ICR 11.1 by Radcliffe Cardiology

Volume 11 • Issue 1 • Spring 2016

www.ICRjournal.com

Choice of Intracoronary Imaging: When to use Intravascular Ultrasound or Optical Coherence Tomography Sudheer Koganti, Tushar Kotecha and Roby D Rakhit

Fractional Flow Reserve: Does a Cut-off Value add Value? Shah R Mohdnazri, Thomas R Keeble and Andrew Sharp 72 yearsSP old, Male/Stable angina Hypertension (+) Dyslipidemia (+) Diabetis (+) BMI 27.5 Cr 0.9 mg/dL

Impact of Mitral Regurgitation on Clinical Outcomes After Transcatheter Aortic Valve Implantation Crochan J O’Sullivan, David Tüller, Rainer Zbinden and Franz R Eberli

Simulator Training in Interventional Cardiology Abhishek Joshi and Andrew Wragg 1.25 mm Classic crown

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02/05/2016 15:42

Volume 11 • Issue 1 • Spring 2016

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

Fernando Alfonso

A Pieter Kappetein

Hospital Universitario de La Princesa, Madrid

Andrew Archbold

Thoraxcenter, Erasmus University Medical Center, Rotterdam

London Chest Hospital, Barts Health NHS Trust, London

Demosthenes Katritsis

Sergio Baptista

Tim Kinnaird

Hospital CUF Cascais and Hospital Fernando Fonseca, Portugal

Marco Barbanti

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

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

Ferrarotto Hospital, Catania

Olivier Bertrand

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

Jeffrey Popma Beth Israel Deaconess Medical Center, Boston

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

Elliot Smith

Quebec Heart-Lung Institute, Laval University, Quebec

Azeem Latib San Raffaele Hospital, Milan

London Chest Hospital, Barts Health NHS Trust, London

Lutz Buellesfeld

Didier Locca

Lars Søndergaard

University Hospital, Bern

Lausanne University Hospital, Lausanne

Jonathan Byrne

Roxana Mehran

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

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Mount Sinai Hospital, New York

Gregg Stone

Thomas Modine 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

Keith Oldroyd

Renu Virmani

Golden Jubilee National Hospital, Glasgow

CVPath Institute, Maryland

Crochan J O’Sullivan Triemli Hospital, Zurich

London Chest Hospital, Barts Health NHS Trust, London

Thomas Johnson

Nicolo Piazza

Nina C Wunderlich

University Hospitals Bristol, Bristol

McGill University Health Center, Montreal

Cardiovascular Center Darmstadt, Darmstadt

Eric Eeckhout Centre Hospitalier Universitaire Vaudois, Lausanne

Sameer Gafoor CardioVascular Center, Frankfurt

Juan Granada CRF Skirball Research Center, New York

Mark Westwood

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

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

•

Human heart for medical study © angelhell | istockphoto.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2016 All rights reserved

Radcliffe Cardiology

ISSN: 1756–1477 • eISSN: 1756–1485

Established: June 2006 Frequency: Bi-annual Current issue: Spring 2016

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

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

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

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

ICR_11.1.indd 2

outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

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

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

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

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

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

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Contents

Foreword 6 Simon

Kennon

Editor-in-Chief, ICR

Editorial 8 Angela

Hoye

Coronary Section Editor, ICR

Coronary 11

Choice of Intracoronary Imaging: When to use Intravascular Ultrasound or Optical Coherence Tomography

Sudheer Koganti, Tushar Kotecha and Roby D Rakhit

Fractional Flow Reserve: Does a Cut-off Value add Value?

Shah R Mohdnazri, Thomas R Keeble and Andrew SP Sharp

Coronary Intervention With the Excimer Laser: Review of the Technology and Outcome Data

John Rawlins, Jehangir N Din, Suneel Talwar and Peter O’Kane

Patient Selection and Procedural Considerations for Coronary Orbital Atherectomy System

Yohei Sotomi, Richard A Shlofmitz, Antonio Colombo, Patrick W Serruys and Yoshinobu Onuma

Primary Angioplasty for Patients in Cardiogenic Shock: Optimal Management

Jubin Joseph, Tiffany Patterson, Satpal Arri, Hannah McConkey and Simon R Redwood

Determining the Most Appropriate Mode of Coronary Artery Revascularisation in Patients With Diabetes

Ehrin J Armstrong and Stephen W Waldo

The use of the Cre8 Stent in Patients With Diabetes Mellitus

Didier Carrié

Dual Antiplatelet Therapy After Drug-eluting Stent Implantation

Giulia Magnani and Marco Valgimigli

Structural 54

Impact of Mitral Regurgitation on Clinical Outcomes After Transcatheter Aortic Valve Implantation

Crochan J O’Sullivan, David Tüller, Rainer Zbinden and Franz R Eberli

Hybrid Imaging in the Catheter Laboratory: Real-time Fusion of Echocardiography and Fluoroscopy During Percutaneous Structural Heart Disease Interventions

Jan Balzer, Tobias Zeus, Verena Veulemans and Malte Kelm

Hypertension 65

Interventional Therapies for Resistant Hypertension: A Brief Update Lisa Brandon and Faisal Sharif

Simulation Training 70

ICR_contents_11.1.indd 4

Simulator Training in Interventional Cardiology Abhishek Joshi and Andrew Wragg

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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 includes three expert reviews of established technologies which I think many interventional cardiologists will find both interesting and useful: one on the relative merits of intravascular ultrasound and optical coherence tomography; one reviewing

the value of FFR thresholds; and one on the excimer laser. Timely reviews of ‘DAPT after DES’ and of the optimal interventional management of cardiogenic shock will also be applicable to the daily practice of many interventional cardiologists. Two novel technologies are reviewed: the orbital atherectomy system offers hope of advances in the treatment of calcified coronary arteries; the Cre8 stent similarly offers hope of progress in the treatment of diabetic coronary disease. Further, the optimal general approach to diabetic coronary artery disease, and the mode of revascularisation in particular, is reviewed by Armstrong and Waldo. The strength of the coronary section of this issue of the journal is testament to the expertise, hard work and enthusiasm of Angela Hoye, who I would like to welcome to the Editorial Board of Interventional Cardiology Review as the Coronary Section Editor. Angela has also contributed an excellent editorial (page 8). The structural section of this issue is less extensive than usual, perhaps the calm before the storm of analysis that will inevitably follow the recent presentation and publication of the PARTNER 2a data. Balzer et al. have reviewed the EchoNavigator fusion imaging system, which aims to facilitate structural interventions including transcatheter aortic valve implantation. O’Sullivan et al. have reviewed the literature relating to the impact of mitral regurgitation on TAVI outcomes – an issue of concern in the assessment of a significant minority of potential TAVI patients. The final ‘structural’ paper is a comprehensive review of interventional therapies for resistant hypertension by Brandon and Sharif. Finally, and of relevance to both coronary and structural interventionalists as well as to trainees and for those providing the training, Joshi and Wragg have written knowledgeably on the value of simulation training in general, and for interventional cardiologists in particular. n

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Your Daily Practice Companion 05/05/2016 00:04

Editorial From the Coronary Section Editor

Angela Hoye is an Interventional Cardiologist at Castle Hill Hospital, Hull and a Senior Lecturer in Cardiology at the Centre for Cardiovascular and Metabolic Research, Hull York Medical School. Dr Hoye joins Interventional Cardiology Review as the Coronary Section Editor from the Spring 2016 issue onward.

t is my great honour to join Interventional Cardiology Review as Coronary Section Editor. In the modern era we are all increasingly busy and it is a pleasure to be part of a journal that helps to maintain an up-to-date knowledge of clinical practice.

I practice as an Interventional Cardiologist in a univesrsity hospital in Hull, UK, and have a particular interest in undertaking complex coronary interventions. I have a clinical research background, founded more than 10 years ago during a PhD Fellowship in Rotterdam under the supervision of Professor Patrick W Serruys. Since then, I have continued to undertake clinical research projects, particularly in challenging areas such as chronic total occlusions. I hope to bring my clinical, as well as my research, interests to influence the Coronary Section Editor role at Interventional Cardiology Review. I have been lucky enough to regularly travel to meetings all over the world and keep abreast of new developments in our field. We have an exciting year ahead of us with several important clinical trials due to report. In particular, the results of the EXCEL (Effectiveness of Left Main Revascularization) and NOBLE (Nordic-Baltic-British Left Main Revascularization) studies could impact greatly on our therapy of left main stem disease. In many parts of the world, left main stem lesions are still very much the domain of our cardiac surgery colleagues, however these trials have the potential to alter practice if the angioplasty results are as favourable as anticipated. The field of stent design has undergone huge transformation in recent years and continues to evolve. I am particularly looking forward to learning more about current and new bioabsorbable stent technologies. Advances in the field not withstanding, there remain several important on-going issues in interventional cardiology that are not yet fully clarified. One area is that of anti-platelet therapy: the battle between balancing the need for anti-platelet therapy to reduce the catastrophic event of stent thrombosis, and the risk of bleeding which, too, can be disastrous for the patient. Every day, we use our clinical judgement to weigh up these risks and individually tailor patient management. However, questions remain. How can we better predict bleeding? What is the ideal type, dose, and duration of anti-platelet therapy? What about patients who require anti-coagulation? This clinical problem is becoming even more pertinent in contemporary practice as our population ages. It is now common to undertake coronary interventions on patients aged >80 years, however there is a paucity of evidence in this age group. Such interventions are often more complex; however, although the risks are higher, these patients have potentially the most to gain. Quality of life in this age group is commonly felt to be more important than longevity. We need specific research in this population so that we can improve risk stratification in older patients, as well provide an evidence-base to guide best practice.

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Editorial From the Coronary Section Editor

There are still challenges in the field of coronary intervention. A particularly challenging patient group is those with refractory angina who do not have a revascularisation option perhaps because of diffuse, distal disease. Such patients have poor quality of life as well as an increased mortality rate. Although there have been several pharmacological and non-pharmacological treatments shown to improve quality of life, convincing evidence regarding reduction in ischaemic burden and mortality is lacking. Furthermore, technologies such as coronary sinus occlusion and enhanced external counter-pulsation are not widely funded / available. More work is needed to continue to develop these concepts as well as other therapies such as arteriogenesis that have the potential to transform the management of patients with otherwise “untreatable” disease. These technologies may also have a role to facilitate the treatment of chronic total occlusions (CTOs) where the highest success rates are seen only in the hands of experts. Other innovations might include “forward-looking” imaging technology – could this facilitate a high successful recanalization rate for all operators performing CTO angioplasty? Comprehensive reviews are important to clarify best practice and I am impressed by the quality of the articles published in Interventional Cardiology Review. The journal has a great team in place and it is a pleasure to work with them to continue to develop and maintain the journal’s high standards. Comments and feedback from readers would be very much welcomed; my aims are to continue to develop the journal, increase its readership, and maintain its reputation for quality. n

Hoye EDITORIAL_FINAL.indd 10

I N T E R V E N T I O N A L C AR DI OLOGY R E V I E W

05/05/2016 00:31

Coronary

Choice of Intracoronary Imaging: When to use Intravascular Ultrasound or Optical Coherence Tomography Sudheer Koganti, 1,2 Tushar Kotecha 2,3 and Roby D Rakhit 2,3 1. Barts, Heart Centre; 2. University College London Institute of Cardiovascular Science; 3. Royal Free Hospital, London, UK

Abstract Intracoronary imaging has the capability of accurately measuring vessel and stenosis dimensions, assessing vessel integrity, characterising lesion morphology and guiding optimal percutaneous coronary intervention (PCI). Coronary angiography used to detect and assess coronary stenosis severity has limitations. The 2D nature of fluoroscopic imaging provides lumen profile only and the assessment of coronary stenosis by visual estimation is subjective and prone to error. Performing PCI based on coronary angiography alone is inadequate for determining key metrics of the vessel such as dimension, extent of disease, and plaque distribution and composition. The advent of intracoronary imaging has offset the limitations of angiography and has shifted the paradigm to allow a detailed, objective appreciation of disease extent and morphology, vessel diameter, stent size and deployment and healing after PCI. It has become an essential tool in complex PCI, including rotational atherectomy, in follow-up of novel drug-eluting stent platforms and understanding the pathophysiology of stent failure after PCI (e.g. following stent thrombosis or in-stent restenosis). In this review we look at the two currently available and commonly used intracoronary imaging tools – intravascular ultrasound and optical coherence tomography – and the merits of each.

Keywords Intracoronary imaging, intravascular ultrasound, optical coherence tomography Disclosure: The authors have no conflicts of interest to declare. Received: 13 January 2016 Accepted: 8 February 2016 Citation: Interventional Cardiology Review, 2016;11(1):11–6 DOI: 10.15420/icr.2016:6:1 Correspondence: Roby Rakhit, Consultant Interventional Cardiologist, Department of Cardiology, Royal Free Hospital, Pond Street, London, NW3 2QG, UK. E: roby.rakhit@nhs.net

Intracoronary imaging is able to aid the interventional cardiologist in the characterisation of atherosclerotic plaque morphology, in optimising stent sizing, and in minimising the complications associated with percutaneous coronary intervention (PCI). Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are commonly used methods, while newer spectroscopic methods are under development.

is possible with radiofrequency-based technology such as IVUS virtual histology.2 IVUS virtual histology may assist in characterisation of plaque morphology by differentiating between various types of plaque using colour coding. As a result of limited resolution, IVUS cannot reliably identify the separation between intima and media and the relation between adventitia and peri-adventitial structures (see Figure 1).3

Intravascular Ultrasound Versus Optical Coherence Tomography: Technology

In contrast to IVUS, intracoronary imaging by OCT is obtained using near-infrared light. The first generation of OCT imaging was based on occlusive balloon technology called time domain (TD) imaging. Use of frequency domain (FD) imaging, also referred to as Fourier domain spectral imaging, has now surpassed TD imaging.4 FD imaging does not require occlusion of the proximal artery with a balloon as high viscosity liquids such as contrast media can be used to purge blood from the vessel, while imaging is completed rapidly. Current commercially available OCT catheters consist of a single-mode optical fibre in a hollow metal wire torque that rotates at a speed of 100 rps. The axial and lateral resolutions of OCT are 10–20 μm and 20 μm, respectively – which is superior to that of IVUS. However, better resolution comes at a drawback of limited penetration – a maximum of 2 mm.5 With acquisition speeds of up to 25 mm/s, rapid imaging of coronary artery can be achieved within a few seconds. Commercially available OCT catheters can be inserted into coronary artery on a 0.014 inch guide wire and are compatible with guiding catheters sized 5Fr or larger. For optimal imaging quality, a bloodless field is required, which can be achieved with injection of 12–15 ml of

Table 1 displays a technical comparison of the IVUS and OCT imaging methods. The principle of IVUS imaging is based on the ultrasound waves produced by the oscillatory movement of a transducer.1 Commercially available IVUS systems have transducers mounted on catheters that are compatible with guiding catheters in sizes of 5Fr or larger. These catheters can be inserted into the coronary artery over a 0.014 inch conventional guide wire and imaging can be obtained by manual or motorised pullback. Motorised pullbacks are carried out at a speed of 0.5 mm/s, thus a 50 mm coronary artery can be imaged in approximately 90s. Integrated IVUS consoles add to the rapidity of imaging, but mobile IVUS carts are also available. When co-registration of IVUS with angiography becomes available, this will be a useful adjunct in locating the anatomical lesion precisely. Once the pullback is recorded, measurements of the lumen can be carried out either manually or using automated software. Greyscale IVUS has an axial resolution of 100–150 μm, lateral resolution of 200 μm1 and penetration depth of 4–8 mm. Post-processing of greyscale IVUS images

Rakhit_FINAL.indd 11

05/05/2016 15:30

Coronary Table 1: Technical Comparison of IVUS and OCT

Source of image

IVUS

OCT

Ultrasound

Near infrared light

(10–40 MHz) Minimum guide catheter size

5Fr

5Fr (although 6Fr preferable)

Axial resolution

100–150 μm

10–20 μm

Lateral resolution

200 μm

20 μm

Penetration depth

4–8 mm

2 mm

Acquisition speed

0.5 mm/s

25 mm/s

Blood clearance

Not required

Contrast 10–15 ml

IVUS = intravascular ultrasound; OCT = optical coherence tomography.

Figure 1: IVUS (A) and OCT (B) Showing a Normal Segment of Coronary Artery A

Note the clear demarcation of trilmainar structure of coronary artery in the OCT (B) image. i = intima; m = media; a = adventitia; IVUS = intravascular ultrasound; OCT = optical coherence tomography.

Figure 2: IVUS Showing a Circumferential Calcified Lesion (A) and Eccentric Mixed Plaque (B) A

optimising PCI results. Co-registration of OCT with angiography can be a useful adjunct in locating anatomical lesions precisely, reducing the chances of geographical miss.

Intravascular Ultrasound Versus Optical Coherence Tomography: Safety and Feasibility One of the limitations of earlier TD-OCT imaging was the requirement to have a bloodless field for adequate imaging. This was achieved by proximal occlusion of the coronary artery with a semi-compliant balloon followed by flushing of the artery with ringer’s lactate solution. Although this method was not associated with any serious complications, minor complications such as transient ST elevation with associated chest pain were common.6 Furthermore, the acquisition time was longer with a pullback speed of only 0.5–3.0 mm/s. In comparison, current FD-OCT imaging does not require balloon occlusion of coronary artery and, with higher pullback speeds, a bloodless field can be achieved by contrast injection. Both IVUS and current-generation FD-OCT have been shown to have a favourable safety profile. An integrated biomarker and imaging substudy (IBIS-4) assessed the feasibility and the procedural and longterm safety of OCT and IVUS in patients with ST-elevation MI (STEMI) undergoing primary PCI.7 In this prospective cohort study, 103 patients with STEMI who underwent serial three-vessel coronary imaging during primary PCI were compared with 485 patients with STEMI undergoing primary PCI without additional imaging after 13 months. Feasibility (defined as the number of pullbacks suitable for analysis) and safety (defined as the frequency of peri-procedural complications and major adverse cardiac events [MACE, a composite of cardiac death, MI and any clinically indicated revascularisation at 2 years]) outcomes were recorded. Successful imaging was achieved in <90 % of patients at baseline and follow-up using IVUS and OCT. Although peri-procedural complications occurred with OCT imaging (<2.0 % versus 0 % with IVUS), long-term safety was favourable with both modalities, with no significant difference in MACE rates at 2 years.7 Of note, the majority of OCT-related complications were transient ST elevation due to coronary spasm, which in clinical practice can be mitigated by administering intracoronary nitrates prior to imaging.

