ICR 14.1 by Radcliffe Cardiology

Interventional Cardiology Review Volume 14 • Issue 1 • Spring 2019

Volume 14 • Issue 1 • Spring 2019

www.ICRjournal.com

OCT-guided Percutaneous Coronary Intervention in Bifurcation Lesions Luca Longobardo, Alessio Mattesini, Serafina Valente and Carlo Di Mario

Large Bore Vascular Closure: New Devices and Techniques Maarten P van Wiechen, Jurgen M Ligthart and Nicolas M Van Mieghem

TAVI for Pure Native Aortic Regurgitation: Are We There Yet? Eduardo A Arias, Amit Bhan, Zhan Y Lim and Michael Mullen

Patent Foramen Ovale Closure in 2019 Joel P Giblett, Omar Abdul-Samad, Leonard M Shapiro, Bushra S Rana and Patrick A Calvert

ISSN: 1756-1477

Patent Foramen Ovale Seen in 3D

A Guidewire in Advanced Distal to the Bifurcation Carina

Calcification of the Posterior Arterial Wall

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Volume 14 • Issue 1 • Spring 2019

www.ICRjournal.com

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

Editorial Board Fernando Alfonso

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

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

Demosthenes Katritsis

Jeffrey Popma

Athens Euroclinic, Athens

Beth Israel Deaconess Medical Center, Boston

Tim Kinnaird

Gennaro Sardella

University Hospital of Wales, Cardiff

Sapienza University of Rome, Rome

Ajay Kirtane

Andrew SP Sharp

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

Royal Devon and Exeter Hospital and University of Exeter, Exeter

Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib

Elliot Smith

Lutz Buellesfeld

Didier Locca

London Chest Hospital, Barts Health NHS Trust, London

Sergio Baptista

Hospital CUF Cascais and Hospital Fernando Fonseca, Cascais

Marco Barbanti

Ferrarotto Hospital, Catania

Olivier Bertrand

University Hospital, Bern

Jonathan Byrne

King’s College Hospital, London

Antonio Colombo

San Raffaele Hospital, Milan

Justin Davies

Imperial College NHS Trust, London

Carlo Di Mario

Royal Brompton & Harefield NHS Foundation Trust, London

London Chest Hospital, Barts Health NHS Trust, London

San Raffaele Hospital, Milan

Lausanne University Hospital, Lausanne

Lars Søndergaard

Roxana Mehran

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Mount Sinai Hospital, New York

Thomas Modine

Gregg Stone

CHRU de Lille, Lille

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

Jeffrey Moses

Corrado Tamburino

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

Ferrarotto & Policlinico Hospital and University of Catania, Catania

Marko Noc

Nicolas Van Mieghem

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Erasmus University Medical Center, Rotterdam

Sameer Gafoor

Keith Oldroyd

CVPath Institute, Maryland

CardioVascular Center, Frankfurt

Golden Jubilee National Hospital, Glasgow

Juan Granada

Crochan J O’Sullivan

CRF Skirball Research Center, New York

Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

Eric Eeckhout

Centre Hospitalier Universitaire Vaudois, Lausanne

University Hospitals Bristol, Bristol

Cover image © Shutterstock

A Pieter Kappetein

McGill University Health Center, Montreal

Renu Virmani Mark Westwood

Cardiovascular Center Darmstadt, Darmstadt

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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 thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1756–1477 • eISSN: 1756–1485

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Established: June 2006 | Frequency: Tri-annual | Current issue: Spring 2019

Aims and Scope

Submissions and Instructions to Authors

• 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.

• 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, Jonathan McKenna jonathan.mckenna@radcliffe-group.com

Structure and Format • Interventional Cardiology Review is a tri-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

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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 abstracted, indexed and listed in PubMed, Embase, Scopus and Google Scholar. All articles are published in full on PubMed Central one month after publication.

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

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Open Access, Copyright and Permissions Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/ legalcode). Radcliffe Cardiology retain all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor.

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

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Contents

Foreword Simon Kennon

DOI: https://doi.org/10.15420/icr.2019.14.1.FO1

Coronary OCT-guided Percutaneous Coronary Intervention in Bifurcation Lesions

Luca Longobardo, Alessio Mattesini, Serafina Valente and Carlo Di Mario DOI: https//:doi.org/10.15420/icr.2018.17.2

Contemporary Management of Stent Failure: Part One

Nikhil Pal, Jehangir Din and Peter O’Kane DOI: https://doi.org/10.15420/icr.2018.39.1

Structural Large-bore Vascular Closure: New Devices and Techniques

Maarten P van Wiechen, Jurgen M Ligthart and Nicolas M Van Mieghem DOI: https://doi/10.15420/icr.2018.36.1

Cerebral Embolic Protection in TAVI: Friend or Foe

Michael Teitelbaum, Rafail A Kotronias, Luciano A Sposato and Rodrigo Bagur DOI: https://doi.org/10.15420/icr.2018.32.2

TAVI for Pure Native Aortic Regurgitation: Are We There Yet?

Eduardo A Arias, Amit Bhan, Zhan Y Lim and Michael Mullen DOI: https//doi.org/10.15420/icr.2018.37.1

How to Make the TAVI Pathway More Efficient

Didier Tchetche, Chiara de Biase, Bruno Brochado and Antonios Mastrokostopoulos DOI: https://doi.org/10.15420/icr.2018.28.2

Patent Foramen Ovale Closure in 2019

Joel P Giblett, Omar Abdul-Samad, Leonard M Shapiro, Bushra S Rana and Patrick A Calvert DOI: https://doi.org/10.15420/icr.2018.33.2

Device-Related Thrombus After Left Atrial Appendage Closure

Philippe Garot, Bertrand Cormier and Jérôme Horvilleur DOI: https://doi.org/10.15420/icr.2018.21.3

Why Did COAPT Win While MITRA-FR Failed? Defining the Appropriate Patient Population for MitraClip

Kimberly Atianzar, Ming Zhang, Zachary Newhart and Sameer Gafoor DOI: https://doi.org/10.15420/icr.2018.40.1

Erratum Erratum to: Common and Uncommon CTO complications

Johannes Rigger, Colm G. Hanratty and Simon J Walsh DOI: https://doi.org/10.15420/icr.2018.35.1

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Foreword

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

his issue of Interventional Cardiology Review contains a particularly broad selection of acronyms: from OCT to LAAO via PFO, TAVI, COAPT and MITRA-FR.

Coronary papers are in the minority on this occasion, but the two papers cover three fundamental issues in the field of stent failure, bifurcation disease and intracoronary imaging. The management of stent failure by Nikhil Patel et al. is part one of a comprehensive mini-series. The structural papers cover a wide variety of technologies. I must congratulate Joel Giblett et al. on the clarity of their paper on contemporary management of PFOs, while Philippe Garot et al. provide expert guidance in their article ‘Device-Related Thrombus After Left Atrial Appendage Closure’. Kimberly Atianzar et al. talk us through the enormous amount we have learnt from the near simultaneous publication of the two recent MitraClip papers, COAPT and MITRA-FR, with opposite outcomes. As we start to use third- and fourth-generation transcatheter aortic valve implantation (TAVI) devices, vascular access complications become relatively more common and large bore closure devices are an area of increasing interest to TAVI operators. Maarten P van Wiechen et al. have provided an excellent review of techniques and devices available. Despite the sophistication of current TAVI prostheses, the management of pure aortic regurgitation remains difficult and Eduardo Arias et al. have comprehensively explored the issues that need to be addressed when considering transcatheter treatment of such patients. The role of cerebral protection in TAVI remains uncertain and, as such, the analysis of this issue by Michael Teitelbaum et al. is welcome. The wide variety of devices and procedures discussed in the issue serve to emphasise the problems we are likely to encounter in future with funding and with lab space. In this context the paper by Didier Tchetche et al. on how to make the TAVI pathway more efficient, is important both in principle and in practice.

DOI: https://doi.org/10.15420/icr.2019.14.1.FO1

Access at: www.ICRjournal.com

Coronary

OCT-guided Percutaneous Coronary Intervention in Bifurcation Lesions Luca Longobardo, 1,2 Alessio Mattesini, 2 Serafina Valente 2 and Carlo Di Mario 2 1. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 2. Interventional Structural Cardiology Division, Department of Heart, Lung and Vessels, Careggi University Hospital, Florence, Italy

Abstract Coronary artery bifurcation lesions remain challenging despite significant advancements in stent technology and development of specific bifurcation stenting approaches. Optical coherence tomography (OCT) is the intracoronary imaging technique with the highest resolution and can generate automatically contoured lumen areas across the variable geometry of bifurcation lesions. Knowledge of plaque severity and composition facilitates planning of the best strategy for percutaneous coronary intervention (PCI) and stenting. In particular, the provisional stent strategy preferred in this context can be modified when there is high risk of side-branch compromise at the ostium after main vessel stenting. OCT is unique because it allows the identification of the site of guide wire crossing, an important determinant of the final result. OCT can also be used to assess the procedural success of new dedicated bifurcation stent technologies and for the evaluation at follow-up of potential predictors of stent thrombosis, including stent malapposition, stent under-expansion and stent-edge dissection. Finally, the development of 3D OCT allows a better evaluation of coronary anatomy – particularly of side branch ostium that is difficult to visualise by 2D OCT – further improving the value of this technique in guiding PCI in these patients.

Keywords Bifurcation lesions, imaging, optical coherence tomography, percutaneous coronary intervention, stenting Disclosure: The authors have no conflicts of interest to declare. Received: 23 May 2018 Accepted: 4 October 2018 Citation: Interventional Cardiology Review 2019;14(1):5–9. DOI: https//:doi.org/10.15420/icr.2018.17.2 Correspondence: Carlo Di Mario, Interventional Structural Cardiology Division, Department of Heart, Lung and Vessels, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy. E: carlo.dimario@unifi.it Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Coronary artery bifurcation lesions are treated in 15–20 % of percutaneous coronary intervention (PCI) procedures and are still plagued by worse outcomes.1 This is in spite of recent significant advancements in stent technology in general and in bifurcation stenting techniques in particular. Conventional angiography provides only limited information about bifurcation anatomy, plaque distribution and stent apposition and expansion. As for all complex lesions, intravascular ultrasound (IVUS) has shown advantages over conventional angiographic guidance. Optical coherence tomography (OCT) has a resolution 10 times higher than that of IVUS and is able to provide valuable information at each step of PCI. This includes the measurement of coronary lumen in the mother vessel and daughter branches, the detection of plaque location, the planning of the most convenient stenting approach and the evaluation of stent expansion and strut apposition.2

Optical Coherence Tomography Imaging and Analysis OCT examination of bifurcation lesions should be performed in both the main vessel (MV) and the side branch (SB). Predilatation is often required to allow lesion crossing and effective blood clearance during the examination. Automatic pullbacks are performed (usually at 20 mm/s) during contrast injection at a rate of 3 ml/s (right coronary) to 4–5 ml/s (left

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coronary) – ideally using a power injector. Full replacement of blood with clear crystalloid contrast is fundamental to clear the blood from the vessel to obtain diagnostic images, which can be challenging in large vessels. Optimal sitting of the guiding catheter should be checked before starting the pullback. A 6 Fr catheter is normally sufficient for optimal imaging, allowing the use of 6 Fr guiding catheters as standard. The OCT catheter is inserted distal to the lesion or stent to be examined, and the pullback continued until either the guiding catheter is reached or the maximal pullback length is completed. A longitudinal cross section of the entire vessel length is automatically generated and the cross sections of interest can be scrolled. Moreover, the real-time co-registration of OCT images with angiography facilitates combined angiographic and intracoronary high-resolution imaging of coronary arteries directly at the catheter laboratory, where the exact localisation of the acquired OCT frame can be displayed side-by-side on the angiogram. This allows a more precise identification of the carina and side-branches. Because of the clear interface between the lumen and wall, current software provides automatic detection of the lumen area and the percentage of area of stenosis, comparing user-defined reference and stenotic segments. Most OCT users value the possibility to detect in approximately 70 % of distal reference segments the media and obtain a manual measurement of the media-to-media diameter.

Access at: www.ICRjournal.com

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Coronary Table 1: Strengths and Limitations of 2D Optical Coherence Tomography Strengths

Limitations

• H igh resolution (axial 10–20 μm, lateral 20–40 μm). • Reliable evaluation of coronary anatomy, lumen area and lesion severity. • Detailed assessment of plaque composition and distribution. • Improved planning of the appropriate revascularisation strategy. • Valuable guide for SB rewiring. • Accurate detection of stent under-expansion, stent strut malapposition and stent edge dissection.

• L ow tissue penetration (approximately 2 mm) • The need for contrast injection. • Risk of SB dissection (if vessel is small). • Difficult evaluation of large vessels (improved by 3D OCT). • Difficult evaluation of SB ostium (improved by 3D OCT). • The need for specific training. • High cost.

Figure 1: Bifurcation Characteristics Guiding the Interventional Approach Two-stent approach

Plaque distribution >50–60°

<50°

Bifurcation angle ≥2.5 mm

Diameter side branch Length side branch stenosis

Only ostial

<2.5 mm

>5 mm

The left panel summarises the elements that suggest a provisional approach, including an eccentrically distributed plaque placed opposite to the carina, a bifurcation angle ≥50–60°, a diameter of the distal side branch reference segment ≥2.5 mm and evidence of ostial SB stenosis. The right panel summarises the elements that contribute to side branch ostium stenosis after bifurcation main vessel stenting, suggesting the use of the two-stent approach.

The recent Optical Coherence Tomography Compared With Intravascular Ultrasound And Angiography To Guide Coronary Stent Implantation: A Multicenter Randomized Trial In Percutaneous Coronary Intervention (ILUMIEN III: OPTIMIZE PCI) study obtained superior results compared with the previous OCT/IVUS head-to-head comparisons.3 The study employed a specific OCT-guided stent optimisation algorithm based on measurement of the external elastic lamina in the proximal and distal reference segments, designed to achieve larger stent dimensions and more complete lesion coverage. However, the low-depth penetration of light through lipid-rich plaque often results in an inability of OCT to visualise the true vessel size (delineated by the external elastic lamina) at the lesion site, which is why the use of the media-to-media diameter is widespread. While the main goal of the OCT examination is the identification of proximal and distal reference in the main vessel and the length of the lesion, OCT examination of the SB may be helpful if there are doubts about plaque burden both in terms of severity and length, which are the two main determinants of the need for a two-stent technique. Because each OCT round requires 10–15 ml of contrast, in general the assessment should be performed once before stenting and after

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Optical Coherence Tomography-guided Decision Making Coronary Bifurcation Anatomy, Lesion Severity and Choice of Revascularisation Strategy

OCT = optical coherence tomography; SB = side branch.

Provisional approach

optimisation of the stent results based on the diameter measurements obtained with the pre-stent OCT. The repetition of the OCT pullback in the SB after stenting can be avoided when the SB is small or only a provisional approach with no SB stent has been used. On the contrary, in the case of two-stent implantation, the evaluation of SB ostium is of particular importance, often difficult with angiography or OCT examination of the MV alone. 3D OCT reconstruction can, in part, overcome some of the limitations of 2D OCT, allowing a better view of SB ostium and with immediate detection and colour coding of the malapposed struts.4 The strengths and limitations of 2D OCT are summarised in Table 1.

OCT provides an accurate evaluation of all the segments of the vessel involved in the bifurcation, including the proximal and distal MV and the SB, with the difficulties related to the assessment of SB ostium discussed in the previous section. Careful evaluation of bifurcation anatomy and plaque distribution is of great importance because it influences the main decision in the revascularisation strategy: is a single stent likely to maintain good flow in the side-branch as well (provisional single stent) or should a two stent strategy should be the preferred approach from the outset? OCT can identify plaque severity in the main vessel and, when this is distributed eccentrically opposite to the carina, the chances of SB occlusion are small. The other four elements important for the decision (SB ostial stenosis, bifurcation angle, length of the proximal SB disease, diameter of the distal SB reference segment) can be explored only in part from a MV OCT run. However, in general, the combination of OCT and angiographic information are sufficient for an informed decision (Figure 1). Highly significant correlation between the measurements of coronary lumen performed by OCT and IVUS has been reported, with slight, predictable, overestimation of lumen areas by IVUS.5,6 Watanabe et al. demonstrated that a bifurcation angle <50 % and a length from the proximal branching point to the carina tip of <1.70 mm had a significant prognostic power in predicting SB obstruction after MV stenting.7 Furthermore, high lipid content in the MV lesion and contralateral location of lipid in the bifurcation area – particularly in the proximal wall opposite to the flow divider that is the area with a higher risk of developing vulnerable plaques and vessel rupture – have been shown to contribute to SB ostium stenosis after MV provisional stenting.8 In this context, OCT is able to provide important information about plaque composition and vulnerability compared with IVUS and angiography, being able to effectively detect lipid content of the plaque. This should be taken into account by the operator when choosing between a single- versus two-stent revascularisation strategy. Indeed, when the risk of SB closure is low, a provisional SB stent implantation strategy should be considered the standard approach for treatment of bifurcation lesions.9 However, when the aforementioned parameters suggest a high risk of SB ostium stenosis or when an ostial stenosis of ≥50 % extending >2.5 mm from the carina is detected, a two-stent technique should be preferred.10,11

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OCT in Bifurcation Lesions Figure 2: Use of OCT at Different Stages of Assessment I

III

Panel I. OCT baseline lesion assessment. A: Proximal lumen reference; B, C: Quality characterisation of plaque composition showing fibro lipidic plaque with mild calcifications; D: MLA: 2.80 mm2; E: Distal lumen reference. Panel II. OCT assessment post stent deployment. A: Proximal stent edge; B: Pre-bifurcartion cross section; C: Cross section at the bifurcation site with jailed wire into the side branch (*); D: Distal stent edge. Panel III. OCT-guided side branch rewiring and kissing balloon optimisation. A: Better stent expansion at the proximal edge and (B) proximally to the bifurcation site; C: Stent cells are well opened at the bifurcation site after rewiring and kissing balloon dilatation (* indicates the only malapposed strut); D: Cross section after the bifurcation site showing good stent apposition and expansion without stent deformation after kissing balloon optimisation. Panel IV. OCT assessment of the side branch after stent implantation. A, B: Cross sections show optimal stent implantation proximally to the bifurcation; C: Widely opened side branch ostium without significant stent malapposition; D: No evidence of dissection at the side branch ostium with MLD of 2.6 mm; E, F: Distally to the side branch ostium there is evidence of fibro-lipidic plaque without significant stenosis of the lumen. OCT = optical coherence tomography; MLA = minimal lumen area; MLD = minimal lumen diameter.

Moreover, OCT detects calcium effectively, and can provide information about its thickness and area, along with identifying plaques associated with poor stent expansion that should prompt consideration for pre-stent lesion preparation with techniques such as rotational atherectomy, orbital atherectomy, or cutting or scoring balloons.12

Stent Choice, Implantation and Side Branch Rewiring Selecting the correct stent size is particularly relevant in bifurcation lesions because stent oversizing in the MV can determine SB distortion and narrowing because of carina shifting.7 Stents should be sized according to the distal MV reference diameter (Figure 2) and permanent drug-eluting stents should be the stents of choice.10,13 As mentioned, OCT provides reliable measurement of the coronary lumen, improving the selection of the correct stent size, as well as the correct balloon size for the proximal MV stent dilatation, considered a standard step in bifurcation treatment.10 One of the most unique roles played by OCT in the treatment of bifurcation lesions is to guide and optimise SB rewiring. Indeed, wire recrossing to the SB is necessary when a two-stent strategy is chosen or when there is an impaired SB flow after stenting the MV â&#x20AC;&#x201C; frequently this step of the procedure can prove challenging. OCT allows a careful evaluation of wire positions after stent rewiring to ensure optimal SB recrossing and to exclude accidental rewiring outside the stent (Figure 3). It has been widely demonstrated that a distal stent cell for recrossing

INTERVENTIONAL CARDIOLOGY REVIEW

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reduces the extent of the metallic carina and favours appropriate stent expansion and stent strut apposition at the ostium of the SB.14,15 In this context, 3D-OCT provides more valuable information than 2D. It allows improved assessment of the SB ostium and rewiring position into the SB and a good detection of the configuration of overhanging stent in front of the SB ostium, reducing the incidence of incomplete stent apposition compared with 2D.4,15,16 OCT has also been used to evaluate the effectiveness of new devices dedicated to bifurcation lesions. The efficacy of the Tryton dedicated side branch stent (Tryton Medical) was tested in small populations17,18 then more widely in the Prospective, Single Blind, Randomized Controlled Study to Evaluate the Safety and Effectiveness of the Tryton Side Branch Stent Used With DES in the Treatment of De Novo Bifurcation Lesions in the MB and SB in Native Coronaries (TRYTON) trial,19 which failed to demonstrate superiority of this new stent above conventional provisional stenting. Similarly, OCT was used to evaluate the STENTYS stent (STENTYS SA), a provisional, self-expanding nitinol drug-eluting or bare-metal stent reported to have a good success rate along with a low rate of major adverse cardiac events.20

Evaluation of Stent Implantation After Percutaneous Coronary Intervention After the implantation of one or more stents in the bifurcation, OCT is definitely the technique of choice for the assessment of the final

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Coronary Figure 3: Example of OCT Assessment of Side-branch Rewiring After Stent Implantation

A: The guidewire is advanced distal to the bifurcation carina; B: The stent crossing site is located at the level of a very distal cell (C) with the wire correctly positioned in the side branch. *indicates the guidewire. OCT = optical coherence tomography.

treatment results (Figure 2). Indeed, stent under-expansion, stent strut malapposition, and stent-edge dissection are particularly common in bifurcation lesions and, while often missed by angiography,21 can be accurately detected with the high-resolution images provided by OCT. These findings seem to be related with an increased stent thrombosis and stent restenosis risk.21 Stent under-expansion, defined as an in-stent minimum lumen area <70 % of the average reference lumen area22 or as a minimal stent area of the proximal and/or distal segment <90 % of the proximal and/or distal reference lumen area respectively23, has been correlated with a increased risk of all-cause mortality, myocardial infarction and target lesion revascularisation in several trials that used OCT for the assessment of PCI results. These include the Clinical Impact of OCT Findings During PCI II (CLI-OPCI II)22 and the ILUMIEN III: OPTIMIZE

l Suwaidi J, Berger PB, Rihal CS, et al. Immediate and A longterm outcome of intracoronary stent implantation for true bifurcation lesions. J Am Coll Cardiol 2000;35:929–36. https://doi.org/10.1016/S0735-1097(99)00648-8; PMID: 10732890. Di Mario C, Iakovou I, van der Giessen WJ, et al. Optical coherence tomography for guidance in bifurcation lesion treatment. EuroIntervention 2010;6(Suppl J):J99–106. https://doi. org/10.4244/EIJV6SUPJA16; PMID: 21930500. Ali ZA, Maehara A, Généreux P, et al. Optical coherence

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PCI3 studies. The same trials reported a high incidence of stent strut malapposition and stent edge dissection,3,22 although the clinical importance of these findings is debated.3,21–23 However, evidence of suboptimal stent implantation provided by OCT can prompt the interventionalist to improve the stent placement, guiding the choice of the proper balloon size for post-dilatation and reducing the risk of poor outcomes for the patient.

Conclusion OCT is a fundamental tool in the interventional cardiologist’s arsenal for the treatment of complex coronary lesions such as bifurcation lesions. Indeed, OCT provides valuable additional information compared with angiography and IVUS that can guide the operator at each step of the PCI – from the planning of the appropriate revascularisation strategy to the assessment of final results.

tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial. Lancet 2016;388:2618–28. https://doi.org/10.1016/S01406736(16)31922-5; PMID: 27806900. Nagoshi R, Okamura T, Murasato Y, et al. Feasibility and usefulness of three-dimensional optical coherence tomography guidance for optimal side branch treatment in coronary bifurcation stenting. Int J Cardiol 2018;250;270–4. https://doi.org/10.1016/j.ijcard.2017.09.197; PMID: 29030141.

kamura T, Onuma Y, Garcia-Garcia HM, et al. First-in-man O evaluation of intravascular optical frequency domain imaging (OFDI) of Terumo: A comparison with intravascular ultrasound and quantitative coronary angiography. EuroIntervention 2011;6:1037–45. https://doi.org/10.4244/EIJV6I9A182; PMID: 21518674. Gonzalo N, Serruys PW, García-García HM, et al. Quantitative ex vivo and in vivo comparison of lumen dimensions measured by optical coherence tomography and intravascular ultrasound in human coronary arteries. Rev

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OCT in Bifurcation Lesions

Esp Cardiol 2009;62:615–24. https://doi.org/10.1016/S03008932(09)71328-4; PMID: 19480757. Watanabe M, Uemura S, Sugawara Y, et al. Side branch complication after a single-stent crossover technique: prediction with frequency domain optical coherence tomography. Coron Artery Dis 2014;25:321–9. https://doi. org/10.1097/MCA.0000000000000091; PMID: 24769514. 8. Kini AS, Vengrenyuk Y, Pena J, et al. Plaque morphology predictors of side branch occlusion after provisional stenting in coronary bifurcation lesion: Results of optical coherence tomography bifurcation study (ORBID). Catheter Cardiovasc Interv 2017;89:259–68. https://doi.org/10.1002/ccd.26524; PMID: 27029714. 9. Chen SL, Santoso T, Zhang JJ, et al. A randomized clinical study comparing double kissing crush with provisional stenting for treatment of coronary bifurcation lesions: results from the DKCRUSH-II (Double Kissing Crush versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions) trial. J Am Coll Cardiol 2011;57:914–20. https://doi.org/10.1016/j.jacc.2010.10.023; PMID: 21329837. 10. Lassen JF, Holm NR, Banning A, et al. Percutaneous coronary intervention for coronary bifurcation disease: 11th consensus document from the European Bifurcation Club. EuroIntervention 2016;12:38–46. https://doi.org/10.4244/ EIJV12I1A7; PMID: 27173860. 11. Foin N, Mattesini A, Ghione M, et al. Tools & techniques clinical: Optimising stenting strategy in bifurcation lesions with insights from in vitro bifurcation models. EuroIntervention 2013;9:885–7. https://doi.org/10.4244/EIJV9I7A144; 7.

