of evaluating the reduction in median total new lesion volume between the test and control cohorts, assessed using MRI studied at 2–7 days after TAVI. Further data from ongoing clinical trials should shed light on this issue. A number of other accessory devices have been developed and include dedicated preshaped guidewires, improved temporary pacemaker technologies, novel percutaneous closure devices and new valvuloplasty systems.2

Evolution in Technology The current practice of TAVI has been revolutionised by the low-profile designs of current TAVI systems, dedicated user-friendly delivery systems, heart valves with proven midterm durability, precise positioning during deployment with repositioning and retrieval features and various newly developed THV mechanisms for reducing paravalvular aortic regurgitation. It is predicted that in the future TAVI systems will include even lower-profile delivery systems and ongoing refinements of THV designs to further reduce complication rates. The durability of THVs has remained a limitation in the expansion of TAVI to lower-risk patients. The 5-year follow-up data from PARTNER is reassuring in that there were no episodes of structural valve failure and mean gradient and effective orifice areas remained stable.18 However, longer follow-up data on THVs is required to determine whether they are equivalent to the most durable surgical bioprosthetic valves. With the possibility of transcatheter valvein-valve treatment to extend the duration of THVs it is possible that the uncertainty regarding long-term durability may become less concerning.

Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006–8. DOI: 10.1161/01.CIR.0000047200.36165.B8; PMID: 12473543 Vahl TP, Kodali SK, Leon MB. Transcatheter aortic valve replacement 2016: A modern-day “through the looking-glass” adventure. J Am Coll Cardiol 2016;67:1472–87. DOI: 10.1016/j. jacc.2015.12.059; PMID: 27012409 Vahanian A, Ottavio A, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). The joint task force on the management of valvular heart diseae of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012;33:2451–96. DOI: 10.1093/eurheartj/ehs109; PMID: 22922415 Wenaweser P, Stortecky S, Schwander S, et al. Clinical outcomes of patients with estimated low or intermediate surgical risk undergoing transcatheter aortic valve implantation. Eur Heart J 2013;34:1894–905. DOI: 10.1093/

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Conclusion In order to predict the future, one must create it. Over the past 14 years, TAVI has evolved to become a viable alternative to SAVR for patients with severe AS with high or excessive risk. Rapid advances in technology have resulted in a simplified procedure and reduced complications. In the future, THV durability and expansion of clinical indications (e.g., asymptomatic severe AS, moderate AS and heart failure, severe aortic regurgitation) will be important issues. By 2020, it is highly probable, given the aforementioned improvements in complication rates and clinical outcomes, that the majority of patients with AS (and in the longer term, the majority of patients with aortic valve disease) will be treated with a transcatheter based bioprosthesis system.70 The use of these systems will be expanded in parallel to treat non-aortic valvular heart diseases as already demonstrated in ‘offlabel’ cases. 71 Dedicated transcatheter devices for the different valves are meanwhile in development. n

eurheartj/eht086; PMID: 23487519 Piazza N, Kalesan B, van Mieghem N, et al. A 3-center comparison of 1-year mortality outcomes between transcatheter aortic valve implantation and surgical aortic valve replacement on the basis of propensity score matching among intermediate-risk surgical patients. JACC Cardiovasc Interv 2013;6:443–51. DOI: 10.1016/j.jcin.2013.01.136; PMID: 23702009 D’Errigo P, Barbanti M, Ranucci M, et al. Transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis: results from an intermediate risk propensity-matched population of the Italian OBSERVANT study. Int J Cardiol 2013;167:1945–52. DOI: 10.1016/j. ijcard.2012.05.028; PMID: 22633667 Thyregod HG, Steinbrüchel DA, Ihlemann N, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol 2015;65:2184–94. DOI: 10.1016/j.jacc.2015.03.014; PMID: 25787196

Leon MB, Smith CR, Mack MJ, et al. PARTNER 2 Investigators. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324 9. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714–20. DOI: 10.1093/eurheartj/ ehi471; PMID: 16141261 10. Andersen HR, Knudsen LL, Hasenkam JM. Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs. Eur Heart J 1992;13:704–8. DOI: 704-708; PMID: 1618213 11. Duncan A, Ludman P, Banya W, et al. Long-term outcomes after transcatheter aortic valve replacement in high-risk patients with severe aortic stenosis: the U.K. Transcatheter Aortic Valve Implantation Registry. JACC Cardiovasc Interv 2015;8:645–53. DOI: 10.1016/j.jcin.2015.01.009; PMID: 25946435 12. Gilard M, Eltchaninoff H, Iung B, et al. for the FRANCE 2 Investigators. Registry of transcatheter aortic-valve

Structural implantation in high-risk patients. N Engl J Med 2012;366: 1705–15. DOI: 10.1056/NEJMoa1114705; PMID: 22551129 13. Walther T, Hamm CW, Schuler G, et al. for the GARY Executive Board. Perioperative results and complications in 15,964 transcatheter aortic valve replacements: prospective data from the GARY registry. J Am Coll Cardiol 2015;65:2173–80. DOI: 10.1016/j.jacc.2015.03.034; PMID: 25787198 14. Leon MB, Smith CR, Mack M, et al. for the PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/NEJMoa1008232; PMID: 20961243 15. Popma JJ, Adams DH, Reardon MJ, et al. for the CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. DOI: 10.1016/j.jacc.2014.02.556; PMID: 24657695 16. Smith CR, Leon MB, Mack MJ, et al. for the PARTNER Trial Investigators. Transcatheter versus surgical aorticvalve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 17. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937 18. Mack MJ, Leon MB, Smith CR, et al. for the PARTNER 1 Trial Investigators. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): A randomized controlled trial. Lancet 2015;385:2477–84. DOI: 10.1016/S0140-6736(15)60308-7; PMID: 25788234 19. Reardon MJ, Adams DH, Kleiman NS, et al. 2-year outcomes in patients undergoing surgical or self-expanding transcatheter aortic valve replacement. J Am Coll Cardiol 2015;66:113–21. DOI: 10.1016/j.jacc.2015.05.017; PMID: 26055947 20. Athappan G, Gajulapalli RD, Sengodan P, et al. Influence of transcatheter aortic valve replacement strategy and valve design on stroke after transcatheter aortic valve replacement: a meta-analysis and systematic review of literature. J Am Coll Cardiol 2014;63:2101–10. DOI: 10.1016/j.jacc.2014.02.540; PMID: 24632286 21. Kodali S, Thourani VH, White J, et al. Early clinical and echocardiographic outcomes after SAPIEN 3 transcatheter aortic valve replacement in inoperable, high-risk and intermediate-risk patients with aortic stenosis. Eur Heart J 2016;37:2252–62. DOI: 10.1093/eurheartj/ehw112; PMID: 27190101 22. Urena M, Webb JG, Eltchaninoff H, et al. Late cardiac death in patients undergoing transcatheter aortic valve replacement: Incidence and predictors of advanced heart failure and sudden cardiac death. J Am Coll Cardiol 2015;65:437–48. DOI: 10.1016/j.jacc.2014.11.027; PMID: 25660921 23. Durand E, Borz B, Godin M, et al. Transfemoral aortic valve replacement with the Edwards SAPIEN and Edwards SAPIEN XT prosthesis using exclusively local anesthesia and fluoroscopic guidance: feasibility and 30-day outcomes. JACC Cardiovasc Interv 2012;5:461–7. DOI: 10.1016/j.jcin.2012.01.018; PMID: 22560979 24. Motloch LJ, Rottlaender D, Reda S, et al. Local versus general anesthesia for transfemoral aortic valve implantation. Clin Res Cardiol 2012;101:45–53. DOI: 10.1007/s00392-011-0362-8; PMID: 21931964 25. Kasel AM, Shivaraju A, Schneider S, et al. Standardized methodology for transfemoral transcatheter aortic valve replacement with the Edwards SAPIEN XT valve under fluoroscopy guidance. J Invasive Cardiol 2014;26:451–61. PMID: 25198489 26. Babaliaros V, Devireddy C, Lerakis S, et al. Comparison of transfemoral transcatheter aortic valve replacement performed in the catheterization laboratory (minimalist approach) versus hybrid operating room (standard approach): outcomes and cost analysis. JACC Cardiovasc Interv 2014;7: 898–904. DOI: 10.1016/j.jcin.2014.04.005; PMID: 25086843 27. Barbanti M, Capranzano P, Ohno Y, et al. Early discharge after transfemoral transcatheter aortic valve implantation. Heart 2015;101:1485–90. DOI: 10.1136/heartjnl-2014-307351; PMID: 26076940 28. 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. DOI: 10.1016/j.jacc.2011.12.015; PMID: 22365423 29. Yang TH, Webb JG, Blanke P, et al. Incidence and severity of paravalvular aortic regurgitation with multidetector computed tomography nominal area oversizing or undersizing after transcatheter heart valve replacement with the Sapien 3: a comparison with the Sapien XT. JACC Cardiovasc Interv 2015;8:462–71. DOI: 10.1016/j.jcin.2014.10.014; PMID: 25790764 30. Khalique OK, Kodali SK, Paradis JM, et al. Aortic annular sizing using a novel 3-dimensional echocardiographic method: use and comparison with cardiac computed tomography. Circ Cardiovasc Imaging 2014;7:155–63. DOI: 10.1161/ CIRCIMAGING.113.001153; PMID: 24221192 31. Patsalis PC, Al-Rashid F, Neumann T, et al. Preparatory balloon aortic valvuloplasty during transcatheter aortic valve implantation for improved valve sizing. JACC Cardiovasc Interv