IVUS = intravascular ultrasound

highly viscous medium such as contrast, either by hand or by use of a power injector. Blood clearance can be challenging through a 5Fr catheter, therefore 6Fr or larger is generally recommended. Caution needs to be exercised in people with renal impairment where multiple pullbacks are contemplated due to the risk of contrast nephropathy. Current commercially available OCT software automatically detects the lumen, allows marking of every frame and gives user-defined proximal and distal reference frames with dimensions. Furthermore, every pullback of the coronary artery can be viewed in cross-sectional frames (see Figure 1), longitudinal view and lumen profile view. Cross-sectional views are helpful in detailed study of plaque where as longitudinal and lumen profile views can be used for longitudinal measurements such as stent length. 3D reconstruction is possible and may assist in detailed assessment of bifurcation lesions and in

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In another registry-based study, OCT and IVUS were shown to have comparable safety and feasibility profiles.8 Analysis of 3,045 OCT pullbacks from 1,142 patients and 5,148 IVUS pullbacks from 2,476 patients revealed seven complications related to OCT and 12 to IVUS imaging. Transient ST-elevation requiring withdrawal of the imaging catheter was noted with OCT, whereas IVUS appears to have been associated with coronary spasm, thrombus formation, dissection of the imaged vessel and stent deformation.8

Is one Choice of Intracoronary Imaging Superior to the Other and What are the Clinical Scenarios Where They Should be Used? Intravascular Ultrasound Over the past two decades, IVUS has become the reference tool for intracoronary imaging. Advances in IVUS technology have resulted in better resolution and penetration: IVUS can now be used to assess plaque characteristics, volume and constituents (see Figure 2; Table 2).9 Coronary arterial and lumen dimensions, particularly minimal luminal area (MLA), can be measured accurately by IVUS algorithms, which can assist in the decision-making process for revascularisation.10 One of the most important roles of IVUS is in optimising PCI, particularly in complex

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Intracoronary Imaging: When to use IVUS and OCT

Table 2: Clinical Situations in Which IVUS and OCT Can be Useful Clinical situation

IVUS

OCT

superior

Reason

Imaging of left main stem

✓

IVUS has greater penetration depth

Imaging of large coronary arteries

✓

IVUS has greater penetration depth

Renal impairment

✓

OCT requires additional contrast injection to create a bloodless field

Assessment of calcification

✓

Aorto-ostial lesions

✓

The guide catheter needs to be fully engaged to clear blood for OCT and therefore difficult to image aorto-ostial lesions

Plaque characterisation

✓

OCT provides superior image quality enabling assessment of plaque content and cap thickness

Assessment of dissection

✓

Both modalities can be used, but OCT provides superior image quality

Assessment of thrombus

✓

OCT provides superior image quality and is able to differentiate between red and white thrombus

Stent expansion and apposition

✓

Both modalities can be used, but OCT provides superior image quality

Evaluation of in-stent restenosis

✓

Both modalities can be used, but OCT provides superior image quality

IVUS = intravascular ultrasound; OCT = optical coherence tomography.

lesions subsets such as left main stem (LMS), calcific and bifurcation lesions.11 IVUS can be used to optimise PCI as it has a role in stent sizing and in detecting adequate stent expansion and strut malapposition (see Figure 3).12 IVUS, with its better penetration, is superior to OCT in assessing the remodelling patterns of the vessel wall. IVUS-detected positive vessel remodelling of the coronary artery is associated with late stent thrombosis following drug-eluting stent (DES) implantation.13

Optical Coherence Tomography OCT, with even better resolution when compared with IVUS, can be used in assessing plaque characteristics14 and constituents15 and in optimising PCI.16 However, with limited penetration, assessment of plaques with thickness of >1.0–1.5 mm is not possible with OCT.4,17 Up to 25 % of acute coronary syndrome events are secondary to thrombus present on a non-ruptured plaque, also called an erosion.15,18 OCT helps in accurately identifying eroded plaques, where if no lumen narrowing is present stenting may not be needed. The presence of thin-cap fibroatheroma (TCFA), defined as lipid plaque thickness of <65 µm, is predictive of future adverse cardiac events.18 However, interpretation of TCFA on OCT requires caution as artefacts due to tangential dropout can lead to misinterpretation.19 The superior

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Figure 3: OCT Showing a Well-opposed Stent (A) and Malapposed Stent (B); IVUS Showing a Well-opposed Stent (C) and Malapposed Stent (D)

IVUS = intravascular ultrasound; OCT = optical coherence tomography.

resolution of OCT means it can detect TCFA with adequate sensitivity/ specificity,20 and also detects the presence of macrophages21 and neovessels, and lipid volume – the features of so-called vulnerable plaque (see Figure 4). Furthermore, OCT not only identifies the presence of thrombus, but can also distinguish between red and white thrombus often seen in STEMI (see Figure 5; Table 2).20 Injury to the vessel wall post-PCI reflected by the presence of intimal tears, edge dissections, tissue prolapse, presence of thrombus and incomplete stent apposition can be readily assessed by OCT, which allows for optimisation, as required.16 Two further areas where imaging with OCT is useful are capability of detecting thin neo-intima in follow-up imaging after DES implantation22 and in delineating tissue characteristics of in-stent restenosis (see Figure 4).23 OCT is superior to IVUS in identifying uncovered stent struts. Sub-analysis of the Optical Coherence Tomography for Drug Eluting Stent Safety (ODESSA) trial showed 8 % of the stented segments with no detectable neointima by IVUS were found to have neo-intimal coverage by OCT.24

Is There Evidence Supportive of One Modality Over the Other? In the field of interventional cardiology, any new diagnostic tool or treatment modality needs to be associated with better clinical outcomes before being incorporated into guidelines and adapted widely in the clinical environment. Here, we review the data supporting the use of these imaging techniques in contemporary clinical practice.

Intravascular Ultrasound A meta-analysis of IVUS-guided PCI by Zhang et al. showed improved clinical outcomes.25 In their analysis, over 19,000 patients across eleven studies (one randomized controlled trial and 10 registries) were included. Compared with angiography alone, IVUS-guided DES implantation was associated with reduced rates of death, MACE and stent thrombosis. No difference was found in the rates of MI, target lesion and target vessel revascularisation.

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Coronary Figure 4: OCT Showing a Thin-walled Plaque (A), Ruptured Plaque (B) and In-stent Restenosis (C)

in non-LMS lesions with MLA >4 mm2, lesions with MLA <4 mm2 may need to be physiologically tested before intervention.31

Optical Coherence Tomography

Currently trial data looking at OCT use and clinical outcomes are limited. The Centro per la Lotta contro l’Infarto-Optimisation of Percutaneous Coronary Intervention (CLI-OPCI) study compared outcomes between patients undergoing PCI under angiography guidance alone versus angiography plus OCT guidance.32 The group that underwent PCI with angiography and OCT guidance had overall significantly lower rates of cardiac death, MI and repeat revascularisation. Furthermore, OCT revealed adverse features following PCI in almost 35 % of patients who needed further intervention. C

OCT = optical coherence tomography.

Figure 5: OCT Showing Red Thrombus Resulting in Image Dropout (A) and White Thrombus Within a Previously Implanted Stent With no Image Dropout (B) A

OCT = optical coherence tomography.

The non-randomised Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) study analysed 3,349 patients in whom IVUS was used to guide PCI.26 IVUS guidance changed the PCI strategy in 74 % of cases. IVUS guidance compared with angiography alone was associated with reduced 1-year rates of stent thrombosis, MI and MACE following DES implantation. IVUS can be a useful adjunct in the assessment of LMS disease. IVUS generated MLA correlates with fractional flow reserve (FFR) in the absence of proximal left anterior descending and circumflex artery disease. IVUS MLA of <5.9 mm2 correlates well with FFR of <0.75.27 However, caution need to be exercised in Asian patients who have smaller coronary arteries. Kang et al. showed that an MLA cut-off of <4.1 mm2 correlated with FFR <0.7528 in a Korean population. In nonLMS lesions, the correlation of IVUS derived MLA with FFR is weak with limited accuracy.29 The reasons for this are lesion location in the coronary tree, lesion length, eccentricity, entrance and exit angles, shear forces, reference vessel dimensions, and the amount of viable myocardium subtended by the lesion.30 Although it is safe to defer PCI

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The Observational Study of Optical Coherence Tomography in Patients Undergoing Fractional Flow Reserve and Percutaneous Coronary Intervention (ILUMIEN) I study assessed how the clinical decisionmaking process is influenced when OCT is added to angiography and FFR.33 This study enrolled 418 patients scheduled for PCI from 35 international centres, including patients with stable and unstable coronary syndromes, prospectively in a non-randomised fashion. Once recruited, the majority of patients underwent pre-PCI FFR and OCT imaging. OCT imaging influenced physician decision-making processes pre-PCI in 57 % and post-PCI in 27 % of cases. Additional in-stent post-dilatation was carried out in 81 % and additional stent placement in 12 % of the cases. Device-oriented MACE (cardiac death, MI and target lesion revascularisation) and patient-oriented MACE (all-cause death, MI and any repeat revascularisation) were rare in hospital and at 30 days. The rates of other events such as stent thrombosis were also extremely low.33 The ILUMIEN II study showed the degree of stent expansion achieved after OCT versus IVUS guidance to be comparable.34 In this retrospective study, propensitymatched analysis of 354 patients who underwent OCT in the ILUMIEN I trial and 586 patients from the IVUS substudy of the ADAPT-DES trial based on reference vessel diameter, lesion length, calcification, and reference segment availability was comparable between OCT and IVUS guidance, as were the rates of major stent malapposition, tissue protrusion, and stent-edge dissection.34 The ongoing Optical Frequency Domain Imaging Versus Intravascular Ultrasound In Percutaneous Coronary Intervention (OPINION – OFDI) and ILUMIEN III randomised trials will further help in elucidating the potential of OCT versus IVUS in optimising PCI outcomes. The OPINION – OFDI study has completed recruitment with 800 patients divided equally between OCT and IVUS arms.35 The preliminary results showed comparable safety profiles and stent expansion with OCT and IVUS guidance immediately after PCI. The follow-up results at 1 year, including outcome data, are awaited. As with IVUS, the OCT-derived MLA of 1.9 mm2 correlates well with an FFR of <0.75.36 Another study of 56 stable patients reported OCT-derived MLA of 1.95 mm2 correlating well with an FFR of <0.80, with a sensitivity of 82 % and specificity of 63 %. However, 5 of the 26 patients with MLA >1.95 mm2 had an FFR of <0.80, suggesting that OCT cannot be a surrogate for FFR.37

Guidelines The American College of Cardiology Foundation/American Heart Association/Society for Cardiac Angiography (ACC/AHA/SCAI) 31 and European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS)38 guidelines on myocardial revascularisation have issued a class II recommendation for IVUS with

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Intracoronary Imaging: When to use IVUS and OCT

Table 3: Current Guidelines for Use of IVUS and OCT ESC IVUS Class IIa (level of evidence: B)

AHA/ACC Class IIa (level of evidence: B)

IVUS in selected patients to optimise

IVUS is reasonable for the assessment of angiographically indeterminant

stent implantation. IVUS to assess severity and optimise treatment

left main CAD

of unprotected LMS lesions

Class IIa (level of evidence: C)

IVUS and coronary angiography are reasonable 4 to 6 weeks and 1 year

IVUS to assess mechanisms of stent failure.

after cardiac transplantation to exclude donor CAD, detect rapidly

progressive cardiac allograft vasculopathy and provide prognostic

information

Class IIa (level of evidence: B)

IVUS is reasonable to determine the mechanism of stent restenosis

Class IIb (level of evidence: B)

IVUS may be reasonable for the assessment of non-left main coronary

arteries with angiographically intermediate coronary stenoses (50–70 %

diameter stenosis)

IVUS may be considered for guidance of coronary stent implantation,

particularly in cases of left main coronary artery stenting

Class IIb (level of evidence: C)

IVUS may be reasonable to determine the mechanism of stent

OCT

thrombosis

Class IIa (level of evidence: C)

The appropriate role for optical coherence tomography in routine clinical-decision making has not been established

OCT to assess mechanisms of stent failure

Class IIb (level of evidence: C)

OCT in selected patients to optimise stent implantation

AHA/ACC = American Heart Association/American College of Cardiology Foundation; CAD = coronary artery disease; ESC = European Society of Cardiology; IVUS = intravascular ultrasound; LMS = left main stem; OCT = optical coherence tomography.

varying levels of evidence depending on the indication (see Table 3). OCT, Owing to a lack of clinical data, OCT is not included in the US guidelines, whereas the European guidelines have given a class II recommendation for OCT (see Table 3).

Future Directions It is evident that both technologies have advantages and limitations. More technological adaptions are under way to enhance the use of IVUS and OCT. For example, OCT equipment that can complete pullback of entire coronary artery with in one heartbeat to minimise artefacts is undergoing experiments.39 Micro-OCT that has the ability to study endothelium and macrophages in vivo in detail is also under development.40 Experiments looking into feasibility of photo acoustic imaging in humans one are also underway.41

Conclusion Intracoronary imaging has given a new dimension to the field of interventional cardiology. When choosing the modality of intracoronary imaging, the anatomic location in the coronary tree appears to be a good discriminator. IVUS has better data when it comes to LMS-related

Garcia-Garcia HM, Gogas BD, Serruys PW, Bruining N. IVUS-based imaging modalities for tissue characterization: similarities and differences. Int J Cardiovasc Imaging 2011;27 :215–24. DOI: 10.1007/s10554-010-9789-7; PMID: 21327914. Gogas BD, Farooq V, Serruys PW, Garcia-Garcia HM. Assessment of coronary atherosclerosis by IVUS and IVUSbased imaging modalities: progression and regression studies, tissue composition and beyond. Int J Cardiovasc Imaging 2011;27 :225–37. DOI: 10.1007/s10554-010-9791-0; PMID: 21373888. Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478–92. PMID: 11300468.

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lesions, whereas OCT seems to be superior in arteries with an MLA of <3 mm2. When it comes to establishing diagnosis and optimising stent deployment, OCT has the advantage of better resolution. However, when it comes to assessing the significance of intermediate coronary stenosis, physiological assessment with FFR should remain the first choice as IVUS- and OCT-derived MLA cut-off values have at best moderate correlation and accuracy. IVUS and OCT are safe and feasible to use in modern cardiac catheter laboratory practice. In the hands of an experienced operator, imaging can be done rapidly with minimal or no complications. With advantages and limitations of one modality over the other, intracoronary imaging with IVUS and or OCT have the potential to complement each other. Future data justifying their routine use based on improved clinical endpoint data is forthcoming. The future of intracoronary imaging is likely to incorporate co-registration with angiography as standard, hybrid and molecular imaging. Future technological advances in intracoronary imaging provide further exciting opportunities for a better understanding of the coronary disease process and response to revascularisation. n

Prati F, Guagliumi G, Mintz GS, et al. Expert review document part 2: methodology, terminology and clinical applications of optical coherence tomography for the assessment of interventional procedures. Eur Heart J 2012;33 :2513–20. DOI: 10.1093/eurheartj/ehs095; PMID: 22653335. Terashima M, Kaneda H, Suzuki T. The role of optical coherence tomography in coronary intervention. Korean J Intern Med 2012;27 :1–12. DOI: 10.3904/kjim.2012.27.1.1; PMID: 22403493: epub ahead of press. Takarada S, Imanishi T, Liu Y, et al. Advantage of nextgeneration frequency-domain optical coherence tomography compared with conventional time-domain system in the assessment of coronary lesion. Catheter Cardiovasc Interv 2010;75 :202–6. DOI: 10.1002/ccd.22273; PMID: 19937788. Taniwaki M, Radu MD, Garcia-Garcia HM, et al. Longterm safety and feasibility of three-vessel multimodality intravascular imaging in patients with ST-elevation myocardial infarction: the IBIS-4 (integrated biomarker and imaging

study) substudy. Int J Cardiovasc Imaging 2015;31 :915–26. DOI: 10.1007/s10554-015-0631-0; PMID: 25721728. 8. Van der Sijde JKA, van Geuns R-J, Valgimigli M, et al. Safety of optical coherence tomography in daily practice: how does it compare to intravascular ultrasound? EuroIntervention 2015;Abstracts EuroPCR 2015. 9. Nissen SE, Yock P. Intravascular ultrasound: novel pathophysiological insights and current clinical applications. Circulation 2001;103 :604–16. PMID: 11157729. 10. Waksman R, Kitabata H, Prati F, et al. Intravascular ultrasound versus optical coherence tomography guidance. J Am Coll Cardiol 2013;62 :S32–40. DOI: 10.1016/j.jacc.2013.08.709; PMID: 24135661. 11. Kim JS, Hong MK, Ko YG, et al. Impact of intravascular ultrasound guidance on long-term clinical outcomes in patients treated with drug-eluting stent for bifurcation lesions: data from a Korean multicenter bifurcation registry. Am Heart J 2011;161 :1:80–7. DOI: 10.1016/j.ahj.2010.10.002;

05/05/2016 15:30

Coronary PMID: 21167352. 12. Parise H, Maehara A, Stone GW, et al. Meta-analysis of randomized studies comparing intravascular ultrasound versus angiographic guidance of percutaneous coronary intervention in pre-drug-eluting stent era. Am J Cardiol 2011;107:374–82. DOI: 10.1016/j.amjcard.2010.09.030; PMID: 21257001. 13. Guagliumi G, Sirbu V, Musumeci G, et al. Examination of the in vivo mechanisms of late drug-eluting stent thrombosis: findings from optical coherence tomography and intravascular ultrasound imaging. JACC Cardiovasc Interv 2012;5 :12–20. DOI: 10.1016/j.jcin.2011.09.018; PMID: 22230145. 14. Jang IK, Bouma BE, Kang DH, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol 2002;39 :604–9. PMID: 11849858. 15. Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106 :1640–5. PMID: 12270856. 16. Gonzalo N, Serruys PW, Okamura T, et al. Optical coherence tomography assessment of the acute effects of stent implantation on the vessel wall: a systematic quantitative approach. Heart 2009;95 :1913–9. DOI: 10.1136/ hrt.2009.172072; PMID: 19671534. 17. Manfrini O, Mont E, Leone O, et al. Sources of error and interpretation of plaque morphology by optical coherence tomography. Am J Cardiol 2006;98 :156–9. PMID: 16828584. 18. Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20 :1262–75. PMID: 10807742. 19. van Soest G, Regar E, Goderie TP, et al. Pitfalls in plaque characterization by OCT: image artifacts in native coronary arteries. JACC Cardiovasc Imaging 2011;4 :810–3. DOI: 10.1016/j. jcmg.2011.01.022; PMID: 21757174. 20. Kume T, Akasaka T, Kawamoto T, et al. Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J 2006;152 :755 e751–4. PMID: 16996853. 21. MacNeill BD, Jang IK, Bouma BE, et al. Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease. J Am Coll Cardiol 2004;44 :972–9. PMID: 15337206. 22. Matsumoto D, Shite J, Shinke T, et al. Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography. Eur Heart J 2007;28 :961–7. PMID: 17135281.