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PMID: 24280162. 12. K ubo T, Shimamura K, Ino Y, et al. Superficial calcium fracture after PCI as assessed by OCT. JACC Cardiovasc Imaging 2015;10:1228–9. https://doi.org/10.1016/j.jcmg.2014.11.012; PMID: 25797130. 13. Mattesini A, Secco GG, Dall’Ara G, et al. ABSORB biodegradable stents versus second-generation metal stents: A comparison study of 100 complex lesions treated under OCT guidance. JACC Cardiovasc Interv 2014;7:741–50. https://doi.org/10.1016/j.jcin.2014.01.165; PMID: 25060016. 14. Alegría-Barrero E, Foin N, Chan PH, et al. Optical coherence tomography for guidance of distal cell recrossing in bifurcation stenting: choosing the right cell matters. EuroIntervention 2012;8:205–13. https://doi.org/10.4244/ EIJV8I2A34; PMID: 22581489. 15. Fujimura T, Okamura T, Tateishi H, et al. Serial changes in the side-branch ostial area after main-vessel stenting with kissing balloon inflation for coronary bifurcation lesions, assessed by 3D optical coherence tomography. Eur Heart J Cardiovasc Imaging 2018;19:1117–25. https://doi.org/10.1093/ ehjci/jex213; PMID: 29069325. 16. Koiwaya H, Takemoto M, Ogata K, et al. The impact of threedimensional optical coherence tomography and kissingballoon inflation for stent implantation to bifurcation lesions. J Cardiol Cases 2016;13:133–6. https://doi.org/10.1016/ j.jccase.2015.12.003 17. Tyczynski P, Ferrante G, Kukreja N, et al. Optical coherence tomography assessment of a new dedicated bifurcation

stent. EuroIntervention 2009;5:544–51. https://doi.org/10.4244/ EIJV5I5A89; PMID: 20142174. 18. F errante G, Kaplan AV, Di Mario C. Assessment with optical coherence tomography of a new strategy for bifurcational lesion treatment: The tryton side-branch stent. Catheter Cardiovasc Interv 2009;73:69–72. https://doi.org/10.1002/ ccd.21803; PMID: 19089962. 19. Genereux P, Kumsars I, Lesiak M, et al. A randomized trial of a dedicated bifurcation stent versus provisional stenting in the treatment of coronary bifurcation lesions. J Am Coll Cardiol 2015;65:533–43. https://doi.org/10.1016/j.jacc.2014.11.031; PMID: 25677311. 20. Verheye S, Grube E, Ramcharitar S, et al. First-in-man (FIM) study of the Stentys bifurcation stent – 30 days results. EuroIntervention 2009;4:566–71. https://doi.org/10.4244/ EIJV4I5A96; PMID: 19378675. 21. Burzotta F, Talarico GP, Trani C, et al. Frequency-domain optical coherence tomography findings in patients with bifurcated lesions undergoing provisional stenting. Eur Heart J Cardiovasc Imag 2014;15:547–55. https://doi.org/10.1093/ehjci/ jet231; PMID: 24255135. 22. Prati F, Romagnoli E, Burzotta F, et al. Clinical impact of OCT findings during PCI: The CLI-OPCI II study. JACC Cardiovasc Imaging 2015;8:1297–305. https://doi.org/10.1016/j. jcmg.2015.08.013; PMID: 26563859. 23. Santos MC, Lin T, Barlis P. In-stent restenosis associated with stent malapposition: seven year optical coherence tomography findings. Int J Cardiol 2011;147:149–51. https://doi. org/10.1016/j.ijcard.2010.02.068; PMID: 20227776.

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Contemporary Management of Stent Failure: Part One Nikhil Pal, Jehangir Din and Peter O’Kane Dorset Heart Centre, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK

Abstract The occurrence of in-stent restenosis (ISR) still remains a daunting challenge in the current era, despite advancements in coronary intervention technology. The authors explore the underlying pathophysiology and mechanisms behind ISR, and describe how the use of different diagnostic tools helps to best elucidate these. They propose a simplistic algorithm to manage ISR, including a focus on how treatment strategies should be selected and a description of the contemporary technologies available. This article aims to provide a comprehensive outline of ISR that can be translated into evidence-based routine clinical practice, with the aim of providing the best outcomes for patients.

Keywords Coronary heart disease, bare metal stent, drug-eluting stent, stent failure, in-stent restenosis Disclosure: PO is a speaker and proctor for Philips and Abbott Vascular. All other authors have no conflicts of interest to declare. Received: 14 December 2018 Accepted: 21 January 2019 Citation: Interventional Cardiology Review 2019;14(1):10–6. DOI: https://doi.org/10.15420/icr.2018.39.1 Correspondence: Peter O’Kane, Dorset Heart Centre, Royal Bournemouth Hospital, Castle Lane East, Bournemouth BH7 7DW, UK. E: Peter.O’Kane@rbch.nhs.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The reduction in risk of cardiac death offered by revascularisation in patients with moderate to large amount of stress-induced myocardial ischaemia has driven advancements in percutaneous coronary intervention (PCI) technology over the last four decades.1 However, despite significant progress in the techniques, equipment and pharmacotherapy, target lesion failure remains the Achilles heel of a PCI approach in patients with coronary heart disease. The advent of the bare metal stent (BMS) introduced a major shift and promised improved outcomes over percutaneous balloon angioplasty (POBA). The BMS prevented the elastic recoil and constrictive remodelling that was seen frequently with POBA (32–55% incidence).2,3 However, it was soon realised that the benefits of deploying a metallic scaffold were still accompanied with a significant (17–41%) incidence of restenosis within the stented segment.4–7 Further research and development in stent technology led to the emergence of drug-eluting stents (DES), with successive generations produced on platforms with different anti-proliferative drugs, advanced polymers, improved stent cell design and thinner metallic struts. This promised to solve the spectre of in-stent restenosis (ISR) completely by preventing early tissue formation after stent deployment. These improvements have certainly led to superior results with reduced target lesion failure and target lesion revascularisation, MI and stent thrombosis when compared with BMS or the earlier generation of DES.8,9

approach for identifying the mechanism of ISR and describe strategies to select devices for therapy and illustrate this with clinical cases (Figures 1–6).

Definition of In-stent Restenosis ISR is angiographically defined as >50% reduction in luminal area within the stent or in the adjacent native vessel (5 mm of the proximal or distal stent edge).12 The clinical definition, however, includes the angiographic appearance and the presence of one of the following: • clinical symptoms suggestive of coronary heart disease; • ECG changes suggestive of underlying coronary ischaemia; • significant limitation in coronary flow as measured by a positive haemodynamic assessment such as fractional flow reserve or instantaneous wave-free ratio (iFR); • minimum cross-sectional area of <4 mm2 (6 mm2 for left main stem) using intravascular ultrasound; or • a reduction of >70% in luminal area, even in the absence of symptoms.13 Mehran’s classification system was developed for morphological classification of BMS ISR, but it has also shown prognostic value in DES ISR as well.14,15 As per the classification, the ISR is described to be focal, diffuse, proliferative or occlusive, and it helps in predicting the rate of revascularisation (19%, 35%, 50% and 98%, respectively).14

Risk Factors for Developing In-stent Restenosis However, despite these major developments, the incidence of DES ISR remains between 5 and 10% and is an independent predictor of mortality, thereby making it the foremost adversary of an interventional cardiologist in the modern era.10,11 This review highlights a simplified

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Several factors play important roles in the development of ISR in BMS and DES (Figure 7). Diabetes is perhaps the most well-established patient risk factor for ISR, particularly with BMS – the rate of BMS ISR may be as high as 30–50%.16–19 There are various lesion characteristics

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Contemporary Management of Stent Failure Figure 1: Chronic Total Occlusion of Left Anterior Descending Artery Secondary to Stent Failure

Figure 3: Stent Failure Secondary to Undersized Stent

Patient with stable angina and anterior wall perfusion defect admitted for percutaneous coronary intervention of the left anterior descending (LAD) artery with chronic total occlusion (CTO). Previous drug-eluting stent (DES) to proximal LAD was inserted >10 years ago, with visible unstented segment present at point of CTO with further DES in LAD beyond this. Contralateral biradial arterial access with lesion crossed easily anterogradely using a Sion Blue wire (Asahi) and Turnpike LP catheter (Teleflex). After pre-dilatation using 1 mm, 2 mm and 3 mm noncompliant (NC) balloons sequentially, intravascular ultrasound (IVUS) was performed. This confirmed a new lesion at LAD ostium (Aii and green *), area of bridging distally to the old stent, area of unstented segment between the two stents (Aiii and yellow *) and undersized stents, which were well apposed to the atheroma (Ai and Aiv purple *). The lesion was then further dilatated using a 3 × 10 mm Angiosculpt (Philips) and stented using a 3 × 38 mm DES, which was post-dilatated with 3.5 mm and 4.0 mm NC balloons. Final IVUS confirmed well-apposed stent at ostium (Bi) and at distal edge (Bii).

The right coronary artery (RCA) had previous percutaneous coronary intervention (PCI) with first generation drug-eluting stent (Cypher, Cordis) in 2008, with a subsequent very late stent thrombosis at 2 years with percutaneous balloon angioplasty only. Patient had recurrence of stable angina and was admitted for PCI to the RCA after previous pressure wire had found fractional flow reserve of 0.78. Angiographic images of the RCA pre-PCI are depicted in A. Intravascular ultrasound (IVUS) showed an eccentric lesion within the mid-RCA stent with 180° calcific plaque (A1) and more distally confirmed the presence of undersized stent in a large vessel (A2). The vessel was then pre-dilatated with 4.0 mm noncompliant balloon in the mid-proximal segment of the stented vessel and 3.5 mm × 10.0 mm AngioSculpt (Philips) in the focal area of calcific plaque (A1). Given previous first generation (undersized) DES, the RCA was treated with new contemporary DES (4 mm × 38 mm, 4 mm × 38 mm and 4 mm × 28 mm) rather than a drug-eluting balloon. Post dilatation was performed using a 4 × 20 mm noncompliant balloon to 20 atm. Final angiographic and IVUS result confirmed well-deployed stents with satisfactory final result (B and B1).

Figure 2: Stent Failure Secondary to Probable Stent Fracture in Mid-LAD Stents

This 85-year-old patient had previous aortic valve replacement and coronary artery bypass surgery with left internal mammary artery (LIMA) to the left anterior descending (LAD) artery. Five years later he developed angina and had subsequent percutaneous coronary intervention mid-LAD with two drug-eluting stents (DES) instead of treatment to an insertional LIMA graft stenosis. However, he was then admitted with unstable angina and a recent cardiac MRI had shown viability with inducible ischaemia in the LAD territory. From the left radial artery, angiography of LAD via LIMA graft clearly showed an insertion stenosis (A) which was treated with a single 2.75 × 24.0 mm DES post dilated with 3 x 8 mm noncompliant (NC) balloon (B). Intravascular ultrasound (IVUS) confirmed lesion (A1) and showed the native LAD stent that was likely fractured with occlusive plaque within. Angiography of native left coronary artery revealed tight ostial stenosis and, as expected, complete occlusion in the mid vessel within the stented segment (C and D). Pressure wire of LAD into the major diagonal branch revealed instantaneous wave-free ratio (iFR) 0.35 (C1), with two very clear step-up segments on SyncVision (Philips) scout iFR pullback (C2). On IVUS both segments corresponded to severe lesions of new ostial disease (C3) and in-stent restenosis (C4) due to neo-intimal hyperplasia and relative underexpansion of the previous stents. Both areas were treated with pre-dilatation using 2.5 mm, 3.0 mm and 3.5 mm NC balloons and AngioSculpt (Philips) 3 mm × 10 mm to treat the under-expanded segment successfully. The ostial de novo disease was treated with 3.5 mm × 23 mm DES and a 3.0 x 20 drug-eluting balloon was used for the proximal-mid vessel in-stent restenosis. Final angiographic (E and F) and IVUS (E1 and E2) confirmed well-apposed stent. The optimal result in the LAD was achieved, while leaving the area of stent fracture in the bridging segment untreated.

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Figure 4: Anterior ST-elevation MI Secondary to a Very Late Stent Thrombosis of Left Anterior Descending Artery Stent Failure

Left anterior descending (LAD) artery had been stented in 2006 with 2.75 mm × 23.0 mm Cypher (Cordis) and post-dilatated with 3 x 8 mm noncompliant (NC) balloon without intracoronary imaging (A and B). Patient was admitted with ST-elevation MI and there was complete occlusion of the proximal LAD with Thrombolysis in MI (TIMI) flow score of 0 (C). This lesion was predilatated with a 2.5 mm NC balloon and TIMI 3 flow was restored. Intravascular ultrasound (IVUS) was performed which confirmed that the area of occlusion was in an undersized stent at the LAD ostium and proximally, which was apposed to the atheroma (Di and Dii), and in-segment stenosis distal to the stent (Diii). Pre-dilatation of the lesion with 3.0 mm and 3.5 mm noncompliant balloons optimised the area of in-stent restenosis without need for scoring balloons, given the absence of fibrocalcific plaque. Given that the very late stent thrombosis was in a first generation undersized drug-eluting stent (DES), the lesion was covered with a second generation (3.0 × 18 and 3.5 × 38 mm) DES to cover the left main stem and postdilatated up to 4.5 mm proximally. Final angiographic and IVUS results were satisfactory (Ei–iii).

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Coronary Figure 5: Treatment of Severe In-stent Restenosis in Left Main Stem, Left Anterior Descending Artery and Left Circumflex Artery

Figure 7: Factors Influencing the Development of In-stent Restenosis

Pharmacological Drug resistance (dual antiplatelet therapy) Hypersensistivity to drug Hypersensistivity to polymer

Biological Plasma proteolytic enzymes Matrix metalloproteinases

Patient Diabetes Older Age Female Genetic Mechanical Stent malappostion Stent underexpansion Edge trauma Geographical miss Stent fracture This 82-year-old man had been treated with percutaneous coronary intervention to left main stem bifurcation with stenting to left anterior descending (LAD) artery and left circumflex artery (LCX) in 2013. He presented with unstable angina and had angiographically clear severe in-stent restenosis in the left main stem (LMS; A green *), LAD and LCX (B purple * and yellow *). After initial pre-dilatation with a 3 mm noncompliant (NC) balloon in both vessels, optical coherence tomography (OCT) was performed; this confirmed severe neointimal hyperplasia in LAD and LCX stents (Ci and Cii). In view of the vast bulk of material within the stent and fact that 3 mm × 15 mm NC kissing balloons did not fully expand (D), laser artherectomy was performed using 0.9 mm ELCA catheter (Philips) followed by use of Wolverine 3 mm × 10 mm cutting balloon (Boston Scientific). The initial intention was not to insert a further DES into the LCX, so an AngioSculpt X (Philips) 3.5 mm × 10 mm drug-eluting balloon was inflated on LCX to high pressure. However, OCT showed extensive fragmented tissue (not shown), so it was decided to use DES in a systematic bifurcation two-stent technique. The LAD was first stented with 3.5 mm × 23.0 mm to ostium and then LCX to LMS was treated with a 3.5 mm × 23 mm DES in a reverse TAP technique. Final kissing balloons expanded well (F) and final proximal optimisation technique to LMS with 4 × 8 mm performed. The final angiographic images were optimal (G and H).

Lesion Type B/C Long> 20mm Small vessel < 3mm Calcified Bifurcation disease Chronic total occlusion Ostial or tortuous segment

The factors that influence the development of in-stent restenosis can be divided into five categories: patient, lesion, mechanical (related to the index percutaneous coronary intervention), pharmacological and biological factors.16 The lesion characteristics highlighted may lead to non-uniform drug distribution of the stent and thus contribute to a higher incidence of in-stent restenosis.

Figure 8: Simplified Approach to Stent Failure Cases Stent Failure Anglographically severe/critical Unstable patient

YES

Figure 6: Stent Failure Secondary to Severe Calcification and Neo-atherosclerosis in Left Circumflex Artery

Intra-coronary imaging

NIH/NA

Haemodynamically significant?

YES

Under-expanded stent

Under-sized stent

Edge lesion

Atherectomy Scoring balloon

Cutting balloon Rotational

Excimer laser

DEB or DES depending on situation

Scoring balloon

NC balloon

DEB

DES

Finding severe/critical angiographic disease within a stent that is being considered for further percutaneous coronary intervention (PCI) should be guided by intra-coronary imaging. Less severe angiographic disease should be assessed by pressure wire assessment before proceeding with image-guided PCI. The most common causes of stent failure are highlighted, with suggestions of PCI tools to best prepare the vessel for further DES or DEB. DEB = drug-eluting balloon; DES = drug-eluting stent; NC = non-compliant; NIH/NA = neointimal hyperplasia/neo-atherosclerosis

Patient with a previous history of coronary artery bypass graft and percutaneous coronary intervention (PCI) with stable angina was admitted for elective coronary angiography. Moderate to severe in-stent restenosis was found in the mid segment of the native ungrafted left circumflex artery (LCX) and further severe calcified disease in the proximal LCX (A and B). Intravascular ultrasound (IVUS) confirmed the burden of calcification (Panel Bi) especially at the ostium. Balloon pre-dilation with a 2.5 mm x 20 mm noncompliant (NC) balloon showed proximal non-expansion (C) and hence this segment was modified with laser atherectomy using a 0.9 mm excimer laser atherectomy catheter set at 80 mmJ/mm2 and 80 Hz for approximately 10,000 pulses (D). AngioSculpt (Philips) 3 mm × 10 mm now clearly expands (E). The disease was further treated with a 3.5 mm × 33 mm drug-eluting stent (DES) to cover it and left main stenting with proximal optimisation technique was performed using a 4 mm x 8 mm NC balloon. A further 2.75 x 33 DES was overlapped more distally and post-dilatated with a 3 mm x 20 mm NC balloon to high pressure. Final angiographic images (F and G) with IVUS (Fi and Gi) confirmed well-deployed stents with optimal expansion.

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that lead to non-uniform drug distribution and thus contribute to a higher incidence of ISR. The presence of moderate or severe calcification is perhaps one of the most challenging aspects of PCI in contemporary practice. There is clear evidence that the degree of lesion calcification directly affects stent expansion. In many large-scale clinical studies, calcification has been shown to be proportionally linked to stent failure, with increased rates of target lesion failure, target vessel revascularisation, MI and death in patients with the most lesion calcification. 20,21 Advancing a stent through a calcified tortuous vessel may lead to disruption of polymer and/or

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Contemporary Management of Stent Failure drug on the surface, which can reduce the efficacy of even the bestdesigned DES. PCI of long lesions (>20 mm) and small calibre vessels (<3 mm and especially those <2.5 mm) carries a much higher risk of ISR and such characteristics are often seen when treating chronic total occlusion. The risk of ISR doubles if the length of the stented segment is >35 mm compared to <20 mm.12,22,23 The relation of vessel diameter to ISR was reported in the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, where vessel size <3 mm was related to a significantly higher incidence of ISR.24 Bifurcation lesions, especially those treated with a double stent (the main vessel and side branch technique), have a higher incidence of stent failure, particularly in the side branch.25

Pathophysiology of In-stent Restenosis It has been observed that ISR secondary to BMS versus DES has different characteristics, with important ones being time lag from stent implantation to presentation, morphology of the ISR itself and response to treatment.26,27 BMS ISR presents early (typically 6–8 months) as compared to DES ISR (typically after 2 years) which often has a delayed presentation.28 The initial inflammatory process ensues soon after the stent is implanted, and is characterised by deposition of platelets and fibrin, as well as adhesions of circulating neutrophils and macrophages. Over several weeks these cells are replaced by chronic inflammatory cells, which include macrophages and giant cells. Simultaneously, this vascular injury from the stent struts in the intima induces the initial stimuli for vascular smooth muscle cell proliferation and activation. As a result, the vascular smooth muscle cells migrate from the tunica media, and the myofibroblasts migrate from the tunica adventitia into the tunica intima, forming an extracellular matrix. This is proven by the systemic surge in the levels of the inflammatory markers post PCI and also by the presence of inflammatory cells in the plaque.29 These processes culminate in the formation of a neointimal layer over the stented segment, with its luminal side covered by the endothelial cells.22,30 DES ISR is characterised by delayed healing of the vessel wall secondary to stent components such as the durable polymer. Though the durable polymer facilitates drug delivery, it also results in a chronic nonspecific inflammatory process (especially the durable polymer on first generation DES), which results in incomplete neo-endothelialisation, and occasionally can cause a specific hypersensitivity reaction.31 This led to the development of biodegradable polymers, but recent data have suggested similar safety and efficacy of biodegradable polymer DES compared to second generation durable polymer DES.32 The above pathogenic processes lead to different time of onset and morphological characteristics. While BMS ISR peaks around 3–6 months after stent implantation and has a diffuse pattern of neointima formation, DES ISR has a predominantly focal pattern, with onset after 6–9 months and increasing up to 2 years after implantation.31,33

Neo-atherosclerosis When describing the pathophysiology of ISR, it is important to understand the process of neo-atherosclerosis. As with native vessel, the atherosclerotic process can affect neointima as well. This occurs due to incomplete endothelialisation, which is seen more

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commonly in DES as compared to BMS, primarily due to the elution of the drug itself.34,35 This results in uptake of circulating lipids and formation of plaque, which is thin-capped and occurs earlier in DES than BMS (2 years versus 6 years, respectively).34 There are several independent risk factors that lead to neo-atherosclerosis: young age, longer duration after stent implantation, sirolimus or paclitaxeleluting stents, smoking, chronic kidney disease and LDL-cholesterol >3.9 mmol/l.34 ISR was earlier considered to be a benign clinical pathology, but can can present as acute coronary syndrome (ACS).36,37 Magalhaes et al. found that the incidence of ACS in the patient presenting with DES-ISR (second-generation DES) requiring target vessel revasculariation was 66.7%, and MI was 5.2%.38 This occurs as a result of an acceleration of the neo-atherosclerotic process, which culminates in plaque rupture and thrombus formation, possibly manifesting as late stent thrombosis.39 It is also important to remember that stable patients with ISR have a favourable prognosis, and should be assessed with contemporary validated technologies such as pressure wire before undertaking PCI.40,41

Diagnosis and Evaluation of In-stent Restenosis Selective coronary angiography is the initial diagnostic tool to diagnose and assess ISR, despite its limited resolution. Although modern features of fluoroscopic equipment, such as stent enhancement, permit diagnosis of an underexpanded stent, it is rare for coronary angiography alone to provide sufficient insight into the mechanism of stent failure. Intra-coronary imaging tools such as intravascular ultrasound and optical coherence tomography (OCT) are now recommended for PCI for stent failure, since either imaging technique allows detailed assessment of the native vessel and stented segment to provide precise mechanistic information (Figure 8).42 Such factors that might easily be identified are stent undersizing, underdeployment or underexpansion, geographical miss of the lesion and stent fracture.43,44 Intra-coronary imaging also assists the visualisation of neo-intimal hyperplasia, neoatherosclerosis, edge stenosis, underlying calcification and provides clear instruction on what devices are necessary to prepare the lesion and then accurately size and expand the stent.45 Evidence supports this approach. For example, intravascular ultrasound-guided revascularisation has been shown to provide better clinical and angiographic results,46,47 with a 1 mm2 increase in minimal stent area found to be associated with a 20% decrease in BMS ISR.27,48 OCT has a better axial resolution (15 μm), which helps to morphologically differentiate between the homogenous high signal tissue band of BMS (constituted by neointimal hyperplasia which is rich in vascular smooth muscle cells) and the heterogeneous, focal and layered tissue band of DES (rich in proteoglycan and fibrin content).27,49 Also, before considering therapy on angiographic diagnosed ISR in stable patients, it is important to assess whether the lesion is causing ischaemia and guide therapy using adjunctive and validated technology such as pressure wire (Figure 8).40,41 It has been previously shown that coronary angiography alone correlates poorly with the functional significance of moderate ISR lesions.41,50 With the advent of the iFR and SyncVision technology, it is now possible to simultaneously assess the functional significance of the lesion, measure the length of the expected stented segment and predict the post revascularistion iFR, all of which can be performed without inducing hyperaemia.51

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Coronary Treatment of In-stent Restenosis Bare Metal Stent In-stent Restenosis Over the years, several advancements have been made in the treatment of ISR with an initial focus on BMS-ISR, which had a high incidence rate.4–6 Identification of the mechanism of ISR is critical to the understanding of how best to deal with the lesion. For instance, an undersized stent with minimal intra-luminal material may best be optimised by just balloon dilatation (Figure 8). More complex mechanisms of ISR such as severe neointimal hyperplasia or neo-atherosclerosis may require debulking strategies, using tools such as scoring balloons or atherectomy (Figure 2). There have been many studies comparing alterative PCI strategies for treatment of ISR (Table 1). Two trials studying the role of rotational atherectomy in treatment of BMS ISR produced conflicting results. Rotational atherectomy had significantly lower target lesion failure rates in the Rotational Atherectomy Versus Balloon Angioplasty for Diffuse In-stent Restenosis (ROSTER) trial, while POBA had significantly lower restenosis in the Angioplasty Versus Rotational Atherectomy for Treatment of Diffuse In-stent Restenosis Trial (ARTIST).52,53 The use of excimer laser atherectomy confers several advantages, such as the ability to modify plaque behind stent struts, decreased potential risk of distal emboli and lower risk of stent fracture or entrapment.54–56 These advantages have translated into superior outcomes such as greater acute luminal gain when treating complex DES ISR, as recently reported by Ichimoto et al.57 In chronically occluded ISR or where there is an inability to cross the lesion with disease-modifying devices, excimer laser atherectomy is the better option. Once the existing stent has been adequately optimised, the next decision is how to prevent future ISR due to vessel injury and provide a long-term durable solution. The use of a drug-eluting balloon (DEB) potentially confers certain advantages over a DES. These include homogenous distribution of the drug in the vessel wall (especially if the original stent was suboptimally expanded), absence of polymer leading to reduction in the chronic inflammatory process, and reduced number of layers of the stent struts.58 The clinical and angiographic advantage of paclitaxel-eluting balloon (PEB) compared with POBA and PES in the treatment of BMS ISR was shown in the Treatment of In-stent Restenosis by Paclitaxel Coated PTCA Balloons (PACCOCATH ISR) I and II and Paclitaxel-Eluting PTCA-balloon catheter in Coronary Artery Disease (PEPCAD) II trials, respectively.59–61 The role of PEB in treatment of BMS ISR was further established when it demonstrated comparable results against the everolimus-eluting stent (EES) in the Restenosis Intra-Stent of Bare Metal Stents (RIBS) V and Treatment of In-Stent restenosis (TIS) trials.62,63 The use of DES in the treatment of BMS ISR was evaluated and firmly confirmed by the Sirolimus-Eluting Stent for In-Stent Restenosis (SISR) and the TAXUS Paclitaxel-Eluting Coronary Stent in the Treatment of In-Stent Restenosis (TAXUS V ISR) trials, both revealing lower rates of binary restenosis and better clinical outcomes with DES compared to complex brachytherapy.64,65 Similarly, when DES was compared to POBA for treating BMS ISR, it showed superior results in the ISAR-DESIRE and RIBS II trial.66,67

Table 1: Trials Evaluating the Treatment of In-stent Restenosis Using Contemporary Technologies Trial

Treatments Compared

Results

Lesion Preparation in In-stent Restenosis ISAR-DESIRE 470 Scoring balloon versus POBA

In-segment percentage diameter stenosis: 35.0 ± 16.8% versus 40.4 ± 21.4%; p=0.047

ROSTER52

Rotablation versus POBA

Repeat stenting: 10% versus 31%; p≤0.001

ARTIST53

Rotablation versus POBA

Restenosis rate: 64.8% versus 51.2%; p=0.039

Ichimoto et al.57 ELCA versus no ELCA

Acute luminal gain: 1.64 ± 0.48 mm versus 1.26 ± 0.42 mm; p≤0.001

Use of drug-eluting balloons in bare metal stent in-stent restenosis PACCOCATH ISR I and II59,60

PEB versus POBA

MACE: 11% versus 46%; p=0.001 Binary restenosis: 6% versus 51%; p≤0.001

PEPCAD II61

PEB versus PES

MACE: 9% versus 22%; p=0.08  Binary restenosis: 7% versus 20%; p=0.06

RIBS V62

PEB versus EES

MACE: 8% versus 6%; p=0.60 Binary restenosis: 9.5% versus 4.7%; p=0.22

TIS63

PEB versus EES

MACE: 10.29% versus 19.12%; p=0.213 Binary restenosis: 8.7% versus 19.12%; p=0.078

Use of drug-eluting stents in bare metal stent in-stent restenosis SISR64

SES versus brachytherapy

Binary restenosis: 19.8% versus 29.5%; p=0.07

TAXUS V ISR65

PES versus brachytherapy

MACE: 11.5% versus 20.1%; p=0.02  Binary restenosis: 14.5% versus 31.2%; p≤0.001

ISAR-DESIRE66

DES (SES + PES) versus POBA

Binary restenosis: 14.3% (SES) and 21.7% (PES) versus 44.6% (POBA); p≤0.001

RIBS II67

SES versus POBA Binary restenosis: 11% versus 39%; p≤0.001

Use of drug-eluting balloons in drug-eluting stent in-stent restenosis PEPCAD-DES74

PEB versus POBA

MACE + stent thrombosis: 16.7% versus 50.0%; p<0.001  Binary restenosis: 17.2% versus 58.1%; p<0.001

PEPCAD China PEB versus PES ISR75

LLL: 0.46 ± 0.51 versus 0.55 ± 0.61 mm; p for non-inferiority = 0.0005

ISAR-DESIRE 376 PEB versus PES versus POBA

Diameter stenosis, PEB versus PES: 38 ± 21.5% versus 37.4 ± 21.8%; p for noninferiority = 0.007

RIBS IV79

Clinical outcome: 20.1% versus 12.3%; p=0.04

DEB versus EES

Use of drug-eluting stents in drug-eluting stent in-stent restenosis ISAR-DESIRE 280 SES versus PES

LLL: 0.40 ± 0.65 mm versus 0.38 ± 0.59 mm; p=0.85  Binary restenosis: 19.6% versus 20.6%; p=0.69

RESTENT-ISR81

EES versus ZES

LLL: 0.40 ± 0.56 versus 0.45 ± 0.61 mm; p=0.57 MACE: 15.8% versus 22.6%; p=0.276

RIBS III82

Hetero-DES versus control

Binary restenosis: 22% versus 40%; p=0.008  MACE: 23% versus 35%; p=0.039

BMS = bare metal stent; DEB = drug-eluting balloon; DES = drug-eluting stent; EES = everolimus-eluting stent; ELCA = excimer coronary laser atherectomy; ISR = in-stent restenosis; LLL = late lumen loss; MACE = major adverse cardiac events; PEB = paclitaxeleluting balloon; PES = paclitaxel-eluting stent; POBA = plain old balloon angioplasty; SES = sirolimus-eluting stent; ZES = zotarolimus-eluting stent.