2013;6:965–71. DOI: 10.1016/j.jcin.2013.05.006; PMID: 24050862 32. Abdel-Wahab M, Mehilli J, Frerker C, et al. for the CHOICE investigators. Comparison of balloon-expandable vs selfexpandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA 2014;311:1503–14. DOI: 10.1001/jama.2014.3316; PMID: 24682026 33. Abel-Wahab M, Neumann FJ, Mehilli J, et al. 1-Year outcomes after transcatheter aortic valve replacement with balloonexpandable versus self-expandable valves: results from the CHOICE randomized clinical trial. J Am Coll Cardiol 2015;66: 791–800. DOI: 10.1016/j.jacc.2015.06.026; PMID: 26271061 34. O’Sullivan CJ, Stortecky S, Buellesfeld L, et al. Preinterventional screening of the TAVI patient: how to choose the suitable patient and the best procedure. Clin Res Cardiol 2014;103:259–74. DOI: 10.1007/s00392-014-0676-4; PMID: 24515650 35. Stortecky S, Buellesfeld L, Wenaweser P, et al. Atrial fibrillation and aortic stenosis: impact on clinical outcomes among patients undergoing transcatheter aortic valve implantation. Circ Cardiovasc Interv 2013;6:77–84. DOI: 10.1161/ CIRCINTERVENTIONS.112.000124; PMID: 23386662 36. Amat-Santos IJ, Rodés-Cabau J, Urena M, et al. Incidence, predictive factors, and prognostic value of new-onset atrial fibrillation following transcatheter aortic valve implantation. J Am Coll Cardiol 2012;59:178–88. DOI: 10.1016/j.jacc.2011.09.061; PMID: 22177537 37. Lange R, Bleiziffer S, Mazzitelli D, et al. Improvements in transcatheter aortic valver implantation outcomes in lower surgical risk patients: a glimpse into the future. J Am Coll Cardiol 2012;59:280–7. DOI: 10.1016/j.jacc.2011.10.868; PMID: 22196885 38. Mack MJ, Brennan JM, Brindis R, et al. for the STS/ACC TVT Registry. Outcomes following transcatheter aortic valve replacement in the United States. JAMA 2013;310:2069–77. DOI: 10.1001/jama.2013.282043; PMID: 24240934 39. Siontis GCM, Praz F, Pilgrim T, et al. Transcatheter aortic valve implantation vs. Surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials. Eur Heart J 2016;37:3503–12. DOI: 10.1093/ eurheartj/ehw225; PMID: 27389906 40. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 2016;387:2218–25. DOI: 10.1016/S0140-6736(16)30073-3; PMID: 27053442 41. Herrmann HC, Thourani VH, Kodali SK, et al. One-year clinical outcomes with SAPIEN 3 transcatheter aortic valve replacement in high-risk and inoperable patients with severe aortic stenosis. Circulation 2016;134:130–40. DOI: 10.1161/ CIRCULATIONAHA.116.022797; PMID: 27400898 42. Brennan JM, Edwars FH, Zhao Y, et al. for the DEcIDE AVR (Developing Evidence to Inform Decisions about Effectiveness-Aortic Valve Replacement) Research Team. Long-term safety and effectiveness of mechanical versus biologic aortic valve prostheses in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. Circulation 2013;127:1647–55. DOI: 10.1161/ CIRCULATIONAHA.113.002003; PMID: 23538379 43. Wenaweser P, Buellesfeld L, Gerckens U, Grube E. Percutaneous aortic valve replacement for severe aortic regurgitation in degenerated bioprosthesis: the first valve in valve procedure using the Corevalve Revalving system. Catheter Cardiovasc Interv 2007;70:760–4. DOI: 10.1002/ccd.21300; PMID: 17932876 44. Webb JG, Wood DA, Ye J, et al. Transcatheter valvein-valve implantation for failed bioprosthetic heart valves. Circulation 2010;121:1848–57. DOI: 10.1161/ CIRCULATIONAHA.109.924613; PMID: 20385927 45. Dvir D, Webb JG, Bleiziffer S, et al. for the Valve-in-Valve Intgernational Data Registry Investigators. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA 2014;312:162–70. DOI: 10.1001/jama.2014.7246; PMID: 25005653 46. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement of aortic stenosis, with or without associated aortic regurgitation. Circulation 2005;11:920–5. DOI: 10.1161/01.CIR.0000155623.48408.C5; PMID: 15710758 47. O’Sullivan CJ, Windecker S. Implications of bicuspid aortic valves for transcatheter aortic valve implantation. Circ Cardiovasc Interv 2013;6:204–6. DOI: 10.1161/ CIRCINTERVENTIONS.113.000461; PMID: 23780294 48. Philip F, Faza NN, Schoenhagen P, et al. Aortic annulus and root characteristics in severe aortic stenosis due to bicuspid aortic valve and tricuspid aortic valves: implications for transcatheter aortic valve therapies. Catheter Cardiovasc Interv 2015;86:E88–98. DOI: 10.1002/ccd.25948; PMID: 25914355 49. Mylotte D, Lefevre T, Sondergaard L, et al. Transcatheter aortic valve replacement in bicuspid aortic valve disease. J Am Coll Cardiol 2014;64:2330–9. DOI: 10.1016/j.jacc.2014.09.039; PMID: 25465419 50. O’Sullivan CJ, Stefanini GG, Stortecky S, et al. Coronary revascularization and TAVI: before, during, after or never? Minerva Med 2014;105:475–85. PMID: 25274461 51. Stefanini GG, Stortecky S, Cao D, et al. Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation. Eur Heart J 2014;35:2530–40. DOI: 10.1093/ eurheartj/ehu074; PMID: 24682843

52. Nombela-Franco L, Ribeiro HB, Urena M, et al. Significant mitral regurgitation left untreated at the time of aortic valve replacement: a comprehensive review of a frequent entity in the transcatheter aortic valve replacement era. J Am Coll Cardiol 2014;63:2643–58. DOI: 10.1016/j.jacc.2014.02.573; PMID: 24681140 53. Bedogni F, Latib A, Brambilla N, et al. Interplay between mitral regurgitation and transcatheter aortic valve replacement with the CoreValve revalving system: a multicentre registry. Circulation 2013;128;2145–53. DOI: 10.1161/ CIRCULATIONAHA.113.001822; PMID: 24088530 54. Sabaté M, Canovas S, Garcia E, et al. In hospital and midterm predictors of mortality after transcatheter aortic valve implantation: data from the TAVI National Registry 2010-2011. Rev Esp Cardiol 2013;66:949–58. DOI: 10.1016/j. rec.2013.07.003; PMID: 24774108 55. Zahn R, Gerckens U, Linke A, et al. Predictors of one-year mortality after transcatheter aortic valve implantation for severe symptomatic aortic stenosis. Am J Cardiol 2013;112: 272–9. DOI: 10.1016/j.amjcard.2013.03.024; PMID: 23578349 56. Barbanti M, Webb JG, Hahn RT, et al. for the Placement of Aortic Transcatheter Valve Trial Investigators. Impact of preoperative moderate/severe mitral regurgitation on 2-year outcome after transcatheter and surgical aortic valve replacement: insight from the Placement of Aortic Transcatheter Valve (PARTNER) Trial Cohort A. Circulation 2013;128:2776–84. DOI: 10.1161/ CIRCULATIONAHA.113.003885; PMID: 24152861 57. Nombela-Franco L, Eltchaninoff H, Zahn R, et al. Clinical impact and evolutation of mitral regurgitation following transcatheter aortic valve replacement: a meta-analysis. Heart 2015;101:1395–405. DOI: 10.1136/heartjnl-2014-307120; PMID: 26060121 58. Barbanti M, Ussia GP, Tamburino C. Percutaneous treatment of aortic stenosis and mitral regurgitation in the same patient: first human cases description. Catheter Cardiovasc Interv 2011;78:650–5. DOI: 10.1002/ccd.23015; PMID: 21793170 59. Madder RD, Safian RD, Gallagher M, et al. The first report of transcatheter aortic valve implantation and percutaneous mitral valve repair in the same patient. JACC Cardiovasc Interv 2011;4:824. DOI: 10.1016/j.jcin.2011.05.009; PMID: 21777894 60. Lindman BR, Maniar HS, Jaber WA, et al. Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: insights from the Placement of Aortic Transcatheter Valves II inoperable cohort. Circ Cardiovasc Interv 2015;8:e002073. DOI: 10.1161/ CIRCINTERVENTIONS.114.002073; PMID: 25855679 61. Généreux P, Stone GW, O’Gara PT, et al. Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis. J Am Coll Cardiol 2016;67:2263–88. DOI: 10.1016/j.jacc.2016.02.057; PMID: 27049682 62. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57–185. DOI: 10.1016/ j.jacc.2014.02.536; PMID: 24603191 63. Roy DA, Schaefer U, Guetta V, et al. Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation. J Am Coll Cardiol 2013;61:1577–84. DOI: 10.1016/ j.jacc.2013.01.018; PMID: 23433565 64. Eggebrecht H, Besethorn M, Haude M, et al. Outcomes of transfemoral transcatheter aortic valve implantation at hospitals with and without on-site cardiac surgery department: insights from the prospective German aortic valve replacement quality assurance registry (AQUA) in 17919 patients. Eur Heart J 2016;37:2240–8. DOI: 10.1093/eurheartj/ ehw190; PMID: 27190093 65. Knipp SC, Matatko N, Wilhelm H, et al. Cognitive outcomes three years after coronary artery bypass surgery: relation to diffusion-weighted magnetic resonance imaging. Ann Thorac Surg 2008;85:872–9. DOI: 10.1016/j.athoracsur.2007.10.083; PMID: 18291160 66. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007;6:611–9. DOI: 10.1016/S1474-4422(07)70170-9; PMID: 17582361 67. Bernick C, Kuller L, Dulberg C, et al. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology 2001;57:1222–9. PMID: 11591840 68. Rodés-Cabau J, Kahlert P, Neumann FJ, et al. Feasibility and exploratory efficacy evaluation of the Embrella Embolic Deflector system fort he prevention of cerebral emboli in patients undergoing transcatheter aortic valve replacement: the PROTAVI-C pilot study. JACC Cardiovasc Interv 2014;7: 1146–55. DOI: 10.1016/j.jcin.2014.04.019; PMID: 25341709 69. Lansky AJ, Schofer J, Tcheteche D, et al. A prospective randomized evaluation of the TriGuard HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070–8. DOI: 10.1093/eurheartj/ehv191; PMID: 25990342 70. Wenaweser P, Praz F, Stortecky S. Transcatheter aortic valve implantation: today and tomorrow. Swiss Med Wkly 2016;146:w14299. DOI: 10.4414/smw.2016.14299; PMID: 26999727 71. Praz F, Windecker S, Huber C, Carrel T, Wenaweser P. Expanding Indications for transcatheter heart valve interventions. JACC Cardiovasc Interv 2015;8:1777–96. DOI: 10.1016/j.jcin.2015.08.015; PMID: 26718509