Rakhit_FINAL.indd 16

23. Habara M, Terashima M, Nasu K, et al. Difference of tissue characteristics between early and very late restenosis lesions after bare-metal stent implantation: an optical coherence tomography study. Circ Cardiovasc Interv 2011;4 :232–8. DOI: 10.1161/CIRCINTERVENTIONS.110.959999; PMID: 21610225. 24. Guagliumi G, Musumeci G, Sirbu V, et al. Optical coherence tomography assessment of in vivo vascular response after implantation of overlapping bare-metal and drug-eluting stents. JACC Cardiovasc Interv 2010;3 :531–9. DOI: 10.1016/j. jcin.2010.02.008; PMID: 20488410. 25. Zhang Y, Farooq V, Garcia-Garcia HM, et al. Comparison of intravascular ultrasound versus angiography-guided drug-eluting stent implantation: a meta-analysis of one randomised trial and ten observational studies involving 19,619 patients. EuroIntervention 2012;8 :855–65. DOI: 10.4244/ EIJV8I7A129; PMID: 23171805. 26. Witzenbichler B, Maehara A, Weisz G, et al. Relationship between intravascular ultrasound guidance and clinical outcomes after drug-eluting stents: the assessment of dual antiplatelet therapy with drug-eluting stents (ADAPTDES) study. Circulation 2014;129 :463–70. DOI: 10.1161/ CIRCULATIONAHA.113.003942; PMID: 24281330. 27. Jasti V, Ivan E, Yalamanchili V, et al. Correlations between fractional flow reserve and intravascular ultrasound in patients with an ambiguous left main coronary artery stenosis. Circulation 2004;110 :2831–6. PMID: 15492302. 28. Kang SJ, Lee JY, Ahn JM, et al. Intravascular ultrasoundderived predictors for fractional flow reserve in intermediate left main disease. JACC Cardiovasc Interv 2011;4 :1168–74. DOI: 10.1016/j.jcin.2011.08.009; PMID: 22115656. 29. Abizaid A, Mintz GS, Pichard AD, et al. Clinical, intravascular ultrasound, and quantitative angiographic determinants of the coronary flow reserve before and after percutaneous transluminal coronary angioplasty. Am J Cardiol 1998;82 :423–8. PMID: 9723627. 30. Pijls NH, Sels JW. Functional measurement of coronary stenosis. J Am Coll Cardiol 2012;59 :1045–57. DOI: 10.1016/j. jacc.2011.09.077; PMID: 22421298. 31. Lotfi A, Jeremias A, Fearon WF, et al. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the Society of Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2014;83 :509–18. DOI: 10.1002/ccd.25222; PMID: 24227282. 32. Prati F, Di Vito L, Biondi-Zoccai G, et al. Angiography alone versus angiography plus optical coherence tomography

33.

34.

35.

36.

37.

38.

39.

40.

41.

to guide decision-making during percutaneous coronary intervention: the Centro per la Lotta contro l’InfartoOptimisation of Percutaneous Coronary Intervention (CLI-OPCI) study. EuroIntervention 2012;8 :823–9. DOI: 10.4244/ EIJV8I7A125; PMID: 23034247. Wijns W, Shite J, Jones MR, et al. Optical coherence tomography imaging during percutaneous coronary intervention impacts physician decision-making: ILUMIEN I study. Eur Heart J 2015;36 :3346–55. DOI: 10.1093/eurheartj/ ehv367; PMID: 26242713. Maehara A, Ben-Yehuda O, Ali Z, et al. Comparison of Stent Expansion Guided by Optical Coherence Tomography Versus Intravascular Ultrasound: The ILUMIEN II Study (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention). JACC Cardiovasc Interv 2015;8 :1704–14. DOI: 10.1016/j.jcin.2015.07.024; PMID: 26585621. Akasaka T. OPINION: OPtical frequency domain imaging versus INtravascular ultrasound in percutaneous coronary InterventiON. Presented at: EuroPCR, Paris, France, 20 May 2015. Shiono Y, Kitabata H, Kubo T, et al. Optical coherence tomography-derived anatomical criteria for functionally significant coronary stenosis assessed by fractional flow reserve. Circ J 2012;76 :2218–25. PMID: 22785153. Gonzalo N, Escaned J, Alfonso F, et al. Morphometric assessment of coronary stenosis relevance with optical coherence tomography: a comparison with fractional flow reserve and intravascular ultrasound. J Am Coll Cardiol 2012;59 :1080–9. DOI: 10.1016/j.jacc.2011.09.078; PMID: 22421301. Kolh P, Windecker S. ESC/EACTS myocardial revascularization guidelines 2014. Eur Heart J 2014;35 :3235–6. DOI: 10.1093/ eurheartj/ehu422; PMID: 25482397. Wang T, Pfeiffer T, Regar E, et al. Heartbeat OCT: in vivo intravascular megahertz-optical coherence tomography. Biomed Opt Express 2015;6 :5021–32. DOI: 10.1364/ BOE.6.005021; PMID: 26713214. Liu L, Gardecki JA, Nadkarni SK, et al. Imaging the subcellular structure of human coronary atherosclerosis using microoptical coherence tomography. Nat Med 2011;17 :1010–4. DOI: 10.1038/nm.2409; PMID: 21743452. Desjardins AE, van der Voort M, Roggeveen S, et al. Needle stylet with integrated optical fibers for spectroscopic contrast during peripheral nerve blocks. J Biomed Opt 2011;16 :077004. DOI: 10.1117/1.3598852; PMID: 21806284.

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Coronary

Fractional Flow Reserve: Does a Cut-off Value add Value? Sha h R Mohdna z r i , 1 ,2 Th o m a s R Ke e b l e 1 ,2 a n d A n d r e w S P S h a r p 3 ,4 1. The Essex Cardiothoracic Centre, Basildon, UK; 2. Anglia Ruskin University, Chelmsford, UK; 3. Royal Devon and Exeter Hospital, Exeter, UK; 4. University of Exeter, Exeter, UK

Abstract Fractional flow reserve (FFR) has been shown to improve outcomes when used to guide percutaneous coronary intervention (PCI). There have been two proposed cut-off points for FFR. The first was derived by comparing FFR against a series of non-invasive tests, with a value of ≤0.75 shown to predict a positive ischaemia test. It was then shown in the DEFER study that a vessel FFR value of ≥0.75 was associated with safe deferral of PCI. During the validation phase, a ‘grey zone’ for FFR values of between 0.76 and 0.80 was demonstrated, where a positive non-invasive test may still occur, but sensitivity and specificity were sub-optimal. Clinical judgement was therefore advised for values in this range. The FAME studies then moved the FFR cut-off point to ≤0.80, with a view to predicting outcomes. The ≤0.80 cut-off point has been adopted into clinical practice guidelines, whereas the lower value of ≤0.75 is no longer widely used. Here, the authors discuss the data underpinning these cut-off values and the practical implications for their use when using FFR guidance in PCI.

Keywords Coronary physiology, fractional flow reserve, pressure wire Disclosure: SRM and TRK have received research support from Volcano Corporation. ASPS has received consultancy fees from Volcano Corporation. Acknowledgements: The authors would like to acknowledge the support of Mike Parker, Medical Statistician at the Postgraduate Medical Institute at Anglia Ruskin University, Chelmsford, UK. ASPS would like to acknowledge institutional support from the Gawthorn Cardiac Trust and the Exeter National Institute for Health Research Clinical Research Facility. Received: 13 January 2016 Accepted: 25 February 2016 Citation: Interventional Cardiology Review, 2016;11(1):17–26 DOI: 10.15420/icr.2016:7:2 Correspondence: Andrew SP Sharp, Consultant Cardiologist, Royal Devon and Exeter Hospital, Barrack Rd, Exeter, Devon EX2 5DW, UK. E: drandrewsharp@gmail.com

Fractional flow reserve (FFR) is an index used to describe the physiological significance of a coronary stenosis. It measures the pressure drop under conditions of maximal hyperaemia between the aorta and a selected vessel location distal to an angiographic lesion.1 Several FFR studies have identified patient groups in whom coronary stenting is associated with improved outcomes when compared with medical therapy (and vice versa). FFR-guided treatment prevents unnecessary stenting and therefore coronary physiology has been associated with improved outcomes at reduced cost, a rare combination in a new technology.2–7 Coronary physiological assessment is now an integral part of the modern catheterisation laboratory, with a level 1A recommendation by the European Society of Cardiology (ESC) for use in stable patients in whom evidence of ischaemia is not already available.8 Routine use of FFR, however, requires some understanding of the strengths and weaknesses of the technology, to best apply the results obtained from the individual patient on the catheter laboratory table.

Ischaemic Heart Disease and Coronary Revascularisation Angina is the clinical manifestation of myocardial ischaemia in patients with stable coronary artery disease (CAD). It is caused by transient imbalance between blood supply and metabolic demand.9 The myocardial ischemia that causes angina is, however, not simply a question of a ‘blocked pipe’; rather, ischaemia is a result of complex pathophysiological mechanisms that include obstructive epicardial CAD, inflammation, microvascular coronary dysfunction, endothelial dysfunction, thrombosis and angiogenesis (see Figure 1).10

Sharp_FINAL.indd 17

Obstructive epicardial CAD is only one of the factors that contributes to myocardial ischaemia and yet, in the treatment of ischaemic heart disease (IHD), great (some would say overwhelming) emphasis is given to identifying and eliminating obstructive epicardial CAD over other potential causes of ischaemia, some of which may have key therapeutic roles in treating patients with IHD. The reason for this emphasis is obvious – obstructive epicardial CAD is easily identified, easily understood and relatively easily treated by angiography and stenting or bypass grafting. Doing so, however, does not always relieve ischaemia.

Concept and Validation of Fractional Flow Reserve When FFR is used to identify a potentially ischaemia-causing lesion, the aim is to identify deficient blood flow distal to a coronary lesion. However, unlike coronary pressure, measurement of coronary blood flow in the catheter laboratory is not technically straightforward. Given the theoretical linear correlation between pressure and flow under conditions of minimal, constant coronary microvascular resistance, the pressure traces that we acquire with a standard coronary pressure wire are used to estimate blood flow; pressure wires do not directly measure blood flow. This theoretical linear relationship between blood pressure and flow is achieved by inducing maximum hyperaemia in the distal bed through pharmacological means, which lowers microvascular resistance, rendering it of minimal significance within the equation governing the relationship between blood pressure and flow within a closed fluid-filled system.11

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Coronary Figure 1: Myocardial Ischaemia is a Result of a Complex Multifactorial Pathophysiological Mechanism Microvascular coronary dysfunction

Obstructive epicardial CAD

Endothelial dysfunction

Myocardial ischaemia

Inflammation

Thrombosis

Angiogenesis

CAD = coronary artery disease.

Figure 2: Summary of the DEFER Study Design

Patients scheduled for elective PCI with single-vessel CAD, stenosis ≥50 % in a native coronary artery, without proof of lschaemia (n=325)

Randomisation

Exclusion criteria: 1. Total occlusion of the target artery 2. Acute Q-wave infarction 3. Unstable angina 4. Small-sized target artery (<2.5 mm)

Performance of PCI n=158

Deferral of PCI n=167

FFR ≥0.75 n=91

FFR <0.75 n=76

FFR <0.75 n=68

FFR ≥0.75 n=90

No PCI

PCI

Defer group

Reference group

Perform group

Follow-up CAD = coronary artery disease; FFR = fractional flow reserve; PCI = percutaneous coronary intervention. Source: Pijls, et al. 2007.

Since the initial development of the tool, FFR has been comprehensively validated as an invasive physiological index of ischaemia against other non-invasive modalities, including positron emission tomography, dobutamine stress echocardiogram and exercise stress testing (see Table 1).12–16 Furthermore, FFR values have been demonstrated to improve and non-invasive evidence of ischaemia resolve after revascularisation. The initial equation for FFR measurement (FFR=mean distal coronary pressure minus mean central venous pressure divided by mean aortic pressure minus central venous pressure [Pd–Pv/Pa–Pv] measured during stable, steady-state hyperaemia) incorporated central venous pressure values, as right atrial pressure impacted on the transmyocardial pressure gradient across a coronary artery; however, in order to simplify measurement,3–7 outcome studies removed the central venous pressure from the equation, leaving Pd/Pa, thus sacrificing theoretical fidelity to create a more accessible clinical tool. Outcome studies therefore used a version of the FFR equation that had already moved away from the theoretical physiological basis of its derivation, to improve adoption in the real world.

Sharp_FINAL.indd 18

FFR Cut-off Values There have been two proposed cut-off values for FFR, whereby treatment decisions are decided according to whether the result lies on one side of the cut-off value or another. An FFR value of ≤0.75 was first validated against a series of non-invasive tests and represented a value that predicted a positive non-invasive ischaemia test (see Table 1). Several independent studies have since demonstrated that FFR values between 0.67 and 0.75 accurately predict positive myocardial perfusion scintigraphy, exercise treadmill and stress echo results (see Table 1).17–27 Note that, as with all in vivo tests, variability was seen across the studies. One value for FFR did not consistently predict the same thing in different populations; nor did it consistently predict response again the same test. Some of these studies also incorporated right atrial pressure, whereas others did not; this introduces a source of variability that we no longer account for in the real world. Minor variability is expected with any in vivo tool, but it is a point of potential significance when one considers the importance of a ‘cut-off’ value in clinical decision making. What appeared consistent across several studies, was that values between 0.76 and 0.80 showed sub-optimal specificity for predicting non-invasive test results and these values were, therefore, labelled as being in the ‘grey zone’, whereby clinician judgement would be required to decide whether a lesion was ischaemia-producing, based on the broader clinical picture.17–27 Despite the obvious minor variability in the measurement and predictive performance of FFR in clinical studies, it is clear from these studies that using an FFR cut-off value of ≤0.75 has a good chance of identifying ischaemia in the vessel being examined.

Percutaneous Coronary Intervention of Functionally Non-significant Stenosis The DEFER study examined the outcomes of treating FFR-negative lesions with either stenting with percutaneous coronary intervention (PCI; Perform group) or PCI deferral (Defer group), on the basis of an FFR value of ≥0.75 (see Figure 2).3 Although the coronary interventional technologies deployed in this study were of a different era, the pattern appeared clear – stenting of lesions using PCI without a substantial pressure drop did not derive outcome benefits over 5 years of followup, and may have caused harm. Event-free survival at 5 years was 79 % in the Defer group and 73 % in the Perform group, confirming no advantage from PCI of non-flow-limiting lesions (P=0.52; see Table 2). A composite endpoint of death and MI favoured deferral in lesions with an FFR of ≥0.75. More recent data from Korea suggest that the use of drug-eluting stents do not change this concept; there appears to be little advantage to stenting vessels that do not exhibit a significant pressure drop.28

Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention In the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) studies, the prognostic significance of stenting was examined in patients with multi-vessel disease who were receiving optimal medical therapy, to establish whether FFR guidance could improve outcomes. Within these studies, the FAME investigators abolished the grey zone, creating a single FFR cut-off value for predicting outcome of ≤0.80. The logic behind this, is that in identifying a patient who has ischaemia (as defined by an FFR value that would predict a positive non-invasive test), there is a certain ‘cliff-edge’ phenomenon to this result; either the patient does or does not have

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Table 1: Studies Comparing FFR Against Non-invasive Tests Study

Year

Patients/lesions Clinical setting

Ischaemia test

(n/n)

Best FFR cut-off

Accuracy (%)

value

Intravenous adenosine infusion (140 μg/kg/min) Pijls, et al.15 Pijls, et

al.1

1995

60/60

SVD

EX-ECG

0.74

1996

45/45

SVD

EX-ECG, MPS, DSE

0.75

Jiminez-Navarro, et al.17

2001

21/21

SVD

DSE

0.75

Rieber, et al.18

2004

48/48

MVD

MPS, DSE

0.75

76–81

al.19

2005

47/47

MVD

MPS, DSE

0.75

Hacker, et al.20

2005

50/50

SVD

MPS

0.75

271/271

0.75

Erhard, et

Total or average (as applicable) Intracoronary adenosine bolus (maximum 40–60 μg) Tron, et al.21

1995

62/70

1, 2 and 3-VD

MPS

0.69

Bartunek, et al.22

1997

37/37

SVD

DSE

0.67

Caymaz, et al.23

2000

30/40

SVD

MPS

0.75

Fearon, et al.

2000

10/10

SVD

MPS

0.75

Chamuleau, et al.25

2001

127/61

MVD

MPS

0.74

Seo, et al.26

2002

25/25

Previous MI

MPS

0.75

Kruger, et al.

2005

42/42

ISR

MPS

0.75

Samady, et al.34

2006

48/48

Previous MI

MPS, DSE

0.78

2012

232/299

MVD

MPS

0.76

613/732

0.74

1995

60/60

SVD

EX-ECG, MPS

0.66

1996

75/75

SVD

DSE

0.75

2000

46/46

SVD

MPS

0.75

2001

57/57

Previous MI

MPS

0.78

2002

165/194

Previous MI

MPS

0.75

2004

55/55

Ostial

MPS, EX-ECG, DSE

0.75

2004

20/20

SVD

MPS

0.75

2005

147/155

Restenosis

MPS

0.75

2007

36/36

MVD

MPS

0.75

Total or average (as applicable)

661/698

0.74

Total or average (as applicable)

1,545/1,701

0.74

van de Hoef, et

al.61

Total or average (as applicable) Other methods of vasodilatation used to derive FFR De Bruyne, et al.14 (Intracoronary papaverine or adenosine) Bartunek, et al.35 (Intracoronary papaverine or adenosine) Abe, et al.62 (Intravenous ATP) De Bruyne, et

al.36

(Intravenous or intracoronary adenosine or intravenous ATP) Yanagisawa, et al.63 (Intracoronary papaverine) Ziaee, et al.37 (Intravenous or intracoronary adenosine) Morishima, et al.64 (Intracoronary papaverine) Kobori, et al.65 (Intracoronary papaverine) Ragosta, et al.38 (Intracoronary adenosine, 30–40 μg in the RCA, 80–100 μg in the LCA)

for all studies ATP = adenosine triphosphate; DSE = dobutamine stress echocardiogram; EX ECG = exercise electrocardiography; FFR = fractional flow reserve; ISR = in-stent restenosis; LCA = left coronary artery; MPS = myocardial perfusion scintigraphy; MVD = multivessel disease; NA = not applicable; RCA = right coronary artery; SVD = single-vessel disease; VD = vessel disease. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cardiology, van de Hoef, et al., 2013 (DOI: 10.1038/nrcardio.2013.86).66

ischaemia at that point. However, a value that lies within a few points of this proposed cut-off value, whether currently ischaemic or not, may still serve to identify a patient at risk of progressing to events in the next few years, although data have shown that the lower the FFR value, the more likely a lesion is to lead to a clinical event during the next 5 years.29 This concept was supported by findings from a recent observational study, further confirming the gradient of risk seen within

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FFR values, a gradient that appeared detectable even in those within the grey zone.30 The first FAME study examined patients with multi-vessel coronary artery disease referred for PCI and performed FFR in each lesion deemed to be more than 50 % diameter luminal stenosis by visual assessment (see Figure 3).4,31 Patients were then randomised to

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Coronary Table 2: Summary of Results From the DEFER Study Year

Patients (n)

Participants

Endpoint FFR cut-off Adenosine

Mean FFR

Treatment

Event-free

Primary

survival

endpoint 0.52

P value 2007

325 [comprising:

Stable angina

Event-free Defer if

IV (140 μg/kg/min)

Defer (n=91):

PCI/BMS

Defer group

181 with FFR ≥0.75

patients scheduled

survival

or IC (15 μg in

0.87±0.07

versus

(n=91) 79 %

randomised to PCI or

for PCI with

the RCA or

Perform (n=90):

FFR-guided

Perform group

Defer; 144 with FFR

single-vessel

20 μg in the LCA)

0.87±0.06

deferral

(n=90) 73 %

<0.75 allocated to

disease

FFR ≥0.75

Registry (n=144):

registry]

0.56±0.16

BMS = bare-metal stent; FFR = fractional flow reserve; IC = intracoronary; IV = intravenous; LCA = left coronary artery; PCI = percutaneous coronary intervention; RCA = right coronary artery. Source: Pijls, et al. 2007.