Drug-eluting Stent In-stent Restenosis DES ISR is associated with worse outcomes than BMS ISR, and this has led to the development of different treatment strategies using

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DES or PEB.68,69 Lesion preparation in the treatment of -limus DES ISR was studied in the Intracoronary Stenting and Angiographic

INTERVENTIONAL CARDIOLOGY REVIEW

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Contemporary Management of Stent Failure Results: Drug-Eluting Stents for In-Stent Restenosis (ISAR-DESIRE) 4 trial, where the use of a scoring balloon before DEB resulted in a significantly lower percentage of diameter stenosis and restenosis rate compared to POBA.70 This difference is contributed by better precision, power (15–25 times higher than POBA), uniform expansion and safety (lower dissection and perforation rates) of the angiosculpt scoring balloon compared to POBA.71–73 Given that most contemporary cases of ISR are in DES and not BMS, the option of simply re-treating the lesion with another DES is usually not ideal. As described above, DEB offers several advantages, and these have been established in the treatment of DES ISR as well. PEB was found to be better or equally effective in treating DES ISR when compared to POBA or PES, as studied in the PEPCAD-DES and PEPCAD China ISR and ISAR-DESIRE 3 trials, respectively.74–76 Similarly, Naganuma et al. reported no difference in the target vessel revascularisation and MACE endpoints, when bifurcation BMS/DES ISR was treated using either EES or PEB.77 When PEB was compared to EES in the treatment of DES ISR, conflicting results were revealed by the Drug-Eluting Balloon for In-Stent Restenosis (DARE) trial and the recently published 3-year outcome data from the RIBS IV trial.78,79 Thus there is a sufficient body of evidence supporting the use of DEB in the treatment of DES ISR where clinically suited and indicated. Treating DES ISR secondary to stent undersizing, edge dissection or stent fracture is best treated using another DES. The role of similar DES (homo) or different DES (hetero) has been evaluated to understand if a similar or different anti-proliferative drug offers any advantage. This has been studied in the ISAR-DESIRE 2, New Generation Drug Eluting Stent for In-stent Restenosis of Drug Eluting Stent (RESTENT-ISR) and RIBS III trials.80–82 While the ISAR-DESIRE 2 and RESTENT-ISR revealed no significant difference between the use of homo or hetero stents, RIBS

Petretta M, Acampa W, Daniele S, et al. Long-term survival benefit of coronary revascularization in patients undergoing stress myocardial perfusion imaging. Circ J 2016;80:485–93. https://doi.org/10.1253/circj.CJ-15-1093; PMID: 26686993. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994;331:496–501. https://doi.org/10.1056/ NEJM199408253310802; PMID: 8041414. Holmes DR, Vlietstra RE, Smith HC, et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA Registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C–81. https://doi. org/10.1016/0002-9149(84)90752-5; PMID: 6233894. Fishman RF, Kuntz RE, Carrozza JP, et al. Long-term results of directional coronary atherectomy: predictors of restenosis. J Am Coll Cardiol 1992;20:1101–10. https://doi.org/10.1016/07351097(92)90365-T; PMID: 1401610. Le Feuvre C, Bonan R, Lespérance J, et al. Predictive factors of restenosis after multivessel percutaneous transluminal coronary angioplasty. Am J Cardiol 1994;73:840–4. https://doi. org/10.1016/0002-9149(94)90806-0; PMID: 8184804. Bakhai A, Booth J, Delahunty N, et al. The SV Stent study: a prospective, multicentre, angiographic evaluation of the BiodivYsio phosphorylcholine coated small vessel stent in small coronary vessels. Int J Cardiol 2005;102:95–102. https:// doi.org/10.1016/j.ijcard.2004.04.001; PMID: 15939104. Agostoni P, Valgimigli M, Biondi-Zoccai GL, et al. Clinical effectiveness of bare-metal stenting compared with balloon angioplasty in total coronary occlusions: insights from a systematic overview of randomized trials in light of the drug-eluting stent era. Am Heart J 2006;151:682–9. https://doi. org/10.1016/j.ahj.2005.05.001; PMID: 16504632. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet 2010;375:201– 9. https://doi.org/10.1016/S0140-6736(09)62127-9; PMID: 20060578. Harjai KJ, Kondareddy S, Pinkosky B, et al. Everolimuseluting stents versus sirolimus- or paclitaxel-eluting stents: two-year results from the Guthrie Health Off-Label Stent (GHOST) Registry. J Interv Cardiol 2013;26:153–62. https://doi.

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III found significantly better clinical and angiographic outcomes in the hetero-DES group. An alternative concept to the repeated use of DES when a DEB alone is considered inadequate has been to consider bioresorbable devices. This could potentially offer the opportunity of treating ISR without implanting long-term multiple layers of stents (known as the ‘onion skin’). Absorb (Abbott Vascular) had been the most widely used bioresorbable vascular scaffold since first-in-man studies in simple de novo lesions in 2006.83 In recently published literature, rates of target lesion failure rates at 12 months of 9.1–12.2% have been reported with bioresorbable vascular scaffolds in the treatment of BMS/DES ISR.84,85 Although used by some operators in ISR cases, the relative large strut thickness (160 μm), footprint and need for near-perfect lesion preparation significantly restricted use in stent failure for the majority of BVS implanters. Absorb was removed from the market in 2017 after several studies pointed to increased scaffold thrombosis rates compared to DES and failure to match target lesion failure/target vessel revascularisation rates within the first 3 years while the device resorbed.

Conclusion Stent failure through in-stent restenosis remains an occurrence that interventional cardiologists will face on a routine basis. Utilisation of diagnostic tools, such as pressure wire assessment and intracoronary imaging, provide better insights compared with angiography alone, and permit more focussed therapies to treat these lesions. The repeat revascularisation often requires adjunctive devices to optimise the outcome and provide long-term durable result. Although data are available to currently support the PCI strategies that we have discussed in this paper, further research will be necessary to distinguish which are the superior PCI techniques within this heterogeneous patient cohort.

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Am Heart J 2004;147:16–22. https://doi.org/10.1016/j.ahj.2003.07.002; PMID: 14691413. vom Dahl J, Dietz U, Haager P et al. Rotational atherectomy does not reduce recurrent in-stent restenosis. Results of the Angioplasty Versus Rotational Atherectomy for Treatment of Diffuse In-stent Restenosis Trial (ARTIST). Circulation 2002;105:583–8. PMID: 11827923. Dahm JB, Kuon E. High-energy eccentric excimer laser angioplasty for debulking diffuse in-stent restenosis leads to better acute- and 6-month follow-up results. J Invasive Cardiol 2000;12:335–42. PMID: 10904438. Nishino M, Mori N, Takiuchi S, et al. Indications and outcomes of excimer laser coronary atherectomy: efficacy and safety for thrombotic lesions – the ULTRAMAN registry. J Cardiol 2017;69:314–9. https://doi.org/10.1016/j. jjcc.2016.05.018; PMID: 27381939. Mehran R, Mintz GS, Satler LF, et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty: mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–9. PMID: 9337188. Ichimoto E, Kadohira T, Nakayama T, De Gregorio J. Longterm clinical outcomes after treatment with excimer laser coronary atherectomy for in-stent restenosis of drug-eluting stent. Int Heart J 2018;59:14–20. https://doi.org/10.1536/ihj.16638; PMID: 29332914. Chin K. In-stent restenosis: the gold standard has changed. EuroIntervention 2011;7(Suppl K):K43–6. https://doi. org/10.4244/EIJV7SKA7; PMID: 22027726. Scheller B, Hehrlein C, Bocksch W, et al. Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355:2113–24. https://doi. org/10.1056/NEJMoa061254; PMID: 17101615. Scheller B, Hehrlein C, Bocksch W, et al. Two year followup after treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. Clin Res Cardiol 2008;97:773–81. https://doi.org/10.1007/s00392-008-0682-5; PMID: 18536865. Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxelcoated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation 2009;119:2986–94. https://doi.org/10.1161/ CIRCULATIONAHA.108.839282; PMID: 19487593. Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting stent in patients with bare-metal stent– in-stent restenosis: the RIBS V clinical trial (Restenosis Intra-Stent of Bare Metal Stents: Paclitaxel-Eluting Balloon Vs Everolimus-Eluting Stent). J Am Coll Cardiol 2014;63:1378–86. https://doi.org/10.1016/j.jacc.2013.12.006; PMID: 24412457. Pleva L, Kukla P, Kusnierova P, et al. Comparison of the efficacy of paclitaxel-eluting balloon catheters and everolimuseluting stents in the treatment of coronary in-stent restenosis: the Treatment of In-Stent Restenosis study. Circ Cardiovasc Interv 2016;9:e003316. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003316; PMID: 27069104. Holmes DR, Teirstein P, Satler L, et al. Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial. JAMA 2006;295:1264–73. https://doi.org/10.1001/jama.295.11.1264; PMID: 16531619. Stone GW, Ellis SG, O’Shaughnessy CD, et al. Paclitaxeleluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA 2006;295:1253–63. https://doi. org/10.1001/jama.295.11.1253; PMID: 16531618. Kastrati A, Mehilli J, von Beckerath N, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005;293:165– 71. https://doi.org/10.1001/jama.293.2.165; PMID: 15644543. Alfonso F, Pérez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial. J Am Coll Cardiol 2006;47:2152–60. https://doi.org/10.1016/j. jacc.2005.10.078; PMID: 16750678. Alfonso F, Byrne RA, Rivero F, Kastrati A. Current treatment of in-stent restenosis. J Am Coll Cardiol 2014;63:2659–73. https:// doi.org/10.1016/j.jacc.2014.02.545; PMID: 24632282.

69. Latib A, Mussardo M, Lelasi A, et al. Long-term outcomes after the percutaneous treatment of drug-eluting stent restenosis. JACC Cardiovasc Interv 2011;4:155–64. https://doi. org/10.1016/j.jcin.2010.09.027; PMID: 21349453. 70. Kufner S, Joner M, Schneider S, et al. Neointimal modification with scoring balloon and efficacy of drug-coated balloon therapy in patients with restenosis in drug-eluting coronary stents: a randomized controlled trial. JACC Cardiovasc Interv 2017;10:1332–40. https://doi.org/10.1016/j.jcin.2017.04.024; PMID: 28683939. 71. de Ribamar Costa J Jr, Mintz GS, Carlier SG, et al. Nonrandomized comparison of coronary stenting under intravascular ultrasound guidance of direct stenting without predilation versus conventional predilation with a semicompliant balloon versus predilation with a new scoring balloon. Am J Cardiol 2007;100:812–7. https://doi.org/10.1016/j. amjcard.2007.03.100; PMID: 17719325. 72. Takano M, Yamamoto M, Murakami et al. Optical coherence tomography after new scoring balloon angioplasty for in-stent restenosis and de novo coronary lesions. Int J Cardiol 2010;141:e51–3. https://doi.org/10.1016/j.ijcard.2008.11.154; PMID: 19128844. 73. Weisz G, Metzger DC, Liberman HA, et al. A provisional strategy for treating true bifurcation lesions employing a scoring balloon for the side branch. Catheter Cardiovasc Interv 2013;82:352–9. https://doi.org/10.1002/ccd.24630; PMID: 22927100. 74. Rittger H, Brachmann J, Sinha AM, et al. A randomized, multicenter, single-blinded trial comparing paclitaxelcoated balloon angioplasty with plain balloon angioplasty in drug-eluting stent restenosis: the PEPCAD-DES study. J Am Coll Cardiol 2012;59:1377–82. https://doi.org/10.1016/j. jacc.2012.01.015; PMID: 22386286. 75. Xu B, Gao R, Wang J, et al. A prospective, multicenter, randomized trial of paclitaxel-coated balloon versus paclitaxel-eluting stent for the treatment of drug-eluting stent in-stent restenosis: results from the PEPCAD China ISR trial. JACC Cardiovasc Interv 2014;7:204–11. https://doi. org/10.1016/j.jcin.2013.08.011; PMID: 24556098. 76. Byrne RA, Neumann FJ, Mehilli J, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drugeluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2013;381:461–7. https://doi.org/10.1016/S01406736(12)61964-3; PMID: 23206837. 77. Naganuma T, Latib A, Costopoulos C, et al. Drug-eluting balloon versus second-generation drug-eluting stent for the treatment of restenotic lesions involving coronary bifurcations. EuroIntervention 2016;11:989–95. https://doi. org/10.4244/EIJY14M11_01; PMID: 25405656. 78. Baan J, Claessen BE, Dijk KB, et al. A randomized comparison of paclitaxel-eluting balloon versus everolimus-eluting stent for the treatment of any in-stent restenosis: the DARE trial. JACC Cardiovasc Interv 2018;11:275–83. https://doi. org/10.1016/j.jcin.2017.10.024; PMID: 29413242. 79. Alfonso F, Pérez-Vizcayno MJ, Cuesta J, et al. 3-year clinical follow-up of the RIBS IV clinical trial: a prospective randomized study of drug-eluting balloons versus everolimus-eluting stents in patients with in-stent restenosis in coronary arteries previously treated with drug-eluting stents. JACC Cardiovasc Interv 2018;11:981–91. https://doi. org/10.1016/j.jcin.2018.02.037; PMID: 29798776. 80. Mehilli J, Byrne RA, Tiroch K, et al. Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study. J Am Coll Cardiol 2010;55:2710–6. https://doi.org/10.1016/j. jacc.2010.02.009; PMID: 20226618. 81. Hong SJ, Ahn CM, Kim BK, et al. Prospective randomized comparison of clinical and angiographic outcomes between everolimus-eluting vs zotarolimus-eluting stents for treatment of coronary restenosis in drug-eluting stents: intravascular ultrasound volumetric analysis (RESTENT-ISR Trial). Eur Heart J 2016;37:3409–18. https://doi.org/10.1093/ eurheartj/ehw389; PMID: 27634828. 82. Alfonso F, Pérez-Vizcayno MJ, Dutary J, et al. Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis: results from a prospective multicenter study (RIBS III [Restenosis IntraStent: Balloon Angioplasty Versus Drug-Eluting Stent]). JACC Cardiovasc Interv 2012;5:728–37. https://doi.org/10.1016/j. jcin.2012.03.017; PMID: 22814777. 83. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008;371:899–907. https://doi.org/10.1016/S0140-6736(08)60415-8; PMID: 18342684. 84. Jamshidi P, Nyffenegger T, Sabti Z, et al. A novel approach to treat in-stent restenosis: 6- and 12-month results using the everolimus-eluting bioresorbable vascular scaffold. EuroIntervention 2016;11:1479–86. https://doi.org/10.4244/ EIJV11I13A287; PMID: 27107313. 85. Moscarella E, Lelasi A, Granata F, et al. Long-term clinical outcomes after bioresorbable vascular scaffold implantation for the treatment of coronary in-stent restenosis: a multicenter Italian experience. Circ Cardiovasc Interv 2016;9:e003148. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003148; PMID: 27059683.

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Large-bore Vascular Closure: New Devices and Techniques Maarten P van Wiechen, Jurgen M Ligthart and Nicolas M Van Mieghem Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands

Abstract Endovascular aneurysm repair, transcatheter aortic valve implantation and percutaneous mechanical circulatory support systems have become valuable alternatives to conventional surgery and even preferred strategies for a wide array of clinical entities. Their adoption in everyday practice is growing. These procedures require large-bore access into the femoral artery. Their use is thus associated with clinically significant vascular bleeding complications. Meticulous access site management is crucial for safe implementation of large-bore technologies and includes accurate puncture technique and reliable percutaneous closure devices. This article reviews different strategies for obtaining femoral access and contemporary percutaneous closure technologies.

Keywords Transcatheter aortic valve implantation, endovascular aneurysm repair, mechanically circulatory support, vascular access, vascular closure device Disclosure: The authors have no conflicts of interest to declare. Received: 8 November 2018 Accepted: 22 January 2019 Citation: Interventional Cardiology Review 2019;14(1):17–21. DOI: https://doi/10.15420/icr.2018.36.1 Correspondence: Nicolas Van Mieghem, Department of Interventional Cardiology, Thoraxcenter, Erasmus MC, Office Nt 645, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. E: n.vanmieghem@erasmusmc.nl Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Minimally invasive procedures such as endovascular aneurysm repair (EVAR), transcatheter aortic valve implantation (TAVI) and implantation of mechanical circulatory support (MCS) are gaining ground on traditional surgery.1–3 These procedures require large-bore access, which is inherently associated with vascular complications and bleeding. Despite the reduction in size of these devices (Table 1), vascular- and bleeding complications are frequent and are reported as high as 20% in TAVI and 12–22% in EVAR.4–7 These adverse events lead to prolonged hospitalisation, the need for packed cell transfusion and an increased short and longer-term mortality.8 Common risk factors for access site complications are female sex, extremes of weight, renal insufficiency and anticoagulation use.9–10 This article focuses on strategies for femoral access and closure when using large-bore devices.

Obtaining Access Good closure starts with good access. The ideal puncture site is located in the common femoral artery between the inferior border of the inferior epigastric artery (IEA) that marks the retroperitoneal space and above the femoral bifurcation. Punctures that are too high are non-compressible and are associated with retroperitoneal bleeding.11 Punctures below the femoral bifurcation, in a small calibre artery, are unsuitable for large-sized sheaths used in EVAR, TAVI and mechanical LV support and should not be closed with percutaneous closure devices per respective instructions for use. There are different strategies for obtaining peripheral access for large-bore devices.

Anatomical Landmarks When using anatomical landmarks, the operator identifies the inguinal ligament by connecting the anterior-superior iliac spine with the

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symphysis pubis. Under palpation of the femoral pulse, the needle is inserted into the common femoral artery just below the imaginary line of the inguinal ligament. This strategy is highly dependent on operator experience, which is dropping with increasing numbers of procedures performed via the radial artery – the so-called radial paradox.12,13 A retrospective study by Pitta et al. found that in approximately 13% of the cases, the actual access site was located outside the optimal location, when solely anatomical landmarks were used for puncture guidance. Access outside the target location was associated with more vascular complications.14

Ultrasound-guided Access Ultrasound-guided access is performed using a linear ultrasound probe. The first step is to visualise the common femoral artery bifurcation in a longitudinal view to determine the exact bifurcation location and extent of arterial wall calcifications. The probe is then turned counter-clockwise to get a cross-sectional view of the femoral artery above the bifurcation. Vein and artery are distinguished by means of compression. The femoral artery is punctured under a 45° angle, the correct needle pathway and vessel entry is confirmed by ultrasound (Figure 1). Ultrasound-guided access precludes radiation and is easy to apply after a steep learning curve. It provides a real-time image of the puncture site of interest. Ultrasound allows: • the differentiation of non-compressible and pulsatile arteries from compressible veins; • the identification of the femoral bifurcation;

Access at: www.ICRjournal.com

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Structural Table 1: Different Large-bore Devices and Their Sheath Sizes Large-bore Devices

Sheath Size

TAVI Devices

14–19 Fr

Acurate Neo

18 Fr, 19 Fr

Evolut PRO

16 Fr

Evolut R

14 Fr

Lotus Edge

14 Fr, 15 Fr

Portico

18 Fr, 19 Fr

Sapien 3

14 Fr, 16 Fr

EVAR

18–24 Fr

Figure 1: Ultrasound-guided Access

Mechanical Support Impella 2.5

13–14 Fr

Impella CP

14 Fr

Impella 5.0

21 Fr

Pulsecath 2L

17 Fr

Pulsecath 3L

21 Fr

EVAR = endovascular aneurysm repair; TAVI = transcatheter aortic valve implantation.

• the appreciation of the degree, location and distribution of calcifications and the selection of a puncture site without anterior wall calcification; • the monitoring of needle entry into the vessel, avoiding side or posterior wall puncture.15

Compared with fluoroscopic guidance, ultrasound guidance reduces the number of attempts and median time to access.16

Fluoroscopic-guided Access Fluoroscopic-guided access assumes a consistent spatial relationship between the common femoral artery and femoral head.17 Under X-ray, a radiopaque instrument, such as a haemostat or puncture needle, is placed over the femoral head to locate the appropriate height for puncture. Assumptions may be inaccurate in patients with high femoral bifurcations. Alternatively, a wire or (e.g. pigtail) catheter can be inserted from a contralateral access and navigated towards the level of the ipsilateral femoral head to serve as a target for the fluoroscopyguided puncture. A small contrast injection through the pigtail catheter may further map the common femoral artery and serve as a bull’s eye for the operator. Fluoroscopy-guided arterial puncture is effective and associated with a low incidence of vascular complications, but it has not been shown to be superior to the use of anatomical landmarks.18–20 The major downside of this technique is its reliance on radiation, in particular to the operator’s hands.

Surgical Cut-down Surgical cut-down can expose the common femoral artery and allows for direct-vision access and allows for direct-suture closure. Surgical cut-down is associated with a longer procedure time, increased length of hospitalisation and more wound infections.21–23 Complications seem to occur less frequently when an oblique incision is chosen over a vertical incision.24

Vascular Closure Surgical Closure In principle, a surgical suture technique is applied for closure after surgical cut-down for femoral access. Surgical cut-down and closure

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A: Common femoral artery and femoral vein (semi-compressed). Dashed line: Needle pathway. B: Calcification of the posterior arterial wall marked in red. CFA = common femoral artery. V = femoral vein.

increases the chance for wound infection or iatrogeneous femoral nerve damage. At present, most TAVI and EVAR procedures are performed in a total percutaneous matter, but a surgical cut-down may still be preferred in selected patients, such as the very obese or those with femoral grafts or stents.25

Suture-based Closure Devices The vast majority of large-bore vessel closure is performed by percutaneous suture- based techniques like the Prostar® XL and multiple ProGlide® (Abbott Vascular) vascular closure devices (VCD) (Figure 2). Both devices are predominantly inserted using a preclosure technique.

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Large-bore Vascular Closure Figure 2: Commercially Available Vascular Closure Devices Prostar® XL

ProGlide®

MANTA™

PerQseal®

InSeal

Suture-based 8.5–10 Fr (off-label use > 10 Fr) CE mark

Suture-based 5–8 Fr (off-label use > 8 Fr) CE mark

Collagen-based 10–14 Fr (14 Fr system) 14–22 Fr (18 Fr system) CE mark

Patch-based < 24 Fr

Membrane-based 14–21 Fr

CE mark

Source: Abbott Vascular, Essential Medical, InSeal Medical and Vivasure Medical.

Figure 3: Forest Plot Showing Odds Ratio for Any Bleeding and Any Vascular Complication Any bleeding (VARC-2) OR MANTA™ Suture-based VCD Study Total Weight MH, Fixed, 95% CI Events Total Events Biancari et al. 2018 27 107 26 115 27.8% 1.16 [0.62, 2.14] de Palma et al. 2018 14 89 43 257 27.7% 0.93 [0.48, 1.79] Moriyama et al. 2018 21 111 37 111 44.5% 0.47 [0.25, 0.87] Total (95% CI) 307 483 100.0% 0.79 [0.55, 1.13] 62 106 Total events Heterogeneity: chi2=4.48, d.f.=2 (p=0.11); I2=55% 0.2 Test for overall effect: Z=1.31 (p=0.19)

OR MH, fixed, 95% CI

0.5 1 2 5 Favours MANTA Favours suture-based VCD

Any vascular complication (VARC-2) OR Suture-based VCD MANTA Study Total Weight MH, Fixed, 95% CI Events Total Events Biancari et al. 2018 14 107 17 115 37.7% 0.87 [0.40, 1.86] de Palma et al. 2018 6 89 8 257 10.2% 2.25 [0.76, 6.67] Moriyama et al. 2018 16 111 23 111 52.1% 0.64 [0.32, 1.30] Total (95% CI) 307 483 100.0% 0.89 [0.56, 1.42] 36 48 Total events Heterogeneity: chi2=3.61, d.f.=2 (p=0.16); I2=45% 0.2 Test for overall effect: Z=0.48 (p=0.63)

OR MH, fixed, 95% CI

0.5 1 2 5 Favours MANTA Favours suture-based VCD

*Biancari et al. comprises only data on major and life threatening bleeding, minor bleeding data not available. MH = Mantel-Haenszel test; VARC-2 = Valve Academic Research Consortium-2; VCD = vascular closure device.