INTERVENTIONAL CARDIOLOGY REVIEW

Structural

Valve Clinic, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

Abstract Surgical treatment is the gold standard treatment of functional tricuspid regurgitation (FTR) but this carries high risks of morbidity and mortality. Percutaneous procedures are an attractive alternative to surgery for selected patients deemed to be high-risk surgical candidates. A number of tricuspid transcatheter devices have been developed to treat FTR, but at present, evidence of their efficacy and safety is scarce. Preliminary data have shown promising results, but ongoing and future studies will provide a clearer picture of the benefits of these new techniques.

Keywords Tricuspid regurgitation, transcatheter, annuloplasty, tricuspid valve spacer Disclosure: The authors have no conflicts of interest to declare. Received: 4 October 2016 Accepted: 9 March 2017 Citation: Interventional Cardiology Review 2017;12(1):51–5. DOI: 10.15420/icr.2017:3:2 Correspondence: Maurizio Taramasso, Cardiovascular Surgery Department, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland. E: Maurizio.Taramasso@usz.ch.

The leading aetiology of tricuspid regurgitation (TR) in developed countries is functional, secondary to left side heart disease and pulmonary hypertension.1 Currently, moderate-to-severe TR affects approximately 1.6 million patients in the United States, of whom only 8,000 undergo tricuspid surgery annually;2 this results in an extremely large number of untreated patients with significant TR, a condition that has been clearly associated with risk of mortality and cardiovascular events.3

of the different devices favourably compares to that of conventional surgical treatment.7

The high prevalence of TR is in part due to the undertreatment as TR was wrongly considered a benign and reversible condition in the past. In fact, due to the incorrect concept that TR would disappear once the primary left heart disease (LHD) had been treated, surgical avoidance of tricuspid valve (TV) repair was for many years easily accepted in patients with functional tricuspid regurgitation (FTR). Thereafter, many investigators progressively reported findings in favour of a more aggressive surgical approach to FTR. Furthermore, the most recent guidelines recommend surgical repair of concomitant TR during left valve surgery in patients with tricuspid annular dilatation with non-severe TR, to reduce the occurrence of late TR in patients who underwent LHD surgery.4,5

A deep knowledge of the complex anatomy of the TV is a mandatory pre-requisite to understand the challenges encountered in developing percutaneous tricuspid therapy.

TV surgery is associated with a high risk of morbidity and mortality in cases of TR recurrence after left heart surgery (up to 25 % in some series), particularly because these patients are typically referred to surgical treatment only when they develop severe incapacitating symptoms of right heart failure and organ dysfunction.6,7 Percutaneous procedures are an attractive alternative to surgery for patients deemed to be high-risk surgical candidates. Numerous tricuspid transcatheter devices have been developed to treat FTR. At present, clinical experiences with transcatheter TV therapies are still preliminary, and data to support their efficacy are scarce. However, initial experiences are promising and the safety profiles

This review will explore the available technologies that are currently under evaluation and their preliminary clinical results.

Anatomy and Pathophysiology of Functional Tricuspid Regurgitation: Interventional Considerations

The normal TV apparatus is composed of three leaflets (septal, posterior and anterior), chordae tendineae, and two or three welldeveloped papillary muscles (see Figure 1). Several structures of major surgical importance surround the TV, such as the right coronary artery, the atrioventricular (AV) node, the bundle of His and the coronary sinus. The non-planar and non-circular structure of the tricuspid annulus must be considered when considering tricuspid repair technologies. The normal shape of the tricuspid annulus is semi-lunar and it is larger compared with the mitral one. In physiological conditions, the tricuspid annulus has a non-planar three-dimensional saddle-shape configuration. Such a characteristic is absent in cases of functional TR, in which the annulus becomes enlarged, more circular and flattened. Annular dilatation occurs mainly in its anterior–posterior aspect. The consequence of severe functional TR is further right ventricular (RV) dilatation with progressive papillary muscles displacement and consequent tethering of the leaflets. The development of FTR can be classified into three progressive stages of the disease (see Figure 2):8,9

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Structural Figure 1: Anatomy of the Tricuspid Valve in a Cadaveric Heart: Surgical View

or with initial signs of RV dysfunction, who are deemed to be either at high risk for conventional open heart surgery or inoperable. Some of the concepts that have been developed for the percutaneous treatment of mitral regurgitation may be adapted to percutaneous repair of the TV. Since the initial mechanism leading to FTR is annular dilatation was elucidated, most of the current transcatheter technologies aim to fix annular dilatation by means of a tricuspid annuloplasty, the gold standard surgical treatment in this setting.

The red spot indicates the location of the atrioventricular node; CS = coronary sinus.

Figure 2: Pathophysiology of Functional Tricuspid Regurgitation

Once the safety profile of percutaneous tricuspid annuloplasty becomes proven, a concomitant tricuspid valve repair during transcatheter mitral valve intervention will likely be justified even in Stage 1 of the disease (significant annular dilatation even in absence of severe TR), to reduce the risk of late TR occurrence, similarly to what is recommended for cases of concomitant surgical treatment of TR during left valve surgery. This is merely a speculative assumption in the absence of supportive data, but such an aggressive treatment of concomitant TR could, in the near future, mimic the present surgical management approach.

Transcatheter Repair Techniques Annuloplasty Devices The TriCinch™ system

Phase I Initial Right Ventricular (RV) dilatation results in Tricuspid Annulus (TA) dilatation

Phase II Progressive RV and TA dilatation results in lack of leaflets coaptation

Phase III Progressive RV distortion results in tethering of the leaflets, pulmonary hypertension

Figure modified from Taramasso et al. Eur Heart J. 2016 Jan 21. pii: ehv766.

• Stage 1: annular dilatation. FTR is invariably associated with tricuspid annular dilatation, typically secondary to RV enlargement. Annular dilatation can be also initiated by right atrial enlargement, especially in patients with chronic atrial fibrillation. In the first phase of the disease, the tricuspid annulus is dilated, but the degree of TR is not yet severe. • Stage 2: progressive TV annulus enlargement prevents normal leaflet coaptation. Dilatation of the tricuspid annulus is not symmetrical; it occurs mainly in its anterior and posterior segments, which corresponds to the free wall of the RV. In this phase, FTR severity become significant and there is initial RV dilatation and deformation. • Stage 3: RV dilatation and dysfunction, and TV tethering. The consequence of severe FTR is progressive RV dilatation and dysfunction. Progressive RV dilatation causes displacement of papillary muscles and consequent leaflet tethering.

The Role of Interventional Tricuspid Regurgitation Therapy: Treatment and ‘Prevention’ Patients who could benefit from transcatheter treatment of TR are those with symptomatic TR irrespective of maximal medical therapy

The TriCinch™ system (4Tech Cardio Ltd) is a percutaneous device designed to cinch and remodel the tricuspid annulus through a transfemoral venous access.10,11 Annular dimension reduction and consequent improvement of leaflet coaptation is achieved by means of stainless steel corkscrew fixation into the anteroposterior TV annulus (see Figure 3A). The ideal site for anchor implantation is defined by a careful analysis of the computed tomography (CT) scan, usually close to the anteroposterior commissure. The corkscrew is connected through a dacron band to a self-expanding nitinol stent. Following corkscrew implantation, the device is pulled caudally to bring the anterior annulus towards the septum, until the desired reduction of TR is observed during live echocardiography. Optimal tension is maintained by the delivery of a nitinol self-expanding stent in the inferior vena cava. The size of the stent is evaluated on a pre-procedural CT scan. The procedure is carried out under general anaesthesia, with transoesophageal echocardiography (TEE) and/or intracardiac echocardiography (ICE) guidance. A coronary wire is positioned in the right coronary artery during the procedure and its patency is confirmed with ad hoc injections. First-in-man data for this procedure were reported in 2016.10 The multicentre Percutaneous Treatment of Tricuspid Valve Regurgitation With the TriCinch System (PREVENT) feasibility and safety trial (NCT02098200) is ongoing in Europe. CE mark approval is expected in 2017.