Table 3: Summary of Results From the FAME Study Year

Patients

Participants

Endpoints

(n)

FFR cut-off Adenosine

Mean FFR

Treatment

Endpoints

P value

value FFR-

Angio-

RR with

guided

FFR

group

guidance

13.2

18.3

0.72

(95 % CI) 2009

1,005

Stable angina

Death, MI

(or ACS if >5

or repeat

FFR ≤0.80

days post event) revascularisation

Central IV

Overall cohort:

Angio-guided

(140 μg/kg/

0.71 ±0.18

versus

min)

Ischaemic lesions:

FFR-guided

Multi-vessel

0.60±0.14

PCI (DES)

disease referred

Non-ischaemic

for PCI

lesions: 0.88±0.05

0.02

(0.54–0.96)

ACS = acute coronary syndrome; DES = drug-eluting stent; FAME = Fractional Flow Reserve versus Angiography for Multivessel Evaluation; FFR = fractional flow reserve; IV = intravenous; PCI = percutaneous coronary intervention. Source: Tonino, et al. 2009.

Figure 3: Summary of the FAME Study Design Patients with multivessel CAD. stenosis ≥50 % in at least two of the three major epicardial vessels, where investigator feels stenting is required

ldentification of aII lesions with stenosis ≥50 % for which stenting is planned

Randomisation

Angiography-guided PCI

Exclusion criteria: 1. Significant LMS disease 2. Previous CABG 3. Recent ST elevation Ml (< 5 days) 4. Recent non-ST elevation Ml (< 5 days) if the peak CK is >1000 IU 5. Cardiogenic shock 6. Extremely tortuous or calcified coronary vessels 7. Life expectancy <2 years 8. Pregnancy 9. Contraindication for DES placement

FFR-guided PCI

Measurements of FFR for all indicated stenoses Stent sited for all indicated stenoses

Stent sited for stenoses with FFR ≤0.80

1-year follow-up CABG = coronary artery bypass grafting; CAD = coronary artery disease; DES = drug-eluting stent; FFR = fractional flow reserve; LMS = left main stem; PCI = percutaneous coronary intervention. Sources: Tonino, et al. 2009; Fearon, et al. 2007.

either angiography-guided PCI, where the operator stented any lesion of >50 % severity that they deemed required PCI, or FFRguided PCI, where all lesions with an FFR ≤0.80 were treated, and the rest deferred. Better outcomes were demonstrated among the patients treated using FFR-guidance compared with those who received PCI on the basis of angiographic severity alone. The primary endpoint, a composite of death, MI and repeat revascularisation,

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occurred in 67 patients (13.2 %) in the FFR group and 91 patients (18.3 %) in the angiography group (RR 0.72; 95 % CI [0.54–0.96]; P=0.02; see Table 3).4

Having the COURAGE to Re-assert the Role of Percutaneous Coronary Intervention in Patients With Stable Angina The importance of the FAME-2 study has to be set into context of the field as it existed in 2007/2008. Following the publication of the COURAGE trial results in 2007, the role of PCI in stable angina was being openly questioned.32 Comparing the event rates in IHD populations, no difference was demonstrated between the group randomised to optimal medical therapy (OMT; with bailout PCI at the investigator’s discretion) versus those randomised to PCI using bare-metal stents. There are many important aspects of the COURAGE trial that are occasionally overlooked, which are relevant to the understanding of the importance of the FAME-2 study and the simple message that this study was then able to put forward. Importantly, in the COURAGE trial, bailout revascularisation was required in 32 % of the medical therapy group – a highly selected, low-to-medium cardiovascularrisk group of patients, randomised to receive intensive, personalised medical therapy. High rates of beta-blocker tolerance at 5 years were demonstrated in the group: 85 % in those receiving PCI plus OMT and 86 % in those receiving OMT alone (see Table 4).32 This 32 % bailout rate is not an inconsiderable failure rate for medical therapy as a primary strategy. Any mechanism that can identify these patients up front and lessen the need for bailout revascularisation would be desirable, especially in the real world, where patients tend to have lower rates of compliance with prescribed drugs.

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Table 4: Summary of Results From the COURAGE Trial Year

Patients (n)

Participants

Primary outcome

Assigned groups, Follow-up PCI (patients [n])

duration

Primary outcome Hazard

treatment

(events [n])

P value

ratio for PCI (95 % CI)

PCI + OMT

2007

2,287 of

Stable angina

Death from

1,149 (total

35,539

or objective evidence

any cause

patients

of ischaemia

Non-fatal MI

screened

or angina with coronary

OMT

OMT plus OMT plus

alone

routine

1,138

Median:

BMS

randomised)

4.6 years

(n=1.046)

1,077 (PCI

(IQR 3.3–5.7) (97 %)

attempted)

bailout

PCI

211

202

1.05

0.62

(0.87–1.27)

DES (n=31)

stenosis ≥80 %

(3 %)

BMS = bare-metal stent; DES = drug-eluting stent; IQR = interquartile range; MI = myocardial infarction; OMT = optimal medical therapy; PCI = percutaneous coronary intervention. Source: Boden, et al. 2007

The FAME-2 Study In the FAME-2 study, patients with IHD on optimal medical therapy underwent pressure wiring of all vessels with angiographically identifiable lesions.6 All pressure wire-positive patients (FFR≤0.80) were then randomised to PCI or OMT (see Figure 4). This study was stopped prematurely at a mean follow-up of 7 months due to a significant between-group difference in the incidence of the primary endpoint (4.3 % in the PCI-plus-OMT group versus 12.7 % in the OMT-alone group; hazard ratio [HR] with PCI 0.32; 95 % CI [0.19–0.53]; P<0.001; see Table 5). The primary superiority endpoint of this trial, a reduction in the rate of death, MI and urgent revascularisation, was met, principally through a reduction in the rate of urgent revascularisation. Urgent revascularisation was performed in 49 (11.1 %) patients in the OMT group versus seven (1.6 %) patients in the PCI group (HR with PCI 0.13; 95 % CI [0.06–0.30]; P<0.001; see Table 6). The strength of this particular endpoint is often discussed. Half of these patients (n=27 [48.2 %]) had blinded adjudication committee evidence of instability (increased troponin levels, ECG changes at rest) and therefore had clear evidence of a significant acute coronary problem. In 29 patients (51.8 %) who underwent urgent revascularisation, unstable angina was diagnosed based on clinical features with no evidence of ischaemic ECG changes or positive cardiac biomarkers (see Table 7).6 Excluding the patients without objective evidence of an acute problem, the difference between the PCI group (seven patients) and the difference in patients with unstable ECGs (read by a blinded committee) or increased troponin levels (27 patients) remains significant. (P<0.001; see Table 7).6 However, there were no significant differences between the PCI group and the OMT group with regards to rates of all-cause mortality (0.2 % versus 0.7 %, respectively; P=0.31) and MI (3.4 % versus 3.2 %, respectively; P=0.89; see Table 6). The FAME-2 study is sometimes criticised for stopping early and for the nature of the events that drove the primary endpoint. This point of view does not take account of the statistical realities of a trial looking at outcomes for stable IHD in the modern era, where ethics requires exclusion of those patients at the highest risk from their coronary disease. Because of the low likelihood of death or MI in a chronic, low- to medium-risk stable heart disease population in the modern era, the FAME-2 primary endpoint was going to be

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Figure 4: Summary of the FAME-2 Study Design. Stable patients with multi-vessel IHD, scheduled for one-, two- or three-vessel DES stenting

FFR in all indicated stenoses

There is at least one stenosis with FFR ≤0.80

There is no stenosis with FFR ≤0.80

1 : 1 Randomisation

PCI + OMT

OMT

Cohort A

OMT

Cohort B

Follow-up after 1 and 6 months, and 1, 2, 3, 4 and 5 years DES = drug-eluting stent; FFR = fractional flow reserve; IHD = ischaemic heart disease; OMT = optimal medical therapy; PCI = percutaneous coronary intervention. Source: De Bruyne, et al. 2012.

driven by the rate of unplanned revascularisation regardless of the number of randomised patients. Without a more than five-fold increase in the sample size, which would have no doubt rendered the trial financially impossible to perform, there is no way this study could have predicted death. To illustrate this fact, there were only four deaths in the trial (one in the PCI group and three in the OMT group) at the time point when the trial was stopped, having identified that the primary endpoint had been met and that this fact was highly unlikely to change. These very low death rates emphasise that in the modern era of OMT no technology would be able to predict death in low- to medium-risk patients without conducting a large trial, only to demonstrate a small actual difference in death rates. If we exclude those with high mortality risk (such as ongoing class IV angina, poor left ventricular function, left main stenosis, ‘surgical disease’, etc), we will find it hard to predict death. We examined the study protocol and the clinical events in the primary endpoint report from the FAME-2 study.7 The 2-year study results reported six versus eight deaths and 26 versus 30 MI events

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Coronary Table 5: Summary of Results From the FAME-2 Study Year

Patients Participants

Endpoints

(n)

FFR cut-

Adenosine

Mean FFR

Treatment Follow-up

off value

Endpoints

PCI + 2012

888 out

Stable angina

of 1,220 enrolled

Death, MI,

FFR ≤0.80

Standard

In lesions with FFR FFR-guided

213±128 days

ACS (if >5 days repeat

practice

≤0.80: 0.64±0.13

(PCI + OMT)

post event),

revascularisation

P value

duration

PCI (DES) +

(IV (140 μg/kg/ (range 0.19–0.80)

OMT versus 214±127 days

Patients

min) or

FFR-guided PCI

OMT alone

considered

IC (50 μg)

+ OMT group:

206±119 days

0.68±0.10

(Registry group)

for PCI

OMT

OMT (%)

only (%)

4.3

12.7

<0.001

8.1 %

19.5 %

<0.001

(OMT)

OMT alone: 0.68±0.15 2014* As above As above

As above

2 years

ACS = acute coronary syndrome; DES = drug-eluting stent; FAME = Fractional Flow Reserve versus Angiography for Multivessel Evaluation; FFR = fractional flow reserve; IC = intracoronary; IV = intravenous; OMT = optimal medical therapy; PCI = percutaneous coronary intervention. Sources: De Bruyne, et al. 2012; 2014. *Primary endpoint of the FAME-2 study.

Table 6: Clinical Events in the FAME-2 Study Events

Randomly assigned groups

Table 7: Sub-group Analysis of Patients who Underwent Urgent Revascularisation in the FAME-2 Study P value Registry

n (%)

Primary endpoint

cohort

Patients

(n=166)

(n [%])

(n=447)

alone

with PCI

PCI + OMT OMT alone Hazard ratio

(n=441)

(95 % CI)

(n=447)

(n=441)

with PCI

56 (12.7)

0.32 (0.19–0.53)

7 (1.6)

49 (11.1)

0.13

19 (4.3)

<0.001

5 (3.0)

1 (0.2)

3 (0.7)

0.33 (0.03–3.17)

0.31

cause MI

15 (3.4)

14 (3.2)

1.05 (0.51–2.19)

0.89

3 (1.8)

Urgent

7 (1.6)

49 (11.1)

0.13 (0.06–0.30)

<0.001

4 (2.4)

revascularisation 0.22

3 (1.8)

P value

(n [%])

Hazard ratio

Components of primary endpoint Death from any

Randomly assigned groups

PCI + OMT OMT

(95 % CI) Total

56 (100)

<0.001

(0.06–0.30) MI

12 (21.4)

Unstable angina +

15 (26.8)

4 (0.9)

23 (5.2)

<0.001

(0.04–0.43)

ischaemia on ECG Unstable angina

0.13

29 (51.8)

–

diagnosed based

Death or MI

15 (3.4)

17 (3.9)

0.61 (0.28–1.35)

Cardiac death

1 (0.2)

0.96 (0.06–15.17) 0.98

Any

14 (3.1)

86 (19.5)

0.14 (0.08–0.26)

<0.001

6 (3.6)

Non-urgent

7 (1.6)

38 (8.6)

0.17 (0.08–0.39)

<0.001

2 (1.2)

Summary of Fractional Flow Reserve Cut-off Values Used in Studies to Date

1 (0.2)

2 (0.5)

0.49 (0.04–5.50)

0.56

1 (0.6)

Definite/probable 5 (1.1)

1 (0.2)

4.98 (0.59–42.25) 0.10

1 (0.6)

We have several previously proposed FFR cut-off values, each of which has been validated in selected patient populations. A cut-off of ≤0.75 has been shown to predict a positive non-invasive test with good accuracy. It has also been shown that, if one performs PCI on a patient with an FFR of ≥0.75, one is not likely to reduce the rate of death/MI (see Table 2). A cut-off value of ≤0.80 has also been shown to predict outcomes following PCI in stable disease populations with multi-vessel disease and to further improve clinical outcomes in patients on OMT.4,6

Revascularisation

revascularisation Stroke stent thrombosis FAME = Fractional Flow Reserve versus Angiography for Multivessel Evaluation; OMT = optimal medical therapy; PCI = percutaneous coronary intervention. Source: De Bruyne, et al. 2012.

observed between the two groups. By comparing two proportions,33 we calculated the predicted sample sizes necessary to show a difference between death and MI at 2 years, when the study was originally due to report. These sample sizes were: death or MI (n=7,828), MI (n=19,486) and death (n=22,748; see Figure 5). Clearly, the sample size needed to show a difference in death/MI would have been huge and not easily possible to achieve given the cost of catheter laboratory-based trials. While the sample size for MI might be expected to fall if we take into account the different nature of MI within PCI trials (peri-procedural versus spontaneous), the sample size required would be still have to be significantly larger than that of FAME-2 study if we wanted to examine death/MI as a powered endpoint. The alternative would be a longer period of follow-up, which presumes that events will separate between the two groups after 1 year.

Sharp_FINAL.indd 22

on clinical features ECG = electrocardiogram; FAME = Fractional Flow Reserve versus Angiography for Multivessel Evaluation; MI = myocardial infarction. OMT = optimal medical therapy; PCI = percutaneous coronary intervention. Source: De Bruyne, et al. 2012.

These cut-off values are clear and send a simple message to operators – that physiological guidance can help us make treatment decisions on our patients. If cut-off values are to be helpful, on a perpatient level; howeverwe need to know of any potential downsides of basing our treatment decisions on FFR results.

Potential Downsides of a Binary Cut-off Value in FFR The clarity of the existing cut-off values for FFR helps make pressure wire technology accessible and easy to use, but questions remain regarding how to interpret these data. In order for a cut-off to have statistical and clinical power, it must clearly demarcate a difference

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between those above that value and those below. It must be robust, reproducible and have low false-positive and false-negative rates. After all, a binary cut-off means that if the result is 0.81, the test tells us not to perform PCI. If the result is 0.80, the test tells us to proceed. This approach may apply to particular populations, but what about the single patient in front of us? Is FFR robust enough as a test to reliably do this? Furthermore, and perhaps most importantly, are we applying our use of FFR to the same types of patients as were recruited to the key trials described above, who have been shown to benefit from this approach as a group?

Figure 5: An Illustration of How Many Patients Would Have Been Required in the FAME-2 Study to Show Difference in Rates of Death and/or MI

22,748

19,486

7,828

Routes and Doses of Adenosine Administration During the initial FFR validation work against non-invasive ischaemia tests, two routes of administration were used to establish cut-off values – intravenous adenosine and intracoronary adenosine.1,14,15,17–27,34–38 The adenosine doses that had diagnostic ability to identify ischaemiaproducing lesions against non-invasive tests were 140 μg/kg/min and up to maximum of 40–60 μg for intravenous administration of adenosine and intracoronary adenosine, respectively (see Table 1). In DEFER and FAME-2 studies, operators used either intravenous or intracoronary adenosine, whereas in the first FAME study, central intravenous adenosine administration (see Tables 2, 3 and 5) was used.3,4,6,7 It is important to note that higher doses of adenosine have not been validated in clinical outcome studies and increasing the adenosine dose may alter the treatment threshold by lowering systemic blood pressure and altering the ratio between Pd and Pa (as opposed to altering the ratio by lowering peripheral microvascular resistance). The agreement between intravenous and intracoronary adenosine is generally good at recommended doses.39,40 However, the chances of securing the same dichotomous treatment recommendation by each method of adenosine administration falls to 78 % at FFR values of approximately 0.8041 and there is a hyperaemic dose–response relationship seen with intracoronary doses of >60 μg.42 The route of adenosine administration differs from centre to centre,43 and while FFR measurement with central administration of intravenous adenosine is considered the gold standard, in the era of transradial PCI, intracoronary or peripheral intravenous administration of adenosine is more practical, although this does give similar FFR results to centrally administered adenosine.44,45

Broader FFR Limitations FFR has several other limitations. Identification of a functionally significant coronary stenosis by FFR may be obscured by the magnitude of residual coronary microvascular resistance during hyperaemia. This can occur in the presence of high left ventricular end-diastolic pressure and/or diseases which particularly affect the microvasculature.46 Decisions based on FFR cut-off values (e.g. defer/ perform based on FFR ≤0.80) have also been shown to change once right atrial pressure is incorporated into the FFR calculation.47 Variable haemodynamic responses can also confound measurement, particularly when adenosine infusions are administered centrally48 and recorded measurements can vary according to differing operator/FFR console interpretations of minimum Pd/Pa during the hyperaemic response.49,50 Furthermore, functional significance of a stenosis may be overestimated where the vessel in question gives off important collaterals to a chronic total occlusion (CTO) vascular territory, and often normalised in a donor vessel with moderate stenosis following

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Sharp_FINAL.indd 23

1,632

Sample size for death Sample size for MI Sample size for death or MI Protocol sample size

Sample sizes calculated from the FAME-2 study to detect differences in rates of clinical events. FAME = Fractional Flow Reserve versus Angiography for Multivessel Evaluation. MI = myocardial infarction. Source: De Bruyne, et al. 2014.

successful CTO PCI.51 Recanalisation of a CTO was also shown to result in a modest increase in the FFR of the predominant collateral donor vessel and was associated with a reduction in donor vessel coronary flow. As expected, a larger increase in FFR is associated with greater coronary stenosis in donor artery severity.52 These everyday factors can reclassify lesion significance where values fall near a cut-off value and may result in inappropriate treatment decisions if operators make their decisions based solely on a cut-off value.

Which Patients had Events in the Studies to Date? Were They Clustered Around the Cut-off Value? Johnson et al. showed within a large, patient-level meta-analysis of multiple FFR trials that FFR values of <0.67 most clearly identified those at risk of MI or death.18 In fact, the mean FFR values obtained from ischaemic vessels in the DEFER, FAME and FAME-2 studies were 0.56±0.16, 0.60±0.14 and 0.68±0.10, respectively (see Tables 2, 3 and 5),3,4,6,7 which are more severe than the results we see when we use pressure wire technology in routine clinical practice to assess an intermediate stenosis of uncertain significance. Operators have frequently considered tight lesions to be more at risk of events and would not look for another test when treating such patients who have clear symptoms of angina. The available FFR trial data support that concept.