The Prostar XL device is inserted over a guidewire. Its position in the artery is confirmed when pulsatile flow evades the main tube of the device. Four pre-prepared sutures inside the device are pulled out while maintaining the device in the same position. This allows four needles to be pulled back, leaving the sutures in place. The arteriotomy can be closed by pulling the sutures and closing the knots. The ProGlide technique typically requires two devices for large-bore arteriotomies. The devices are inserted before the procedure and are deployed at the 10 o’clock and 2 o’clock position. After the procedure is concluded, the introducer sheath is removed. The sutures are

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approximated and the vessel wall is closed.26 Both suture-based techniques can be executed with a safety wire in place in order to use additional suture- or plug-based closure devices if there is incomplete arteriotomy closure. ProGlide was originally introduced to clinical practice for small-bore arteriotomy closure, but its use was extended to EVAR, first under surgical cut-down and later in a completely percutaneous fashion.27 Compared to surgical cut-down, there are fewer groin complications when using a VCD, and the procedural time is shorter (91 minutes ± 32 versus 153 minutes ± 112; p<0.05).28,29

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Structural A propensity matched analysis in TAVI patients by Barbash et al. showed lower rates of major vascular complications with use of ProGlide compared to Prostar XL (1.9% versus 7.4%; p<0.001) and lower rates of major (3.2% versus 16.7%; p<0.001) and minor bleedings (8.9% versus 13.6%; p=0.032).7 Conversely, a study in an Italian hospital reported more vascular complications with ProGlide versus Prostar XL closure (24.0% versus 11.4%; p=0.007).30 Basically, local experience will determine suture-based closure success and it is recommended that each operator or centre adopts and masters one suture-based technique. Suture-based closure has also been successfully applied for closure of axillary and subclavian arteriotomies.31,32

Collagen-based Closure The MANTA™ VCD (Essential Medical) is a collagen-based closure device (Figure 2). It consists of a poly-lactic coglycolic toggle within the artery, connected to a bovine collagen plug, exterior to the vessel wall. A stainless-steel lock is tampered down pushing the collagen and toggle together in order to sandwich the arterial puncture site between the toggle and the collagen. The proper amount of tension that the operator has to apply is indicated by the appearance of a green marker on the device handle. The toggle and collagen plug resolve completely in 6 months.33 The MANTA has a 14 Fr and 18 Fr version for arteriotomy closure between 10 and 14 Fr and 14 and 22 Fr, respectively, and obtained the CE mark in 2016. The MANTA has also been applied for completely percutaneous closure of axillary arteriotomies after TAVI.34,35 There are no randomised head-to-head comparisons, but retrospective data show lower bleeding complications and comparable vascular complications with the MANTA device compared to the Prostar XL (Major bleeding 2.3% versus 9.3%; p=0.03; major vascular 2.3% versus 0.4%; p=0.48).36 A propensity matched analysis by Moriyama et al. confirmed less VARC-2 bleeding (18% versus 33%; p=0.01) but no difference in vascular complications (14% versus 21%; p=0.21) with MANTA.37 Biancari et al. found no significant difference between the MANTA and ProGlide in terms of bleeding (22% versus 25%; p=0.469) or major vascular complications (12% versus 9%; p=0.498)38 (Figure 3).

reenhalgh RM, Brown LC, Kwong GP, et al. Comparison G of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR Trial 1), 30-day operative mortality results: randomised controlled trial. Lancet. 2004;364:843–8. https://doi.org/10.1016/S01406736(04)16979-1; PMID: 15351191. Prinssen M, Verhoeven EL, Buth J, et al. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med. 2004;351:1607–18. https://doi.org/10.1056/NEJMoa042002; PMID: 15483279. Durko AP, Osnabrugge RL, Van Mieghem NM, et al. Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections. Eur Heart J. 2018;39:2635–42. https://doi. org/10.1093/eurheartj/ehy107; PMID: 29546396. Carroll JD, Vemulapalli S, Dai D, et al. Procedural experience for transcatheter aortic valve replacement and relation to outcomes: the STS/ACC TVT Registry. J Am Coll Cardiol. 2017;70:29–41. https://doi.org/10.1016/j.jacc.2017.04.056; PMID: 28662805. Linke A, Wenaweser P, Gerckens U, et al. Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study. Eur Heart J. 2014;35:2672–84. https://doi.org/10.1093/eurheartj/ehu162; PMID: 24682842. Nelson PR, Kracjer Z, Kansal N, et al. A multicenter, randomized, controlled trial of totally percutaneous access versus open femoral exposure for endovascular aortic aneurysm repair (the PEVAR Trial). J Vasc Surg. 2014;59: 1181–93. https://doi.org/10.1016/j.jvs.2013.10.101;

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The MANTA device has a short mean time to haemostasis, ranging from 22 seconds to 2 minutes 23 seconds. There is no comparable time to haemostasis data for other VCDs.35,36,39

Miscellaneous Other novel dedicated large-bore closure devices include the InSeal (InSeal Medical) and PerQseal® (Vivasure Medical) VCD (Table 2). The InSeal VCD is a membrane-based device consisting of a selfexpanding nitinol frame, a biodegradable membrane and a bioresorbable polyglycolic acid (PGA) tether. The InSeal device is introduced with the membrane in a collapsed configuration. The sheath is then pulled back and the release wire is pulled to deploy the VCD. The membrane is pushed against the arteriotomy site by the nitinol frame and traction is kept by keeping the tether fixed to the skin using a steristrip or suture. The flexible membrane should compensate for arterial wall irregularities and calcifications. The specially designed frame allows re-access within 26 weeks. The first in human experience showed technical and therapeutic success in all nine cases.40 Unpublished post CE mark clinical experience showed a mean time to haemostasis <1 minute and 0% Major VARC-2 vascular complications and 7.7% bleeding complications in a series of 52 patients.41 The PerQseal VCD consists of a flexible intravascular patch supported by a scaffold. The surface of the patch is textured to promote adherence to the vessel wall. An external locator extends through the arteriotomy, which keeps the patch in place. The implant is fully absorbable after 180 days. It received the CE mark in 2016. In 120 patients, from the unpublished Frontier series of studies, including TAVI, EVAR and thoracic endovascular aortic repair, no major vascular complications occurred.42

Conclusion The use of large-bore arteriotomies is peaking with the expanding market of structural heart interventions and MCS. Indeed, catheterbased techniques, such as EVAR and TAVI have greatly replaced conventional surgical operations. Optimal access site management, including the proper puncture and arteriotomy closure technique, is pivotal to secure procedural safety and will ultimately determine the success of catheter-based therapies in clinical practice.

PMID: 24440678. Barbash IM, Barbanti M, Webb J, et al. Comparison of vascular closure devices for access site closure after transfemoral aortic valve implantation. Eur Heart J. 2015;36:3370–9. https://doi.org/10.1093/eurheartj/ehv417; PMID: 26314688. 8. 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. https://doi. org/10.1016/j.jcin.2007.12.006; PMID: 19463301. 9. Sherev DA, Shaw RE, Brent BN. Angiographic predictors of femoral access site complications: implication for planned percutaneous coronary intervention. Catheter Cardiovasc Interv. 2005;65:196–202. https://doi.org/10.1002/ccd.20354; PMID: 15895402. 10. Tavris DR, Gallauresi BA, Lin B, et al. Risk of local adverse events following cardiac catheterization by hemostasis device use and gender. J Invasive Cardiol. 2004;16:459–64. PMID: 15353824. 11. Illescas FF, Baker ME, McCann R, et al. CT evaluation of retroperitoneal hemorrhage associated with femoral arteriography. AJR Am J Roentgenol. 1986;146:1289–92. https:// doi.org/10.2214/ajr.146.6.1289; PMID: 3486570. 12. Rafie IM, Uddin MM, Ossei-Gerning N, et al. Patients undergoing PCI from the femoral route by default radial operators are at high risk of vascular access-site complications. EuroIntervention. 2014;9:1189–94. https://doi. org/10.4244/EIJV9I10A200; PMID: 24561736. 7.

13. A zzalini L, Tosin K, Chabot-Blanchet M, et al. The benefits conferred by radial access for cardiac catheterization are offset by a paradoxical increase in the rate of vascular access site complications with femoral access: the campeau radial paradox. JACC Cardiovasc Interv. 2015;8: 1854–64. https://doi.org/10.1016/j.jcin.2015.07.029; PMID: 26604063. 14. Pitta SR, Prasad A, Kumar G, et al. Location of femoral artery access and correlation with vascular complications. Catheter Cardiovasc Interv. 2011;78:294–9. https://doi.org/10.1002/ ccd.22827; PMID: 21413114. 15. Sardar MR, Goldsweig AM, Abbott JD, et al. Vascular complications associated with transcatheter aortic valve replacement. Vasc Med. 2017;22:234–44. https://doi. org/10.1177/1358863X17697832; PMID: 28494713. 16. Seto AH, Abu-Fadel MS, Sparling JM, et al. Real-time ultrasound guidance facilitates femoral arterial access and reduces vascular complications: FAUST (Femoral Arterial Access With Ultrasound Trial). JACC Cardiovasc Interv. 2010;3:751–8. https://doi. org/10.1016/j.jcin.2010.04.015; PMID: 20650437. 17. Dotter CT, Rosch J, Robinson M. Fluoroscopic guidance in femoral artery puncture. Radiology. 1978;127:266–7. https://doi. org/10.1148/127.1.266; PMID: 635197. 18. Abu-Fadel MS, Sparling JM, Zacharias SJ, et al. Fluoroscopy vs. traditional guided femoral arterial access and the use of closure devices: a randomized controlled trial. Catheter Cardiovasc Interv. 2009;74:533–9. https://doi.org/10.1002/ ccd.22174; PMID: 19626694. 19. Fairley SL, Lucking AJ, McEntegart M, et al. Routine use of fluoroscopic-guided femoral arterial puncture to minimise

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Large-bore Vascular Closure

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26.

vascular complication rates in CTO intervention: multi-centre UK experience. Heart Lung Circ. 2016;25:1203–9. https://doi. org/10.1016/j.hlc.2016.04.006; PMID: 27265645. Chinikar M, Ahmadi A, Heidarzadeh A, Sadeghipour P. Imaging or trusting on surface anatomy? A comparison between fluoroscopic guidance and anatomic landmarks for femoral artery access in diagnostic cardiac catheterization. A randomized control trial. Cardiovasc Interv Ther. 2014;29:18–23. https://doi.org/10.1007/s12928-013-0203-y; PMID: 23959379. Nakamura M, Chakravarty T, Jilaihawi H, et al. Complete percutaneous approach for arterial access in transfemoral transcatheter aortic valve replacement: a comparison with surgical cut-down and closure. Catheter Cardiovasc Interv. 2014;84:293–300. https://doi.org/10.1002/ccd.25130; PMID: 23873857. Kadakia MB, Herrmann HC, Desai ND, et al. Factors associated with vascular complications in patients undergoing balloon-expandable transfemoral transcatheter aortic valve replacement via open versus percutaneous approaches. Circ Cardiovasc Interv. 2014;7:570–6. https://doi.org/10.1161/ CIRCINTERVENTIONS.113.001030; PMID: 25027520. Buck DB, Karthaus EG, Soden PA, et al. Percutaneous versus femoral cutdown access for endovascular aneurysm repair. J Vasc Surg. 2015;62:16–21. https://doi.org/10.1016/ j.jvs.2015.01.058; PMID: 25827969. Slappy AL, Hakaim AG, Oldenburg WA, et al. Femoral incision morbidity following endovascular aortic aneurysm repair. Vasc Endovascular Surg. 2003;37:105–9. https://doi. org/10.1177/153857440303700204; PMID: 12669141. Toggweiler S, Webb JG. Challenges in transcatheter aortic valve implantation. Swiss Med Wkly. 2012;142:w13735. https:// doi.org/10.4414/smw.2012.13735; PMID: 23255233. Toggweiler S, Leipsic J, Binder RK, et al. Management of vascular access in transcatheter aortic valve replacement: part 1: basic anatomy, imaging, sheaths, wires, and access routes. JACC Cardiovasc Interv. 2013;6:643–53. https://doi. org/10.1016/j.jcin.2013.04.003; PMID: 23866177.

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27. K rajcer Z, Howell M. A novel technique using the percutaneous vascular surgery device to close the 22 french femoral artery entry site used for percutaneous abdominal aortic aneurysm exclusion. Catheter Cardiovasc Interv. 2000;50:356–60. PMID: 10878639. 28. Jahnke T, Schafer JP, Charalambous N, et al. Total percutaneous endovascular aneurysm repair with the dual 6-F Perclose-AT preclosing technique: a case-control study. J Vasc Interv Radiol. 2009;20:1292–8. https://doi.org/10.1016/ j.jvir.2009.06.030; PMID: 19695904. 29. Lee WA, Brown MP, Nelson PR, Huber TS. Total percutaneous access for endovascular aortic aneurysm repair (“Preclose” technique). J Vasc Surg. 2007;45:1095–101. https://doi. org/10.1016/j.jvs.2007.01.050; PMID: 17398056. 30. Barbanti M, Capranzano P, Ohno Y, et al. Comparison of suture-based vascular closure devices in transfemoral transcatheter aortic valve implantation. EuroIntervention. 2015;11:690–7. https://doi.org/10.4244/EIJV11I6A137; PMID: 26499222. 31. Schafer U, Ho Y, Frerker C, et al. Direct percutaneous access technique for transaxillary transcatheter aortic valve implantation: “the Hamburg Sankt Georg approach”. JACC Cardiovasc Interv. 2012;5:477–86. https://doi.org/10.1016/ j.jcin.2011.11.014; PMID: 22625184. 32. van Mieghem NM, Luthen C, Oei F, et al. Completely percutaneous transcatheter aortic valve implantation through transaxillary route: an evolving concept. EuroIntervention. 2012;7:1340–2. https://doi.org/10.4244/EIJV7I11A210; PMID: 22157411. 33. van Gils L, Daemen J, Walters G, et al. MANTA, a novel plugbased vascular closure device for large Bore arteriotomies: technical report. EuroIntervention. 2016;12:896–900. https://doi. org/10.4244/EIJV12I7A147; PMID: 27639742. 34. De Palma R, Ruck A, Settergren M, Saleh N. Percutaneous axillary arteriotomy closure during transcatheter aortic valve replacement using the MANTA device. Catheter Cardiovasc Interv. 2018;92:998–1001. https://doi.org/10.1002/ccd.27383;

PMID: 29068128. 35. V an Mieghem NM, Latib A, van der Heyden J, et al. Percutaneous plug-based arteriotomy closure device for large-bore access: a multicenter prospective study. JACC Cardiovasc Interv. 2017;10:613–9. https://doi.org/10.1016/ j.jcin.2016.12.277; PMID: 28335899. 36. De Palma R, Settergren M, Ruck A, et al. Impact of percutaneous femoral arteriotomy closure using the MANTATM device on vascular and bleeding complications after transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2018;92:954–61. https://doi.org/10.1002/ccd.27595; PMID: 29575678. 37. Moriyama N, Lindstrom L, Laine M. Propensity-matched comparison of vascular closure devices after transcatheter aortic valve replacement using MANTA versus ProGlide. EuroIntervention. 2018. https://doi.org/10.4244/EIJ-D-18-00769; PMID: 30295293; epub ahead of press. 38. Biancari F, Romppanen H, Savontaus M, et al. MANTA versus ProGlide vascular closure devices in transfemoral transcatheter aortic valve implantation. Int J Cardiol. 2018;263:29–31. https://doi.org/10.1016/j.ijcard.2018.04.065; PMID: 29681408. 39. van Gils L, De Jaegere PP, Roubin G, Van Mieghem NM. The MANTA vascular closure device: a novel device for large-bore vessel closure. JACC Cardiovasc Interv 2016;9: 1195–6. https://doi.org/ 10.1016/j.jcin.2016.03.010; PMID: 27282604. 40. Kambara AM, Bastos Metzger P, Ribamar Costa J et al. First-in-man assessment of the InSeal VCD, a novel closure device for large puncture accesses. EuroIntervention. 2015;10:1391–5. https://doi.org/10.4244/EIJV10I12A242; PMID: 24345407. 41. Kornowski R. Large-hole trans-femoral closure – the InSeal device. Presented at TVT 2017, Chicago, 14–17 June 2017. 42. Popma J. New fully absorbable patch-based large-hole vascular closure device. Presented at TCT 2017, Denver, 29 October–2 November 2017.

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Structural

Cerebral Embolic Protection in TAVI: Friend or Foe Michael Teitelbaum, 1 Rafail A Kotronias, 2,3,4 Luciano A Sposato 5 and Rodrigo Bagur 1,4,6 1. London Health Sciences Centre, London, Ontario, Canada; 2. Oxford University Clinical Academic Graduate School, University of Oxford, Oxford, UK; 3. Oxford Heart Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 4. Keele Cardiovascular Research Group, Institute for Applied Clinical Science and Centre for Prognosis Research, Institute of Primary Care and Health Sciences, University of Keele, Stoke-on-Trent, UK; 5. Department of Clinical Neurological Sciences, Stroke, Dementia & Heart Disease Laboratory, London, Ontario, Canada; 6. Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada

Abstract Cerebrovascular accidents including stroke or transient ischaemic attack are one of the most feared complications after transcatheter aortic valve implantation. Transcatheter aortic valve implantation procedures have been consistently associated with silent ischaemic cerebral embolism as assessed by diffusion-weighted MRI. To reduce the risk of cerebrovascular accidents and silent emboli, cerebral embolic protection devices were developed with the aim of preventing procedural debris reaching the cerebral vasculature. The authors summarise the available data regarding cerebral embolic protection devices and its clinical significance.

Keywords Cerebrovascular accidents, stroke, transient ischaemic attack, transcatheter aortic valve implantation, ischaemic cerebral embolism, diffusion-weighted MRI, risk, cerebral embolic protection devices, procedural debris Disclosure: The authors have no conflict of interest to declare. Received: 12 August 2018 Accepted: 22 November 2018 Citation: Interventional Cardiology Review 2019;14(1):22–5. DOI: https://doi.org/10.15420/icr.2018.32.2 Correspondence: Rodrigo Bagur, Division of Cardiology, London Health Sciences Centre, University Hospital, 339 Windermere Rd, London, Ontario N6A 5A5, Canada. E: rodrigobagur@yahoo.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Since its introduction in 2002, transcatheter aortic valve implantation (TAVI) has provided an alternative to surgical aortic valve replacement (SAVR) in patients considered inoperable or either at high or intermediate risk for SAVR.1 However, one of the most feared complications of TAVI are cerebrovascular accidents (CVA) including stroke or transient ischaemic attack. Further to this, TAVI procedures have been consistently associated with silent ischaemic cerebral embolism as assessed by diffusion-weighted MRI (or high-intensity transient signals) assessed by transcranial Doppler.2–7 To reduce the risk of CVA and silent emboli, cerebral embolic protection devices (CEPDs) were developed. These devices aim to prevent procedural debris reaching the cerebral vasculature. CEPDs have been shown to be effective in the filtration of debris and decreasing the volume of ischaemic embolic lesions,8 hence, with the potential for decreasing the risk of clinically evident CVA. In this article, we summarise the available data regarding CEPDs and their clinical significance.

Types of Embolic Protection Devices CEPDs are mesh filters to prevent embolic material from entering the carotid arteries. They differ in pore size, location of deployment, and chemical composition. With current techniques, successful deployment is achieved over 90% of cases, with success rates ranging from 64%–100%.8 Materials captured by the filters include thrombus, arterial wall tissue, valve tissue, calcification and foreign material.9–11

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In the Cerebral Protection in Transcatheter Aortic Valve Replacement (SENTINEL) trial, histopathologic debris were found within filters in 99% of patients.12 The Embrella Embolic Deflector (Edwards Lifesciences) uses two heparincoated membranes with 100 µm pores. Once deployed in the aortic arch, it covers the brachiocephalic and left common carotid arteries. This CEPD was the first to be studied for safety and efficacy.13–15 TriGuard (Keystone Heart) is a nitinol-coated device with 250 µm pores. Unlike other embolic protection devices, the TriGuard covers the left subclavian artery in addition to the brachiocephalic and left common carotid.16–18 This distinction is of potential clinical relevance, as the distribution of post-TAVI cerebral infarcts may also be weighted towards the posterior circulation.19 Sentinel (Claret Medical/Boston Scientific, previously named Montage) is a dual filter with 140 µm pores. The two filters are placed into the brachiocephalic and left common carotid arteries.11,12,20,21 Sentinel captures procedural debris, in contrast to the above two devices which simply deflect debris and allow its passage to downstream vessels. However, Sentinel does not protect the left vertebral artery which accounts for up to 20% of total brain perfusion.22,23 Therefore, it has recently been trialled in combination with the Wirion embolic protection system (Allium Medical) for posterior territory protection.23

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Cerebral Embolic Protection in TAVI Embolic Protection Devices and Silent Ischaemic Lesions Several studies have shown that up to 80% of patients who have undergone TAVI were found to have new silent cerebral ischaemic embolic lesions, and these lesions affected the two cerebral hemispheres and circulation territories in most patients.2–6 In the literature, the rate of new silent cerebral ischaemic lesions can be very high (>90% of patients), but substantial variations are observed, with others reporting lesions in 62% of patients.21,24,25 The absence of a centralised core lab for analysis means that comparisons between studies are difficult to make. This is worthy of exploration in future studies. New persistent clinical neurological impairment has been encountered in approximately 3–6% of patients.2–6 Hence, beyond the risk of overt CVA after TAVI, there have been concerns regarding silent ischaemic lesions and its clinical consequences. The recent Neurologic Academic Research Consortium (NeuroARC) consensus statement has defined covert central nervous system (CNS) infarction or Type 2.a as “brain, spinal cord, or retinal cell death attributable to focal or multifocal ischaemia, based on neuroimaging or pathological evidence of CNS infarction, without a history of acute neurological symptoms consistent with the lesion location”.26 NeuroARC agrees with the lack of a conclusive link between acute procedure-related subclinical brain lesions and long-term neurological or cognitive outcomes.26 In fact, NeuroARC proposed the term “covert CNS infarction” mainly to recognise that these events may not necessarily be free of clinical consequences, and that detection of neurological or cognitive sequelae depends on the nature, sensitivity, and timing of assessments.26 The use of CEPD might be associated with smaller volume of these silent ischaemic lesions, however, data from meta-analysis failed to demonstrate reduction in the number of new-single, multiple, and total number of lesions.8 Furthermore, when diffusion-weighted MRI was performed at follow-up, several embolic ischaemic lesions disappeared over time and even shortly after TAVI.2,3,14,21

Embolic Protection Devices and Clinical Outcomes Cerebrovascular Accidents Whenever we see reports stating that Sentinel CEPD captures debris in 99% of patients, it is logical to think that the prevention of clinically apparent CVAs (stroke or transient ischaemic attack) should be the primary motivation for the use of CEPD.12 However, data up to early 2017 from five studies did not show statistically significant differences in effect estimates for TAVI with CEPD, compared to no CEPD, in terms of 30-day stroke (RR 0.70; 95% CI [0.38–1.29]; I2=0%).8 Interestingly, an updated 2018 meta-analysis did find a statistically significant reduction in 30-day stroke rate with CEPD use (OR 0.55; 95% CI [0.31–0.98]; p=0.04; I2=0%).27 The difference between these two meta-analyses was that the latter included a propensity-matched study published at the end of 2017, which found strokes in 1.4% (4/280) of CEPD patients and 4.6% (13/280) of non-CEPD patients at 7 days.28 This study also provided information regarding the severity of strokes, and there was no significant difference in non-disabling stroke rates with EPD versus no-EPD at 7 days. However, among more severe CVA, a significant difference was encountered, with 0.4% (1/280) among CEPD patients and 3.2% (9/280) among non-CEPD patients experiencing disabling strokes at 7 days.28

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Even if the 2018 meta-analysis reached statistical significance for 30-day strokes, and even though the authors pointed out that this result was driven by the addition of the propensity-matched study, the upper margin of the CI seems very close to no effect.27 It is also worth mentioning that the incidence of CVAs has considerably declined. Data from the Transcatheter Valve Therapy registry has shown 30-day stroke rates about 2.1%, which slightly decreased over a 4-year period from 2.3% in 2012 and 2013 to 1.9% in 2015 (p=0.026).29 In addition, the 1-year stroke rate obtained by linkage with US Centers for Medicare & Medicaid Services administrative data was 3.8% overall.29 Contemporaneous data using different TAVI technologies showed a stroke rate at 30 days below 2% (1.4%–1.9%).30–34 Hence, with the growing experience of operators and heart teams and transcatheter valves technology iterations, contemporaneous data further support a decrease in the incidence of CVAs and this should also be taken into consideration at the time of choosing to use a CEPD.

Mortality The current literature does not support a clear mortality benefit for the use of CEPD in patients undergoing TAVI, but data is limited. The only randomised controlled trial (RCT) that had mortality as a pre-specified primary endpoint was the SENTINEL trial.12 The primary safety endpoint was the occurrence of major adverse cardiac and cerebrovascular events (MACCE) at 30 days compared to a historical performance goal.12 MACCE was defined as all death, all strokes (disabling and non-disabling) and acute kidney injury (stage 3) according to the Valve Academic Consortium-2 definitions.35 MACCE in the control arm occurred in 9.9% and was not statistically different compared with the device and safety arms (p=0.405). Our 2017 meta-analysis of five studies showed no significant differences in point-estimate for 30-day mortality (RR 0.58; 95% CI [0.20–1.64]; I2=0%).8 The updated 2018 meta-analysis explored the 30-day mortality rate and included six studies, four RCTs and two non-RCTs, adding the above mentioned propensity-matched study.27,28 Nonetheless, no differences in effect estimates were found (OR 0.43; 95% CI [0.18–1.05]; I2=0%). Of note, four of the six studies included ≤50 patients. The largest data comes from the propensity score matched study by Seeger and colleagues,where 0.7% (2/280) of CEPD patients and 2.9% (8/280) of non-CEPD patients died within 30 days of their procedure (p=0.06).28 In their multivariable analysis, only the Society of Thoracic Surgeons score for mortality (p=0.02) and TAVI procedures with no CEPD (p=0.02) were independent predictors for the occurrence of death or stroke.