The Trialign™ system The Trialign™ system (Mitralign Inc.) is designed to perform a percutaneous suture annuloplasty of the TV, replicating the surgical bicuspidation technique, which is based on reducing annular dilatation and improving TV competency by plication of the posterior tricuspid annulus (see Figure 3B).12,13 With the Trialign device, the posterior leaflet is plicated by means of a pair of pledgeted sutures, which are implanted transanular from the ventricle to the atrium. Through right jugular access, the system is advanced in the right atrium, and then across the TV into the RV on fluoroscopic and TEE guidance.

INTERVENTIONAL CARDIOLOGY REVIEW

Transcatheter Therapies Figure 3: Transcatheter Tricuspid Valve Repair Devices: (A) TriCinchâ&#x201E;˘; (B) Trialignâ&#x201E;˘; (C) Cardioband; and (D) Millipede

Part of this figure is modified from Taramasso et al. Eur Heart J. 2016 Jan 21. pii: ehv766.

The catheter is articulated under the annulus towards the anteroposterior commissure. The catheter tip is positioned approximately 2â&#x20AC;&#x201C;5 mm from the hinge point of the leaflet and a wire is advanced with radiofrequency across the annulus into the right atrium (RA), where it is snared and externalised. This wire is then used to advance the pledget-delivery catheter across the annulus into the RV. The pledget is then delivered and compressed so that it is positioned on both the ventricular and atrial sides of the annulus. These steps are repeated on the opposite commissure of the posterior leaflet. The two pledgets on the anteroposterior and posteroseptal commissure are then pulled together and locked in place to plicate the posterior annulus and bicuspidalise the TV. The Trialign system is currently undergoing evaluation in prospective multicentre US feasibility of a Percutaneous Tricuspid Valve Annuloplasty System for Symptomatic Chronic Functional Tricuspid Regurgitation (SCOUT) (NCT02574650) and European CE-mark (SCOUT-II) studies. The distinctive features of the Trialign system are that it is based on a surgical technique, the footprint of the final implant is small, the leaflets remain untouched, and future access to the TV for pacing or transcatheter treatment is maintained.

Cardioband Tricuspid The Cardioband system (Valtech Cardio) is a transfemoral fully percutaneous direct annuloplasty device, which gained CE mark approval in 2015 for the treatment of high-risk patient with functional mitral regurgitation.14,15 In the standard procedure, a surgical-like band is delivered through trans-septal access in the left atrium and implanted on the atrial side of the posterior mitral annulus, from lateral to medial trigon, by means of multiple anchor elements. Final adjustment of the

INTERVENTIONAL CARDIOLOGY REVIEW

Cardioband size under echocardiography and fluoroscopic guidance provides a reduction of the septolateral diameter of the mitral valve, with consequent improvement of leaflet coaptation and reduction of valve regurgitation. A feasibility trial has demonstrated safety and efficacy of the Cardioband in the mitral position.14 The same concept has been recently used to treat FTR, as the Cardioband device closely reproduces the gold standard surgical treatment, ring annuloplasty. The same device is used by means of a transfemoral venous approach. A slightly modified delivery system is used, with different steering curves compared with the mitral procedure, to facilitate the implant on the tricuspid annulus. The band is implanted on the mural part of the tricuspid annulus, from the anteroseptal commissure to the initial part of the septal annulus. Final adjustment provides a marked reduction in the anteroseptal valve diameter and reduction of TR by forcing the leaflet coaptation (see Figure 3C). Clinical experience with the Cardioband system in the tricuspid position is limited; to date, only five patients have been treated (unpublished data).

The Millipede system The Millipede annular ring (Millipede) is a direct annuloplasty device that has been developed to treat TR and mitral regurgitation. This device mimics surgical annuloplasty by transcatheter implantation of an expandable and contractable ring that uses a novel attachment technique with many small, barbed anchors to secure it in place on the atrial side of the tricuspid annulus (see Figure 3D). Prior to ring fixation, the annulus is expanded by a dilator to the size and shape of the ring. The ring is then anchored to the annulus and contracts to a predefined size, therefore resulting in size reduction of the annulus. Early first-in-human Phase I studies of this procedure took place in

Structural Figure 4: Transcatheter Tricuspid Valve Repair Devices: (A) Caval implant and (B) FORMA Repair System device

Modified from Taramasso et al. Eur Heart J. 2016 Jan 21. pii: ehv766.

2015 (unpublished data). The device was deployed temporarily during the course of valve surgery, under direct surgical vision. It was verified no interference with electrical conduction or trouble with anchoring, and the ring achieved reduction in annular diameter. A Phase II study of pre-clinical procedures using transcatheter delivery began in 2016 (NCT02607527).

Leaflet Repair Devices Edge-to-edge Repair in the Tricuspid Position with the MitraClip® System Intervention edge-to-edge repair with the MitraClip® system (Abbott Vascular, Inc.) is a validated technique to treat mitral regurgitation of both degenerative and functional aetiology. The same concept has been tested in patients with severe symptomatic TR deemed to be at high risk for surgery.16 The procedure has been performed with a transjugular or transfemoral venous approach; the latter is preferred most frequently. To date, approximately 70 cases have been performed worldwide (unpublished data). Bench-test models have shown that the ideal location to place the clip to achieve the most pronounced reduction of TR in the presence of functional regurgitation is the anteroseptal commissure.17 The use of the MitraClip system for the TV raised some specific issues due to the complexity of the TV itself, as the MitraClip system was designed specifically for the mitral valve. In the future, the technique must be refined and the device modified for dedicated use in TV disease. Combining the edge-to-edge repair with another percutaneous technique of TR annulus reduction to facilitate the clip placement may also be considered. Intraprocedural imaging remains a major issue, as TEE is commonly suboptimal. Usually a combination of TEE, transthoracic echocardiography (TTE), ICE and fluoroscopy is used to achieve suitable imaging. Fusion imaging technologies such as the EchoNavigator® (Philips) have also been used to improve intraprocedural guidance.

Tricuspid valve spacer The concept of using a valve spacer to provide a surface for native leaflet coaptation in the presence of functional regurgitation has initially been

investigated in the mitral position. The FORMA Repair System (Edwards Lifesciences) consists of a spacer and a rail that is anchored at the RV apex, through a venous subclavian access (see Figure 4A). The spacer is a foam-filled polymer balloon that passively expands via holes in the spacer shaft. Two radiopaque markers help to initially position the spacer using fluoroscopy. The device is fixed at the distal end in the RV myocardium. The fixation mechanism consists of a six-pronged nitinol anchor that is designed to minimise both the risk of penetration of the epicardial surface and the prong exposure in the RV. The optimal position of the device must be perpendicular to the valve plane to allow all leaflets to coapt with the device. The device is locked proximally, and the excess rail is coiled and placed within a subcutaneous pocket. The device was applied for first-in-human experience in seven patients.18 All patients were successfully implanted with no major complication. The degree of TR was reduced by one degree in three patients and by two degrees in four patients. At 30 days, all patients but one demonstrated improvement in functional status and in quality of life.18 Further feasibility data will be obtained from a prospective registry study (Early Feasibility Study of the Edwards Tricuspid Transcatheter Repair System; NCT02471807).

Caval Valve Implantation: the Caval Valve Implantation Concept An alternative approach to the percutaneous treatment of TV is to implant a transcatheter prosthesis in the inferior vena cava (single-valve approach) or in combination with a superior vena cava valve (dualvalve approach) to prevent damage to the liver and other organs (see Figure 4B). In the presence of advanced RV dysfunction, the single-valve approach seems to be safer compared with the dual-valve approach as it is less likely to increase RV preload. The rationale for this procedure is to reduce hepatic, abdominal and peripheral venous congestion leading to amelioration of right heart failure. Different devices have been implanted using this approach and there is no consensus on what would the ideal caval valve implantation (CAVI) prosthesis be. Acute haemodynamic as well as clinical improvements at follow-up have been reported with balloon-expandable and also with self-expandable valves.19,20

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Transcatheter Therapies At present, two different clinical CAVI trials are enrolling high-risk patients with severe symptomatic TR: the Treatment of Severe Secondary Tricuspid Regurgitation in Patients With Advance Heart Failure With Caval Vein Implantation of the Edwards Sapien XT Valve (TRICAVAL) study in Europe (NCT02387697) and the Heterotopic Implantation Of the Edwards-Sapien XT Transcatheter Valve in the Inferior Vena Cava for the Treatment of Severe Tricuspid Regurgitation (HOVER) trial in the US (NCT02339974). The main advantage of the CAVI is that is technically easy to perform. Although preliminary results are promising, the main disadvantage of this approach is the complete absence of a clinical or surgical background. Moreover, the long-term effects of a ‘ventricularisation’ of the RA are unknown. Dedicated CAVI devices are under preclinical development.