What do Existing FFR Cut-off Values Tell us About Intermediate Stenoses? Importantly, no randomised FFR study to date has examined a cohort of angiographically intermediate lesions, where the use off FFR has been tested in the scenario of treatment uncertainty (Tables 2, 3 and 5). Despite this, many operators use FFR to assess these patients in the real world. This observation has obvious importance, as the further a value is away from a cut-off point (strongly ischaemic versus trivial obstruction), the stronger it becomes at predicting outcomes when dichotomised to PCI performance/deferral. Intermediate stenoses, however, tend to have intermediate FFR values that cluster around the cut-off point. The average FFR value in the ADVISE (Adenosine Vasodilator Independent Stenosis Evaluation) registry of intermediate coronary lesions was 0.81.53

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Coronary Figure 6: Schematic Diagram Illustrating Coronary Physiology Measurement Zones

Epicardial artery

Microvasculature

associated with a significantly increased rate of major adverse cardiac events throughout 10 years of follow-up, regardless of the FFR cut-off applied. CFR has demonstrated abnormal flow, which is a marker of adverse outcomes and in this case, FFR has not been able to identify this finding using pressure alone. In contrast, an abnormal FFR with a normal CFR was associated with equivalent clinical outcomes when compared with normal results of both parameters; this can be explained by the fact that abnormal blood flow is one of the principal drivers of ischaemia and therefore outcomes.56

Who in Particular Might Have ‘False Positive’ Results, Whereby the FFR Value is <0.80, but who Have Good Blood Flow and low Risk? FFR

IMR

CFR

CFR = coronary flow reserve; FFR = fractional flow reserve; IMR = index of microvascular resistance.

The Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) and Evaluation of iFR vs FFR in Stable Angina or Acute Coronary Syndrome (iFR Swedeheart) studies, expected to report results in late 2016/early 2017, will be the first major studies to report outcomes with FFR and instantaneous wave-free ratio (iFR) in a large (n=4,500) population of angiographically intermediate lesions.54,55 These studies will provide us with the definitive assessment of the ability of an FFR cut-off value of ≤0.80 and an iFR cut-off value of <0.90 to predict outcomes in intermediate lesions and establish whether the two modalities have similar predictive powers for future events.

If we get an FFR Value of 0.81 in an Angiographically Intermediate Stenosis, Could This Still be an Ischaemia-causing Lesion? The degree of blood pressure drop across a lesion is related to the absolute flow rate across that lesion. The whole point of FFR is for an intracoronary pressure gradient to tell us what intracoronary blood flow is doing; however, in low-flow situations, a pressure drop may be underestimated and in high-flow situations, a pressure drop may overestimate the degree of obstruction.56 High blood flow creates greater friction and separation losses, causing a pressure drop, whereas low flow does the opposite, minimising observed pressure loss.57 Using Doppler-derived flow measurements, such as coronary flow velocity reserve (CFR) and the index of microcirculatory resistance, can help to identify such cases, but these techniques are time consuming and not widely available outside of a research setting (see Figure 6). Treatment recommendation discordance (perform PCI versus deferral) between dichotomised findings derived from FFR and CFR has been reported in up to 30–40 % of coronary stenoses.58,59 Van de Hoef et al. studied 157 intermediate coronary stenoses evaluated by FFR and CFR in which revascularisation was deferred and followed-up for 11.7 years.56 Discordance between the FFR and CFR treatment recommendation occurred in 31 % and 37 % of stenoses at the 0.75 and 0.80 FFR cut-off values, respectively, and was explained by the degree of microvascular resistance during basal and hyperaemic conditions. Compared with concordant normal (‘defer’) dichotomised results of FFR and CFR, a ‘normal’ FFR with an abnormal CFR was

Sharp_FINAL.indd 24

Patients with healthy microvasculature but focal epicardial lesions can exhibit a large pressure drop across a stenosis upon introduction of adenosine. CFR studies in these patients show that the microvasculature is able to dilate such that blood flow can sometimes be increased more than three-fold across these stenoses. Of course, if a patient is able to mount a substantial increase in blood flow across an epicardial stenosis, the stenosis is not ‘flow limiting’ and is therefore unlikely to benefit from PCI as far as symtoms are concerned. Unfortunately, such patients tend to be young and have a longer lifespan to reflect on the worth of a possibly unnecessary stent procedure.

What Happens When we Dichotomise Continuous Data? Cut-off values are artificial constructs designed to assist us in clinical decision making. However, by their nature they are conceived by analysis of groups of patients, rather than the potentially variable individual on one’s catheter laboratory table. FFR reproducibility data from the DEFER study were analysed to see the effects of FFR measurement variability on FFR-guided treatment strategy.60 This analysis showed that outside the FFR range of 0.75–0.85, classification certainty (PCI performance versus deferral) from a single FFR result is >95 %. However, closer to its cut-off value, certainty falls to <80 % within the range of 0.77–0.83; reaching a nadir of 50 % at the precisely defined cut-off point of 0.80. In clinical practice, this means that each time a single FFR value falls between the range of 0.75–0.85, there is a chance that the FFR-derived dichotomous revascularisation recommendation will change if the measurement is repeated 10 minutes later, with a 0.80 result shown to be as repeatable as a coin toss.60 This is not a limitation of FFR; rather, this is a limitation of any measured clinical variable where so many physiological factors input into the result. The consequences for the operator, however, are obvious. If we transfer all of our clinical judgement onto a single dichotomous variable, we will sometimes get a variable answer. For a group of patients, if we subjugate our judgement to the test, we will be right considerably more often than we are wrong, whether we are looking for ischaemia or prognosis in those patients. However, this is of little comfort to the patient whose result leads to ‘treat’, when they could have been deferred, and vice versa. Fortunately, however, therefore, there remains a role for clinician judgement in the interpretation of all available variables, be they clinical, angiographic or physiological. Operators are encouraged to bear these points in mind when they use FFR, which in our view should be seen as a generally faithful servant, rather than a rigid, incontrovertible master.

Conclusion FFR is now a staple tool in the modern catheter laboratory. Like all tests of a human physiological parameter, it has both strengths and

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FFR Cut-off Value

limitations. The data on which FFR has been validated come from specific sub-groups of angiographic populations and has not yet been categorically proven in all populations. In particular, it has not yet been tested in intermediate lesions within outcome studies, although such studies are ongoing. We should therefore use the information provided by FFR as part of a broader view of our patient. FFR cut-off values are a summation of what these studies tells us and are extremely useful in making what could be a complex tool simple and accessible to all interventional cardiologists. However,

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Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334 :1703–8. PMID: 8637515. Bech GJW, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001;103 :2928–34. PMID: 11413082. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49 :2105–11. PMID: 17531660. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360 :213–24. DOI: 10.1056/NEJMoa0807611; PMID: 19144937. Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. Circulation 2010;122 :2545–50. DOI: 10.1161/ CIRCULATIONAHA.109.925396; PMID: 21126973. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367 :991–1001. DOI: 10.1056/ NEJMoa1205361; PMID: 22924638. De Bruyne B, Fearon WF, Pijls NH, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014;371 :1208–17. DOI: 10.1056/NEJMoa1408758; PMID: 25176289. Authors/Task Force members, Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35 :2541–619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339. Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34 :2949–3003. DOI: 10.1093/ eurheartj/eht296; PMID: 23996286. Marzilli M, Merz CN, Boden WE, et al. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol 2012;60 :951–6. DOI: 10.1016/j.jacc.2012.02.082; PMID: 22954239. Pijls NH, van Son JA, Kirkeeide RL, et al. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before and after percutaneous transluminal coronary angioplasty. Circulation 1993;87 :1354– 67. PMID: 8462157. De Bruyne B, Baudhuin T, Melin JA, et al. Coronary flow reserve calculated from pressure measurements in humans. Validation with positron emission tomography. Circulation 1994;89 :1013–22. PMID: 8124786. De Bruyne B, Paulus WJ, Pijls NHJ. Rationale and application of coronary transstenotic pressure gradient measurements. Cathet Cardiovasc Diagn 1994;33 :250–61. PMID: 7874721. De Bruyne B, Bartunek J, Sys SU, Heyndrickx GR. Relation between myocardial fractional flow reserve calculated from coronary pressure measurements and exercise-induced myocardial ischemia. Circulation 1995;92:39–46. PMID: 7788914. Pijls NHJ, Van Gelder B, Van der Voort P, et al. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92 :3183–93. PMID: 7586302. Pijls NHJ, Willem Bech GJ, El Gamal MIH, et al. Quantification of recruitable coronary collateral blood flow in conscious humans and its potential to predict future ischemic events. J Am Coll Cardiol 1995;25 :1522–8. PMID: 7759702. Jimenez-Navarro M, Alonso-Briales JH, Hernandez Garcia MJ, et al. Measurement of fractional flow reserve to assess moderately severe coronary lesions: correlation with dobutamine stress echocardiography. J Interv Cardiol 2001;14 :499–504. PMID: 12053641. Rieber J, Jung P, Erhard I, et al. Comparison of pressure measurement, dobutamine contrast stress echocardiography

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21.

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23.

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25.

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31.

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33.

34.

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the value derived is not absolute and the dichotomous partition of a naturally variable physiologically parameter reduces the power of the information received. The lower the FFR, the more potent the predictive power for outcomes and operators should be cognisant of this finding. Basic principles tell us that a policy of simplistic absolutism is rarely in the interests of our patients and FFR is no different in that respect. We recommend widespread adoption of FFR in all modern catheter laboratories, but recommend it as an adjunct to clinical decision making, not a replacement for it, as no tool purporting to measure a human physiological parameter is perfect. n

and SPECT for the evaluation of intermediate coronary stenoses. The COMPRESS trial. Int J Cardiovasc Interv 2004;6 :142–7. PMID: 16146908. Erhard I, Rieber J, Jung P, et al. The validation of fractional flow reserve in patients with coronary multivessel disease: a comparison with SPECT and contrast-enhanced dobutamine stress echocardiography. Z Kardiol 2005;94 :321–7. PMID: 15868360. Hacker M, Rieber J, Schmid R, et al. Comparison of Tc-99m sestamibi SPECT with fractional flow reserve in patients with intermediate coronary artery stenoses. J Nucl Cardiol 2005;12 :645–54. PMID: 16344226. Tron C, Donohue TJ, Bach RG, et al. Comparison of pressurederived fractional flow reserve with poststenotic coronary flow velocity reserve for prediction of stress myocardial perfusion imaging results. Am Heart J 1995;130 :723–33. PMID: 7572579. Bartunek J, Van Schuerbeeck E, de Bruyne B. Comparison of exercise electrocardiography and dobutamine echocardiography with invasively assessed myocardial fractional flow reserve in evaluation of severity of coronary arterial narrowing. Am J Cardiol 1997;79 :478–81. PMID: 9052353. Caymaz O, Fak AS, Tezcan H, et al. Correlation of myocardial fractional flow reserve with thallium-201 SPECT imaging in intermediate-severity coronary artery lesions. J Invasive Cardiol 2000;12 :345–50. PMID: 10904440. Fearon WF, Takagi A, Jeremias A, et al. Use of fractional myocardial flow reserve to assess the functional significance of intermediate coronary stenoses. Am J Cardiol 2000;86 :1013– 4, A10. PMID: 11053717. Chamuleau SA, Meuwissen M, van Eck-Smit BL, et al. Fractional flow reserve, absolute and relative coronary blood flow velocity reserve in relation to the results of technetium-99m sestamibi single-photon emission computed tomography in patients with two-vessel coronary artery disease. J Am Coll Cardiol 2001;37 :1316–22. PMID: 11300441. Seo JK, Kwan J, Suh JH, et al. Early dipyridamole stress myocardial SPECT to detect residual stenosis of infarct related artery: comparison with coronary angiography and fractional flow reserve. Korean J Intern Med 2002;17 :7–13. PMID: 12014218. Kruger S, Koch KC, Kaumanns I, et al. Use of fractional flow reserve versus stress perfusion scintigraphy in stent restenosis. Eur J Intern Med 2005;16 :429–31. PMID: 16198903. Park SH, Jeon KH, Lee JM, et al. Long-term clinical outcomes of fractional flow reserve-guided versus routine drug-eluting stent implantation in patients with intermediate coronary stenosis: five-year clinical outcomes of DEFER-DES trial. Circ Cardiovasc Interv 2015;8. pii: e002442. DOI: 10.1161/ CIRCINTERVENTIONS.115.002442; PMID: 26643736. Johnson NP, Toth GG, Lai D, et al. Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes. J Am Coll Cardiol 2014;64 :1641–54. DOI: 10.1016/j. jacc.2014.07.973; PMID: 25323250. Adjedj J, De Bruyne B, Floré V, et al. Significance of intermediate values of fractional flow reserve in patients with coronary artery disease. Circulation 2016;133 :502–8. DOI: 10.1161/CIRCULATIONAHA.115.018747; PMID: 26733607. Fearon WF, Tonino PA, De Bruyne B, Siebert U, et al. Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study. Am Heart J 2007;154 :632–6. PMID: 17892983. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356 :1503–16. PMID: 17387127. Casagrande JT, Pike MC. An improved approximate formula for calculating sample sizes for comparing two binomial distributions. Biometrics 1978;34 :483–6. PMID: 719125. Samady H, Lepper W, Powers ER, et al. Fractional flow reserve of infarct-related arteries identifies reversible defects on noninvasive myocardial perfusion imaging early after myocardial infarction. J Am Coll Cardiol 2006;47 :2187–93. PMID: 16750683. Bartunek J, Marwick TH, Rodrigues ACT, et al. Dobutamineinduced wall motion abnormalities: Correlations with myocardial fractional flow reserve and quantitative coronary angiography. J Am Coll Cardiol 1996;27 :1429–36. PMID: 8626954. De Bruyne B, Pijls NH, Bartunek J, et al. Fractional flow reserve in patients with prior myocardial infarction. Circulation

2001;104 :157–62. PMID: 11447079. 37. Ziaee A, Parham WA, Herrmann SC, et al. Lack of relation between imaging and physiology in ostial coronary artery narrowings. Am J Cardio l 2004;93 :1404–7, A9. PMID: 15165925. 38. Ragosta M, Bishop AH, Lipson LC, W et al. Comparison between angiography and fractional flow reserve versus single-photon emission computed tomographic myocardial perfusion imaging for determining lesion significance in patients with multivessel coronary disease. Am J Cardiol 2007;99 :896–902. PMID: 17398179. 39. Schlundt C, Bietau C, Klinghammer L, et al. Comparison of intracoronary versus intravenous administration of adenosine for measurement of coronary fractional flow reserve. Circ Cardiovasc Interv 2015;8 . pii: e001781. DOI: 10.1161/ CIRCINTERVENTIONS.114.001781; PMID: 25908694. 40. Jeremias A, Whitbourn RJ, Filardo SD, et al. Adequacy of intracoronary versus intravenous adenosine-induced maximal coronary hyperemia for fractional flow reserve measurements. Am Heart J 2000;140 :651–7. PMID: 11011341. 41. Lim W, Koo B, Nam C, et al. Variability of fractional flow reserve according to the methods of hyperemia induction. Catheter Cardiovasc Interv 2015;85 :970–6. DOI: 10.1002/ ccd.25752; PMID: 25413590. 42. Casella G, Leibig M, Schiele TM, et al. Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve? Am Heart J 2004;148 :590–5. PMID: 15459587. 43. Tebaldi M, Biscaglia S, Pecoraro A, et al. Fractional flow reserve implementation in daily clinical practice: A European survey. Int J Cardiol 2016;207 :206–7. DOI: 10.1016/j. ijcard.2016.01.097; PMID: 26803245. 44. Scott P, Sirker A, Dworakowski R, et al. Fractional flow reserve in the transradial era: will hand vein adenosine infusion suffice?: A comparative study of the extent, rapidity, and stability of hyperemia from hand and femoral venous routes of adenosine administration. JACC Cardiovasc Interv 2015;8 :527–35. DOI: 10.1016/j.jcin.2014.10.027; PMID: 25819188. 45. Seo MK, Koo BK, Kim JH, et al. Comparison of hyperemic efficacy between central and peripheral venous adenosine infusion for fractional flow reserve measurement. Circ Cardiovasc Interv 2012;5 :401–5. DOI: 10.1161/ CIRCINTERVENTIONS.111.965392; PMID: 22647519. 46. Leonardi RA, Townsend JC, Patel CA, et al. Left ventricular end-diastolic pressure affects measurement of fractional flow reserve. Cardiovasc Revasc Med 2013;14 :218–22. DOI: 10.1016/j. carrev.2013.06.001; PMID: 23886870. 47. Layland J, Wilson AM, Whitbourn RJ, et al. Impact of right atrial pressure on decision-making using fractional flow reserve (FFR) in elective percutaneous intervention. Int J Cardiol 2013;167 :951–3. DOI: 10.1016/j.ijcard.2012.03.087; PMID: 22475843. 48. Tarkin JM, Nijjer S, Sen S, et al. Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study. Circ Cardiovasc Interv 2013;6 :654–61. DOI: 10.1161/CIRCINTERVENTIONS.113.000591; PMID: 24254709. 49. Echavarria-Pinto M, Petraco R, van de Hoef TP, et al. Fractional flow reserve and minimum Pd/Pa ratio during intravenous adenosine infusion: very similar but not always the same. EuroIntervention 2016;11 :1013–9. DOI: 10.4244/ EIJY14M10_09; PMID: 25366652. 50. Kern MJ, Seto AH. Selecting the right fractional flow reserve in an unsteady state: keep it simple. JACC Cardiovasc Interv 2015;8 :1028–30. DOI: 10.1016/j.jcin.2015.02.019; PMID: 26205442. 51. Sachdeva R, Agrawal M, Flynn SE, et al. Reversal of ischemia of donor artery myocardium after recanalization of a chronic total occlusion. Catheter Cardiovasc Interv 2013;82 :E453–8. DOI: 10.1002/ccd.25031; PMID: 23703834. 52. Ladwiniec A, Cunnington MS, Rossington J, et al. Collateral donor artery physiology and the influence of a chronic total occlusion on fractional flow reserve. Circ Cardiovasc Interv 2015;8 . pii: e002219. DOI: 10.1161/ CIRCINTERVENTIONS.114.002219; PMID: 25805570. 53. Petraco R, Escaned J, Sen S, et al. Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry. EuroIntervention 2013;9 :91–101. DOI: 10.4244/EIJV9I1A14; PMID: 22917666.

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Coronary 54. Imperial College London. Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation. (DEFINEFLAIR). Available at: https://clinicaltrials.gov/ct2/show/ NCT02053038 (accessed 2 March 2016). 55. Gotberg M, Christiansen EH, Gudmundsdottir I, et al. Instantaneous Wave-Free Ratio versus Fractional Flow Reserve guided intervention (iFR-SWEDEHEART): Rationale and design of a multicenter, prospective, registry-based randomized clinical trial. Am Heart J 2015;170 :945–50. DOI: 10.1016/j.ahj.2015.07.031; PMID: 26542503. 56. van de Hoef TP, van Lavieren MA, Damman P, et al. Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. Circ Cardiovasc Interv 2014;7 :301–11. DOI: 10.1161/ CIRCINTERVENTIONS.113.001049; PMID: 24782198. 57. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis. Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33 :87–94. PMID: 4808557.

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58. Meuwissen M, Siebes M, Chamuleau SAJ, et al. Hyperemic stenosis resistance index for evaluation of functional coronary lesion severity. Circulation 2002;106 :441–6. PMID: 12135943. 59. Meuwissen M, Chamuleau SA, Siebes M, et al. The prognostic value of combined intracoronary pressure and blood flow velocity measurements after deferral of percutaneous coronary intervention. Catheter Cardiovasc Interv 2008;71 :291– 7. DOI: 10.1002/ccd.21331; PMID: 18288725. 60. Petraco R, Sen S, Nijjer S, et al. Fractional flow reserve–guided revascularization: practical implications of a diagnostic gray zone and measurement variability on clinical decisions. JACC Cardiovasc Interv 2013;6 :222–5. DOI: 10.1016/j.jcin.2012.10.014; PMID: 23517831. 61. van de Hoef TP, Nolte F, Damman P, et al. Diagnostic accuracy of combined intracoronary pressure and flow velocity information during baseline conditions: adenosine-free assessment of functional coronary lesion severity. Circ Cardiovasc Interv 2012;5 :508–14. DOI: 10.1161/ CIRCINTERVENTIONS.111.965707; PMID: 22787017. 62. Abe M, Tomiyama H, Yoshida H, Doba N. Diastolic fractional

63.