Neurocognitive Function The evaluation of neurocognitive function after TAVI has not been systematically assessed in studies comparing CEPD with no CEPD. Moreover, different scores and tests were utilised among comparative studies, precluding therefore, a head-to-head comparison and fair interpretation of the results. The Montreal Cognitive Assessment (MoCA) was used in three studies, and the proportion of patients with CEPD showing worsening neurocognitive function ranged from 11%–27% and from 23%–33% in patients with no CEPD. 14,17,20 The National Institutes of Health Stroke Scale was used in three studies,and the proportion of patients with CEPD showing worsening neurocognitive function ranged from 0%–18%, and from 4.5%–23%

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Structural in patients with no CEPD.17,20,21 The Mini-Mental State Examination (MMSE) was used in one study and did not show differences between CEPD versus no CEPD.14 As previously stated, there are inconsistencies between new ischaemic lesions and clinically apparent neurologic impairment. Indeed, previous studies could not find a measurable neurocognitive impairment in patients with silent ischaemic embolism pre- and post-TAVI.2,3,5,6 Two studies have shown a significant improvement in MMSE scores 3 months after TAVI, and one study showed a significant improvement in MoCA score at 30 days compared with baseline in the CEPD group, but no differences over time with no CEPD.7,14,36 The TriGuard HDH Embolic Deflection Device During Transcatheter Aortic Valve Replacement (DEFLECT-III) trial showed no statistical significance between groups of treatment at 30-day follow-up.17 It is noteworthy that when the authors adjusted for age, the mean MoCA score improved from baseline to discharge and 30 days in patients who received CEPD; however, the mean MoCA score worsened from baseline to discharge and, interestingly, rebounded to approximately the baseline mean score at 30 days in the control group.17 The SENTINEL trial used a comprehensive neurocognitive assessment tailored for TAVI patients and designed to evaluate seven domains of neurocognitive function. The use of CEPD did not show any change in neurocognitive function, but there was correlation between new lesion volume and number of lesions and neurocognition at 30 days.12 Ghanem and colleagues reported a long-term follow-up on this matter and interestingly enough 91% of patients had preserved cognitive skills throughout the first 2 years after TAVI.37 It is important to note that this study also showed that the cognitive trajectory was affected by the patient’s age, but not by the absence of silent ischaemic emboli or the use of CEPD.

Statistical Methods for Interpreting Results and Limitations There were eight pair-wise comparison studies.12,14,15,17,20,21,28,38 Five were RCTs.12,17,20,21,38 Two were non-randomised studies,14,15 and one used a propensity-score matching strategy to adjust for confounders.28 Among the RCTs, one trial38 adequately described the random sequence generation methods, two trials21,38 adequately described the allocation concealment, and four trials12,20,21,38 adequately described

agur R, Pibarot P, Otto CM. Importance of the valve B durability-life expectancy ratio in selection of a prosthetic aortic valve. Heart 2017;103:1756–9. https://doi.org/10.1136/ heartjnl-2017-312348; PMID: 28903992. Kahlert P, Knipp SC, Schlamann M, et al. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study. Circulation 2010;121:870–8. https://doi. org/10.1161/CIRCULATIONAHA.109.855866; PMID: 20177005. Ghanem A, Muller A, Nahle 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. https:// doi.org/10.1016/j.jacc.2009.12.026; PMID: 20188503. Arnold M, Schulz-Heise S, Achenbach S, et al. Embolic cerebral insults after transapical aortic valve implantation detected by magnetic resonance imaging. JACC Cardiovasc Interv 2010;3:1126–32. https://doi.org/10.1016/j.jcin.2010.09.008; PMID: 21087747. Rodes-Cabau J, Dumont E, Boone RH, et al. Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches. J Am Coll Cardiol 2011;57:18–28. https://doi.org/10.1016/j. jacc.2010.07.036; PMID: 21185496. Fairbairn TA, Mather AN, Bijsterveld P, et al. Diffusionweighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation:

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the blinding methods for adjudication outcomes. Four studies followed the intention-to-treat analysis to handle missing data,12,17,20,21 and two of them used a modified intention-to-treat analysis.17,21 The rate of loss to follow-up was high in most of the randomised-studies.12,17,20,21 In the non-randomised studies,adjustment for confounders was not reported.14,15 Due to the nature of observational studies, potential selection bias cannot be ruled out in these studies. Selective reporting bias also could not be ruled out in all studies. Therefore, as previously stated,8 the quality of overall evidence was low to very low with the main limitation being serious risk of bias and imprecision.

Future Perspectives Even though the use of CEPD provide reduction in lesion volume in the protected territories, a significant number of insults can come from territories supplied by the vertebral arteries, i.e. the posterior lobes and the cerebellum/brainstem.4,23 In this regard, the Sentinel CEPD protects only nine out of 28 brain regions, because of the dual blood supply of the posterior circulation.23,28 Hence, as with TAVI itself, we are still in the early days of CEPD and further research is warranted to determine patients at high risk for systemic embolisation such as those with extensive atherosclerosis or complex aortic atheroma burden.39 New CEPDs are being developed. The Emboliner Embolic Protection Catheter (Emboline) is designed to provide improved cerebral protection and to capture both cerebral and non-cerebral debris. It also allows for the operator to pass material through the mesh as required. The SafePass trial will include up to 60 patients from five centres in Germany, the Netherlands and Israel and will assess the safety and technical performance of the Emboliner.

Conclusion The literature supports a reduction in lesion volume and total lesion volume with CEPD use, but this has not been translated into a substantial reduction in post-procedural or 30-day stroke and/or 30-day mortality. The clinical significance of silent ischaemic emboli is another important question that will require further evaluation, especially as TAVI begins to be utilised in younger patient populations, where there is even less evidence regarding a potential protective effect size. At the very least, CEPD is a promising technology and with further refinement may potentially reduce cerebral risk or neurocognitive function impairment in TAVI patients. Specialised neurological assessment following TAVI should be routine and further emphasised.

assessment of predictive risk factors and the relationship to subsequent health status. Heart 2012;98:18–23. https://doi. org/10.1136/heartjnl-2011-300065; PMID: 21737581. 7. Kahlert P, Al-Rashid F, Dottger P, et al. Cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study. Circulation 2012;126:1245-55. https://doi.org/10.1161/CIRCULATIONAHA.112.092544; PMID: 22899774. 8. Bagur R, Solo K, Alghofaili S, et al. Cerebral Embolic Protection devices during transcatheter aortic valve implantation. systematic review and meta-analysis. Stroke 2017;48:1306–15. https://doi.org/10.1161/STROKEAHA.116.015915; PMID: 28411259. 9. Van Mieghem NM, Schipper ME, Ladich E, et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement. Circulation 2013;127:2194–201. https://doi.org/10.1161/ CIRCULATIONAHA.112.001091; PMID: 23652860. 10. Van Mieghem NM, El Faquir N, Rahhab Z, et al. Incidence and predictors of debris embolizing to the brain during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2015;8:718–24. https://doi.org/10.1016/j.jcin.2015.01.020; PMID: 25946445. 11. Schmidt T, Akdag O, Wohlmuth P, et al. Histological findings and predictors of cerebral debris from transcatheter aortic valve replacement: The ALSTER experience. J Am Heart Assoc 2016;5:e004399. https://doi.org/10.1161/JAHA.116.004399;

PMID: 27930358. 12. K apadia SR, Kodali S, Makkar R, et al. Protection against cerebral embolism during transcatheter aortic valve replacement. J Am Coll Cardiol 2017;69:367–77. https://doi. org/10.1016/j.jacc.2016.10.023; PMID: 27815101. 13. Nietlispach F, Wijesinghe N, Gurvitch R, et al. An embolic deflection device for aortic valve interventions. JACC Cardiovasc Interv 2010;3:1133–8. https://doi.org/10.1016/j. jcin.2010.05.022; PMID: 21087748. 14. Rodés-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. 2014;7:1146–55. https://doi. org/10.1016/j.jcin.2014.04.019; PMID: 25341709. 15. Samim M, Agostoni P, Hendrikse J, et al. Embrella embolic deflection device for cerebral protection during transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2015;149:799– 805 e1-2. https://doi.org/10.1016/j.jtcvs.2014.05.097; PMID: 25455466. 16. 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. https://doi.org/10.4244/EIJY15M04_01; PMID:25868876. 17. Lansky AJ, Schofer J, Tchetche D, et al. A prospective randomized evaluation of the TriGuard™ HDH embolic

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Cerebral Embolic Protection in TAVI

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DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070–8. https://doi.org/10.1093/eurheartj/ehv191; PMID: 25990342. Samim M, van der Worp B, Agostoni P, et al. TriGuard™ HDH embolic deflection device for cerebral protection during transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2017;89:470–7. https://doi.org/10.1002/ccd.26566; PMID: 27121306. Fanning JP, Wesley AJ, Walters DL et al. Topographical distribution of perioperative cerebral infarction associated with transcatheter aortic valve implantation. Am Heart J 2018;197:113–23. https://doi.org/10.1016/j.ahj.2017.12.008; PMID: 29447771. 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. https://doi.org/10.4244/EIJV12I4A84; PMID: 27436602. Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis. The CLEAN-TAVI randomized clinical trial. JAMA 2016;316:592–601. https://doi.org/10.1001/jama.2016.10302; PMID: 27532914. Bogren HG, Buonocore MH, Gu WZ. Carotid and vertebral artery blood flow in left-and right-handed healthy subjects measured with MR velocity mapping. J Magn Reson Imaging 1994;4:37–42. https://doi.org/10.1002/jmri.1880040110; PMID: 8148554. Van Gils L, Kroon H, Daemen J, et al. Complete filter-based cerebral embolic protection with transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2018;91:790–97. https:// doi.org/10.1002/ccd.27323; PMID: 28895285. 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

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J Cardiothorac Surg 2011;40:475–9. https://doi.org/10.1016/j. ejcts.2010.11.070; PMID: 21256045. Van Belle E, Hengstenberg C, Lefevre T, et al. Cerebral Embolism During Transcatheter Aortic Valve Replacement: The BRAVO-3 MRI Study. J Am Coll Cardiol 2016;68:589–99. https:// doi.org/10.1016/j.jacc.2016.05.006; PMID: 27208464. Lansky AJ, Messé SR, Brickman AM, et al. Proposed standardized neurological endpoints for cardiovascular clinical trials: an academic research consortium initiative. J Am Coll Cardiol 2017;69:679–91. https://doi.org/10.1016/j. jacc.2016.11.045; PMID: 28183511. Testa L, Latib A, Casenghi M, et al. Cerebral protection during transcatheter aortic valve implantation: an updated systematic review and meta-analysis. J Am Heart Assoc 2018;7: https://doi. org/10.1161/JAHA.117.008463; PMID: 29728369. Seeger J, Gonska B, Otto M, et al. Cerebral embolic protection during transcatheter aortic valve replacement significantly reduces death and stroke compared with unprotected procedures. JACC Cardiovasc Interv 2017;10:2297–303. https:// doi.org/10.1016/j.jcin.2017.06.037; PMID: 28917515. Grover FL, Vemulapalli S, Carroll JD, et al. 2016 Annual Report of The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Ann Thorac Surg 2017;103:1021–35. https://doi.org/10.1016/j. athoracsur.2016.12.001; PMID: 27955994. Wendler O, Schymik G, Treede H, et al. SOURCE 3 registry: design and 30-day results of the European postapproval registry of the latest generation of the SAPIEN 3 transcatheter heart valve. Circulation 2017;135:1123–32. https://doi. org/10.1161/CIRCULATIONAHA.116.025103; PMID: 28104716. Bagur R, Teefy PJ, Kiaii B, et al. First North American experience with the transfemoral ACURATE-neo™ selfexpanding transcatheter aortic bioprosthesis. Catheter Cardiovasc Interv 2017;90:130–8. https://doi.org/10.1002/ ccd.26802; PMID: 27677241. Grube E, Van Mieghem NM, Bleiziffer S, et al. Clinical outcomes with a repositionable self-expanding transcatheter aortic valve prosthesis: The International FORWARD study.

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J Am Coll Cardiol 2017;70:845–53. https://doi.org/10.1016/j. jacc.2017.06.045; PMID: 28797353. Forrest JK, Mangi AA, Popma JJ, et al. Early outcomes with the Evolut PRO repositionable self-expanding transcatheter aortic valve with pericardial wrap. JACC Cardiovasc Interv 2018;11:160–8. https://doi.org/10.1016/j. jcin.2017.10.014; PMID: 29348010. Mollmann H, Hengstenberg C, Hilker M, et al. Real-world experience using the ACURATE neo prosthesis: 30-day outcomes of 1,000 patients enrolled in the SAVI TF registry. EuroIntervention 2018;13:e1764–70. https://doi.org/10.4244/EIJD-17-00628; PMID: 29131801. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document (VARC-2). Eur J Cardiothorac Surg 2012;42:S45–60. https://doi.org/10.1093/ejcts/ezs533; PMID: 23026738. Knipp SC, Kahlert P, Jokisch D, et al. Cognitive function after transapical aortic valve implantation: a single-centre study with 3-month follow-up. Interact Cardiovasc Thorac Surg 2013;16:116–22. https://doi.org/10.1093/icvts/ivs461; PMID: 23148084. Ghanem A, Kocurek J, Sinning JM, et al. Cognitive trajectory after transcatheter aortic valve implantation. Circ Cardiovasc Interv 2013;6:615–24. https://doi.org/10.1161/ CIRCINTERVENTIONS.112.000429; PMID: 24129642. Wendt D, Kleinbongard P, Knipp S, et al. Intraaortic protection from embolization in patients undergoing transaortic transcatheter aortic valve implantation. Ann Thorac Surg 2015;100:686–91. https://doi.org/10.1016/j. athoracsur.2015.03.119; PMID: 26234838. Bagur R, Rodés-Cabau J, Doyle D, et al. Transcatheter aortic valve implantation with “no touch” of the aortic arch for the treatment of severe aortic stenosis associated with complex aortic atherosclerosis. J Card Surg 2010;25:501–3. https://doi.org/10.1111/j.1540-8191.2010.01066.x; PMID: 20626520.

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Structural

TAVI for Pure Native Aortic Regurgitation: Are We There Yet? Eduardo A Arias, 1 Amit Bhan, 2 Zhan Y Lim 3 and Michael Mullen 2 1. Interventional Cardiology Department, National Institute of Cardiology Ignacio Chávez, Mexico City, Mexico; 2. Barts Heart Centre, St Bartholomew’s Hospital, London, UK; 3. Cardiology Department, Khoo Teck Puat Hospital, Singapore

Abstract Treatment of degenerative aortic stenosis has been transformed by transcatheter aortic valve implantation (TAVI) over the past 10–15 years. The success of various technologies has led operators to attempt to broaden the indications, and many patients with native valve aortic regurgitation have been treated ‘off label’ with similar techniques. However, the alterations in the structure of the valve complex in pure native aortic regurgitation are distinct to those in degenerative aortic stenosis, and there are unique challenges to be overcome by percutaneous valves. Nevertheless some promise has been shown with both non-dedicated and dedicated devices. In this article, the authors explore some of these challenges and review the current evidence base for TAVI for aortic regurgitation.

Keywords Aortic valve stenosis, native aortic valve regurgitation, second generation TAVI device, TAVI, transcatheter valve interventions, valvular heart disease Disclosure: The authors have no conflicts of interest to declare. Received: 12 November 2018 Accepted: 7 January 2019 Citation: Interventional Cardiology Review 2019;14(1):26–30. DOI: https//doi.org/10.15420/icr.2018.37.1 Correspondence: Eduardo Arias, National Institute of Cardiology Ignacio Chávez, Juan Badiano 1, Col Sección XVI, Tlalpan, Mexico City, Mexico. E: dreduardoarias@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

During the past decade, transcatheter aortic valve implantation (TAVI) has revolutionised the interventional treatment of aortic stenosis (AS).1 It has rapidly evolved from a treatment used on a compassionate basis for inoperable patients to being the standard of care in high-risk AS.2,3 In that cohort it has proven to be non-inferior to surgical aortic valve replacement (SAVR) in terms of mortality, and superior to optimal medical treatment (OMT) in terms of mortality and rehospitalisations.4,5 Evidence and indications are now moving towards its suitability for intermediate and low-risk profiles. Randomised trials such as Placement of Aortic Transcatheter Valves (PARTNER 2) and Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients (SURTAVI) have shown that TAVI is a safe and effective treatment option for people with intermediate risk; being non-inferior to SAVR overall and superior to surgery when it is performed using the transfemoral approach.6,7 The randomised controlled Nordic Aortic Valve Intervention (NOTION) trial, which included intermediate and low-risk patients, has also confirmed the safety and efficacy in a low-risk setting.8 It is important to clarify that low-risk patients are not necessarily younger patients (the mean age in all the mentioned studies was about 80 years). This leaves unanswered questions about valve durability; as far as we know the incidence of structural valve deterioration after 5 years is very low, but information beyond this time is scarce.9–12 The use of TAVI is continuing to evolve worldwide. Transcatheter heart valves (THV) are being used for valve-in-valve treatment in failing bioprostheses, treatment of bicuspid aortic valves in younger patients with

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ICR_Arias_FINAL.indd 26

complex anatomical features and for native pure aortic regurgitation (NPAR). This is currently an off-label indication as it poses multiple challenges with variable and unpredictable immediate and long-term results.13–15 The aim of this review is to describe: the main differences between AS and NPAR; its impact on procedure complexity; the THVs available for NPAR treatment and current evidence regarding success and short-term results.

Native Aortic Valve Regurgitation From a pathophysiological point of view, severe AS is characterised by pressure overload with consequent concentric hypertrophy and afterload mismatch.16 In most cases, after TAVI is performed and this mismatch corrected, left ventricular ejection fraction increases and there is regression of left ventricular (LV) hypertrophy.17 This explains why patients have the clear benefits of quality of life and life expectancy after TAVI. On the other hand, severe NPAR is characterised by volume overload and eccentric hypertrophy (increased ventricular volume with little increase in wall thickness and increased LV wall stress) associated with LV cavity structural modifications and progressive LV dysfunction.18 These structural modifications are due to cardiomyocyte enlargement triggered by multiple growth factors that modulate cardiac output by means of the FrankStarling mechanism. Once the Frank-Starling mechanism is lost, LV function is irreversibly impaired.19,20 From an anatomic point of view, degenerative AS results from progressive calcification of the aortic valve leaflets and annulus, while NPAR is usually the result of leaflet

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TAVI for Pure Native Aortic Regurgitation Figure 1: Main Differences Between Aortic Stenosis and Aortic Regurgitation on CT Scan

-> A

Annulus AR

Leaflets AR

-> *

C Annulus AS

Leaflets AS

A: Spherical and dilated aortic annulus in AR compared with a more elyptical one in AS; B: Absence of calcium on leaflets in AR compared with heavily calcified leaflets on AS; C: Severe aortic regurgitation (* eccentric LV hypertrophy; -> dilated aortic root); D: Severe aortic regurgitation (* eccentric LV hypertrophy; -> dilated aortic root). AR = aortic regurgitation; AS = aortic stenosis.

Table 1: Available Non-dedicated and Dedicated Transcatheter Aortic Valve Implantation Devices for Native Aortic Valve Regurgitation Valve name

Mechanism

Use in AR

Company

SAPIEN 3 transcatheter heart valve

Balloon expandable

Non-dedicated

Edwards Lifesciences

ACURATE neo™

Self-expandable

Non-dedicated

Boston Scientific

LOTUS

Self-expandable

Non-dedicated

Boston Scientific

CoreValve™ Evolut™ R

Self-expandable

Non-dedicated

Medtronic

JenaValve™

Self-expandable

Dedicated

JenaValve Technology

J·Valve™

Self-expandable

Dedicated

JC Medical

degeneration or incompetence, aortic root dilatation with aortic annulus enlargement, or both. These anatomical differences pose particular challenges for TAVI, which we will discuss later. Figure 1 depicts the main anatomical differences between AS and AR.

Current Management of Aortic Regurgitation Prevalence of AR increases with age and it affects about 13% of patients with isolated, native left-sided valvular heart disease.21 Symptoms related to AR tend to appear late in the history of the disease, once LV dilatation and systolic dysfunction have set in. Patients with severe AR and an ejection fraction <30% have an annual mortality risk of 20%, but unfortunately only 5% of these patients are given SAVR according to data from the Euro Heart Survey on Valvular Heart Disease.21 According to current European and US guidelines, patients with symptomatic moderate/severe AR and decreased LV systolic function (<50%) or severe LV dilatation (LV end-systolic diameter >50 mm; LV end-diastolic diameter >65–70 mm; LV end-systolic volume index >45 ml/m2) should be considered for SAVR.2,3 Nonetheless, there is a high-risk subgroup who are inoperable and who could be considered for TAVI, taking into account the multiple procedural challenges and the fact that it still is an off-label indication.22 To date, the standard of care for severe NPAR is SAVR with TAVI emerging as an option for high-risk or inoperable patients.

Technical Challenges During TAVI for NPAR The main challenge that interventionists face during TAVI for NPAR is the absence of annular and leaflet calcification, which is necessary for device anchoring and stabilisation during deployment. The lack

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of calcium, the increased stroke volume secondary to severe AR and the presence of aortic root dilatation makes device positioning and deployment very difficult and there is a predisposition to embolisation or malposition of the prosthesis with subsequent moderate to severe post-procedural AR (associated with worst clinical outcomes).23 Valve migration can occur to the aorta or deep into the LV up to several hours after implantation.24 Valve oversizing has been proposed to reduce the risk of valve migration. Published data recommend a 15–20% oversize when selecting the THV size with the caution not to oversize beyond 20% due to the risk of annular rupture and conduction system abnormalities.25,26

THV Devices Available for NPAR Second generation THVs that have been used for TAVI for NPAR can be divided into non-dedicated devices: CoreValve Evolut R (Medtronic), Sapien 3 (Edwards Lifesciences), Lotus valve (not commercially available at time of writing) and ACURATE neo (Boston Scientific) and dedicated devices: JenaValve (JenaValve) and the J.Valve (JC Medical).27 Non-dedicated devices are widely used for TAVI for AS (their mechanisms are dependent on annulus and leaflet calcification for fixation), while the dedicated devices have been developed to be implanted in non-calcified valves anchoring in the aortic annulus and clipping the native valve leaflets for stability.28 Self-expandable THVs have been the preferred non-dedicated devices used for TAVI for NPAR with CoreValve being the most widely studied. Self-expandable THVs can be recaptured and repositioned which theoretically make the prosthesis behave in a more predictable manner. 29,30 Experience with ACURATE neo

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Structural Table 2: Main Results of Recent Retrospective Studies Evaluating Early Generation Devices Versus New Generation Devices Device Success

CV Mortality

Second Valve

Author, year

Patients (n)

EGD

NGD

(EGD/NGD)

Roy et al. 201341

100%

74.4%/NA

10.7%*/NA

18.6%/NA

4.7%/NA

331

36%

64%

61.3%/81.1%

23.6%/9.6%*

24.4%/12.7%

18.8%/4.2%

40.4%/9.4%

31%/4%

Yoon et al. 201749

AR >Moderate

254

43%

57%

47%/82%

12%/7%

Sawaya et al. 201750

47.4%

52.6%

54%/85%

11%/5%†

24%/10%

29%/2%

Silaschi et al. 201839

100%

NA/96.7%

NA/10%

NA/0%

De Backer et al. 2018

†

* 1-year mortality; †30-day mortality. AR = aortic regurgitation; CV = cardiovascular; EGD = early generation device; NGD = new generation device.

(transfemoral) is limited to successful case reports and there is a small series of eight patients treated with ACURATE TA (transapical) that showed good results based on its hourglass design, stabilisation arches and upper crown that ensure coaxial alignment and device stability during deployment.31,32 The first successful transfemoral implantation of a Lotus valve in pure NPAR was reported in 2016 and the authors warrant its use based on its repositionability and retrievability.33 Sapien 3 valve (balloon expandable) implantation has been shown to be feasible for NPAR in three cases reported in 2016. Deployment position was more ventricular than that recommended for AS and the annulus oversizing ratio was >15% using from 3 to 10 mm extra volume according to the LV outflow tract dimensions.34,35 The JenaValve, a self–expanding, 32Fr transapical valve with three integrated locators was the first dedicated device to get the CE mark for NPAR based on its anatomically correct positioning in the native cusps and clipping of the THV onto the native leaflets.36,37 Since June 2016, the transapical system is no longer available but development of a new generation transfemoral system is underway and has been used successfully for NPAR in a first-in-human case report in 2017.38 The Longterm Safety and Performance of the JenaValve (JUPITER) registry showed a procedural success rate of 96.7% with 0% incidence of valve malposition and moderate to severe post-procedural AR.39 Another NPAR-dedicated second generation TAVI device is the J-Valve, which has a unique system composed of three U-shape graspers that facilitate intuitive self-positioning implantation providing axial and radial fixation by embracing the native valve leaflets. A successful first-in-human implantation was reported in 2015 but currently, the device is only available in Asia.40 Table 1 shows the different THVs available for NPAR.

TAVI for NPAR: Evidence on Early Generation Devices The first use of TAVI for NPAR was reported by Roy et al. in 2013 and included the retrospective analysis of 43 patients at 14 centres who had TAVI for severe inoperable NPAR. All cases used CoreValve prosthesis and as part of the procedure protocol two pigtail catheters in different sinuses of Valsalva were used to guide THV delivery under rapid pacing. Results included a 97.7% success rate (according to protocol and not VARC-2 guidelines), in 18.6% of the cases a second valve was required during the index procedure for residual AR (all of which had absent valve calcification) and the one-year all-cause mortality was 21.4%.41 Multiple studies followed using early generation devices (CoreValve being the most used followed by Sapien/Sapien

ICR_Arias_FINAL.indd 28

XT, JenaValve, Direct flow and ACURATE TA), and in 2016 Franzone et al. published a meta-analysis of 13 studies with a total of 237 severe inoperable NPAR patients without AS treated with TAVI.42–44 In 80% of the cases a self-expandable valve was used and less than 25% of the cases were treated with devices approved for AR. Device success ranged from 77% to 100% with a 7% incidence of second valve implant due to either device migration or severe post-procedural AR. The primary endpoint of all-cause mortality at 30 days ranged from 0 to 30% with a summary estimate rate of 7%. Moderate to severe postprocedural AR was reported in up to 88% of patients with a summary estimate rate of 9%.45 The JenaValve subgroup had a 0% incidence of moderate to severe post-procedural AR. Given the heterogeneity of the groups and procedural aspects, no solid conclusions in terms of safety and efficacy can be drawn from these initial experiences but all of them showed that TAVI for NPAR is complex, with success rates below those reported for AS and a high incidence of valve malposition and moderate to severe post-procedural AR.