Conclusion Although only preliminary data are currently available, transcatheterbased techniques for the treatment of TR have been rapidly evolving in recent years. However, it is important to point out that at the present stage of the development of these therapies, because data are scarce, it is not possible to make any definitive conclusions around the clinical efficacy or safety. Some of these novel devices are based on well-known surgical techniques that have subsequently progressed to less-invasive approaches, others

Taramasso M, Vanermen H, Maisano F, et al. The growing clinical importance of secondary tricuspid regurgitation. J Am Coll Cardiol 2012;59:703–10. DOI: 10.1016/j.jacc.2011.09.069; PMID: 22340261. Stuge O, Liddicoat J. Emerging opportunities for cardiac surgeons within structural heart disease. J Thorac Cardiovasc Surg 2006;132:1258–61. DOI: 10.1016/j.jtcvs.2006.08.049; PMID: 17140937. Agricola E, Stella S, Gullace M, et al. Impact of functional tricuspid regurgitation on heart failure and death in patients with functional mitral regurgitation and left ventricular dysfunction. Eur J Heart Fail 2012;14:902–8. DOI: 10.1093/eurjhf/ hfs063; PMID: 22552182. 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, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–96. DOI: 10.1093/eurheartj/ehs109; PMID: 22922415. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:e521–643. DOI: 10.1161/ CIR.0000000000000031; PMID: 24589853. Kim YJ, Kwon DA, Kim HK, et al. Determinants of surgical outcome in patients with isolated tricuspid regurgitation. Circulation 2009;120:1672–8. DOI: 10.1161/ CIRCULATIONAHA.109.849448; PMID: 19822809.

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10.

11.

12.

13.

are completely new concepts that should be validated in the clinical setting. The anatomical features of the TV apparatus and right heart chambers have made transcatheter treatment of the TV challenging. Experience with aortic and mitral valve percutaneous interventions has showed us that further research is required before TV transcatheter technology can become a routine therapeutic option in routine clinical practice. Besides technical issues, most importantly there are several clinical issues associated with these techniques. First, it is currently difficult to identify the ideal patients that could most benefit from transcatheter TV treatment, in terms of prognostic and clinical benefit. The second important issue refers to anatomical patient selection, which relates to the TV imaging. While TTE and TEE are the most important diagnostic tool to assess TV, angio-CT is acquiring increasing importance in patient selection and procedural planning in TV percutaneous strategy. Three-dimensional echocardiography will also play an important role, as it allows accurate assessment of the morphology of the valve and of the quantification of TR. Data from the ongoing and upcoming clinical trials should elucidate the missing information. n

odes-Cabau J, Taramasso M, O‘Gara PT. Diagnosis and R treatment of tricuspid valve disease: current and future perspectives. Lancet 2016;388:2431–42. DOI: 10.1016/S01406736(16)00740-6; PMID: 27048553. Taramasso M, Pozzoli A, Guidotti A, et al. Percutaneous tricuspid valve therapies: the new frontier. Eur Heart J 2016: pii: ehv766. [Epub ahead of print]. DOI: 10.1093/eurheartj/ ehv766; PMID: 26802134. Dreyfus GD, Martin RP, Chan KM, et al. Functional tricuspid regurgitation: a need to revise our understanding. J Am Coll Cardiol 2015;65:2331–6. DOI: 10.1016/j.jacc.2015.04.011; PMID: 26022823. Latib A, Agricola E, Pozzoli A, et al. First-in-man implantation of a tricuspid annular remodeling device for functional tricuspid regurgitation. JACC Cardiovasc Interv 2015;8:e211–4. DOI: 10.1016/j.jcin.2015.06.028; PMID: 26585629. Taramasso M, Latib A, Denti P, et al. Percutaneous repair of the tricuspid valve using a novel cinching device: acute and chronic experience in a preclinical large animal model. EuroIntervention 2016;12:918–25. DOI: 10.4244/EIJV12I7A150; PMID: 27639745. Schofer J, Bijuklic K, Tiburtius C, et al. First-in-human transcatheter tricuspid valve repair in a patient with severely regurgitant tricuspid valve. J Am Coll Cardiol 2015;65:1190–5. DOI: 10.1016/j.jacc.2015.01.025; PMID: 25748096. Schofer J, Tiburtius C, Hammerstingl C, et al. Transfemoral tricuspid valve repair using a percutaneous mitral valve repair system. J Am Coll Cardiol 2016;67:889–90. DOI: 10.1016/ j.jacc.2015.11.047; PMID: 26892424.

14. M aisano F, Taramasso M, Nickenig G, et al. Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial. Eur Heart J 2016;37: 817–25. DOI: 10.1093/eurheartj/ehv603; PMID: 26586779. 15. Taramasso M, Guidotti A, Cesarovic N, et al. Transcatheter direct mitral annuloplasty with Cardioband: feasibility and efficacy trial in an acute preclinical model. EuroIntervention 2015;11:e1428–34. DOI: 10.4244/EIJY15M11_06; PMID: 26573974. 16. Hammerstingl C, Schueler R, Malasa M, et al. Transcatheter treatment of severe tricuspid regurgitation with the MitraClip system. Eur Heart J 2016;37:849–53. DOI: 10.1093/eurheartj/ ehv710; PMID: 26744457. 17. Vismara R, Gelpi G, Prabhu S, et al. Transcatheter edge-toedge treatment of functional tricuspid regurgitation in an ex vivo pulsatile heart model. J Am Coll Cardiol 2016;68:1024–33. DOI: 10.1016/j.jacc.2016.06.022; PMID: 27585507. 18. Campelo-Parada F, Perlman G, Philippon F, et al. First-in-man experience of a novel transcatheter repair system for treating severe tricuspid regurgitation. J Am Coll Cardiol 2015;66: 2475–83. DOI: 10.1016/j.jacc.2015.09.068; PMID: 26653620. 19. Lauten A, Doenst T, Hamadanchi A, et al. Percutaneous bicaval valve implantation for transcatheter treatment of tricuspid regurgitation: clinical observations and 12-month follow-up. Circ Cardiovasc Interv 2014;7:268–72. DOI: 10.1161/ CIRCINTERVENTIONS.113.001033; PMID: 24737337. 20. Laule M, Stangl V, Sanad W, et al. Percutaneous transfemoral management of severe secondary tricuspid regurgitation with Edwards Sapien XT bioprosthesis: first-in-man experience. J Am Coll Cardiol 2013;61:1929–31. DOI: 10.1016/ j.jacc.2013.01.070; PMID: 23500268.

Structural

Aortic Dissection: Novel Surgical Hybrid Procedures Alessandro Cannavale, 1 Mariangela Santoni, 2 Fabrizio Fanelli 2 and Gerard O’Sullivan 3 1. Department of Radiology, NHS Greater Glasgow and Clyde, Glasgow, UK; 2. Department of Radiological Sciences, “Sapienza” University of Rome, Rome, Italy; 3. Department of Interventional Radiology, University College Hospital Galway, Galway, Ireland.

Abstract The management of patients with aortic dissection is challenging and its treatment is an area of development and innovation. Conventional surgical techniques are associated with significant risks in terms of mortality and morbidity in such high-risk patients. As a result of cumulative advances in technology, classical surgical techniques have been improved and enhanced by the newer endovascular approaches, leading to novel surgical hybrid procedures. Impressive early results have been seen with frozen elephant techniques, revascularisation of the supra-aortic branches and branched/fenestrated thoracic endovascular aortic repair-alone procedures. This review describes the techniques involved in the latest hybrid procedures for aortic dissection and their outcomes.

Keywords Thoracic aorta, aortic dissection, thoracic endovascular aortic repair, thoracic surgical aortic repair Disclosure: The authors have no conflicts of interest to declare Received: 14 May 2016 Accepted: 19 Jan 2017 Citation: Interventional Cardiology Review 2017;12(1):56–60. DOI: 10.15420/icr.2016:16:3 Correspondence: Alessandro Cannavale MD, EBIR, FCIRSE, NHS Greater Glasgow and Clyde, Department of Radiology, Queen Elizabeth University Hospital, 1345 Govan Road, Glasgow. G51 4TF, UK. E: alessandro.cannavale@hotmail.com

Aortic dissection (AD) is one of the most challenging vascular diseases, with an in-patient mortality as high as 30 %1 and 30-day and 5-year fatality rates of just over 50 % and 60 %, respectively.2 The time course of AD is broadly spit into acute (<14 days), subacute (15–90 days), and chronic (>90 days) phases, and it is split clinically into complicated (i.e. the condition is associated with organ malperfusion syndrome, neurological symptoms and/or uncontrollable hypertension) and uncomplicated (when the patient is asymptomatic and haemodynamically stable) scenarios. 3 The condition is most commonly classified according to the location of the primary entry tear (Stanford classification), with type A relating to the ascending aorta and type B the descending aorta. The dissection flap most commonly develops in the ascending aorta, occurring within 10 cm of the aortic valve in over 90 % of cases.4,5 Type A dissection has a mortality rate approaching 60 % if surgical intervention is not performed early on, yet – even with early intervention – mortality remains at 25 %, and neurological injury occurs in up to 14 % of cases, even in tertiary referral centers.4 The second most frequent site for the intimal tear is just distal to the left subclavian artery (LSA), which is a type B tear.3 In 5–10 % of dissections there is no clearly visible intimal tear, and the condition may be because of the rupture of the aortic vasa vasorum in the media layer, which is known as an intramural haematoma.3 Treatment of an AD is quite complex, as demonstrated by the high morbidity and mortality rates associated with surgical therapy. Endovascular technique is associated with a better outcome but presents some technical limitations secondary to the anatomical characteristics, especially in type A dissections. This is the reason treatment is currently evolving toward the new frontier of hybrid repair. Mitchell et al.5 addressed this concept in 2002, and it was subsequently applied by Criado et al.6 Five different landing

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zones (LZ0–4) have been defined in the aortic arch that can be used in different types of combined procedures. 5,6 The concept of hybrid repair lies in repairing the ascending aorta (if involved) and extending the LZ to allow satisfactory sealing of the stentgraft according to the location of the intimal tear, combining open and endovascular procedures.7 Innovative and advanced surgical and endovascular techniques have recently been highlighted; this review aims to address the most recent techniques of hybrid repair in type A and B AD.