64.

65.

66.

flow reserve to assess the functional severity of moderate coronary artery stenoses: comparison with fractional flow reserve and coronary flow velocity reserve. Circulation 2000;102 :2365–70. PMID: 11067790. Yanagisawa H, Chikamori T, Tanaka N, et al. Correlation between thallium-201 myocardial perfusion defects and the functional severity of coronary artery stenosis as assessed by pressure-derived myocardial fractional flow reserve. Circ J 2002;66 :1105–9. PMID: 12499614. Morishima T, Chikamori T, Hatano T, et al. Correlation between myocardial uptake of technetium-99m-sestamibi and pressure-derived myocardial fractional flow reserve. J Cardiol 2004;43 :155–63. PMID: 15125379. Kobori Y, Tanaka N, Takazawa K, Yamashina A. Usefulness of fractional flow reserve in determining the indication of target lesion revascularization. Catheter Cardiovasc Interv 2005;65 :355–60. PMID: 15926183. van de Hoef TP, Meuwissen M, Escaned J, et al. Fractional flow reserve as a surrogate for inducible myocardial ischaemia. Nat Rev Cardiol 2013;10 :439–52. DOI: 10.1038/ nrcardio.2013.86; PMID: 23752699.

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Coronary

LE ATION.

Coronary Intervention with the Excimer Laser: Review of the Technology and Outcome Data John R a wlins, J e h a n g i r N D i n , S u n e e l Ta l w a r a n d P e t e r O ’ Ka n e Dorset Heart Centre, Royal Bournemouth Hospital, Bournemouth, UK

Abstract Excimer laser coronary atherectomy (ELCA) is a long-established adjunctive therapy that can be applied during percutaneous coronary intervention (PCI). Technical aspects have evolved and there is an established safety and efficacy record across a number of clinical indications in contemporary interventional practice where complex lesions are routinely encountered. The role of ELCA during PCI for thrombus, non-crossable or non-expandable lesions, chronic occlusions and stent under-expansion are discussed in this review. The key advantage of ELCA over alternative atherectomy interventions is delivery on a standard 0.014-inch guidewire. Additionally, the technique can be mastered by any operator after a short period of training. The major limitation is presence of heavy calcification although when rotational atherectomy (RA) is required but cannot be applied due to inability to deliver the dedicated RotaWireTM (Boston Scientific), ELCA can create an upstream channel to permit RotaWire passage and complete the case with RA – the RASER technique.

Keywords Excimer laser coronary atherectomy (ELCA); percutaneous coronary intervention (PCI); non-crossable lesions; chronic total occlusions (CTO); intra-coronary thrombus; under-expanded stents; rotational atherectomy (RA) Disclosure: ST and PO are European Proctors for Spectranetics. JR and JD have no conflicts of interest to declare. Received: 16 December 2015 Accepted: 24 March 2016 Citation: Interventional Cardiology Review, 2016;11(1):27–32. DOI: 10.15420/icr.2016:2:2 Correspondence: Peter O’Kane, Consultant Interventional Cardiologist, Dorset Heart Centre, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, UK. E: peter.o’kane@rbch.nhs.uk

The introduction of lasers for the treatment of vascular atherosclerosis began in the 1980s, initially for the treatment of critical limb ischaemia, 1 followed by trials that supported its use in coronary circulation. 2–5 However, catheters and technique were rudimentary and associated with complications.6,7 Refinements in catheter technology8 and introduction of safe lasing techniques9,10 have led to improvements in clinical outcomes.11

(photomechanical). The fragments released are <10 μm in diameter, avoiding microvascular obstruction as they are absorbed by the reticulo-endothelial system.

The aim of this article is to describe the principles and practice of Excimer laser coronary atherectomy (ELCA), illustrating with case examples and relevant clinical data.

The threshold energy required for the penetration of UV light into tissue and the creation of a steam bubble is called ‘fluence’ (range: 30–80 mJ/mm2). The number of pulses emitted during a 1–second period is the ‘pulse repetition rate’. The duration of each pulse is termed a ‘pulse width’, which is modified according to the nature of the treated lesion for example fibro-calcific lesions require higher fluence and repletion rate for effective ablation (see Figure 2).

Excimer Laser Coronary Atherectomy

Excimer Laser Equipment and General Technique

Excimer lasers are pulsed gas lasers that use a mixture of a rare gas and halogen as an active medium to generate pulses of short wavelength, high-energy ultraviolet (UV) light (see Figure 1). The depth of laser penetration is directly related to its wavelength, with UV laser (shorter wavelength) having less depth of penetration, less heat production and less unwanted tissue damage (see Table 1).

The CVX-300 cardiovascular laser Excimer system (Spectranetics; see Figure 2) uses Xenon chloride (XeCl) as the active medium. The light emitted has a wavelength of 308 nm (in the UVB spectrum) with a tissue penetration depth between 30–0 μm. It is the only coronary laser-emitting device currently approved by the US Food and Drug Administration.

Excimer laser tissue ablation is mediated through three distinct mechanisms: photochemical, photo-thermal and photomechanical. UV laser light is absorbed by intra-vascular material and breaks carbon–carbon bonds (photochemical). It elevates the temperature of intra-cellular water, causing cellular rupture and generates a vapour bubble at the catheter tip (photo-thermal). Expansion and implosion of these bubbles disrupts the obstructive intra-vascular material

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It is essential that safety procedures should be observed when performing laser atherectomy. Prior to activation, all persons in the catheter lab, including the patient, must wear protective tinted spectacles to minimise the risk of retinal exposure to the UV light. All windows should be covered and doors locked. Following this safety checklist, the laser unit is warmed up and the selected catheter is connected and calibrated prior to being introduced into the body. Even when the catheter is in vivo, all staff in the vicinity should wear

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Coronary Figure 2: The Spectranetics CVX-300 Excimer Laser System

Figure 1: Spectrum of Light for Therapeutic Laser use 193 nm

Panel 2i

2090 nm

Control panel

10600 nm

Infrared

Ultraviolet

308 nm

Calibration port

Panel 2iii Panel 2iv

A Concentric CO2

Excimer (CVX-300)

Ho:YAG

Excimer (LASIK- Ophthalmic)

The wavelength of light emitted from a laser is determined by the lasing medium and it is an important factor in determining the properties of the system. Laser light emitted from the Spectranectics CVX-300 excimer (XeCl) laser system is ‘Cool’ (308 nm), which is similar to laser light employed for laser-assisted in situ keratomileusis (LASIC; 193.3 nm) used in ophthalmic surgery. In contrast to infrared lasers, the Excimer laser has a shallow penetration of depth (50 µm) and ablates tissue precisely without excessive heat production and minimises inadvertent tissue damage. Ho:YAG = holmium yttrium aluminium garnet.

Table 1: Types of Laser Categorised by Emitted Light Wavelength Laser type

Panel 2ii

Wavelength

Absorption

(nm)

depth (mm)

mechanism

XeCl (Excimer)

308

0.05

Protein-lipids

Nd:YAG

1,060

2.0

Protein-water

1,320

1.25

Water

Dye

480

0.5

Protein

Argon

488

0.5

Ho:YAG

2,060

0.3

Radiopaque marker

Eccentric

Guidewire lumen

Radiolucent window

Distal tip Panel 2i illustrates the pulse generator. The controls are located on the top of the device, and illustrated in panel 2ii. Two numbers are visible: fluence on the left (indicated by the orange box, in this case set at 45 mJ/mm2), and pulse repetition frequency on the right (in this example, 25 Hz). Panel 2iv illustrates the two available configurations of laser catheter – concentric and eccentric – referring to the orientation of the laser fibres within the catheter. These are directed at the calibration port (panel 2iii) before being introduced into the body.

Table 2: Indications for Excimer Laser Coronary Atherectomy (ELCA) and the Preferred Laser Catheter ELCA indication

Preferred laser catheter (mm)

Acute myocardial infarct, intra-coronary thrombus

0.9–1.4

Uncrossable lesions

0.9 X80

Protein

Chronic total occlusions

0.9 X80

Water

Under-expanded stent

0.9 X80

In-stent restenosis

0.9–2.0 (concentric or eccentric)

Saphenous vein grafts

0.9–2.0

HO:YAG = holmium yttrium aluminium garnet; Nd:YAG = neodymium-doped yttrium aluminium garnet; XeCl = xenon chloride.

eye protection in case the catheter housing breaks, which could release UV light. ELCA catheters are advanced on a short monorail segment (30 mm), compatible with any standard 0.014-inch Q2 guidewire. This is a major advantage over alternative coronary atherectomy techniques that require dedicated guidewires that are often more difficult to deliver distally. Coronary catheters are available in four diameters (0.9, 1.4, 1.7, 2.0 mm; see Table 2) and those most commonly used have a concentric array of laser fibres at the tip. The laser fibres of eccentric laser catheters are focused toward one hemisphere. These devices are primarily used for eccentric lesions or for extensive debulking of in-stent restenosis (ISR). The larger diameter laser catheters (1.7, 2.0 mm) are primarily used in straight sections of vessels with a diameter >3.0 mm and require 7F and 8F guide catheters, respectively. The 0.9- and 1.4-mm devices are used via a 6F guiding system. Care should be taken to select a guiding catheter that provides adequate support and that remains coaxial during lasing. Laser catheter size selection is primarily based on: (a) the severity of the lesion; (b) the reference vessel diameter and; (c) consistency of the target material12 (see Table 2). The 0.9-mm X80 catheter is used in non-crossable, non-dilatable fibrocalcific lesions, due to its enhanced delivery and ability to emit laser energy at high power (80 mJ/mm2) at the highest repletion rate (80 Hz).

of delivered Excimer laser energy creating cavitating microbubbles, which form at the site of energy delivery, increasing the likelihood of traumatic dissection.13 By contrast, saline permits passage of light from the catheter tip to the tissue without any interference so no microbubbles are formed in this milieu. Therefore, a saline flush/infusion technique is used to safely control energy delivery and minimise dissection risk.14,15 Application of laser in blood or contrast media is rarely performed in certain specific situations – such as treatment of an underexpanded stent – and should only be undertaken by experienced laser percutaneous coronary intervention (PCI) operators.16 To clear blood from the catheter–tissue interface, a 1-l bag of 0.9 % saline solution is connected to the manifold via a three-way tap, and a clean 20-ml Luer-Lok™ (Becton Dickinson) syringe replaces the contrast syringe. Once the system has been purged of contrast, confirmed by screening, 5 ml of saline solution should be infused followed by continued injection – at a rate of 1–2 ml/second – throughout laser activation. The guide catheter should be well intubated and coaxial within the artery, ensuring saline delivery to the catheter tip. For the standard coronary catheters activation will automatically cease after 5 seconds with a 10-second rest period. An audible alarm sounds at the end of the rest period to signal when to commence the next laser train. The 0.9-mm X80 catheter permits 10 seconds activation and 5 seconds rest, reflecting its use in more complex lesions.

Saline Infusion Technique Both blood and iodinated contrast media contain non-aqueous cellular macromolecules, such as proteins, and these absorb the majority

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The pulses of laser energy are delivered as the catheter is slowly (0.5 mm/second) advanced through the lesion, allowing adequate

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Figure 3: Tips and Tricks for Successful Laser Atherectomy Define indication Begin lasing

Figure 4: The Use of Excimer Laser Coronary Atherectomy in Intra-coronary Thrombus A

Select ELCA catherel

Safety precautions observed

Manifold cleared of contrast?

Tips for laser success

Select access route

Select appropriate guide

Adequate support? Coaxial?

Once the indication for laser has been defined and the appropriate catheter selected, the access route can be determined. Almost all interventions can be delivered via the radial route, although delivery of an 8F catheter (or equivalent sheathless guide) requires care and many need techniques such as balloon tracking. Once an appropriate coaxial guide has been selected, that maintains good co-coaxial support, then excimer laser coronary atherectomy (ELCA) can be undertaken once adequate safety precautions have been employed.

absorption and ablation. If the catheter is advanced too rapidly the tissue does not have time to absorb the light energy and ablation will be sub-optimal. On completion of several anterograde trains, retrograde lasing can be performed, particularly in severe lesions when there is anterograde resistance.

Contraindications and Avoiding Complications – Tips and Tricks (see Figure 3) Other than lack of informed consent and unprotected left main disease (a relative contraindication) there are no absolute coronary contraindications for ELCA. ELCA complications are similar to those encountered during routine PCI. Specific issues may arise from interruption of the saline flush or contamination with contrast, which can generate excessive heat and increase the risk of vascular perforation. ELCA is not recommended when the operator is aware that there is a long length of sub-intimal guidewire positioning as may exist during hybrid PCI techniques for chronic total occlusions (CTOs).

Clinical Indications for Excimer Laser Coronary Atherectomy As the application of ELCA has been refined, a number of indications have emerged for the technique:

1. Acute Coronary Syndromes and Myocardial Infarction (see Figure 4) The recommended treatment for acute myocardial infarction (AMI) associated with electrocardiogram (ECG) ST segment elevation is primary PCI.17,18 ELCA may be a beneficial given its potential for effective thrombus removal,19 promotion of fibrinolysis,20 plateletstunning effects21 and concomitant plaque debulking.22 We have published case reports of how effective ELCA can be at dealing with a large burden of intra-coronary thrombus providing excellent immediate and long-term results.23,24 However, clinical data supporting the use of ELCA in AMI remain limited. The largest study to date, the Cohort of Acute Revascularization of Myocardial infarction with Excimer Laser (CARMEL) multicentre registry,

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A 73-year-old man presented inferior ST elevation with a thrombotically occluded right coronary artery (A). Initial thrombectomy restored Thrombolysis In Myocardial Infarction (TIMI) 2 flow, but a large volume of thrombus remained in the artery despite repeated passage. excimer laser coronary atherectomy was therefore undertaken, using a 1.4-mm 6F compatible catheter; 4,500 pulses were delivered over 15 trains with a dramatic improvement in thrombotic burden and obstructive stenosis. The case was completed with overlapping drugeluting stent with an excellent final angiographic result.

enrolled 151 AMI patients, 65 % of whom had large thrombus burden in the culprit artery.25 Following ELCA, Thrombolysis In Myocardial Infarction (TIMI) flow grade was significantly increased (1.2 to 2.8), with an associated reduction in angiographic stenosis (83 to 52 %).25 There was a low rate (8.6 %) of major adverse coronary events (MACE). The maximal effect was observed in arteries with a large angiographic thrombus burden. A single randomised trial, the Laser AMI study, has been conducted. This study included 66 patients and sought to demonstrate safety and feasibility. They used optimal lasing technique (saline flushing with slow advancement [0.2–0.5 mm/second]) using the CVX-300 Excimer laser system and treated the majority of lesions with a laser-stent strategy (only two patients required balloon angioplasty prior to stenting). Primary angiographic endpoints were myocardial blush grade, TIMI flow and length-adjusted TIMI frame count. The TIMI score increased from 0.2±0.4 at baseline to 2.65±0.5 post-laser to 2.9±0.3 post-stent (both p<0.01 versus baseline). Similarly, myocardial blush grade increased from 0.12±0.4 to 2.5±0.6 post-laser, and to 2.8±0.4 post-stent. No reflow was observed in 11 % of cases after laser and a major dissection occurred in one case. There were no intraprocedural deaths and 95 % event-free survival at 6 months with LV remodelling occurring in 8 % patients.26 A second, larger study is ongoing and due to report in 2016.

2. Excimer Laser Coronary Atherectomy for Non-crossable/Non-dilatable Lesions (Balloon Failure; see Figure 5) Balloon failure occurs when a lesion cannot be crossed with a low-profile device, or when the balloon inadequately expands with dilatation. This is a situation where ELCA may be applied, with a high success rate in un-crossable or un-dilatable stenoses. However, in cases of significant calcification, the response is less favourable (calcified 79 % versus non-calcified 96 %; p<0.05).27,28 This is because the ablative effects of ELCA on calcium are minimal and success relies

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Coronary Figure 5: The use of Excimer Laser Coronary Atherectomy in a Calcific Undilatable Lesion A

the combination of ELCA and RA the RASER technique and have developed this combination of atherectomy devices in a number of challenging cases.29–31 This combined use of atherectomy devices is particularly effective for non-crossable, non-dilatable calcified stenosis frequently encountered in daily PCI practice. The outcome is predictable and is associated with a low complication rate in experienced hands.29–31

A 69-year-old man with a severe calcific lesion in the proximal portion of a dominant right coronary artery (A). Despite use of a 3.0 x 20-mm noncompliant balloon at high pressure, there was clear failure of lesion expansion (B). Excimer laser atherectomy was undertaken with a 0.9mm X80 catheter, delivering 5,000 pulses over 15 trains. This caused a small proximal localised dissection, but allowed balloon expansion (C) and subsequent treatment with overlapping drug-eluting stents (D).

Figure 6: Excimer Laser Coronary Atherectomy for Stent Underexpansion A

The 0.9-mm X80 catheter is selected in the vast majority of balloon failure cases since this catheter provides the widest range of power and repetition rate to maximise the chances of procedural success. Given that this catheter only requires a 6F guiding system, the application of such techniques can easily be achieved through the transradial approach in keeping with contemporary PCI practice. Other devices that can be used to facilitate the PCI in these situations include the use of the GuideLiner® (Vascular Solutions) for the delivery of the ELCA, although care should be taken to retract the device prior to commencing lasing since the obstruction to blood flow may lead to ischaemia.32 Support strategies that require the use of additional wires (e.g., anchor wires, balloons, etc.) can also be used given that it is possible to safely laser with a second wire in place.

3. Excimer Laser Coronary Atherectomy for Chronic Total Occlusions The role of ELCA in the treatment of CTOs is for resistant lesions: when equipment is unable to cross the lesion or proximal cap despite attaining distal wire position. It may also offer additional benefits as its ablative effect is transmitted through the lesion architecture, potentially weakening bonds between the constituent components of the CTO. In addition, the antithrombotic19,20 and platelet-suppressive21 effects of ELCA may reduce the risk of thrombotic complications during disobilteration. A success rate of 86–90 % for ELCA in CTO cases has been reported.16,29,33 From a technical perspective, saline is often not used at the laser–lesion interface for CTO cases as anterograde injections are usually avoided to prevent extending areas of dissection. In addition, it is unlikely that saline would reach the laser–tissue interface.