TAVI for NPAR: Evidence on New Generation Devices New generation devices (NGDs) such as CoreValve Evolut R, ACURATE neo, Lotus valve and Sapien 3 have features that distinguish them from their predecessors. Characteristics such as retrievability and repositioning in the case of the self-expandable valves and the adaptive seal or skirt found in Sapien 3 and Lotus valve offer a more controlled and predictable TAVI procedure.46,47 Three recent retrospective studies have analysed the use of new generation TAVI devices for NPAR and compared their results with early generation devices. De Backer et al. reported the early safety and clinical efficacy of TAVI for NPAR in 254 patients from 46 centres with an EGD/NGD proportion of 43% and 57%, respectively. Overall device success according to Valve Academic Research Consortium (VARC-2) criteria was 67%, being higher with NGD (82% versus 47% when compared with EGD).9 NGD use was associated with less valve malpositioning and less moderate to severe post-procedural AR. Cardiovascular mortality was also lower with NGD. As part of the study they focused on THV CT-scan sizing and found a significant increase on the incidence of device embolisation with relative THV under or oversizing when compared with neutral sizing. The authors found no causal explanation for this phenomenon other than valve design and absence of calcification.48 Yoon et al. reported 331 severe NPAR patients from 40 centres (36% EGD and 64% NGD). Primary endpoint was all-cause and cardiovascular mortality at one year. Overall device success was 74.3% and again, second valve implantation, moderate to severe post-procedural AR

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TAVI for Pure Native Aortic Regurgitation and cardiovascular mortality were significantly lower with NGD (12.7% versus 24.4%; 4.2% versus 18.8% and 9.6% versus 23.6%, respectively) when compared with EGD. They also found that the absence of calcium or the presence of mild calcification was associated with less frequent device success with EGD but not with NGD. A larger annulus (>25.2mm) was associated with less frequent device success either with EGD or NGD. Finally, they showed that a higher degree of perimeter oversizing index (>15%) was associated with less frequent moderate to severe AR.49 Sawaya et al. performed a retrospective analysis of 78 patients with severe NPAR treated with TAVI. The majority of cases were done under general anaesthesia via transfemoral access with CoreValve; given its radial force at both the annular level and ascending aorta and also because it could be significantly oversized without risk of annular rupture. Results were consistent with those that we have previously described. NGD showed a lower incidence of valve malposition, a lower degree of AR and cardiovascular mortality versus EGD. They also found that a BMI <20kg/m2, Society of Thoracic Surgeons score >8%, major vascular complication or new left bundle branch block, and more than moderate AR were independent predictors of mortality and New York Heart Association III–IV at 30 days after TAVI for NPAR.50 All of these findings were confirmed in a recent meta-analysis.51 Table 2 summarises the main results of these three studies.

Interventional Tips and Tricks for TAVI for NPAR The following recommendations are made based on personal experience and information gathered from published cases. The first and one of the most important steps before TAVI for NPAR is a pre-procedural CT assessment with focus on the annulus area, sinuses of Valsalva and aortic root diameters and device size selection keeping in mind that a 15–20% oversizing index is recommended in this setting (oversizing index formula: [(device nominal perimeter/area) / (annulus/perimeter area measured by CT) – 1] x 100.52 The procedure should be carried out preferably under general anaesthesia, as it can be lengthy and complicated. Transoesophageal echocardiogram can be used to help with valve positioning but more importantly to accurately evaluate

errin N, Frei A, Noble S. Transcatheter aortic valve P implantation: Update in 2018. Eur J Intern Med 2018;55:12–9. https://doi.org/10.1016/j.ejim.2018.07.002; PMID: 30180946. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg 2012;42:S1–44. https://doi. org/10.1093/ejcts/ezs455; PMID: 22922698. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. https://doi.org/10.1016/ j.jacc.2017.03.011; PMID: 28315732. 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. https://doi. org/10.1056/NEJMoa1008232; PMID: 20961243. Eltchaninoff H, Prat A, Gilard M, et al. Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Eur Heart J 2011;32:191-7. https://doi.org/10.1093/eurheartj/ehq261; PMID: 20843959. 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. https://doi.org/10.1056/ NEJMoa1514616; PMID: 27040324. Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. https://doi. org/10.1056/NEJMoa1700456; PMID: 28304219. Sondergaard L, Steinbruchel DA, Ihlemann N, et al.

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11.

12.

13.

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the degree of post-procedural AR. Given the absence of calcification and fluoroscopic landmarks many operators use two pigtail catheters in different sinuses of Valsalva, or CT fusion-guided imaging for valve deployment. Balloon predilatation should not be performed unless it is used to measure the annulus when there is no available CT. Rapid pacing is mandatory for balloon expandable valves and it can also be used with self-expandable valves to reduce the stroke volume, helping to stabilise the aortic annulus and limit THV motion by reducing the regurgitant jet. While deploying the valve, always pay close attention to the haemodynamic profile, particularly to the waveform, the dicrotic notch and the aortic diastolic pressure.53 Whenever using a balloon-expandable valve, keep in mind that variable amounts of extra volume should be added to avoid valve embolisation. Finally, based on the evidence we have presented, the use of NGD should be mandatory in TAVI for NPAR.

Conclusion Patients with NPAR who are candidates for TAVI tend to be in a poorer clinical condition than many contemporary AS patients, due to LV dilatation and dysfunction. These facts alongside the technical difficulties met during the procedure and the lack of transfemoral dedicated devices make TAVI for NPAR an ‘off-label’ treatment. Even though better results are achieved with NGD in terms of lower rates of valve malposition/second valve insertion during index procedure and lower incidence of moderate to severe post-procedural AR, clinical results are far from those achieved with TAVI for AS. To date there are no randomised clinical trials and all the evidence we have comes from retrospective studies with heterogeneous populations and no standardised TAVI protocol for NPAR. New dedicated devices are being designed and those available are evolving to transfemoral as we continue to gain experience of using non-dedicated devices for this patient group. Nonetheless, TAVI for NPAR has to be considered the treatment of choice for inoperable severe AR patients because it offers a better prognosis than optimal medical treatment. TAVI has been established for inoperable or high-risk patients, but we need to improve. TAVI is not yet the standard of care for NPAR, but it is likely to be established as such in time.

Two-year outcomes in patients with severe aortic valve stenosis randomized to transcatheter versus surgical aortic valve replacement: the all-comers nordic aortic valve intervention randomized clinical trial. Circ Cardiovasc Interv 2016;9:pii: e003665. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003665; PMID :27296202. Kumar A, Sato K, Banerjee K, et al. Hemodynamic durability of transcatheter aortic valves using the updated Valve Academic Research Consortium-2 criteria. Catheter Cardiovasc Interv 2018. https://doi.org/10.1002/ccd.27927; PMID: 30312995; epub ahead of press. Eltchaninoff H, Durand E, Barbanti M, Abdel-Wahab M. TAVI and valve performance: update on definitions, durability, transcatheter heart valve failure modes and management. EuroIntervention 2018;14(Suppl AB):AB64–73. https://doi. org/10.4244/EIJ-D-18-00653; PMID: 30158097. Holy EW, Kebernik J, Abdelghani M, et al. Long-term durability and haemodynamic performance of a selfexpanding transcatheter heart valve beyond five years after implantation: a prospective observational study applying the standardised definitions of structural deterioration and valve failure. EuroIntervention 2018;14: e390–6. https://doi.org/10.4244/EIJ-D-18-00041; PMID: 29741488. Barbanti M, Petronio AS, Ettori F, et al. 5-year outcomes after transcatheter aortic valve implantation with corevalve prosthesis. JACC Cardiovasc Interv 2015;8:1084–91. https://doi. org/10.1016/j.jcin.2015.03.024; PMID: 26117458. Takagi H, Mitta S, Ando T. Meta-analysis of valve-invalve transcatheter versus redo surgical aortic valve replacement. Thorac Cardiovasc Surg 2018. https://doi. org/10.1055/s-0038-1668135. PMID: 30114716; epub ahead of press. Das R, Puri R. Transcatheter treatment of bicuspid aortic valve disease: imaging and interventional considerations.

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How to Make the TAVI Pathway More Efficient Didier Tchetche, Chiara de Biase, Bruno Brochado and Antonios Mastrokostopoulos Groupe Cardiovasculaire Interventionnel, Clinique Pasteur, Toulouse, France

Abstract Transcatheter aortic valve implantation (TAVI) has been in use for 16 years. As there has been a rapid expansion in its use, there is a need to optimise TAVI programmes to ensure efficiency. In this article, the authors discuss the reasons why clinicians need to make the TAVI pathway more efficient and describe the most important steps to take from screening to early discharge, including procedural optimisation.

Keywords Early discharge, efficiency, simplification, TAVI, transcatheter aortic valve implantation Disclosure: DT is a consultant for Edwards LifeSciences, Medtronic and Boston Scientific. All other authors have no conflicts of interest to declare. Received: 23 July 2018 Accepted: 19 December 2018 Citation: Interventional Cardiology Review 2019;14(1):31–3. DOI: https://doi.org/10.15420/icr.2018.28.2 Correspondence: Didier Tchetche, Groupe Cardiovasculaire Interventionnel, Clinique Pasteur, 45 Avenue de Lombez, 31076 Toulouse Cedex 3, France. E: d.tchetche@clinique-pasteur.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sixteen years have elapsed since the first transcatheter aortic valve implantation (TAVI) and the procedure has now been widely adopted. The first time the procedure was performed, the patient was under conscious sedation with local anaesthesia for an antegrade-transseptal procedure.1 The pioneering team in Rouen published a series of case reports for patients treated via a transfemoral route using a conscious sedation/local anaesthesia policy. The outcome in this cohort was excellent, with a low 30-day mortality and conversion to general anaesthesia required in only 3.3% of the cases and low 30-day mortality.2 However, in the vast majority of the early cases, general anaesthesia and transoesophageal guidance were used as routine. The main reasons for this were the need for surgical cutdown, because of the large bore sheaths that were used at the time; the need for a thorough assessment of residual aortic regurgitation post-TAVI; and the need for early identification of complications. When the procedure was first in use, we had to deal with multiple potential complications including vascular injuries, aortic annulus rupture, moderate-to-severe perivalvular regurgitation, the need for a permanent pacemaker and stroke.3 Using a general anaesthetic was a safe way to quickly identify life-threatening complications and bail out of the procedure. Where are we in 2019? More than 300,000 TAVIs have been performed worldwide in more than 70 countries across the globe.4 We are no longer using 20–24 Fr introducer sheaths, but devices that are 14–16 Fr compatible, reducing rates of vascular complications.5 Transcatheter heart valves (THV) have improved, allowing more predictable deployment and preventing paravalvular regurgitation. Transfemoral access is used in more than 90% of cases in centres where the procedure is carried out regularly.

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The large and rapid expansion of TAVI has led to constant improvement in techniques and clinical outcomes for patients, but has also presented a new problem: we must treat more patients in a more efficient way with shorter procedures and shorter hospital stays, while maintaining excellent outcomes. The cost-effectiveness of TAVI has been demonstrated in several studies with various types of THV, at least for transfemoral access, even if significant variations in cost can be identified in different countries’ healthcare systems. Even when treating inoperable, high and intermediate-risk patients, the procedure could be more cost-effective by reducing the use of human resources and enabling shorter hospital stays.6 Efficient TAVI has become a contemporary challenge.

How do we Achieve Greater Efficiency for TAVI? The core idea behind an efficient TAVI programme is to be able to treat all patients who need the procedure. It embodies several aspects: optimisation of the screening phase (Table 1), a minimalist approach during the procedure and early discharge without compromising clinical outcomes (as efficient TAVI should aim to eliminate complications).

Efficient Screening Optimising the screening phase is potentially the most important part of an efficient TAVI programme. It should quickly provide the heart team with all the necessary elements for a multidisciplinary discussion: transthoracic echocardiography, multidetector CT of the aortic root and peripheral vasculature, coronary angiogram (according to local practice) and blood tests. In many institutions, a dedicated TAVI coordinator is in charge of scheduling the screening tests during a 2–3-day hospitalisation, gathering all the results for the heart team, scheduling the TAVI procedures and preparing the mode of discharge of the patients after the procedure. This enables the team to screen all eligible patients. This is just one example of how a simple change has led to a more fluid TAVI pathway.

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Actions Needed

Screening

• Coronary angiogram TAVI coordinator 2–3 days • Multidetector CT • Transthoracic echocardiography • Blood tests • Heart team assessment

Procedure

• Conscious sedation • Percutaneous access • Femoral-radial accesses • Fluoroscopic guidance • Direct TAVI • Pacing through wire

Post-operative • Atrioventricular block risk care assessment • No intensive care for selected patients • Early discharge

Personnel Required

Timing

2 operators, <1 hour 2 nurses, 1 anaesthesiologist

Anaesthesia cart C-arm

Sterile table

Standby bypass machine

Echo

Fluoroscopy/ haemodynamics

Standby balloon pump

Cut down table

Fluoroscopy

Phase of Treatment

Figure 1: Before and After the Optimisation of Human Resources During Transfemoral TAVI

TAVI device assembly

Table 1: Summary of the Actions Needed for an Efficient Transfemoral TAVI

Fluoroscopy

Medical team

2 days

Improving the Efficiency of the Procedure Making the procedure more efficient means avoiding steps that are inessential. It starts by identifying the indispensable human resources for a single procedure. The contemporary trend for transfemoral TAVI is to reduce the team to two main operators, an anaesthesiologist, a perioperative nurse to prepare the THV and a circulating nurse to cover logistics in the operating room (Figure 1). A single nurse can prepare any THV while this optimised team can handle the most frequent or life-threatening complications, such as vascular injury or cardiac tamponade. Optimising human resources is a challenge for most hospitals. Apart from saving costs, people can be freed up to do other tasks and the money saved could be invested in a dedicated TAVI coordinator. The procedure involves local anaesthesia and conscious sedation, fully percutaneous femoral access and fluoroscopic guidance.

Anaesthesia cart C-arm

Sterile table

Echo

Fluoroscopy/ haemodynamics

TAVI device assembly Fluoroscopy

Other ways to simplify the procedure have also been introduced, including the avoidance of balloon valvuloplasty before THV (direct TAVI) and pacing through the left ventricular wire. Direct TAVI reduces the potential complications associated with valvuloplasty, such as conduction disturbances, annular rupture and stroke. The goal of pacing through the left ventricle wire is to prevent right ventricular perforation with pacing leads. Diluted contrast (two-thirds dye and one-third saline solution) is also proposed to reduce the risk of contrast-induced nephropathy. Activated clotting time (ACT)-guided procedures are common, aiming at an ACT close to 200–250 seconds to prevent bleeding. The systematic use of protamin post-procedure is debated.

Let us analyse these elements separately. Conscious sedation is the gold standard for transfemoral TAVI because general anaesthesia can be harmful, particularly in older people who can be at increased risk of post-operative delirium and subsequent mortality.7 Foley urinary

Efficient Discharge

catheters, jugular lines or radial access to monitor arterial pressure, are generally avoided. For femoral access, the most popular closure devices are Prostar and ProGlide, which are similar and carry low rates of major vascular complications.8 However, new closure devices are being introduced that may simplify and further secure femoral closure for early ambulation.

The last aspect of an efficient TAVI programme is early ambulation and early discharge, usually within two days. This will ensure an adequate turnover of uncomplicated patients. Local rules have to be determined to make sure that every patient can be safely discharged, particularly without an increased risk of delayed atrioventricular block and with an adequate follow-up.

Many teams are moving to the use of a single femoral access and a radial access as the secondary arterial access to reduce the rate of vascular complications. Given the accuracy of positioning of current THV and their efficiency in mitigating paravalvular regurgitation, the use of transoesophageal echocardiography can be questioned.9 Fluoroscopic guidance has proven its feasibility since the early days in Rouen and it is becoming the rule in most institutions. Having said that, keeping in mind that we should not compromise patient safety, it is generally recommended to have a transthoracic echography machine in the operating room in order to quickly identify complications; at least to verify the absence of pericardial effusion after the THV has been deployed.

As an example, a patient without right bundle branch block at baseline, treated with a balloon-expandable THV without any procedural issue or conduction disturbance could, in theory, be discharged the next day. Other examples are valve-in-valve procedures, even if treated with a self-expandable platform, because the risk of AV block is minimal, as well as any patient with a previous pacemaker. These patients could also be candidates for TAVI without a subsequent stay in intensive care.

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As a word of caution, it is important to identify appropriate candidates for a more efficient approach to this intervention. There are indications for a longer screening period, such as

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How to Make the TAVI Pathway More Efficient baseline renal impairment or geriatric assessment. There are also indications for general anaesthesia, such as a need for a ‘zero contrast’ procedure with transoesophageal echocardiography guidance. In some cases there will also be a need for a longer period of post-operative surveillance, such as high risk of AV block, depressed renal function, vascular complications or the need for blood transfusion.

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. https://doi.org/10.1161/01. CIR.0000047200.36165.B8; PMID: 12473543. 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. https://doi.org/10.1016/j. jcin.2012.01.018; PMID: 22560979. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705–15. https://doi.org/10.1056/

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Conclusion Efficient TAVI relates to the ability to safely treat more patients in an optimised environment in a cost-effective way. Optimisation of human resources and simplification of the procedure are at the core of this strategy. Efficient TAVI has several advantages, including shorter procedures, better recovery, early discharge, lower hospital costs and an increased volume of TAVI procedures.

NEJMoa1114705; PMID: 22551129. Mylotte D, Osnabrugge RLJ, Windecker S, et al. Transcatheter aortic valve replacement in Europe: adoption trends and factors influencing device utilization. J Am Coll Cardiol 2013;62:210–9. https://doi.org/10.1016/j.jacc.2013.03.074; PMID: 23684674. Tchetche D, Van Mieghem NM. New-generation TAVI devices: description and specifications. EuroIntervention 2014;10 (Suppl U):U90–100. https://doi.org/10.4244/EIJV10SUA13; PMID: 25256338. Tchetche D, De Biase C. Optimizing transcatheter aortic valve implantation could make it even more cost-effective! Structural Heart 2017;1:275–6. https://doi.org/10.1080/24748706.2017. 1381358.

Tchetche D, De Biase C. Local anesthesia-conscious sedation: the contemporary gold standard for transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11;579–80. https://doi.org/10.1016/j.jcin.2018.01.238; PMID: 29566804. Barbash IM, Barbanti M, Webb J, et al. Comparison of vascular closure devices for access site closure after transfemoral aortic valve implantation. Eur Heart J 2015;36:3370–9. https://doi.org/10.1093/eurheartj/ehv417; PMID: 26314688. van Gils L, Tchetche D, Latib A, et al. TAVI with current CE-marked devices: strategies for optimal sizing and valve delivery. EuroIntervention 2016;12(Suppl Y):Y22–7. https://doi. org/10.4244/EIJV12SYA6 PMID: 27640026.

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Patent Foramen Ovale Closure in 2019 Joel P Giblett, 1,2 Omar Abdul-Samad, 1 Leonard M Shapiro, 1 Bushra S Rana 1 and Patrick A Calvert 1,2 1. Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK; 2. Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK

Abstract Patent foramen ovale (PFO) is a common abnormality affecting between 20% and 34% of the adult population. For most people it is a benign finding; however, in some the PFO can open widely, enabling a paradoxical embolus to transit from the venous to arterial circulation, which is associated with stroke and systemic embolisation. Percutaneous closure of PFO in patients with cryptogenic stroke has been undertaken for a number of years, and a number of purpose-specific septal occluders have been marketed. Recent randomised controlled trials have demonstrated that closure of PFO in patients with cryptogenic stroke is associated with reduced rates of recurrent stroke. After a brief overview of the anatomy of a PFO, this review considers the evidence for PFO closure in cryptogenic stroke. The review also addresses other potential indications for closure, including systemic embolisation, decompression sickness, platypnoea–orthodeoxia syndrome and migraine with aura. It lays out the pre-procedural investigations and preparation for the procedure. Finally, it gives an overview of the procedure itself, including discussion of closure devices.

Keywords Patent foramen ovale, paradoxical embolus, systemic embolisation, percutaneous closure, cryptogenic stroke, septal occluders, systemic embolisation, decompression sickness, platypnoea–orthodeoxia syndrome Disclosure: PC undertakes proctoring for Abbott and Occlutech. The other authors have no conflicts of interest to declare. Received: 12 September 2018 Accepted: 10 December 2018 Citation: Interventional Cardiology Review 2019;14(1):34–41. DOI: https://doi.org/10.15420/icr.2018.33.2 Correspondence: Patrick Calvert, Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge CB23 3RE, UK. E: patrick.calvert1@nhs.net Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Patent foramen ovale (PFO) is a common abnormality, occurring in 20–34% of the population.1 In the majority of infants, closure of the foramen ovale occurs soon after birth, as negative intrathoracic pressure associated with the first breaths closes the PFO. In some cases, the primum and secundum atrial septa fail to fuse and closure remains incomplete. There is continuing communication between the right and left atria, particularly during actions that cause a sudden rise and fall in intrathoracic pressure, such as coughing, sneezing or straining. The changes can be mimicked by asking the patient to perform and then release a Valsalva manoeuvre. For the majority of people, a PFO will remain undetected or appear only as a chance finding during cardiac investigation. However, some PFOs may open widely and provide a conduit for material such as thrombi, air or vasoactive peptides to travel from the venous to arterial circulation – a paradoxical embolus. This is associated with cryptogenic stroke, systemic embolus, migraine with aura, and decompression sickness in divers. Percutaneous PFO closure provides a practical and elegant solution to this problem in carefully selected individuals.

communication between the right and left atria that persists post-partum in patients with a PFO is caused by a failure of fusion of the two septa rather than a deficiency in either septum (Figure 1). This is distinct from a hole in either septum, which would constitute an atrial septal defect, a separate entity with different functional consequences and indications for closure (Table 1). However, both PFOs and atrial septal defects can permit the transit of a paradoxical embolism. In a PFO, the overlapping anatomy of the primum and secundum atrial septa forms a flap valve that usually only opens when the right atrial pressure exceeds the left atrial pressure. However, since right atrial pressure is usually less than the left atrial pressure, PFOs are functionally closed most of the time. However, this pressure gradient can be reversed by manoeuvres that change the intrathoracic pressure (e.g. coughing, sneezing or straining to defecate), thereby allowing the PFO to open and for blood, thrombus or any other substance to pass from the right to the left atrium.

Indications for Patent Foramen Ovale Closure in 2019 Cryptogenic Stroke

In this review, we evaluate the evidence for PFO closure, discuss which patients should be considered for this treatment and review how the procedure should be undertaken.

Patent Foramen Ovale: The Anatomy During fetal development, the primum and secundum septa develop and overlap. This process occurs normally in patients with a PFO; the

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A cryptogenic stroke is one in which, despite extensive investigations, a clear cause cannot be found. This would include the exclusion of AF; atherosclerotic disease; carotid dissection; and intracerebral pathology, such as haemorrhage or space-occupying lesions.2,3 The cause of stroke remains unknown in up to 40% of patients with a stroke diagnosis. In PFO, the presumed cause of stroke is paradoxical embolus. Since the cause is known, the term is a misclassification but

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Patent Foramen Ovale Figure 1: Echocardiographic Assessment of a Patent Foramen Ovale

The top panels show a transthoracic bubble study demonstrating a PFO. (A) Apical four-chamber view. Agitated saline after intravenous injection is seen to fill the right ventricular cavity (white arrow). (B and C) Agitated saline bubbles are seen in the left atrium and ventricle within three cardiac cycles (blue arrows). Bottom panels. (D) 2D transoesophageal echocardiography image (90 degrees) of a PFO (white arrow), with shunting evident on the colour flow Doppler. (E) The same PFO is seen in 3D, viewed from the left atrium. The points of attachment of the septum primum tissue are shown (white asterisks). The PFO opening into the left atrium is seen between these two points (black arrow). The septum secundum tissue is behind, and this overlap of tissue extends to the roof of the fossa ovalis, demarcated by the white dotted line. The PFO tunnel therefore extends from the top of the fossa ovalis to the PFO opening. FO = fossa ovalis; LA = left atrium; MV = mitral valve; PFO = patent foramen ovale; RA = right atrium.

remains in use throughout the literature. Paradoxical embolus was first described by Zahn in 1881.4 The mechanism of stroke in PFO is translocation of venous thrombus to the arterial circulation under haemodynamic conditions where the PFO is opened. The opening of a PFO occurs during rapid fall and rise in right atrial pressure (e.g. after straining or coughing). Transient increase in right atrial pressure to greater than that of the left atrium opens a communication, and thrombus can transit at that brief moment. Several case studies demonstrating thrombus across a PFO support this mechanism,5â&#x20AC;&#x201C;7 as do studies demonstrating the associations of venous thrombosis and PFO with cryptogenic stroke.8 Two early randomised controlled trials, Evaluation of the STARFlexÂŽ Septal Closure System in Patients With a Stroke or TIA Due to the Possible Passage of a Clot of Unknown Origin Through a PFO

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(CLOSURE I) and PFO and Cryptogenic Embolism (PC-Trial), did not demonstrate superiority of closure compared to medical therapy.9,10 These trials were confounded by a high crossover rate, failure to randomise those patients whose strokes were most likely to have been caused by PFO, limited power and the introduction of bias through inconsistent use of anticoagulants in the medical therapy group.11 Furthermore, the STARFlex occluder used in CLOSURE I was a poor device that has been abandoned in Europe owing to concerns about residual defects and left-sided thrombus formation.12 A number of recent randomised trials have demonstrated that PFO closure is superior to medical therapy. The early results of the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial did not show benefit for PFO closure; however, recently, an extended

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Structural Table 1: Differences Between Patent Foramen Ovale and Atrial Septal Defects Patent Foramen Ovale

Atrial Septal Defect

Anatomy

Failure of fusion of primum and secundum atrial septa leading to flap valve opening

Deficiency in atrial septum resulting in failure of overlap (hole in atrial septum)

Shunt

Right-to-left shunt when right atrial pressure exceeds left atrial pressure (usually transient)

Continuous left-to-right shunting

Frequency

20–34% of adult population1

1.6 per 1,000 live births48

Consequences

Harmless in most people but may permit paradoxical embolus

Continuous left-to-right shunt may cause volume loading of right heart, which may reduce long-term survival if not corrected. May increase pulmonary artery pressure, reduce exercise tolerance and promote arrhythmia. Can also permit paradoxical embolus, and this is an indication for closure

Table 2: Randomised Controlled Trials Comparing Patent Foramen Ovale Closure to Medical Therapy Study

Device

Endpoints

Results

Comments

CLOSURE I9

STARFlex Septal Closure System

909

Composite of death (0–30 days), neurological death (≥31 days), stroke or TIA at 2-year follow-up

Non-significant reduction in primary endpoint (HR 0.78; 95% CI [0.45–1.35]; p=0.37)

Poor effective closure at 2 years, with evidence of left atrial thrombus formation in closure group

PC-Trial10

AMPLATZER PFO Occluder

414

Composite of death, stroke, TIA or peripheral embolism at mean 4.5 years

Non-significant reduction in primary endpoint (HR 0.63; 95% CI [0.24–1.62]; p=0.34)

Underpowered trial with substantial cross-over during follow-up

RESPECT13,14

AMPLATZER PFO Occluder

980

Composite of early death, stroke or TIA

Non-significant reduction in primary endpoint at median follow-up of 2.1 years (HR 0.49; 95% CI [0.22–1.11]; p=0.08).