Hybrid Techniques The classic surgical approach to AD requires cardiopulmonary bypass and deep hypothermic circulatory arrest. The aim is to identify and resect the primary intimal tear and re-approximate the intima and adventitia. Despite surgery, a residual dissection flap and a patent false lumen persist in the arch and descending thoracic aorta in 64–90 % of cases.3 A persisting patent false lumen can lead to distal malperfusion syndrome in the acute setting, with a risk of false lumen dilatation/ aneurysm formation and rupture over the long term.8 The overall mortality in type A dissection is almost three times higher in patients with malperfusion (43.7 %) than in those without (15 %).9 Hybrid techniques (see Table 1) are recommended in the latest guidelines for the treatment of type A AD with distal malperfusion.3 The following novel hybrid techniques overcome the limits of classic open surgery in the treatment of complex Stanford type A and B AD: • elephant trunk (ET) techniques with or without thoracic endovascular aortic repair (TEVAR); • revascularisation of the supra-aortic branches and TEVAR; and • stent-graft repair without surgical supra-aortic vessel revascularisation.

Surgical Hybrid Procedures Table 1: Features of the Different Hybrid Techniques Technique

Indication

Advantages

Disadvantages

Secondary Intervention/

Mortality, %

Endoleak

Stroke/Spinal Cord Ischaemia

Frozen Elephant - Acute type A - Single operation Trunk and aortic dissection - Treats challenging Modifications (DeBakey I) with anatomy distal organ - Stabilisation of the malperfusion dissected aorta - Selected cases and remodelling of coronary artery of the false lumen disease in the descending aorta

- Incomplete seal of Endoleak: 1–15 % 4.1–12.8 the false lumen in Re-intervention: 15.3 % the descending aorta (surgical or endovascular) - Spinal cord ischaemia - Need robust cerebral protection technique - Hypothermia/ circulatory arrest

Stroke: 3.8–6.5 % Spinal cord ischaemia: 2.8–13.4 % (permanent: 1.3–3.2 %)

Revascularisation - Type A aortic of the Supra- dissection aortic Branches/ (LZ0/1) TEVAR - Type B aortic dissection (LZ2) with/without distal malperfusion

- Total arch debranching Endoleak: 0–15 % 4.2–14.9 predictor of mortality/ Re-intervention: stroke 0.0–15.6 % - Second-stage TEVAR

Stroke: 5.9–9.7 % Spinal cord ischaemia: 2.5–6.1 % (permanent)

- Requires advanced skills - Stent occlusion/ compression - Limited bail-out options - Customised/branched stent-grafts cannot be used in emergency situations - High cost

Stroke: 0.0–7.8 % Spinal cord ischaemia: 2.8 %

- Reduction in circulatory arrest time - No need for deep hypothermia

Stent-graft - Type A aortic - Stenting/chimney Repair Without dissection (LZ0/1) technique may Surgery - Type B aortic be used in (stenting/ dissection (LZ2) emergency fenestrated/ - Patients at high settings branched risk for surgery - No need for TEVAR) - Unsuitable for surgical operation conventional TEVAR

Endoleak: up to 0–10 21.6 % (type I) Re-intervention: about 30 % of endoleaks need re-intervention (embolisation/ stent-graft extension)

LZ = landing zone; TEVAR = thoracic endovascular aortic repair.

Elephant Trunk Techniques Generally ET open surgery techniques involve total arch replacement and distal anastomosis with various hypothermia techniques and periods of circulatory arrest. The original ET technique was introduced by Borst et al. in 1983 and consisted of a graft extending from the distal aortic arch into the proximal descending aorta, facilitating a second intervention with thoracotomy or via an endovascular approach10 (see Figure 1). This procedure is associated with a high risk of post-operative mortality and neurological events,10 therefore modifications have been applied such as a short ET, to reinforce the distal anastomosis, or a long ET (recommended length less than 10–12 cm), which improves aneurysm/false lumen thrombosis but has a high risk of paraplegia (8.1 %).10 With the advent of TEVAR, second-stage completion with an endovascular stent-graft is now available. This technique has the advantage of markedly shortening the time to second intervention, which can be performed safely within 1 month, and may be used in both thoracic aortic aneurysm and acute dissection. Reports show an in-hospital mortality of between 4.5 % and 11.1 %, a pooled mortality of 6.1 % and spinal cord ischaemia of 4.6 %.10,11 The main disadvantage appears to be late endoleak, which occurs in up to 7.4 % of cases.10,11 The original ED technique evolved into the frozen elephant trunk (FET), which consists of a hybrid stent-graft prosthesis encompassing a covered stent sutured to the distal end of a conventional tube graft to provide expansive radial force on the distal portion of the ET, allowing a virtual anastomotic seal at the descending aorta 4 (see Figure 2). This technique enables the treatment of patients with challenging anatomy and it also allows treatment of disease in the descending aorta at one sitting without the need for subsequent TEVAR. This technique

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has been used mainly for acute AD (69.8 %) but is also used for aneurysms (30.2 %).10 FET has also been used in chronic AD,12,13 but is only appropriate in selected cases, given the low thrombosis rate of the false lumen in chronic AD, where conventional ET associated with a second intervention on the descending thoracic aorta may be more appropriate.14,15 Despite the benefits offered by FET, it is still associated with considerable mortality and morbidity: reported aggregate 30-day in-hospital mortality is 1.8–17.2 %, while stroke and spinal cord injuries are in the 2.5–20.0 % and 0–21 % ranges, respectively.16-18 Pochettino et al. further developed FET with the antegrade insertion of a stent-graft into the proximal descending aorta during open type-A dissection repair.15 This hybrid approach, of classic arch replacement with downward placement of a stent-graft through an open arch, has stimulated the development of novel grafts such as the E-vita. The E-vita has a Dacron segment that replaces the ascending aorta and arch, together with a stent graft segment, which is positioned in the proximal descending thoracic aorta. Diagrams of E-vita structure and deployment are illustrated in Figure 3. Initial results from the international E-vita open registry are very promising, with in-hospital mortality of 15 % (40/274), 18 % for acute AD, 13 % for chronic AD and 14 % for thoracic aortic aneurysms.17 New strokes have been observed in 6 % (16/274) and spinal cord injury in 8 % (22/274) of patients.17 Hemi-arch replacement associated with antegrade TEVAR is a surgical technique between conventional ET and FET. It has been used in patients with DeBakey type I AD without an intimal tear in the arch.16 This technique showed no difference in false lumen thrombosis and clinical outcomes with total arch replacement. Nevertheless, compared with total arch replacement, the hemi-arch replacement

Structural Figure 1: Elephant Trunk Technique A

Proximal anastomosis

Free end of a classical Elephant Trunk draft

Proximal anastomosis

Free end of a classical Elephant Trunk draft

Second stage graft

Stent

(A) First step: the aortic arch is replaced surgically, then an extension is left free in the descending aorta, for a second stage surgical (B) or endovascular (C) completion.

Figure 2: Frozen Elephant Trunk Technique

had a lower incidence of post-operative transient neurological dysfunction (16.9 % versus 30.9 %; p=0.04), low cardiac output syndrome (5.6 % versus 16.7 %; p=0.03) and prolonged ventilation, i.e. >72 hours (7 % versus 19.0 %; p=0.03).19

Revascularisation of the Supra-aortic Branches and TEVAR

In a single stage operation the ascending aorta and aortic arch are replaced with surgical graft, then the stent-graft is extended into the descending aorta providing immediate seal.

Figure 3: E-vita Structure and Deployment

Novel hybrid techniques aim to reduce the mortality and morbidity following open total arch replacement requiring deep hypothermia and circulatory arrest, and improve distal organ ischaemia because of the contemporaneous treatment of the descending aorta. Revascularisation techniques essentially bypass graft the supraaortic branches and ligate the native branches (‘debranching’). This is followed by endovascular stent-grafting of the aortic arch with or without subsequent TEVAR of the descending aorta. In ‘partial debranching’ the left carotid artery and subclavian artery are revascularised by carotid–carotid or carotid–subclavian bypass; ‘total debranching’ includes revascularisation of the brachiocephalic trunk. These techniques aim to move the origin of the supra-aortic vessel to zone 0, 1 or 2, according to the type of AD, and allow the TEVAR stent-graft to land whether inserted antegradely or retrogradely. Revascularisation differs with LZ: LZ0 requires all three aortic vessels; LZ1 the LSA and left carotid artery and LZ2 the LSA (some studies advocate the safety of LSA coverage without recanalisation).14,20 Kent et al.21 (one patient) and Chang et al.22 (21 patients) have investigated a new technique based on four-branch grafting for acute type A dissection without the need for circulatory arrest and mild hypothermia. In this technique, the 10-mm side branch is used to deploy an antegrade stent-graft in the descending aorta. Reported in-hospital mortality was 4.8 % and there was no caudal stent-graft migration.21 One type 1 endoleak occurred during the procedure and was repaired with a cuff. Complete false lumen thrombosis was obtained in 85 % of patients during the follow-up period.21

(A) First step in the E-vita deployment is to advance an extra stiff guidewire (black arrow) from a common femoral artery access into the aortic arch. (B) Then after surgical aortic arch surgical cut-down the e-vita delivery system is inserted over the wire and the stent-graft is deployed in the descending aorta. (C) Then the graft is released and sutured to the aortic arch.