4. Excimer Laser Coronary Atherectomy in Underexpanded Stents (see Figure 6) An illustration of severe stent under-expansion in the ostium of a large dominant right coronary artery from a female patient who has previously undergone percutaneous coronary intervention a few weeks before in another institution (A). The minimal lumen area (B). From the right radial artery, using a 7F guiding catheter along with a guideliner extension, the lesion was treated with 0.9-mm X80 Excimer laser coronary atherectomy catheter. Seven thousand pulses were delivered and this facilitated balloon angioplasty, with full expansion of a balloon (D). The final angiographic and intravenous ultrasound result is shown in (F) and (E), respectively, with full stent expansion having been achieved.

on the ablation of more pliable tissue within the calcific lesion, which will vary accordingly. In heavily calcified coronary lesions the default technique for the majority of PCI operators remains rotational atherectomy (RA), even among proficient ELCA users. RA requires delivery of a dedicated 0.009-inch guidewire (Rotawire™) into the distal coronary vessel. This wire is less deliverable directly, and it may not be possible either independently or through a micro-catheter. When this situation arises, ELCA can be used to modify the lesion to create a channel through which a Rotawire™ can subsequently be delivered distally (usually via a microcatheter), to permit RA and case completion. We termed

O'Kane_FINAL.indd 30

Stent under-expansion poses a significant risk for stent thrombosis. There are few PCI options available when this occurs. Maximal balloon dilatation (both diameter and pressure) has often already been undertaken, and RA risks metal fragment embolisation and burr stalling. ELCA remains the only technique that is able to modify the underlying resistant atheroma by delivering energy to the abluminal stent surface without disrupting the stent architecture.34,35 While having no impact on the calcification itself, ELCA modifies the plaque behind the stent, which weakens the overall resistance, thus enabling subsequent complete stent expansion.36–38 We have found that delivering high power laser energy (80 mJ/mm2/ 80 Hz), using the 0.9-mm X80 catheter in the absence of saline, or with contrast injection, amplifies the ablative effect. Within a stented environment ‘contrast-mileu’ lasing appears to be safe, facilitating high-pressure balloon stent expansion.36–39 This technique has been evaluated in the ELLEMENT registry of 28 patients.40 Procedural success was achieved in 96.4 % (27/28) of cases, using an increase of either 1 cm2 on intravenous ultrasound

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(IVUS) or 10 % using quantitative coronary angiography derived minimal stent diameter as a definition. This confirmed efficacy, with a low associated MACE rate.40

5. In-stent Restenosis ISR remains a major limitation of PCI following stent implantation with rates of restenosis reported in 10–50 % of patients receiving a baremetal stent,41 although considerably less in the DES era.42 ELCA is a safe and effective technique in the treatment of ISR.43 Excimer laser did not alter stainless-steel stent endurance or liberate any significant material when five types of stainless-steel stents were subjected to 1,000 pulses of laser energy from a 2.0-mm eccentric Excimer laser catheter.35 In a clinical study, the examination of 107 re-stentoic lesions in 98 patients demonstrated that lesions treated with ELCA compared with balloon angioplasty alone, had a greater IVUS cross-sectional area and luminal gain, with more intimal hyperplasia ablation. There was a non-significant trend towards a less frequent need for target vessel revascularisation at 6 months (21 versus 38 %; p=0.083).43 We have observed, using optical coherence tomography (OCT) and optical frequency domain imaging, that during treatment of the restenotic segment, the laser therapy ablates both the luminal and abluminal atherosclerotic material.44 Therefore, if the mechanism of restenosis is in part stent under-expansion, ELCA increases the likelihood of achieving greater stent expansion and more durable longer-term outcomes.

6. Saphenous Vein Grafts Occlusions in old saphenous vein grafts (SVGs) frequently consist of degenerative diffuse plaques often containing thrombus45,46 and prone to distal embolisation.47 Hence, distal protection devices (DPDs) are advocated when attempting SVG-PCI,46 but their bulky nature may prevent distal device delivery. ELCA is a safer alternative, allowing predictable debulking during SVG-PCI.48,49 The low rate of distal embolisation during

10.

11.

12.

13.

Choy DSJ. History and state-of-the-art of lasers in cardiovascular disease. Laser Medicine & Surgery News & Advances 1988;34–8. Cook SI, Eigler NL, Shefer A, et al. Percutaneous excimer laser coronary angioplasty of lesions not ideal for balloon angioplasty. Circulation 1991;84 :632–3. PMID: 1860207 Koster R, Kahler J, Brockhoff C, et al. Laser coronary angioplasty: history, present and future. Am J Cardiovasc Drugs 2002;2 :197–207. PMID: 14727981 Bittl JA, Sanborn TA, Tcheng JE. Clinical success, complications and restenosis rates with excimer laser coronary angioplasty. Am J Cardiol 1992;70 :1553–9. PMID: 1466319 Geschwind HJ, Dubois-Rande JL, Zelinsky R, et al. Percutaneous coronary mid-infrared laser angioplasty. Am Heart J 1991;122 :552–8. PMID: 1858640 Bittl JA, Ryan TJ, Keaney JF. Coronary artery perforation during excimer laser coronary angioplasty. J Am Coll Cardiol 1993;21 :1158–65. PMID: 8459071 Topaz O. Whose fault is it? Notes on “true” versus “pseudo” laser failure. Editorial. Cath Cardiovasc Diagn 1995;36 :1–4. PMID: 7489586 Taylor K, Reiser C. Large eccentric laser angioplasty catheter. In Proceedings of lasers in surgery: advanced characterization, therapeutics and systems. SPIE 1997;2970 :34–41. Tcheng JE. Saline infusion in excimer laser coronary angioplasty. Semin Intervent Cardiol 1996;1 :135–41. PMID: 9552504 Topaz O. A new safer lasing technique for laser facilitated coronary angioplasty. J Intervent Cardiol 1993;6 :297–306. PMID: 10151024 Topaz O. Coronary laser angioplasty. In: Topol EJ (editor). Textbook of Interventional Cardiology . Philadelphia, PA: WB Saunders, 1995;235–55. Topaz O, Safian RD. Excimer laser coronary angioplasty. In: Safian RD, Freed MS (editors). Manual of Interventional Cardiology . 3rd edition. Royal Oaks, MI: Physicians Press 2001;681–91. Baumbach A, Haase KK, Rose C, et al. Formation of pressure waves during in vitro excimer laser irradiation in whole blood

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14.

15.

16.

17.

18.

19.

20.

21.

22.

ELCA of degenerative bypass grafts (1–5 %) may preclude the need for routine DPD in the majority of cases.48 However, OCT images post-SVG ELCA make it is clear that there remains friable fragments that could embolise and cause no-reflow.44 Therefore, when using ELCA for SVGPCI, it is advisable to stent on a DPD system to prevent no-reflow.44 Given advances in CTO success in recent years, SVG-PCI is likely to be less frequently undertaken as operators choose to treat the occluded native vessel. Nonetheless, if SVG-PCI is considered necessary, ELCA remains a useful adjunctive therapeutic intervention.

7. Bifurcations Generally PCI for coronary bifurcation lesions is best treated with a main vessel (MV)-only stenting approach with preservation of side branch (SB), rather than an upstream two-stent strategy. However, in large vessels involving extensive SB disease it may be necessary to stent SB as well. ELCA could potentially be of value in these cases by debulking the SB lesion to permit more predictable success with the MV-only approach. However, in the few cases in our practice in which we have used this technique we have discovered SB dissection because of vessel angulation, which has necessitated SB stenting – thereby defeating the purpose of using ELCA. We have used ELCA more successfully in rare cases of SB restensosis (often due to stent under-expansion) guided by intra-coronary imaging with durable results.

Conclusion The current indications for the use of Excimer laser atherectomy in modern interventional practice are described in this article. A detailed description of the ELCA technique and its potential pitfalls has been illustrated with complex interventional cases. This technology provides a solution to a variety of problems that may be encountered, including massive intra-coronary thrombus, un-crossable lesions and stent under-expansion. Careful case selection, proper use of equipment and safe, efficacious lasing technique all play crucial roles in successful ELCA interventions. n

and the effect of dilution with contrast media and saline. Lasers Surg Med 1994;14 :3–6. PMID: 8127204 Tcheng JE, Wells LD, Phillips HR, et al. Development of a new technique for reducing pressure pulse generation during 308-nm excimer laser coronary angioplasty. Cathet Cardiovasc Diagn 1995;34 :15–22. PMID: 7728846 Deckelbaum LI, Natarajan MK, Bittl JA, et al. Effect of intracoronary saline infusion on dissection during excimer laser coronary angioplasty: a randomized trial. The percutaneous excimer laser coronary angioplasty (PELCA) investigators. J Am Coll Cardiol 1995;26 :1264–9. PMID: 7594041 Topaz O. Laser for total occlusion recanalization. In: Waksman R, Saito S (editors). Chronic Total Occlusions: A Guide to Recalization . Hoboken, NJ: Wiley-Blackwell, 2009. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33 :2569–619. DOI: 10.1093/eurheartj/ehs215; PMID: 22922416 American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol 2013;61 :e78–140. DOI:10.1016/j.jacc.2012.11.019; PMID: 23256914 Dahm JB, Topaz O, Woenckhaus C, et al. Laser facilitated thrombectomy: a new therapeutic option for treatment of thrombus–laden coronary lesions. Cath Cardiovasc Intervent 2002;56 :365–72. PMID: 12112890. Topaz O, Minisi AJ, Morris C, et al. Photoacoustic fibrinolysis: pulsed-wave, mid infrared laser-clot interaction. J Thrombo Thrombolysis 1996;3:209–14. PMID: 10613984 Topaz O, Minisi AJ, Bernardo NL, et al. Alterations of platelet aggregation kinetics with ultraviolet laser emission: the “stunned platelet“ phenomenon. Thromb Haemost 2001;86 :1087–93. PMID: 11686328 Topaz O, Bernardo NL, Shah R, et al. Effectiveness of excimer laser coronary angioplasty in acute myocardial infarction or in unstable angina pectoris. Am J Cardiol 2001;87 :849–55. PMID: 11274939

23. Rawlins J, Sambu N, O’Kane P. Strategies for the management of massive intra-coronary thrombus in acute myocardial infarction. Heart 2013;99 :510. DOI: 10.1136/ heartjnl-2012-303370; PMID: 23376902 24. Whittaker A, Rawlins J, O’Kane P. Contemporary therapy of intracoronary thrombus: laser and bioresorbable scaffold. Cardiovasc Interv Ther 2015;30 :277–8. DOI: 10.1007/s12928014-0280-6 25. Topaz O, Ebersole D, Das T, et al. Excimer laser angioplasty in acute myocardial infarction [the CARMEL multicenter study]. Am J Cardiol 2004;93 :694–701. PMID: 15019871 26. Dorr M, Vogelgesang D, Hummel A, et al. Excimer laser thrombus elimination for prevention of distal embolisation and no-reflow in patients with acute ST elevation myocardial infarction: results from the randomised LaserAMI study. Int J Cardiol 2007;116 :20–6. 27. Bittl JA. Clinical results with excimer laser coronary angioplasty. Semin Intervent Cardiol 1996;1 :129–34. 28. Bilodeau L, Fretz EB, Taeymans Y, et al. Novel use of a high energy excimer laser catheter for calcified and complex coronary artery lesions. Cath Cardiovasc Interv 2004;62 :155–61. PMID: 15170703 29. Fernandez JP, Hobson AR, McKenzie D, et al. Beyond the balloon: excimer coronary laser atherectomy used alone or in combination with rotational atherectomy in the treatment of chronic total occlusions, non-crossable and nonexpansible coronary lesions. EuroIntervention 2013;9 :243–50. DOI: 10.4244/EIJV9I2A40; PMID: 23454891 30. McKenzie DB, Talwar S, Jokhi PP, et al. How should I treat severe coronary artery calcification when it is not possible to inflate a balloon or deliver a RotaWire? Eurointervention 2011;6 :779–83. DOI: 10.4244/EIJV6I6A132; PMID: 21205605 31. Fernandez JP, Hobson AR, McKenzie D, et al. Treatment of calcific coronary stenosis with the use of excimer laser coronary atherectomy and rotational atherectomy. Int Card 2010;2 :801–06. DOI: 10.2217/ica.10.83 32. Sambu N, Fernandez J, Shah NC, O’Kane P. The Guideliner®: an interventionist’s experience of their first 50 cases: ‘the mostly good, rarely bad, beware of the ugly!’ Int Card 2013;5 :389–402. DOI: 10.2217/ica.13.37

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Coronary 33. Holmes DR Jr, Forrester JS, Litvack F, et al. Chronic total obstructions and short term outcome: the excimer laser angioplasty registry experience. Mayo Clin Proc 1993;68 :5–10. PMID: 8417255 34. Papaioannou T, Yadegar D, Vari S, et al. Excimer laser (308 nm) recanalisation of in-stent restenosis: thermal considerations. Lasers Med Sci 2001;16 :90–100. PMID: 11484760 35. Burris N, Lippincott RA, Elfe A, et al. Effects of 308 nanometer excimer laser energy on 316 L stainless-steel stents: implications for laser atherectomy of in-stent restenosis. J Invasive Cardiol 2000;12 :555–9. PMID: 11060568 36. Sunew J, Chandwaney RH, Stein DW, et al. Excimer laser facilitated percutaneous coronary intervention of a nondilatable coronary stent. Cath Cardiovasc Intervent 2001;53 :513–7. PMID: 11515003 37. Fernandez JP, Hobson AR, Mckenzie DB, et al. How should I treat severe calcific coronary artery disease. EuroIntervention 2011;7 :400–7. DOI: 10.4244/EIJV7I3A65; PMID: 21729843 38. Lam SC, Bertog S, Sievert H. Excimer laser in management of underexpansion of a newly deployed coronary stent. Catheter Cardiovasc Interv 2014;83 :E64–8. DOI: 10.1002/

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ccd.25030; PMID: 23703809 39. Egred M. A novel approach for under-expanded stent: excimer laser in contrast medium. J Invasive Cardiol 2012;24 :E161–E163. PMID: 22865316 40. Latib A, Takagi K, Chizzola G, et al. Excimer Laser LEsion modification to expand non-dilatable stents: the ELLEMENT registry. Cardiovasc Revasc Med 2014;15 :8–12. DOI: 10.1016/j. carrev.2013.10.005; PMID: 24290659 41. Lowe H, Oesterle S, Khachigian LM. Coronary in-stent restenosis: current status and future strategies. J Am Coll Cardiol 2002;39 :183–93. PMID: 11788206 42. Dangas G, Claessen B, Caixeta, A, et al. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol 2010;56:1897–907. DOI: 10.1016/j.jacc.2010.07.028; PMID: 21109112 43. 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 44. Rawlins J, Talwar S, Green M, O’Kane P. Optical Coherance Tomography follwoing percutaneous coronary intervention with Excimer Laser coronary atherectomy. Cardiovasc Revasc Med 2014;15 :29–34.

45. Webb JG, Carere RG, Virmani R, et al. Retrieval and analysis of particulate debris after saphenous vein graft intervention. J Am Coll Cardiol 1999;34 :468–75. PMID: 10440161 46. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002;105 :1285–90. PMID: 11901037 47. Bittl JA, Sanborn TA, Yardley DE, et al. Predictors of outcome of percutaneous excimer laser coronary angioplasty of saphenous vein bypass graft lesions. The Percutaneous Excimer Laser Coronary Angioplasty Registry. Am J Cardiol 1994;74 :144–8. PMID: 8023778 48. Giugliano GR, Falcone MW, Mego D, et al. A prospective multicenter registry of laser therapy for degenerated saphenous vein graft stenosis: the COronary graft Results following Atherectomy with Laser (CORAL) trial. Cardiovasc Revasc Med 2012;13 :84–9. DOI: 10.1016/j.carrev.2012.01.004; PMID: 22406059 49. Ebersole D, Dahm JB, Das T, et al. Excimer laser revascularization of saphenous vein grafts in acute myocardial infarction. J Invasive Cardiol 2004;16 :177–80. PMID: 15152140

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Patient Selection and Procedural Considerations for Coronary Orbital Atherectomy System Yohei Sotomi, 1 Richard A Shlofmitz, 2 Antonio Colombo, 3 Patrick W Serruys 4 and Yoshinobu Onuma 5 1. Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2. St Francis Hospital, The Heart Center, Roslyn, New York, USA; 3. EMO-GVM Centro Cuore Columbus, Milan, Italy; 4. International Centre for Circulatory Health, NHLI, Imperial College London, London, UK; 5. ThoraxCenter, Erasmus Medical Center, Rotterdam, The Netherlands

Abstract Despite advances in technology, percutaneous coronary intervention (PCI) of severely calcified coronary lesions remains challenging. Rotational atherectomy is one of the current therapeutic options to manage calcified lesions, but has a limited role in facilitating the dilation or stenting of lesions that cannot be crossed or expanded with other PCI techniques due to unfavourable clinical outcome in long-term follow-up. However the results of orbital atherectomy presented in the ORBIT I and ORBIT II trials were encouraging. In addition to these encouraging data, necessity for sufficient lesion preparation before implantation of bioresorbable scaffolds lead to resurgence in the use of atherectomy. This article summarises currently available publications on orbital atherectomy (Cardiovascular Systems Inc.) and compares them with rotational atherectomy.

Keywords Orbital atherectomy system, percutaneous coronary intervention, severely calcified lesion Disclosure: YS is a consultant for GOODMAN and has received a grant from Fukuda Memorial Foundation for Medical Research and SUNRISE lab. RAS has received speaking honoraria from Cardiovascular Systems Inc. and St Jude Medical. PWS and YO are members of Advisory Board of Abbott Vascular. AC has no conflicts of interest to declare. Acknowledgement(s): The authors thank Robert Kohler from Cardiovascular Systems Inc. for editing and critical review of this manuscript. Received: 31 December 2015 Accepted: 10 March 2016 Citation: Interventional Cardiology Review, 2016;11(1):33–8 DOI: 10.15420/icr.2015:19:2 Correspondence: Yoshinobu Onuma, ThoraxCenter, Ba-583‘s Gravendijkwal 230 3015 CE Rotterdam, The Netherlands. E: yoshinobuonuma@gmail.com

From the early days of percutaneous coronary intervention (PCI) it became apparent that the presence of severe coronary calcification was a predictor of worse clinical outcomes. In the era of plain old balloon angioplasty, severe coronary calcification was associated with an increased risk of coronary dissection and procedural failure, while in the bare-metal stent era, it was associated with a higher incidence of in-stent restenosis and target lesions revascularisations (TLRs).1,2 The advent of drug-eluting stents (DES) changed the landscape of coronary intervention through the reduced risk of restenosis and TLR, thereby allowing the interventional treatment of complex lesions and high-risk patients. However, a recent patient-level pooled analysis from seven contemporary stent trials revealed that patients with severely calcified lesions still have worse clinical outcomes compared with those without severe coronary calcification.3 Patients with severe lesion calcification were less likely to have undergone complete revascularisation, resulting in a higher residual Syntax score, which is a powerful determinant of prognosis.4 Although rotational atherectomy was expected to be one of the solutions, the prospective, randomised ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial did not demonstrate any better clinical outcomes.5,6 The latest ACCF/AHA/SCAI and ESC/EACTS PCI guidelines and European expert consensus on rotational atherectomy state that rotational atherectomy has a limited role in facilitating the dilation or stenting of lesions that cannot be crossed or expanded with PCI.7–12

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Rotational atherectomy should not be performed routinely for de novo lesions or in-stent restenosis.13 Recently, a newly developed atherectomy device, a Diamondback 360® Coronary Orbital Atherectomy System (OAS) (Cardiovascular Systems Inc.) has been approved by the US Food and Drug Administration (FDA) based on the results of the Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions (ORBIT) II trial14 and is a new treatment option for severely calcified coronary lesions. The purpose of this review is to provide insights for procedural considerations and patient selection from the currently available publications assessing the OAS.