Benefit for closure in early as-treated analysis

Subsequent long-term follow up (median 5.9 years) showed significant reduction with closure (HR 0.55; 95% CI [0.31–0.99]; p=0.046) GORE REDUCE15

Helex Septal Occluder or Cardioform Septal Occluder

664

Co-primary endpoints of clinical stroke and incidence of new brain infarction

Significant reduction in clinical stroke at median follow-up of 3.2 years (HR 0.23; 95% CI [0.09–0.62]; p=0.002).

2:1 randomisation to PFO closure

Significant reduction in new brain infarction (relative risk 0.51; 95% CI [0.29–0.91]; p=0.04) CLOSE16

Multiple devices

663

Stroke

Significant reduction in stroke with occlusion compared to antiplatelet therapy only (HR 0.03; 95% CI [0.00–0.26]; p<0.001)

DEFENSE PFO17

AMPLATZER PFO Occluder

120

Stroke, vascular death or Thrombolysis In Myocardial Infarction-defined major bleeding at 2-year follow-up

Significant reduction in primary endpoint with PFO closure. No events in PFO closure arm versus a 12.9% 2-year event rate in medication-only arm (p=0.013)

1:1:1 randomisation PFO closure versus antiplatelets versus anticoagulation

PFO = patent foramen ovale; TIA = transient ischaemic attack.

follow-up of patients demonstrated that there was a reduction in ischaemic stroke compared with medical therapy (HR 0.55; 95% CI [0.31–0.999]; p=0.046; number needed to treat [NNT]=45).13,14 The Gore® Septal Occluder Device for PFO Closure in Stroke Patients (GORE REDUCE) trial demonstrated a significant reduction in clinical ischaemic stroke (1.45% versus 5.5%; p=0.002; NNT=25) compared with antiplatelet therapy alone.15 In the PFO Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) trial, no patients who underwent PFO closure experienced an ischaemic stroke, compared with 14 in the antiplatelet group (HR 0.03; 95% CI [0.00–0.26]; p<0.001; NNT=17).16 Finally, the Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High-Risk PFO (DEFENSE-PFO) study showed a reduction in the composite endpoint of

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stroke, vascular death and Thrombolysis In MI-defined major bleeding at 2 years with PFO closure compared with medical therapy (0% versus 12.9%; p=0.013; NNT=8).17 The results of these randomised controlled trials are summarised in Table 2. Several meta-analyses have confirmed that PFO closure reduces the risk of ischaemic stroke in patients with cryptogenic stroke and PFO.18–20 These have shown that the overall absolute reduction in risk is low (1.0 per 100 patient-years), but this needs to be weighed against the long period of time that young patients are likely to be at risk. It is thought that patients with atrial septal aneurysm or large shunts may obtain greater benefit. Notably, in these trials and meta-analyses, AF was shown to occur more frequently after PFO closure than with

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Patent Foramen Ovale medical therapy alone. This did not seem to counteract the overall stroke reduction in this population. Participants enrolled in these trials were young, with most studies only including those under the age of 60 years. Participants were required to have symptoms consistent with a stroke, with confirmation of ischaemia/infarction on brain imaging. Confirmation of PFO with transoesophageal echocardiography (TOE) was also a requirement for enrolment. The studies excluded patients with an alternative attributable cause for their stroke (discussed in more detail below), and participants could be enrolled no more than 6–9 months after the index stroke. One of the major alternative explanations for embolic stroke is AF, and this was excluded in all patients. These criteria are strict but, in the opinion of the authors, need to be respected in clinical practice since there is little or no evidence for treatment of PFO outside these criteria. Patients who meet these criteria should be considered for closure in preference to medical therapy.

Systemic Embolisation Most paradoxical emboli are likely to present as ischaemic strokes, given the anatomy of the aortic arch. However, systemic embolisation to the gut, limbs and myocardium has been described.7,21–23 There is no evidence from randomised controlled trials that closure of PFO in the case of otherwise unexplained systemic embolisation is protective. Nonetheless, it seems logical that closure would be indicated in select cases. For example, closure of PFO would be indicated in a similar manner to that of cryptogenic stroke for a young patient presenting with ST-elevation MI of embolic source, normal coronary arteries and an absence of risk factors for atherosclerosis. Of course, care must be taken to exclude alternative explanations, and this may require optical coherence tomography to exclude in situ plaque rupture in the coronary artery. Given the myriad causes of myocardial injury, a cardiac MRI is recommended to confirm a pattern consistent with MI.

Decompression Illness Decompression illness is a condition suffered by divers and high-altitude pilots who rapidly transition from high- to low-pressure environments. The sudden change in pressure results in formation of nitrogen bubbles within tissues that accumulate in the venous circulation. These are filtered from the bloodstream via pulmonary capillary diffusion. However, if return to low pressure (ascent from depth in the case of divers) is too rapid, then this pulmonary filtration process is overwhelmed and gas bubbles enter the systemic arterial circulation.24 These bubbles continue to enlarge and result in tissue trauma and even vessel occlusion. This can produce a range of symptoms, including muscle and joint pain, headache, dizziness, fatigue, rash, paraesthesia, breathing difficulties, confusion, motor incoordination and paralysis. The presence of a right-to-left shunt such as a PFO allows nitrogen bubbles to bypass the pulmonary filter. Diving profiles are designed to limit the time at depth and slowly ascend toward the surface in order to minimise the risk of decompression sickness. The occurrence of a decompression illness despite such measures implies an increased risk of right-to-left shunt, and investigation for PFO should be considered.25,26 A longitudinal, non-randomised follow-up study showed a reduction in both symptomatic neurological events and total brain lesions among recreational divers with PFO and decompression illness who had PFO closure, compared with those continuing to dive without closure.27 In cases where a professional diver wishes to continue diving, a PFO

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closure could be recommended. The alternatives – stopping diving or curtailing provocative dive profiles – should also be considered. For recreational diving, the risk–benefit analysis for continued diving with a PFO closure is unclear, but some risk remains.

Platypnoea–orthodeoxia Syndrome Platypnoea–orthodeoxia syndrome (POS) is a rare condition characterised by positional desaturation and dyspnoea in individuals with a PFO. Alteration of the geometry of the atrial septum allows continuous streaming of deoxygenated blood from the inferior vena cava across the PFO in certain body positions. Typically, the desaturation is seen with the patient seated, while oxygen saturations are normal when the patient is lying flat.28 Distortion of the atrial septal geometry may be caused by chest surgery, such as pneumonectomy, aortic dilatation and aortic surgery, or it may not have an identifiable cause. Occasionally, a tricuspid regurgitant jet can be directed across the PFO. POS is unrelated to underlying cavity pressures and responds well to PFO closure, provided that pulmonary artery pressure is not markedly elevated, which is usually not the case. A case series of 54 patients demonstrated that percutaneous closure could be achieved in a safe and effective manner.29

Migraine with Aura Migraine is a common disorder in young people and is associated with aura in approximately a third of cases.30,31 Migraine with aura has been associated with right-to-left shunts, including PFO.32,33 Larger shunts have been found to be particularly associated with migraine with aura.34 The mechanism for the relationship between migraine and PFO is proposed to be the transfer of a vasoactive substance, usually filtered by the pulmonary circulation, into the systemic circulation.32 Non-randomised studies of PFO closure have reported improvement in patients’ symptoms after closure.35 The Migraine Intervention With STARFlex Technology (MIST) trial randomised patients with refractory migraine with aura to percutaneous PFO closure or a sham procedure.36 The trial showed no difference in cessation of headache or reduction in headache-free days. However, the trial assessed a population with a relatively low frequency of migraine, and there was a large number of residual shunts after closure. These problems may have negatively influenced the results. More recently, the Percutaneous Closure of PFO In Migraine With Aura (PRIMA) and Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management (PREMIUM) trials have reported their results.37,38 Both studies were negative for their primary endpoints and, while there were some reductions in headache, the effects were small and occurred at the expense of procedural complications. Overall, there is not enough evidence for PFO closure at present to offer a routine recommendation for therapy for this indication. PFO closure may rarely be considered in carefully selected individuals through a neurology multidisciplinary team, provided there is appropriate consent for procedural risk and with an understanding that an improvement in symptoms would not be certain.

The Patent Foramen Ovale Closure Procedure Pre-Procedure Investigations Since the most common indication for closure is cryptogenic stroke, an emphasis should be placed on work-up for other potential causes of stroke. Brain imaging should be undertaken to confirm the diagnosis

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Structural Figure 2: Percutaneous closure of a Patent Foramen Ovale

(A) Wire crossing a PFO into the left upper pulmonary vein. A sizing balloon is deployed and the quantitative angiographic analysis to size the defect is shown. (B) The Gore Cardioform septal occluder has been deployed through the delivery sheath (red arrow) but has not yet been released. (C) 3D transoesophageal echocardiography image of the device (white arrow) viewed from the left atrium. (D) The device is shown in place after release (purple arrow).

of a stroke of embolic topography. Lacunar strokes are not likely to be embolic in nature. Carotid imaging should be undertaken to exclude significant plaque disease. Thrombophilia screening should be considered but is complex, with results that are sometimes inconsistent and often with a need for repeated investigations. Many thrombophilias predispose to venous more than arterial thrombosis, making interpretation of the results difficult, and this should be done in conjunction with haematologists with an interest in thrombosis. AF is the most common source of thrombus, with studies suggesting that 13% of patients with AF have cardiac thrombus.39 Among patients with non-valvular AF, the thrombus was located in the left atrial appendage in 90%.39 The presence of AF in the context of a stroke is an indication for anticoagulation, and closure of a PFO is not indicated. No study has shown that closure of a PFO confers additional benefit. ECG monitoring is mandatory to exclude AF, and the duration depends upon the patientâ&#x20AC;&#x2122;s risk factors. In young patients (<50 years) with no risk

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factors, we recommend using a minimum of 72-hour ambulatory surface ECG recording, and in those aged >50 years we recommend using 6 months of implantable loop recording (ILR). ILR has the advantage of extended rhythm surveillance; however, it is prone to false positives and false negatives.40â&#x20AC;&#x201C;42 Conclusive evidence for the best strategy to diagnose AF is lacking. Transthoracic echocardiography (TTE) is the key first-line investigation for the exclusion of intracardiac thrombus. Cardiac thrombus is associated with a number of conditions apart from AF, including MI, atrial myxoma, left ventricular aneurysm, non-compaction cardiomyopathy, left ventricular failure and mitral stenosis. All of these need to be excluded prior to consideration of closure of PFO. Bubble contrast echocardiography is a key investigation when working up patients with cryptogenic stroke. In order for a PFO to cause a stroke, it needs the ability to produce a right-to-left shunt. Bubble

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Patent Foramen Ovale Figure 3: Patent Foramen Ovale Closure Devices

(A) The Gore Cardioform septal occluder. (B) The AMPLATZER PFO Occluder. These devices are both approved for PFO closure and are the two most widely deployed occluders.

contrast studies are initially performed using TTE, with no sedation necessary. Agitated saline is injected into a peripheral venous cannula (ideally in the left antecubital fossa), and the patient is asked to perform a Valsalva manoeuvre or to sniff. In the presence of a cardiac shunt, bubbles should appear in the left side within three to four cardiac cycles of arrival in the right atrium. Late appearance of bubbles may reflect pulmonary transit, and performance by an experienced operator is needed. The procedure may require multiple repeats to confirm the diagnosis. Figure 1 shows a bubble study with transmission of bubbles from right to left. A positive bubble study in the setting of cryptogenic stroke is an indication for detailed TOE. This allows the structural team to accurately define the position and anatomy of a PFO. TOE assessment of a PFO is also shown in Figure 1. The study will also exclude the presence of alternative shunts, such as ventricular septal defects, anomalous pulmonary venous drainage and sinus venosus defects. A full description of the TOE assessment of PFO is beyond the scope of this article but is reviewed elsewhere.43 The diagnosis of cryptogenic stroke and PFO will require the input of multiple specialties, including stroke physicians or neurologists, cardiac imaging specialists, radiologists and interventional cardiologists. Some centres use the Risk of Paradoxical Embolism (RoPE) score to help multidisciplinary teams classify the relationship between the stroke and the PFO.44 Consideration of the investigations and the patient as a whole should be undertaken in a multidisciplinary setting.

The Closure Procedure PFO closure is routinely performed as a day-case procedure. The procedure can be performed in a standard catheter laboratory with fluoroscopic guidance and physiological monitoring. Since patients undergoing this procedure will obtain no immediate symptomatic benefit, with only the long-term risk of stroke being reduced, the authors of this review emphasise that all possible steps to reduce complications should be taken: the procedure should be, as far as possible, complication-free. In particular, this means using ultrasound-

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guided femoral venous access, echocardiographic guidance, adequate anticoagulation and special care to reduce risk of air embolus. In the opinion of the authors, periprocedural guidance with TOE or intracardiac echocardiography is mandatory to consistently achieve the best result. General anaesthesia is generally required to facilitate TOE. The procedure is undertaken from the femoral vein, preferably using ultrasound guidance. Adequate anticoagulation should be administered (unfractionated heparin 80â&#x20AC;&#x201C;100 IU/kg). The PFO is crossed with a 6 Fr multipurpose diagnostic catheter. A 0.035Â inch J-tipped guide wire is passed into a pulmonary vein (usually the left upper). This may be exchanged for a stiff wire to assist delivery of balloons. Balloon sizing of the PFO can be performed using quantitative angiographic tools. A left anterior oblique fluoroscopic projection may assist with this, as the septum is seen in profile. Compliant balloons with marked graduations are used, but balloon sizing can still shorten and widen the PFO. This may be desirable if there is a particularly long PFO tunnel, but it can enlarge the hole, thus necessitating a larger device. Similar (and potentially more accurate) information can be obtained through TOE assessment. After sizing, an appropriate device can be selected and its delivery sheath introduced into the left atrium. The left atrial disc is deployed, followed by the right disc. Throughout this procedure, ensuring that the delivery sheath remains de-aired and flushed is crucial to minimise the risk of air or thrombotic embolism. Once the device is placed, confirmation of adequate positioning with echocardiography and fluoroscopy should be performed prior to device release. If the device is found to malpositioned after release, it can still be recovered using a large gooseneck snare. Figure 2 shows the steps involved in a PFO closure procedure. The optimal regimen of antithrombotic therapy after device deployment remains uncertain. Aspirin and clopidogrel are usually given for 6 months in our practice, but evidence for this is limited and practice has varied markedly between trials. Some operators

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Structural preload patients with antiplatelets, but again the evidence for this is uncertain. Single antiplatelet therapy, usually clopidogrel 75 mg daily, is continued indefinitely. The patient should undergo TTE prior to discharge and at 6 weeks to exclude pericardial effusion and device embolisation. Closure rates are high with modern devices, and the principal objective is to stop the PFO flap valve opening wide, which occurs as soon as the device is deployed. Complete closure depends upon endothelialisation of the device and can take up to 6 months, after which time a repeat bubble study can be undertaken to confirm complete closure, although this is not mandated unless the patient plans to dive.

PFO Occluder (Abbott Vascular) are two of the more commonly used devices (Figure 3). The Gore Septal Occluder is constructed from five nitinol wires covered with expanded polytetrafluoroethylene.45 Early clinical experience has shown that it is a versatile device with easy deployment, high procedural success rates and low complication rates.46,47 The AMPLATZER PFO Occluder is also a nitinol-based device. It is the device that has been most commonly used in randomised controlled trials, and the evidence for its use is, therefore, very strong.16,17 Operators should gain experience using different devices in order to give the best possible result for the patient.

Conclusion Closure Devices A large number of devices with varying shapes and sizes have been marketed, with many achieving CE mark status in the EU. In the US, the need for evidence from randomised controlled trials prior to approval means fewer devices have been approved by the Food and Drug Administration. Most devices are of double-disc design, connected by a short waist. The Gore Septal Occluder (WL Gore & Associates) and the AMPLATZER

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alvert PA, Rana BS, Kydd AC, Shapiro LM. Patent foramen C ovale: anatomy, outcomes, and closure. Nat Rev Cardiol 2011;8:148–60. https://doi.org/10.1038/nrcardio.2010.224; PMID: 21283148. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262–8. https://doi.org/10.1056/NEJMoa071422; PMID: 18046029. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35–41. https://doi.org/ 10.1161/01.STR.24.1.35; PMID: 7678184. Zahn F. [Thrombosis of several branches of the inferior vena cava with consecutive emboli in the pulmonary, splenic, renal and right iliac arteries.] Rev Med Suisse Romande 1881;1:227–37 [in French]. Choong CK, Calvert PA, Falter F, et al. Life-threatening impending paradoxical embolus caught “red-handed”: successful management by multidisciplinary team approach. J Thorac Cardiovasc Surg 2008;136:527–28. https://doi. org/10.1016/j.jtcvs.2007.10.090; PMID: 18692671. Madani H, Ransom PA. Paradoxical embolus illustrating speed of action of recombinant tissue plasminogen activator in massive pulmonary embolism. Emerg Med J 2007;24:441. https://doi.org/10.1136/emj.2006.045104; PMID: 17513552. Kim RJ, Girardi LN. “Lots of clots”: multiple thromboemboli including a huge paradoxical embolus in a 29-year old man. Int J Cardiol 2008;129:e50–2. https://doi.org/10.1016/ j.ijcard.2007.06.116; PMID: 17869355. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004;35:46–50. https://doi.org/10.1161/01. STR.0000106137.42649.AB; PMID: 14657451. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012;366:991–9. https://doi.org/10.1056/ NEJMoa1009639; PMID: 22417252. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013;368:1083–91. https://doi.org/10.1056/NEJMoa1211716; PMID: 23514285. Messé SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med 2013;368:1152–3. https://doi.org/10.1056/ NEJMe1301680; PMID: 23514293. Thaler DE, Wahl A. Critique of closure or medical therapy for cryptogenic stroke with patent foramen ovale: the hole truth? Stroke 2012;43:3147–9. https://doi.org/10.1161/ STROKEAHA.112.659599; PMID: 22989503. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013;368:1092–100. https://doi. org/10.1056/NEJMoa1301440; PMID: 23514286. Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017;377:1022–32. https://doi.org/10.1056/ NEJMoa1610057; PMID: 28902590. Søndergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke.

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28.

In this brief review, the main indications for PFO closure (cryptogenic stroke, paradoxical systemic embolisation, POS and decompression illness) have been discussed, together with the strengthening evidence for closure. The skills needed for this procedure need to be learnt with the assistance of an experienced interventional cardiologist, who can proctor and advise those starting out with PFO closure. An attention to detail in the indication for the procedure and minimising the risks to the patient during closure are the key to an effective PFO closure service in 2019 and beyond. n

N Engl J Med 2017;377:1033–1042. https://doi.org/10.1056/ NEJMoa1707404; PMID: 28902580. Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017;377:1011–21. https://doi.org/10.1056/ NEJMoa1705915; PMID: 28902593. Lee PH, Song JK, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO trial. J Am Coll Cardiol 2018;71:2335–42. https://doi.org/10.1016/j. jacc.2018.02.046; PMID: 29544871. Turc G, Calvet D, Guérin P, et al. Closure, anticoagulation, or antiplatelet therapy for cryptogenic stroke with patent foramen ovale: systematic review of randomized trials, sequential meta-analysis, and new insights from the CLOSE study. J Am Heart Assoc 2018;7:e008356. https://doi. org/10.1161/JAHA.117.008356; PMID: 29910193. Abo-Salem E, Chaitman B, Helmy T, et al. Patent foramen ovale closure versus medical therapy in cases with cryptogenic stroke, meta-analysis of randomized controlled trials. J Neurol 2018;265:578–85. https://doi.org/10.1007/ s00415-018-8750-x; PMID: 29356972. Darmoch F, Al-Khadra Y, Soud M, et al. Transcatheter closure of patent foramen ovale versus medical therapy after cryptogenic stroke: a meta-analysis of randomized controlled trials. Cerebrovasc Dis 2018;45:162–9. https://doi. org/10.1159/000487959; PMID: 29597192. Ahmed S, Sadiq A, Siddiqui AK, et al. Paradoxical arterial emboli causing acute limb ischemia in a patient with essential thrombocytosis. Am J Med Sci 2003;326:156–8. https:// doi.org/10.1097/00000441-200309000-00011; PMID: 14501234. Kleber FX, Hauschild T, Schulz A, et al. Epidemiology of myocardial infarction caused by presumed paradoxical embolism via a patent foramen ovale. Circ J 2017;81:1484–9. https://doi.org/10.1253/circj.CJ-16-0995; PMID: 28450663. Pavoni D, Zanuttini D, Spedicato L, et al. Large interatrial thrombus-in-transit resulting in acute myocardial infarction complicated by atrioventricular block and cardiogenic shock. J Am Coll Cardiol 2012;59:1329. https://doi.org/10.1016/j.jacc. 2011.08.084; PMID: 22464262. Butler BD, Hills BA. The lung as a filter for microbubbles. J Appl Physiol Respir Environ Exerc Physiol 1979;47:537–43. https://doi. org/10.1152/jappl.1979.47.3.537; PMID: 533747. Wilmshurst PT, Byrne JC, Webb-Peploe MM. Relation between interatrial shunts and decompression sickness in divers. Lancet 1989;2:1302–6. https://doi.org/10.1016/S0140-6736(89)919119; PMID: 2574256. Torti SR, Billinger M, Schwerzmann M, et al. Risk of decompression illness among 230 divers in relation to the presence and size of patent foramen ovale. Eur Heart J 2004;25:1014–20. https://doi.org/10.1016/j.ehj.2004.04.028; PMID: 15191771. Billinger M, Zbinden R, Mordasini R, et al. Patent foramen ovale closure in recreational divers: effect on decompression illness and ischaemic brain lesions during long-term follow-up. Heart 2011;97:1932–7. https://doi.org/10.1136/ heartjnl-2011-300436; PMID: 21917666. Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causing severe hypoxaemia despite normal right-sided pressures. Report of 11 consecutive cases corrected by percutaneous closure. Eur Heart J 2000;21:483–9. https://doi.

org/10.1053/euhj.1999.1944; PMID: 10681489. 29. S hah AH, Osten M, Leventhal A, et al. Percutaneous intervention to treat platypnea-orthodeoxia syndrome: the Toronto experience. JACC Cardiovasc Interv 2016;9:1928–38. https://doi.org/10.1016/j.jcin.2016.07.003; PMID: 27659570. 30. Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache 2015;55:21–34. https://doi. org/10.1111/head.12482; PMID: 25600719. 31. Lipton RB, Liberman JN, Kolodner KB, et al. Migraine headache disability and health-related quality-of-life: a population-based case-control study from England. Cephalalgia 2003;23:441–50. https://doi.org/10.1046/j.1468-2982.2003.00546.x; PMID: 12807523. 32. Finocchi C, Del Sette M. Migraine with aura and patent foramen ovale: myth or reality? Neurol Sci 2015;36(Suppl 1):61–6. https://doi.org/10.1007/s10072-015-2163-8; PMID: 26017514. 33. Schwerzmann M, Nedeltchev K, Lagger F, et al. Prevalence and size of directly detected patent foramen ovale in migraine with aura. Neurology 2005;65:1415–8. https://doi. org/10.1212/01.wnl.0000179800.73706.20; PMID: 16148260. 34. Anzola GP, Morandi E, Casilli F, Onorato E. Different degrees of right-to-left shunting predict migraine and stroke: data from 420 patients. Neurology 2006;66:765–7. https://doi. org/10.1212/01.wnl.0000201271.75157.5a; PMID: 16534123. 35. Butera G, Biondi-Zoccai GG, Carminati M, et al. Systematic review and meta-analysis of currently available clinical evidence on migraine and patent foramen ovale percutaneous closure: much ado about nothing? Catheter Cardiovasc Interv 2010;75:494–504. https://doi.org/10.1002/ ccd.22232; PMID: 20088014. 36. Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With STARFlex Technology (MIST) trial: a prospective, multicenter, double-blind, sham-controlled trial to evaluate the effectiveness of patent foramen ovale closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008;117:1397–404. https://doi. org/10.1161/CIRCULATIONAHA.107.727271; PMID: 18316488. 37. Mattle HP, Evers S, Hildick-Smith D, et al. Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial. Eur Heart J 2016;37:2029–36. https://doi.org/10.1093/eurheartj/ehw027; PMID: 26908949. 38. Tobis JM, Charles A, Silberstein SD, et al. Percutaneous closure of patent foramen ovale in patients with migraine: the PREMIUM trial. J Am Coll Cardiol 2017;70:2766–74. https://doi. org/10.1016/j.jacc.2017.09.1105; PMID: 29191325. 39. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–9. https://doi.org/10.1016/00034975(95)00887-X; PMID: 8572814. 40. Cotter PE, Martin PJ, Ring L, et al. Incidence of atrial fibrillation detected by implantable loop recorders in unexplained stroke. Neurology 2013;80:1546–50. https://doi.org/10.1212/ WNL.0b013e31828f1828; PMID: 23535493. 41. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014;370:2478–86. https://doi.org/10.1056/NEJMoa1313600; PMID: 24963567. 42. Podd SJ, Sugihara C, Furniss SS, Sulke N. Are implantable

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Patent Foramen Ovale cardiac monitors the ‘gold standard’ for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac monitors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. Europace 2016;18:1000–5. https://doi. org/10.1093/europace/euv367; PMID: 26585596. 43. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010;3:749–60. https://doi.org/10.1016/j. jcmg.2010.01.007; PMID: 20633854. 44. Thaler DE, Ruthazer R, Weimar C2, et al. Recurrent stroke

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predictors differ in medically treated patients with pathogenic vs. other PFOs. Neurology 2014;83:221–6. https://doi. org/10.1212/WNL.0000000000000589; PMID: 24928123. 45. Søndergaard L, Loh PH, Franzen O, et al. The first clinical experience with the new GORE® septal occluder (GSO). EuroIntervention 2013;9:959–63. https://doi.org/10.4244/ EIJV9I8A160; PMID: 23764807. 46. MacDonald ST, Daniels MJ, Ormerod OJ. Initial use of the new GORE(®) septal occluder in patent foramen ovale closure: implantation and preliminary results. Catheter Cardiovasc Interv 2013;81:660–5. https://doi.org/10.1002/ccd.24405;

PMID: 23436483. 47. H ardt SE, Eicken A, Berger F, et al. Closure of patent foramen ovale defects using GORE® CARDIOFORM septal occluder: results from a prospective European multicenter study. Catheter Cardiovasc Interv 2017;90:824–9. https://doi.org/10.1002/ ccd.26993; PMID: 28296023. 48. van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011;58:2241–7. https://doi.org/10.1016/j.jacc.2011.08.025; PMID: 22078432.