Marullo et al.23 and Esposito et al.24 employed an interesting staged approach whereby the ascending aorta is replaced and the arch debranched with a new multi-branched graft. An endograft is then deployed in the arch and proximal descending thoracic aorta if there

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Surgical Hybrid Procedures is a malperfusion syndrome or early evidence of distal aortic dilation. An endograft was deployed in 62.5 % (15/24)23 and 73 % (65/89)24 of patients in the two studies, respectively, resulting in false lumen thrombosis and no resultant endoleaks. In hospital mortality reported in the two studies was 4.2 % and 8.9 %, respectively.23,24

Figure 4: Chimney, Periscope and Sandwich Techniques

Total debranching (LZ0) is still associated with higher risk (OR 11.1; 95 % CI [1.86–65.90]; p=0.010) than a minor surgical operation (LZ1 or LZ2),25 although repair is more stable in L0 and LZ1 than LZ2–4.26

Stent-graft Repair without Surgical Supra-aortic Vessel Revascularisation Originally, treatment of the aortic arch with a stent-graft was difficult because of the lack of a suitable LZ and the need to insert a straight device into a curved structure, leading to a high risk of type I endoleak. To cope with these limitations, branch artery stenting, fenestrated, customised branched stent grafts and multilayer flow modulator stents have been developed.3,20 However, the evolution and application of these stent-grafts has been slower than that of similar devices used in the abdominal aorta, because of the need to avoid occluding the supra-aortic vessels.

Stenting Technique Stenting technique uses parallel stent-grafts as chimneys (that selfexpand when in place), a periscope or sandwiches (see Figure 4) in a variety of aortic pathologies, including acute aortic disease. The use of different types of stents makes this technique easier than fenestrated and branched endografting. High-risk patients presenting in the emergency department with a proximal LZ0 and no other surgical option are suitable candidates for this technique.27,28 Although

(A) Chimney technique: A stent-graft can be antegradely deployed in the left common carotid artery after surgical cutdown (red stent-graft) in combination with a TEVAR stent-graft covering the left subclavian artery, to extent the landing zone. (B) Periscope technique: A periscope stent-graft (red stent-graft) can be inserted from the femoral access, upwards into the left subclavian artery, along side the TEVAR stent-graft and generally it extends below the distal landing zone of the TEVAR stent-graft. (C) Sandwich technique: Two stent-grafts (red stent-grafts) can be deployed in the first TEVAR stent-graft into the visceral vessels (renal arteries in this diagram), then the thoracic graft can be extended in to the thoraco-abdominal aorta (green stent-graft), thereby extending the distal landing zone while preserving visceral vessels patency. TEVAR = thoracic endovascular aortic repair.

Figure 5: Fenestrated Endograft

more than 80 % of cases are successful, drawbacks include chimney stent compression, type I endoleaks and the associated need for re-intervention.27 The classic chimney technique is associated with 10 % mortality and up to 21.6 % occurrence of endoleak (type Ia, 11.8 %), especially in devices positioned in LZ2.29–33

Fenestrated Endografting Fenestrated endografting is another recent development. Fenestrated endovascular aortic repair enables the continuation of blood flow to the arteries through fenestrations in the graft (see Figure 5). Deployment of the endograft in the arch is necessary to adjust the fenestrations to correspond to all vessel ostia. Some second-generation devices use new materials, short-length stent elements and an expansion system to adapt to the curvature of the arch. Fenestrated endografts may be pre-curved and have scallops that interrupt the graft, allowing perfusion of the side vessels. The use of pre-curved fenestrated grafts positioned in LZ0–2 is safe and reliable in the treatment of AD and aneurysms involving the aortic arch34 with 95.8 % operative success (defined as the absence of type I or III endoleaks on postoperative computed tomography scan), 1.6 % 30-day mortality and neurological adverse events in 1.8 % of cases.34 Some authors35 have suggested in-situ laser fenestration of the stent-graft followed by a balloonexpandable covered stent to re-perfuse the LSA.

The fenestrated endograft is usually used to land in Zone 0 and has multiple fenestrations allowing epiaortic vessels perfusion, without the use of brach stent-grafts.

Figure 6: Branched Stent-graft

Branched Endografts Branched endografts are custom-built, with a lead-time of a few weeks (a delay that may be reduced with the use of 3D printing) and are therefore not suitable for acute aortic pathology (see Figure 6). The presence of built-in branches eliminates the need for adjunctive procedures (hybrid repair, extra-anatomic bypasses and chimneys).

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The branched stent-graft is a custom-made stent-graft with one or multiple pre-loaded branches that can be deployed into the left subclavian artery (as shown) and other epiaortic vessels if needed.

Structural Recently Lu et al. reported excellent mid-term results in patients with type A and B chronic AD: only one patient died from retrograde type A AD and no other complications were reported over the 14–66-month follow-up period.36 There was complete thrombosis of the false lumen in all cases. A trial of Medtronic’s off-the-shelf stent-graft Valiant Mona LSA is recruiting participants and the results are expected in 2021.37 Despite promising initial results, the long-term durability of off-theshelf branched stent grafts is yet to be supported by robust evidence.

Multilayer Flow Modulator Stents Multilayer stents are a recent solution for the treatment of complex thoracic aortic aneurysm and dissection. They maintain patency of the visceral and spinal vessels (linear flow) while triggering thrombosis of the false lumen/aneurysm sac via turbulent blood flow. Recent studies38,39 in complex thoracoabdominal aneurysms and type B dissection have had high technical success (98.2–100.0 %) and visceral vessels were patent in almost all cases at 1-year (patency >96 %); no cases of spinal cord ischaemia were reported. Although Vaislic et al.39

1. Sachs T, Pomposelli F, Hagberg R, et al. Open and endovascular repair of type B aortic dissection in the Nationwide Inpatient Sample. J Vasc Surg 2010;52:860–6. DOI: 10.1016/j.jvs.2010.05.008; PMID: 20619592 2. Howard DP, Banerjee A, Fairhead JF, et al.; Oxford Vascular Study. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation 2013;127:2031–7. DOI: 10.1161/CIRCULATIONAHA.112.000483; PMID: 23599348 3. Erbel R, Aboyans V, Boileau C, et al.; ESC Committee for Practice Guidelines. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2873–926. DOI: 10.1093/ eurheartj/ehu281; PMID: 25173340 4. Appoo JJ, Pozeg Z. Strategies in the surgical treatment of type A aortic arch dissection. Ann Cardiothorac Surg 2013;2: 205–11. DOI: 10.3978/j.issn.2225-319X.2013.01.11; PMID: 23977584 5. Mitchell RS, Ishimaru S, Ehrlich MP, et al. First International Summit on Thoracic Aortic Endografting: roundtable on thoracic aortic dissection as an indication for endografting. J Endovasc Ther 2002;9 Suppl 2:II98–105. PMID: 12166849 6. Criado FJ, Barnatan MF, Rizk Y, et al. Technical strategies to expand stent-graft applicability in the aortic arch and proximal descending thoracic aorta. J Endovasc Ther 2002;9 Suppl 2:II32–8. PMID: 12166839 7. Grabenwöger M, Alfonso F, Bachet J et al.; European Association for Cardio-Thoracic Surgery (EACTS); European Society of Cardiology (ESC); European Association of Percutaneous Cardiovascular Interventions (EAPCI). Thoracic Endovascular Aortic Repair (TEVAR) for the treatment of aortic diseases: A position statement from the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg 2012;42:17–24. DOI: 10.1093/ejcts/ezs107. PMID: 22561652 8. Luebke T, Brunkwall J. Type B aortic dissection: a review of prognostic factors and meta-analysis of treatment options. Aorta (Stamford) 2014;2:265–78. DOI: 10.12945/j.aorta.2014. 14-040; PMID: 26798745 9. Trimarchi S, Nienaber CA, Rampoldi V, et al. Contemporary results of surgery in acute type A aortic dissection: The International Registry of Acute Aortic Dissection experience. J Thorac Cardiovasc Surg 2005;129:112–22. DOI: 10.1016/ j.jtcvs.2004.09.005; PMID: 15632832 10. Miyamoto Y. Elephant trunk technique for hybrid aortic arch repair. Gen Thorac Cardiovasc Surg 2014;62:135–41. DOI: 10.1007/ s11748-013-0299-0; PMID: 23943042 11. Obitsu Y, Koizumi N, Iida Y, et al. Long-term results of second-stage thoracic endovascular aortic repair following total aortic arch replacement. Gen Thorac Cardiovasc Surg 2010;58:501–5. DOI: 10.1007/s11748-010-0627-6; PMID: 20941562 12. Leontyev S, Borger MA, Etz CD, et al. Experience with the conventional and frozen elephant trunk techniques: a singlecentre study. Eur J Cardiothorac Surg 2013;44:1076–82; discussion 1083. DOI: 10.1093/ejcts/ezt252; PMID: 23677901

reported that the aneurysm sac was stable in 18/20 patients at 12 months, in type B AD Sultan et al.38 showed initial remodelling with thrombus formation in the sac/false lumen and an average increase in sac volume of 3.3 % at 12 months. This result was confirmed by the global multilayer modulator registry, which reported a total average increase in sac volume of 5.1 %.40 Evidence of the efficacy of multilayer stents in the AD is still quite weak. Much larger and long-term studies, and preferably a randomised trial against best medical therapy/observation, are required.