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Device-Related Thrombus After Left Atrial Appendage Closure Philippe Garot, Bertrand Cormier and Jérôme Horvilleur Hôpital Privé Jacques Cartier, Institut Cardiovasculaire Paris Sud – Ramsay Générale de Santé, Massy, France

Abstract Although left atrial appendage closure (LAAC) has proved non-inferior to oral anticoagulants in patients with AF, there has been recent concern about the occurrence of late complications, especially device-related thrombus (DRT), which was associated with increased risk of stroke. In this article, the incidence, risk factors and time course of DRT after LAAC are discussed, as well as the potential benefits of dedicated strategies in the management of DRT, which remain speculative, especially in patients with a contraindication to oral anticoagulants. In these patients, decision-making should be based on a multidisciplinary evaluation of the ischaemic/bleeding balance on an individual basis.

Keywords Complications, device-related thrombus, left atrial appendage closure, outcomes, stroke, thrombus Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: The authors thank Mrs Catherine Dupic for her helpful assistance in the preparation of this manuscript. Received: 3 July 2018 Accepted: 3 October 2018 Citation: Interventional Cardiology Review 2019;14(1):42–4. DOI: https://doi.org/10.15420/icr.2018.21.3 Correspondence: Philippe Garot, Hôpital Privé Jacques Cartier, Institut Cardiovasculaire Paris Sud, 6 Avenue du Noyer Lambert, 91300 Massy, France. E: p.garot@icps.com.fr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Left atrial appendage closure (LAAC) has been shown to be non-inferior to warfarin in decreasing the risk of stroke and systemic embolism in patients with AF.1–3 In addition to peri-procedural complications (tamponade, device migration, procedure-related stroke or embolism, and vascular complications), there has been growing concern recently about the occurrence of late complications, especially device-related thrombus (DRT). Although DRT has been previously reported in patients enrolled in the Watchman® Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) trial, the incidence, predictors and outcomes of DRT have been recently described in a larger population of 1,739 patients who received a Watchman® device, using data from two randomised trials (PROTECT AF and Evaluation of the Watchman® LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy [PREVAIL]) and two registries (Continued Access to PROTECT [CAP] and Continued Access to PREVAIL [CAP2]).1–5

Incidence, Consequences, Risk Factors and Time Course of Device-Related Thrombus Incidence and Consequences The global incidence of DRT in patients with AF treated by LAAC has been reported to be 3–7%.1–5 Interestingly, DRT has been associated with an average threefold increased risk of stroke or systemic embolism, as well as a greater risk of bleeding, whereas the risk of cardiovascular and all-cause death was not different from that of patients without DRT.2 However, most patients with DRT did not have a stroke or systemic embolism. Indeed, the vast majority of strokes after LAAC (approximately 90%) occurred in patients with greater

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risk factors for stroke in general, and who had no evidence of DRT. Nevertheless, there is a probable causal relationship between DRT and stroke or systemic embolism, since a stroke has been reported to occur within 2 months of DRT detection in a non-negligible proportion of patients (nearly 50%) who had DRT and stroke.

Risk Factors for Device-Related Thrombus There is clear evidence that the risk of DRT is not equal for all LAAC recipients. The risk of DRT is higher among those with larger left atrial appendages, a history of stroke or transient ischaemic attack, permanent AF, lower ejection fraction and vascular disease.2 Interestingly, these conditions are associated with a higher risk of cardiac and arterial thrombosis, and some are components of the CHA2DS2-VASc score. Some instances of DRT are also related to procedural characteristics, since the uncovered area of the left atrial appendage after deep implantation has been shown to be instrumental in thrombus formation.6,7 The question of whether DRT could be related to the post-procedural drug regimen is more controversial. On one hand, most DRTs with the Watchman device have developed after oral anticoagulant discontinuation,but on the other there are multiple observational registries showing that not only dual but also single antiplatelet therapies appear to be a safe option after LAAC, especially in patients with absolute contraindications to anticoagulants.2,6,8–10

Time Course of Device-Related Thrombus After Left Atrial Appendage Closure The time course of thrombus development after LAAC is not clear since DRT is mostly silent, and the imaging protocol follow-up differs

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Device-Related Thrombus After LAAC from one study to another. Dukkipati et al. reported that most DRTs (>80%) were detected beyond 45 days after LAAC procedures. DRT was detected in 13 of 1,706 patients (0.8%) at 45 days, in 12 of 692 (1.7%) at 6 months and in 27 of 1,504 (1.8%) at 12 months.2 It is noteworthy that in the randomised trials, transoesophageal echocardiography (TOE) was performed at 6 weeks, 6 months and 1 year,1,3 while the followup was lighter in all published observational registries. Consequently, registries reporting the lowest rate of DRT were, not surprisingly, those that had no predefined imaging follow-up beyond 6 weeks, as well as those without core lab examination. Given that the time required for device sealing may vary depending on patients, devices and procedures, it is particularly difficult to design one method of imaging follow-up for all patients. US Food and Drug Administration-designed trials have proposed a 6-month follow-up TOE to potentially detect more DRTs but the ideal protocol has yet to be designed. Very late (>1 year post-procedure) DRT has not been assessed and is thought to be less frequent because of device sealing, which remains variable on an individual basis. However, in keeping with our observations regarding late coronary stent thrombosis, caution is warranted in the presence of stroke or systemic embolism >1 year after LAAC, and TOE should be repeated in these patients.

What We Do Not Know and What Is Speculated Potential Unknown Risk Factors for Device-Related Thrombus In addition to the patient- and procedural-level characteristics that have been reported as potential risk factors for DRT, certain general clinical conditions usually associated with thrombosis may well play a role in DRT, such as chronic renal failure, diabetes and hypercoagulability status. Inter-patient response variability to antiplatelet agents has been described after stent thrombosis. Although unproven in the setting of LAAC, it is probable that DRT is more likely to occur among poor responders to antiplatelet drugs. Concern has been raised that certain design characteristics of the device may trigger the development of DRT, such as the protruding central screw being potentially associated with delayed sealing. In the absence of any comparison between the Watchman and Amplatzer™ devices, we cannot conclude whether either of these devices carry an adverse risk of DRT. However, companies have developed strategies to facilitate device sealing, which could result in a decreased rate of DRT.

Should We Manage Patients with a High Risk of Device-Related Thrombus Differently?

Several options should be pointed out, such as postponing the 6-week follow-up TOE to 3–6 months post-procedure, or carrying out more aggressive TOE monitoring in patients at high risk of DRT; however, the latter exposes them to greater discomfort, as well as the risks inherent in additional transoesophageal examinations. In this setting, the benefit of using CT to detect a thrombus should be underlined because repeated TOE assessments are uncomfortable for patients and a potential source of complications. One of the issues related to DRT is that reintroducing anticoagulants is associated with a high bleeding risk. Consequently, preventative and curative options are quite scarce in patients with a contraindication to oral anticoagulants. The answer to the question as to whether the contraindication is “relative” or “absolute” is obvious, and decision-making about DRT management should be based on a multidisciplinary evaluation of the ischaemia/bleeding balance on an individual basis. The appropriate management of patients at low and high risk of DRT is yet to be defined because of the relatively low rate of DRT and ischaemia-related complications. Among 1,739 recipients of a Watchman device, Dukkipaki et al. reported nine strokes in 17 patients with DRT.2 Although potentially underestimated, this should be given careful consideration in view of the risk and the consequences of bleeding in these patients. The use of direct oral anticoagulants, which have been associated with a lower intracranial haemorrhage risk, should be evaluated as a curative strategy for DRT as well as a potential preventive strategy in patients at high risk of thrombosis. Similarly, the role of P2Y12 inhibitors (ticagrelor, prasugrel), which have the potential to better inhibit platelet aggregation compared with clopidogrel, on the surface of the device during the sealing process should be evaluated for safety/efficacy in patients at high-risk of DRT and for those with documented high on-treatment platelet reactivity. Although patients treated with anticoagulants/LAAC for AF are still exposed to risks of recurrent stroke and bleeding, there could be different strategies according to the higher ischaemia/bleeding risk. In patients with a higher ischaemic risk, additional imaging follow-up might be helpful, given that shorter bleeding treatment should be preferably selected in those with a higher bleeding risk. Clearly, uncertainties remain in the management of DRT, including imaging follow-up, prevention and treatment, especially in patients with a contraindication to oral anticoagulants. Since more aggressive TOE surveillance and oral anticoagulant/antiplatelet strategies are not associated with any proven clinical benefits, whether we should implement dedicated strategies in these patients remains speculative and should be considered on an individual basis.

Whether patients at greater risk of DRT should be managed differently is questionable. Better screening and more aggressive drug regimens and DRT detection strategies are potentially beneficial in this subset of patients. DRT develops during the sealing process, before re-endothelialisation has been achieved. Oral anticoagulant and/or antiplatelet agents are given for several months to prevent thrombus formation.

Conclusion

We have learned from PROTECT AF and PREVAIL that TOE at 6 months resulted in the detection of more cases of DRT; however, no benefit was evidenced using this strategy in terms of stroke rate reduction in the whole population.1–3 Case reports have shown DRTs resolving with adequate anticoagulation over several months, which should encourage increased surveillance after LAAC.11,12

The incidence of DRT after LAAC is relatively low (3–7%) and it is more likely to occur in patients with a documented high risk of DRT and after inadequate device positioning. DRT is associated with an average threefold increase in the risk of stroke. In the very high-risk subset of patients with a contraindication to oral anticoagulants, this complication should be weighed up against the risk of non-DRT related stroke, bleeding and intracranial haemorrhage.

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olmes DR, Reddy VY, Turi ZG, et al. PROTECT AF Investigators. H Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. https://doi.org/10.1016/S01406736(09)61343-X; PMID: 19683639. Dukkipati SR, Kar S, Holmes DR Jr, et al. Device-related thrombus after left atrial appendage closure: incidence, predictors, and outcomes. Circulation 2018;138:874–85. https:// doi.org/10.1161/CIRCULATIONAHA.118.035090; PMID: 29752398. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus longterm warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. https://doi.org/10.1016/j.jacc.2014.04.029; PMID: 24998121. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued

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Access Registry. Circulation 2011;123:417–24. https://doi.org/10.1161/CIRCULATIONAHA.110.976449; PMID: 21242484. Holmes DR Jr, Doshi SK, Kar S, et al. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis. J Am Coll Cardiol 2015;65:2614–23. https://doi.org/10.1016/j.jacc.2015.04.025; PMID: 26088300. Pracon R, Bangalore S, Dzielinska Z, et al. Device thrombosis after percutaneous left atrial appendage occlusion is related to patient and procedural characteristics but not to duration of postimplantation dual antiplatelet therapy. Circ Cardiovasc Interv 2018;11:e005997. https://doi.org/10.1161/ CIRCINTERVENTIONS.117.005997; PMID: 29463510. Meier B. What lies beneath left atrial appendage occlusion: know your enemy. Circ Cardiovasc Interv 2018;11:e006360. https://doi.org/10.1161/CIRCINTERVENTIONS.118.006360; PMID: 29463511. Korsholm K, Nielsen KM, Jensen JM, et al. Transcatheter left atrial appendage occlusion in patients with atrial fibrillation and a high bleeding risk using aspirin alone for post-implant

antithrombotic therapy. EuroIntervention 2017;12:2075–82. https://doi.org/10.4244/EIJ-D-16-00726; PMID: 27973336. Fauchier L, Cinaud A, Brigadeau F, et al. Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. J Am Coll Cardiol 2018;71:1528–36. https://doi.org/10.1016/j.jacc.2018.01.076; PMID: 29622159. 10. Boersma LV, Ince H, Kische S, et al. EWOLUTION Investigators. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-year follow-up outcome data of the EWOLUTION trial. Heart Rhythm 2017;14:1302–8. https://doi. org/10.1016/j.hrthm.2017.05.038; PMID: 28577840. 11. Freixa X, Scalone G, Martín-Yuste V, Vidal B. Large protruding thrombus over left atrial appendage occlusion device successfully treated with apixaban. Eur Heart J 2015;36:1427. https://doi.org/10.1093/eurheartj/ehv081; PMID: 25834098. 12. Wong CK, Chan PH, Lam CC, et al. WATCHMAN device-related thrombus successfully treated with apixaban: a case report. Medicine (Baltimore) 2017;96:e8693. https://doi.org/10.1097/ MD.0000000000008693; PMID: 29381951. 9.

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Why Did COAPT Win While MITRA-FR Failed? Defining the Appropriate Patient Population for MitraClip Kimberly Atianzar, 1,2 Ming Zhang, 2 Zachary Newhart 2 and Sameer Gafoor 2,3 1. Medical College of Georgia at Augusta University, Augusta, GA, US; 2. Swedish Heart and Vascular Institute, Seattle, WA, US; 3. CardioVascular Center Frankfurt, Frankfurt, Germany

Abstract In 2018, the world of functional mitral regurgitation changed with the presentation of two trials – Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT). The trials, which seemed to point in two different directions, raised significant questions for the field. This article looks at the differences in effective regurgitant area, guideline-directed medical therapy, patient selection, technical clues and other reasons why the trials had similar aims but very different findings.

Keywords Mitral regurgitation, functional mitral regurgitation, secondary mitral regurgitation, heart failure, congestive heart failure, COAPT, MITRA-FR, effective orifice area, optimal medical therapy Disclosure: SG is a proctor and consultant for Abbott Vascular, Medtronic and Boston Scientific. MZ is a proctor and consultant for Edwards Sapien. All other authors have no conflicts of interest to declare. Received: 17 December 2018 Accepted: 22 January 2019 Citation: Interventional Cardiology Review 2019;14(1):45–7. DOI: https://doi.org/10.15420/icr.2018.40.1 Correspondence: Sameer Gafoor, Swedish Heart and Vascular, Structural Heart and Valve Program, 550 17th Ave Suite 680, Seattle WA 98122, US. E: sameergafoor@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In patients with heart failure and reduced left ventricular ejection fraction (LVEF), secondary (functional) mitral regurgitation, in which the mitral valve leaflets and chordae are essentially normal, is the result of functional and structural alterations of the left ventricle (LV). Severe secondary mitral regurgitation (MR) is a predictor of poor clinical outcomes in this patient population due to more hospitalisations for heart failure (HF), poor quality of life and shortened survival times.1–4 While guideline-directed medical therapy (GDMT) may have an impact on LV function, symptomatology and functional MR severity, there has been no data to show that surgical treatment of secondary MR is associated with lower incidence of death or hospitalisation.5 Percutaneous transcatheter treatment can be used to reduce MR where the anterior and posterior mitral valve leaflets are approximated with the MitraClip device (Abbott Vascular). In the Endovascular Valve Edge-to-Edge Repair Study II (EVEREST II) trial, Feldman et al. showed that although the MitraClip was safer than surgical mitral valve repair, the transcatheter option was not as effective in reducing MR severity among the study group, who mostly had primary MR.6 Prospective clinical trials with hard clinical outcomes on the beneficial effect on secondary MR of enhancing GDMT with percutaneous transcatheter mitral valve repair had not been shown until now.7 At the 2018 Transcatheter Cardiovascular Therapies 30th Scientific Session Conference, Gregg Stone presented the long-awaited and

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ground-breaking results of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) randomised prospective clinical trial. COAPT showed that in more than 600 patients with heart failure and severe functional MR, transcatheter percutaneous mitral valve repair using the MitraClip device in conjunction with GDMT when compared with GDMT alone, not only significantly reduced the primary endpoint of heart failure rehospitalisations by 47%, but also mortality at two years by 38%.7 Additionally, all 10 secondary endpoints met statistical significance in favour of the MitraClip with GDMT over GDMT alone. The reaction of the audience when the primary endpoint results slide was displayed on the screen was enormous, with an audible gasp followed by cheering and clapping. It had been difficult to imagine the clinical outcome of the COAPT trial due to slow enrolment, a lengthy time to complete, but mostly due to ominous predictions in light of the outcomes from the Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) clinical trial. The COAPT trial results were clearly different from the negative results of the MITRA-FR randomised prospective clinical trial presented by Jean François Obadia a month earlier at the 2018 European Society of Cardiology Congress.8 In the MITRA-FR trial, more than 300 HF patients with severe MR were randomised to be treated with medical treatment alone or with percutaneous transcatheter mitral valve repair (MitraClip) along with medical therapy. All the participants were evaluated for a

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Structural primary clinical endpoint at 12 months of a composite of death from any cause or unplanned hospitalisation for HF.8 Dr Obadia discussed the MITRA-FR trial’s negative primary outcome results at 12 months, showing no significant difference in the rate of death or unplanned HF hospitalisations in the intervention and control groups (54.6% versus 51.3%, OR 1.16, 95% CI [0.73 to 1.84], p=0.53).8 The big question was why there was such a significant difference in the results between the MITRA-FR trial and the COAPT trial. Why was the COAPT trial successful where the MITRA-FR trial seems to have failed? There has been much debate about this issue in the cardiovascular world since the two trials were presented.

A Tale of Two Trials Recruitment What is evident is that there were clear differences between the two trials regarding patient selection, medical treatment optimisation, the severity parameters of MR and the setting of the LV volume index parameters. Some of this is due to differences between European and American guidelines. In addition, these differences were only found in a post-hoc analysis and are therefore subject to inherent limitations. Nevertheless, in the MITRA-FR trial, the majority of patients had an average effective regurgitant orifice area (EROA) of 30 mm2 which suggests moderate MR rather than severe, whereas in the COAPT trial, the majority of patients had an average EROA of 40 mm2 which is truly severe MR. The only COAPT subgroup that did not benefit from MitraClip with GDMT was the patients who had an EROA <30 mm2 in setting of a dilated LV (>96 ml/m 2). A significant number of patients (52%) with moderate MR (EROA <30 mm 2) were enrolled in the MITRA-FR trial, whereas only 14% of patients with this parameter were enrolled in the COAPT trial. This suggests that the MitraClip procedure added to medical therapy optimisation does not seem to have a significant beneficial effect on patients with moderate MR and dilated LV cardiomyopathy.

to be more true to life in terms of medical therapy and optimisation. The rates of drug use and medication titration throughout the MITRAFR trial course were not tracked, and although these were guideline directed, they may not have been guideline optimised. Yet the story does not end here – the percentage of drugs used in MITRA-FR was higher than COAPT even if dose optimisation was not checked by a selection committee. In addition, although there were a significant number of HF hospitalisations in the COAPT trial, the doses of medications were not changed significantly.

Size of Study and Study Design The number of patients and follow-up were different between the two trials. The MITRA-FR trial enrolled about 300 patients, 150 in each arm; and the COAPT trial enrolled about 600, 300 in each arm. Perhaps an effect size may not have been seen in MITRA-FR that was seen in COAPT. Although hospitalisations differed early on between the two patient groups in the COAPT trial (partly due to a more rigorous medical arm), mortality did not differentiate until the second year. The follow-up period for MITRA-FR was only 1 year. Perhaps the positive nature of COAPT could be partially down to better design, probably due to more accessible funding.

Technical Success and Procedural Safety Technical success and procedural safety may be different between the two trials. Residual MR class ≥3+ was higher post-clip for MITRAFR compared with COAPT, both acutely (9% versus 5%) and at 12 months (17% versus 5%); procedural complications – although low and improving with current experience – were higher in MITRA-FR than in COAPT (14.6% versus 8.5%), and residual MR class ≥3+ was higher post-clip for MITRA-FR compared with COAPT, both acutely (9% versus 5%) and at 12 months (17% versus 5%).7–8

The patient recruitment process was more selective in the COAPT trial compared with the MITRA-FR trial, as indicated by the slow enrolment and length of time of the trial. One review article describes the difference as proportionate mitral regurgitation (MITRA-FR) and disproportionate mitral regurgitation (COAPT) to the degree of LV dilatation, with the COAPT trial enrolling patients with EROA about 30% higher and LV volumes about 30% smaller than the MITRA-FR trial.9

It is important to note that there was no common core lab evaluation of both trials. More patients in COAPT had more than one clip implanted compared with patients in the MITRA-FR trial. This raises questions over the use of 3D imaging during the procedure. 3D imaging is better than 2D imaging at identifying location of jets, perpendicularity, post-clip leak and mitral valve area. For procedural complications, there was about a twofold higher rate of device implant failure, cardiogenic shock, stroke and tamponade in MITRAFR compared with COAPT, which may be due to different patient populations or patients who are at different stages of the disease. These are significant issues that are likely to be associated with negative primary outcomes.

Medical Therapy and Optimisation

Selecting Patients Who Will Benefit From MitraClip

The ‘guideline-directed’ medical therapy used in the two trials differed significantly. The COAPT patients were under more strict evaluation with HF specialists overseeing the maximal doses tolerated for all medications, before and at the time of the MitraClip intervention. Several critiques of the COAPT trial have pointed out that even at the highest enrolment centre, Cedars-Sinai Medical Center in Los Angeles, with 46 enrolled patients total, that would average about one study patient per month receiving the MitraClip intervention. Only about 1–12% of patients had medication changes during the trial.

Overall, how did the COAPT and MITRA-FR trials help in selecting the most appropriate patient with secondary (functional) MR to receive MitraClip therapy? The COAPT trial shows us that patients have to be symptomatic, have substantial MR and have LV dysfunction (but not too much dysfunction) and be on the highest tolerated doses of HF medications. Patient selection, medical management and procedural timing is key for success. This means that HF physicians will need to be involved (and incentivised) members of the evaluation and management team for mitral valve disease. Periprocedural imaging and procedural technique needs to be optimised and patients with only one clip should be evaluated closely. Patients with at least a 2-year expected lifespan after the procedure may do better from a mortality standpoint, which should be part of the initial screening.

The highly stringent patient selectivity in the COAPT trial is the obvious difference between the two trials. The MITRA-FR trial was designed

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Why Did COAPT Win While MITRA-FR Failed? The Future There are still some unanswered questions from these trials. Some of these are based on COAPT subsets to better identify patients who will benefit from the intervention, such as effects based on patients with or without frailty, medical changes during the trial period, postprocedural high gradient and more. How do we improve the medical and procedural treatment for those in MITRA-FR who are outside the range of COAPT? Will other therapies,such as rings and valve replacement, provide better

Goliasch G, Bartko PE, Pavo N, et al. Refining the prognostic impact of functional mitral regurgitation in chronic heart failure. Eur Heart J 2018;39:39–46. https://doi.org/10.1093/ eurheartj/ehx402; PMID: 29020337. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759–64. https://doi.org/10.1161/01. CIR.103.13.1759; PMID: 11282907. Rossi A, Dini FL, Faggiano P, et al. Independent prognostic value of functional mitral regurgitation in patients with heart failure. A quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 2011;97:1675–80. https://doi.org/10.1136/hrt.2011.225789; PMID: 21807656.

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outcomes, and for which patients? These are questions worthy of consideration and we will undoubtedly see more data in the coming years. At this time, both trials provide guidance we may use to get maximal results in practice, and create opportunities for other mitral valve therapies to also work in the COAPT and MITRA-FR patient spaces. It is important to remember that MR and HF are a vast frontier for us to explore and these two trials are just the beginning. We have neither won nor lost at this time – we are still gathering information about this important disease process, and our patients will look to us for answers in the years ahead.

Sannino A, Smith RL,Schiattarella GG, et al. Survival and cardiovascular outcomes of patients with secondary mitral regurgitation: a systematic review and meta-analysis. JAMA Cardiol 2017;2:1130–9. https://doi.org/10.1001/ jamacardio.2017.2976; PMID: 28877291. Stone GW, Vahanian AS, Adams DH, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles: a consensus document from the mitral valve academic research consortium. J Am Coll Cardiol 2015;66:278– 307. https://doi.org/10.1016/j.jacc.2015.05.046; PMID: 26184622. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–406. https://doi.org/10.1056/NEJMoa1009355;

PMID: 21463154. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018; https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med 2018;379:2297–306. https://doi. org/10.1056/NEJMoa1805374; PMID: 30145927. Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: a new conceptual framework that reconciles the results of the MITRA-FR and COAPT trials. JACC Cardiovasc Imaging 2019;12:353–62. https://doi.org/10.1016/j.jcmg.2018.11.006; PMID: 30553663.

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Erratum

Erratum to: Common and Uncommon CTO complications Johannes Rigger,1,2 Colm G Hanratty1 and Simon J Walsh1 1. Cardiology Department, Belfast Health & Social Care Trust, Belfast, Northern Ireland, UK; 2. Kantonsspital, St Gallen, Switzerland

Citation: Interventional Cardiology Review 2019;14(1):48. DOI: https://doi.org/10.15420/icr.2018.35.1

In the review by Johannes Rigger, Colm G. Hanratty and Simon J Walsh entitled ‘Common and Uncommon CTO Complications’ (Citation: International Cardiology Review 2018;13(3):121–5. DOI: https://doi.org/10.15420/icr.2018.10.2), the following corrections should be made: The second sentence of the abstract on page 121 should read ‘Due to the complexity of the procedures, there is an increased complication rate compared with PCIs for the treatment of non-occlusive disease.’ This is a correction to the sentence ‘Due to the complexity of the procedury have a higher complication rate than PCI interventions for the treatment of non-occlusive disease.’ The the last sentence of the article has been corrected as follows: ‘A significant part of modern CTO PCI includes an awareness of the potential pitfalls of the procedure, being able to recognise these events promptly when they arise and the ability to resolve them when they do occur.’ This is a correction to the sentence 'A significant part of modern CTO PCI includes an awareness of the potential pitfalls of the procedure, being able toto recognise these events promptly when they arise and the ability to resolve them when they do occur.' The editors would like to sincerely apologise for any inconvenience or confusion this may have caused our readers.

Access at: www.ICRjournal.com

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MARCH

21ST & 22ND

2019 PADUA

ITALY

CLIC Critical L imb I schemia Course

COURSE FOCUSED ON DIABETIC FOOT Course Directors: Marco Manzi, MD & Luis Mariano Palena, MD

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ESC Congress Paris 2019 Together with

World Congress of Cardiology 31 August - 4 September

Spotlight Global Cardiovascular Health

Abstract submission: December - 14 February Clinical Case submission: Mid January - 1 March Late-Breaking Science submission: Mid March - 21 May Early registration deadline: 31 May Late registration deadline: 31 July

escardio.org/ESC2019

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ICR 14.1

Articles inside

ICR 14.1