Conclusion Hybrid surgical and endovascular techniques are increasingly being used and developed, improving the morbidity and mortality outcomes for complex patients. The combination of extra-thoracic surgery and TEVAR is currently the most reliable option as it has limited complications and mortality. The endovascular-only approach has shown promising results, but additional long-term studies are warranted. n

13. Ius F, Fleissner F, Pichlmaier M, et al. Total aortic arch replacement with the frozen elephant trunk technique: 10-year follow-up single-centre experience. Eur J Cardiothorac Surg 2013;44:949–57. DOI: 10.1093/ejcts/ezt229; PMID: 23660556 14. Fanelli F, Cannavale A, O’Sullivan GJ, et al. Endovascular repair of acute and chronic aortic type B dissections: main factors affecting aortic remodeling and clinical outcome. JACC Cardiovasc Interv 2016;9:183–91. DOI: 10.1016/j.jcin.2015.10.027; PMID: 26793960 15. Pochettino A, Brinkman WT, Moeller P, et al. Antegrade thoracic stent grafting during repair of acute DeBakey I dissection prevents development of thoracoabdominal aortic aneurysms. Ann Thorac Surg 2009;88:482–9; discussion 489–90. DOI: 10.1016/j.athoracsur.2009.04.046; PMID: 19632398 16. Shrestha M, Bachet J, Bavaria J, et al. Current status and recommendations for use of the frozen elephant trunk technique: a position paper by the Vascular Domain of EACTS. Eur J Cardiothorac Surg 2015;47:759–69. DOI: 10.1093/ejcts/ ezv085; PMID: 25769463 17. Tsagakis K, Pacini D, Di Bartolomeo R, et al. Arch replacement and downstream stent grafting in complex aortic dissection: first results of an international registry. Eur J Cardiothorac Surg 2011;39:87–93; discussion 93–4. DOI: 10.1016/ j.ejcts.2010.03.070; PMID: 20627748 18. Di Bartolomeo R, Pantaleo A, Berretta P, et al. Frozen elephant trunk surgery in acute aortic dissection. J Thorac Cardiovasc Surg 2015;149(2 Suppl):S105–9. DOI: 10.1016/j.jtcvs.2014.07.098; PMID: 25212056 19. Shi E, Gu T, Yu Y, et al. Early and midterm outcomes of hemiarch replacement combined with stented elephant trunk in the management of acute DeBakey type I aortic dissection: comparison with total arch replacement. J Thorac Cardiovasc Surg 2014;148:2125–31. DOI: 10.1016/j.jtcvs.2013.10.058; PMID: 24290707 20. Fanelli F, Dake MD. Standard of practice for the endovascular treatment of thoracic aortic aneurysms and type B dissections. Cardiovasc Intervent Radiol 2009;32:849–60. DOI: 10.1007/s00270-009-9668-6; PMID: 19688371 21. Kent WD, Herget EJ, Wong JK, Appoo JJ. Ascending, total arch, and descending thoracic aortic repair for acute DeBakey type I aortic dissection without circulatory arrest. Ann Thorac Surg 2012;94:e59–61. DOI: 10.1016/j.athoracsur.2012.02.080; PMID: 22916780 22. Chang Q, Tian C, Wei Y, et al. Hybrid total arch repair without deep hypothermic circulatory arrest for acute type A aortic dissection (R1). J Thorac Cardiovasc Surg 2013;146:1393–8. DOI: 10.1016/j.jtcvs.2012.09.041; PMID: 23142116 23. Marullo AG, Bichi S, Pennetta RA, et al. Hybrid aortic arch debranching with staged endovascular completion in DeBakey type I aortic dissection. Ann Thorac Surg 2010;90:1847–53. DOI: 10.1016/j.athoracsur.2010.07.077; PMID: 21095323 24. Esposito G, Cappabianca G, Bichi S, et al. Hybrid repair of type A acute aortic dissections with the Lupiae technique: tenyear results. J Thorac Cardiovasc Surg 2015;149(2 Suppl):S99–104. DOI: 10.1016/j.jtcvs.2014.07.099; PMID: 25256081 25. De Rango P, Cao P, Ferrer C, et al. Aortic arch debranching and thoracic endovascular repair. J Vasc Surg 2014;59:107–14. DOI: 10.1016/j.jvs.2013.07.010; PMID: 24001696 26. De Rango P, Ferrer C, Coscarella C, et al. Contemporary comparison of aortic arch repair by endovascular and open surgical reconstructions. J Vasc Surg 2015;61:339–46. DOI: 10.1016/j.jvs.2014.09.006; PMID: 25441674

27. Shahverdyan R, Gawenda M, Brunkwall J. Triple-barrel graft as a novel strategy to preserve supra-aortic branches in arch-TEVAR procedures: clinical study and systematic review. Eur J Vasc Endovasc Surg 2013;45:28–35. DOI: 10.1016/ j.ejvs.2012.09.023; PMID: 23123094 28. Zhu Y, Guo W, Liu X, et al. The single-centre experience of the supra-arch chimney technique in endovascular repair of type B aortic dissections. Eur J Vasc Endovasc Surg 2013;45:633–8. DOI: 10.1016/j.ejvs.2013.02.016; PMID: 23540806 29. Riambau V. Application of the Bolton Relay Device for thoracic endografting in or near the aortic arch. Aorta (Stamford) 2015;3:16–24. DOI: 10.12945/j.aorta.2015.14-050; PMID: 26798752 30. Lindblad B, Bin Jabr A, Holst J, et al. Chimney grafts in aortic stent grafting: hazardous or useful technique? Systematic review of current data. Eur J Vasc Endovasc Surg 2015;50:722–31. DOI: 10.1016/j.ejvs.2015.07.038; PMID: 26371416 31. Zhang T, Jiang W, Lu H, Liu J. Thoracic endovascular aortic repair combined with assistant techniques and devices for the treatment of acute complicated Stanford type B aortic dissections involving aortic arch. Ann Vasc Surg 2016;32:88–97. DOI: 10.1016/j.avsg.2015.10.030; PMID: 26806251 32. Xue Y, Sun L, Zheng J, et al. The chimney technique for preserving the left subclavian artery in thoracic endovascular aortic repair. Eur J Cardiothorac Surg 2015;47:623–9. DOI: 10.1093/ ejcts/ezu266. PMID: 25009212 33. Yang J, Xiong J, Liu X, et al. Endovascular chimney technique of aortic arch pathologies: a systematic review. Ann Vasc Surg 2012;26:1014–21. DOI: 10.1016/j.avsg.2012.05.014; PMID: 22944571 34. Yokoi Y, Azuma T, Yamazaki K. Advantage of a precurved fenestrated endograft for aortic arch disease: simplified arch aneurysm treatment in Japan 2010 and 2011. J Thorac Cardiovasc Surg 2013;145:S103–9. DOI: 10.1016/j.jtcvs.2012.11.058; PMID: 23410765 35. Redlinger RE Jr, Ahanchi SS, Panneton JM. In situ laser fenestration during emergent thoracic endovascular aortic repair is an effective method for left subclavian artery revascularization. J Vasc Surg 2013;58:1171–7. DOI: 10.1016/ j.jvs.2013.04.045; PMID: 23746832 36. Lu Q, Feng J, Zhou J, et al. Endovascular repair by customized branched stent-graft: A promising treatment for chronic aortic dissection involving the arch branches. J Thorac Cardiovasc Surg 2015;150:1631–8.e5. DOI: 10.1016/j.jtcvs.2015.08.032; PMID: 26384748 37. Evaluation of Valiant Mona LSA Feasibility Study. US National Institutes of Health, 2016. Available at: https://clinicaltrials. gov/ct2/show/NCT02365467 (accessed 2 February 2017) 38. Sultan S, Hynes N. One-year results of the multilayer flow modulator stent in the management of thoracoabdominal aortic aneurysms and type B dissections. J Endovasc Ther 2013;20:366–77. DOI: 10.1583/12-4077MR-R.1; PMID: 23731310 39. Vaislic CD, Fabiani JN, Chocron S, et al.; STRATO Investigators Group. One-year outcomes following repair of thoracoabdominal aneurysms with the multilayer flow modulator: report from the STRATO trial. J Endovasc Ther 2014;21:85–95. DOI: 10.1583/13-4553R.1; PMID: 24502488 40. Sultan S, Sultan M, Hynes N. Early mid-term results of the first 103 cases of multilayer flow modulator stent done under indication for use in the management of thoracoabdominal aortic pathology from the independent global MFM registry. J Cardiovasc Surg (Torino) 2014;55:21–32. PMID: 24356043

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