Diamondback 360 ® Coronary Orbital Atherectomy System The Diamondback 360® Coronary OAS is the device to facilitate stent delivery in patients who are acceptable candidates for PCI due to de novo, severely calcified coronary artery lesions (see Figure 1). The Diamondback 360® Coronary OAS is the device to facilitate stent delivery in patients who are acceptable candidates for PCI due to de novo, severely calcified coronary artery lesions. In October 2013, Cardiovascular Systems Inc. received FDA approval for the use of the Diamondback Coronary OAS in the US, whereas it has yet to receive CE Mark in Europe. Only one size of crown (1.25 mm) is required for the coronary OAS. ViperWire Advance® coronary guide wire (335 cm)

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Coronary Figure 1: Diamondback 360 ® Coronary Orbital Atherectomy System A. Diamondback 360® Coronary Orbital Atherectomy System Device features • Simple device setup • Millisecond feedback to changes in loading • 135 cm usable length

C. Orbital motion

On-handle speed control • Low (SOK) and High Speed (120 K)

Power on/off switch • 8 cm axial travel Electric motor powered handle VIPERWIRE Advance Coronary Guidewire

6 Fr Guide Compatible Saline Sheath

D. Diamond coating

ViperSlide® lubricant • ViperSlide reduces friction during operation • Provides power • Delivers fluid • 20 ml ViperSlide per liter of saline

OAS pump • Mounts directly on to an IV pole • Provides power • Delivers fluid • Includes saline sensor

B. Coronary classic crown 1.25 mm Nose ←6.5 mm→

Guidewire

Crown

←5 mm→ ←5 mm→ Spring tip

0.027"/ 0.69 mm

(minimum)

Driveshaft 135 cm

Procedural Consideration for Coronary Orbital Atherectomy System in Comparison with Rotational Atherectomy

Radial work surface

Bullet Tip Bushing 0.016"/0.41 mm

(A) Diamondback 360® Coronary Orbital Atherectomy System. (B) 1.25 mm coronary classic crown. (C) Orbital motion. (D) Electron micrograph of the crown. (Reprinted with permission from Copyright Cardiovascular Systems Inc.) IV = intravenous; OAS = orbital atherectomy system.

Figure 2: Maximum Lumen Diameters after Orbital Atherectomy with 1.25 mm Classic Crown 1.25 mm Coronary Electric Classic Crown Orbit Results 1 mm/s & 10 mm/s Travel Rate 80KRPM 1 mm/s

80KRPM 10 mm/s

120KRPM 1 mm/s

120KRPM 10 mm/s

2.15 Lumen diameter (mm)

2.05 1.95 1.85 1.75 1.65 1.55 1.45 1.35 1.25

4 6 8 Number of passes Note: First pass for all speeds is done at low speed. Maximum lumen diameter Crown size (mm)

1.25

Rotational speed (rpm)

Maximum lumen Diameter (mm) Average + 2 SD (10 mm/second, 20 passes)*

Maximum lumen Diameter (mm) Average + 2 SD (1 mm/second, 20 passes)*

80,000

1.64

1.53

120,000

1.84

1.68

The graph shows the relationship between number of passes, travel rate, rotational speed and lumen diameter in a carbon block model. A pass is defined as once out and back across the lesion. Orbit data presented are based on a 6 cm pass distance. The table indicates maximum lumen diameter after 5 minutes of orbital atherectomy. A travel rate of 10 mm per second with 20 passes through a 6 cm lesion is approximately 5 minutes of treatment time. A travel rate of 1 mm per second with two passes through a 6 cm lesion is also approximately 5 minutes of treatment time. Actual clinical results may vary. SD = standard deviation. ((c) 2016; reprinted with permission from Copyright Cardiovascular Systems Inc.)

is to be used exclusively with the Diamondback 360® Coronary OAS to enable optimal orbital path and efficient differential sanding.

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The Diamondback 360® Coronary OAS uses a differential sanding mechanism of action to reduce plaque while potentially minimising damage to the medial layer of the vessel. Softer tissue flexes away from the crown while fibrotic tissue or arterial calcium is engaged and treated facilitating stent deployment. A drive shaft with an eccentrically mounted diamond-coated crown provides proximal and distal sanding to reduce occlusive material and restore luminal patency.15 The crown’s orbital diameter expands radially via centrifugal force according to the following formula: F = mv 2/R (F = centrifugal force; m = mass of the crown; v = velocity [device rotational speed]; R = radius of rotation) (see Figure 1). Operators can control the speed of rotation with the knowledge that a higher speed will create a larger sanding diameter by increasing lateral pressure (see Figure 2). Based on carbon block testing, the average particle size created by OAS is 2.04 μm; 98.3 % of particles are smaller than red blood cell diameter; and 99.2 % of particles are smaller capillary diameter (see Figure 3). In the US, a physician training and certification programme based on physician atherectomy experience is required to use OAS. All physicians must complete an online training module and complete six clinical proctored cases. Based on their experience level they may also need to attend a preceptorship course.

Basic procedural consideration for orbital atherectomy can be similar to that of rotational atherectomy.12,16,17 Differential aspects between orbital atherectomy and rotational atherectomy are summarised in Table 1. One advantage of the Diamondback 360 Coronary OAS is the ease of use. The electric handle allows the user to simply plug in the device, and the only portion of the Diamondback 360 Coronary OAS that is not in the operating field is the saline infusion pump.18 The orbital path of the device around the periphery of the lumen allows the crown to attack the plaque, in contrast with the burr of a rotational device, which remains in one place. In both rotational atherectomy and orbital atherectomy, a healthy, compliant tissue should flex away, whereas fibrotic calcific lesions would generate an opposing force, allowing differential cutting and differential sanding, respectively. The OAS uses a principle of off-axis centrifugal force, with the orbital motion diameter being proportional to the applied speed. Operators can adjust the ablation diameter by controlling the rotational speed without changing the device crown size (see Figure 2). The unique crown shape and diamond coating enable ablation of severely calcified lesions forward and backward, minimising burr entrapment rates. The device allows constant blood and saline flow and particulate flushing during orbit, which facilitates cooling, minimising the potential for ischemia and thermal trauma, which can be a potential cause of restenosis. In comparison, rotational atherectomy uses a concentric burr that does not allow blood and micro-debris to flow past the burr. The average particle size created by rotational atherectomy is 5–10 μm,19 while the average particle size by orbital atherectomy is approximately 2 μm,15 resulting in its lower incidence of slow flow or no reflow than that of rotational atherectomy. A case example treated with the OAS is demonstrated in Figure 4. OCT images pre- and post-orbital atherectomy show the appearance of ablated plaque. The ‘guidewire bias’ (intraluminal [eccentric] position

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Table 1: Differential Aspects of the Orbital Atherectomy from the Rotational Atherectomy Rotational Atherectomy

Orbital Atherectomy

Device

Rotablator™ Rotational Atherectomy System

Diamondback 360® Coronary Orbital Atherectomy System

Manufacturer

Boston Scientific Scimed, Maple Grove, Minnesota

Cardiovascular Systems, Inc., St. Paul, Minnesota

Rotation

Rotational motion

Orbital motion

Guidewire

RotaWireTM

ViperWire Advance® Guide Wire

(ROTAWIRE Floppy, ROTAWIRE Extra Support) Lubricant

Rotaglide™

ViperSlide®

Concept

Differential cutting

Differential sanding

Device size selection

1.25, 1.50, 1.75, 2.00, 2.15, 2.25, 2.38, and

1.25 mm (Crown)

2.50 mm (Burr) Plaque modification with small burrs (1.25 mm to 1.5 mm) as initial strategy is default position. A step-up approach is encouraged to limit debris size and complications.12 Ablation speed

Plaque modification usually achieved at low speeds

Low speed (80,000 rpm) or high speed (120,000 rpm).

(135,000 to 180,000 rpm) to reduce risk

Initial treatment for each lesion must start at low speed37

of complications12 Adjustable ablation diameter

No (necessary to change the burr size)

Yes (just control the rotational speed)

Ability to ablate forward and backward

Yes (minimising burr entrapment rates)

Continuous blood flow during ablation

Yes (minimising the potential for ischaemia and thermal trauma)

Temporary pacemaker

Smaller burrs at lower speeds have led to lower

A temporary pacing lead may be necessary when treating lesions

incidence of transient heart block Many operators

in the right coronary and circumflex arteries due to the possible

use atropine to treat, avoiding any complications of

occurrence of electrophysiological alternations.37 However, in a

temporary pacemaker

placement12

real-world setting, only 3.5 % of the patients undergoing orbital atherectomy had a temporary pacemaker placed with 0.9 % requiring activation of pacing38

Flush

Rotablation cocktail with verapamil, nitrates and

No specific recommendation

heparin in saline recommended12 Particle size

5–10 micron19

2 micron15

Incidence of slow flow/no-reflow

6–15

%25,26

0.9 %14

Coronary perforation

0.4–2.5 %5,6,27–30

1.8 %14

Clinical Evaluation for Coronary Orbital Atherectomy System We conducted a literature search to identify all published coronary OAS studies and Summarized their results in Table 2. Two landmark trials (ORBIT I and ORBIT II) from India and the US have demonstrated the clinical safety and efficacy of the OAS, resulting in the approval by FDA in 2013. No clinical data in a direct comparison study between orbital atherectomy and rotational atherectomy is available so far. The first-in-man assessment of the coronary OAS to treat de novo calcified coronary lesions was performed in the ORBIT I clinical trial. 22 Fifty patients with de novo calcified coronary lesions were enrolled in this non-randomised, multi-centre trial in India. Procedural success, defined as ≤20 % residual stenosis after stent placement, was achieved in 94 % of patients. There was no incidence of slow flow or distal embolisation. In contrast to previous

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Figure 3: Particulate Size Distribution Percentage of particulate greater than corresponding particle diameter

100 Percentage of particulate (%)

of the supporting wire) seems important for the effective ablation not only during rotational atherectomy but also during orbital atherectomy. In addition, imaging evaluation by intravascular ultrasound (IVUS) or OCT after the orbital atherectomy might be recommended for sufficient lesion preparation,20,21 since the ablation diameter largely varies depending on the run time, number of passes and rotational speed (see Figure 2). Without imaging assessment, the efficacy of orbital atherectomy could highly depend on the experience of operators.

80 60 40 Average OAS particulate size: 2.04 µm 98.3 % of Particles < Red blood cell diameter 99.2 % of Particles < Capillary diameter

20 0

6 8 10 Particle diameter (µm)

The graph shows the particulate size distribution after orbital atherectomy from a carbon block model. Ninety-nine per cent of particulate caused by the Diamondback 360® orbital atherectomy system is small enough to fit through the capillaries (data on file). © 2016; reprinted with permission from Cardiovascular Systems Inc.)

PCI trials with rotational atherectomy, ORBIT I reported low rates of major adverse cardiac events (MACE) (6 % at 30 days and 8 % at 6 months).22 Long-term follow-up was collected on a single-centre subset of ORBIT I subjects enrolled at CIMS Hospital, India (n=33). Of the 33 subjects, the observed MACE rate at 2 years was 15 % (5/33), 3 years was 18 % (6/33) and 5 years 21 % (7/33).23,24 The ORBIT II trial was a prospective, single-arm multicentre, non-blinded clinical trial that enrolled 443 consecutive patients with severely calcified

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Coronary Table 2: Trials Assessing Orbital Atherectomy System Study Title

Study Design

Patient

Primary Outcome

Secondary Outcome

Results

Reference(s)

Device performance,

Device success 98 %, procedural

20,23,24

Number ORBIT I

A prospective,

single-arm,

procedural success,

multi-centre study

TLR and overall MACE

success 94 %, TLR 2 %, MACE 8 %

rates at 6 months ORBIT II

A prospective,

443

single-arm,

Procedural success

Angiographic success,

Procedural success 88.9 %,

and 30-day MACE

severe angiographic

30-day MACE 10.4 %; 12-month

complications,

MACE 16.4 %; angiographic success

12-month MACE

91.4 %; severe angiographic

multi-centre study

14,39

complications 7.2 % Kini et al.

A retrospective,

double-arm,

(10 OA versus

post-RA (1.14 versus 0.82 mm;

single-centre,

10 RA)

P=0.048). Lower per cent of stent strut

OCT-imaging study

Deeper dissections post-OAS than

malapposition post-OAS than post-RA (4.36 versus 8.02 %; P=0.038).

Ruisi et al. Dib et al.

A single-arm, single-

50 (all transradial NS

centre study

approach)

A prospective,

single-arm, A prospective, single-arm, 100

30-day MACE 0 %; radial artery

occlusion rate 6 % Change in coronary

Presence/absence

flow reserve

of MACE during

multi-centre study COAST

Still ongoing/not published

hospitalisation 30-day MACE

Procedural success

multi-centre study MACE = major adverse cardiac events; NS = not specified; OA(S) = orbital atherectomy (system); OCT = optical coherence tomography; TLR = target lesion revascularisation; RA = rotational atherectomy.

coronary lesions at 49 US sites from 25 May 2010 to 26 November 2012.14 The Diamondback 360® Coronary OAS was used to prepare severely calcified lesions for stent placement. The primary safety endpoint was 89.6 % freedom from 30-day MACE compared with the performance goal of 83 %. The primary efficacy endpoint (residual stenosis <50 % post-stent without in-hospital MACE) was 88.9 % compared with the performance goal of 82 %. Stent delivery was performed successfully in 97.7 % of cases with <50 % residual stenosis in 98.6 % of subjects. Low rates of in-hospital Q-wave MI (0.7 %), cardiac death (0.2 %) and target vessel revascularisation (0.7 %) were reported. The incidence of slow flow or no reflow in the rotational atherectomy has been reported to be 6 % to 15 %,25,26 whereas in the ORBIT II trial the rate of persistent slow flow/no reflow for orbital atherectomy were notably very low, occurring in 0.9 % of patients.14 Perforations occurred in 1.8 % of patients compared with 0.4 % to 2.5 % in the several rotational atherectomy studies reporting on this complication.5,6,27–30 The ORBIT II perforation rate is within the previously reported range. The ORBIT II trial met both the primary safety and efficacy endpoints by significant margins and not only helped facilitate stent delivery, but also improved both acute and 30-day clinical outcomes compared with historical controls in this difficult-to-treat patient population. The comparison study by Kini et al. assessed the mechanistic difference of impact by rotational atherectomy and orbital atherectomy with OCT.31 Although the number of the study population was limited, precise imaging analyses revealed that tissue modification with deep dissections in around a third of lesions after rotational atherectomy and orbital atherectomy; however, post-orbital atherectomy dissections were significantly deeper than post-rotational atherectomy (1.14 versus 0.82 mm; P=0.048). Stents after orbital atherectomy were associated with a significantly lower per cent of stent strut malapposition than those after rotational atherectomy (4.36 versus 8.02 %; P=0.038).

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In comparison with rotational atherectomy, more significant modification of heavily calcified plaques by the orbital atherectomy led to better stent expansion and apposition, which might result in a lower MACE rate in the previous two landmark studies.

Patient Selection for Coronary Orbital Atherectomy System The indication of rotational atherectomy according to the expert consensus and guidelines is for calcified lesions, which, in the absence of plaque modification, confer an increased likelihood of procedural failure, stent under expansion, restenosis and major complications.9,10,12,32 Although routine use of rotational atherectomy did not improve outcomes after DES implantation,5,6 such a device might technically be required in cases of tight and calcified lesions, to allow subsequent passage of balloons and stents. In most cases, the simple passage of a single burr is sufficient to smoothen the vessel lumen, or to disrupt the continuity of intravascular calcium rings, to enable subsequent balloon dilatation and stent implantation. Orbital atherectomy is indicated for severe calcium of coronary de novo lesions. In addition, since the OAS could simplify the procedure with its small crown size and adjustable ablation diameter with the rotational speed control, the procedural simplification could extend the clinical application of the orbital atherectomy device to several potential situations as follows.

Multi-vessel Disease With Severely Calcified Lesions Patients with multi-vessel disease and severely calcified lesions are less likely to have undergone complete revascularisation,3 resulting in a higher residual Syntax score which is a powerful determinant of prognosis.4 Both rotational atherectomy and orbital atherectomy can facilitate the device delivery and complete revascularisation, which could help achieve a lower residual Syntax score. So far there is

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not robust evidence that the decalcification strategy with rotational atherectomy and extensive metallic stent implantation could improve clinical outcomes.5,33 This should be investigated and proved with use of orbital atherectomy.

Lesion Preparation for Implantation of Bioresorbable Scaffolds

Figure 4: Typical Case Example of Angiography and Optical Coherence Tomography Images Pre- and Post-orbital Atherectomy 72 years old, Male/Stable angina Hypertension (+) Dyslipidemia (+) Diabetis (+) BMI 27.5 Cr 0.9 mg/dL

Bioresorbable scaffolds appear to overcome the limitations of the permanent metallic stents, but technically require more extensive lesion preparation, especially in calcified lesions due to its limited mechanical strength. There is resurgence in the use of atherectomy for the purpose of optimal lesion preparation among patients undergoing implantation of bioresorbable scaffolds.34

Ostial lesions, Unprotected Left Main Disease, Chronic Total Occlusions and Stent Ablation As described in the European expert consensus on rotational atherectomy,12 there might still be angiographic settings where a more extensive ablation is desirable, i.e., ostial lesions, unprotected left main disease, chronic total occlusions and stent ablation. Ostial lesions, unprotected left main disease and chronic total occlusions have not been studied in a clinical trial with orbital atherectomy, but crossable lesions might be safely treated with a small crown size and adjustable ablation diameter with the rotational speed control. Stent ablation is contraindicated for orbital atherectomy. Whether orbital atherectomy would improve the outcomes of these lesion settings needs to be proved by future clinical studies.

1.25 mm Classic crown

A’ B’

3.5 x 38 DES

Pre OAS A

C’

OAS run time: 93 s 80,000 rpm x2 120,000 rpm x3 Total ablation volume 2.5 mm3

B’

C’

Post OAS A’

Cost-effectiveness Chamber et al. reported that the coronary OAS device offered a projected cost savings compared with the pooled population of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)/Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials, as high as $4,913 (€4,341), which was enough to offset the cost of the device, while still providing additional savings to the hospital.35,36 Specifically, reduced procedural complications, length of stay and readmission rate contribute to the cost-effectiveness. The economic study based on ORBIT II concluded that even in a low-value scenario, OAS offers a cost per life-year gained or incremental costeffectiveness ratio of $11,895 (€10,511). In the US, treatments are generally considered high value when they cost less than $50,000 (€44,181) per life-year gained, and the OAS result was well below that threshold.

Moussa I, Di Mario C, Moses J, et al. Coronary stenting after rotational atherectomy in calcified and complex lesions. Angiographic and clinical follow-up results. Circulation 1997;96 :128–36. PMID: 9236427 Savage MP, Goldberg S, Hirshfeld JW, et al. Clinical and angiographic determinants of primary coronary angioplasty success. M-HEART Investigators. J Am Coll Cardiol 1991;17 :22–8. PMID: 1987229 Bourantas CV, Zhang YJ, Garg S, et al. Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials. Heart 2014;100 :1158–64. DOI: 10.1136/heartjnl-2013-305180; PMID: 24846971 Farooq V, Serruys PW, Bourantas CV, et al. Quantification of incomplete revascularization and its association with five-year mortality in the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) trial validation of the residual SYNTAX score. Circulation 2013;128 :141–51. DOI: 10.1161/ CIRCULATIONAHA.113.001803; PMID: 23766350 Abdel-Wahab M, Richardt G, Joachim Buttner H, et al. Highspeed rotational atherectomy before paclitaxel-eluting stent

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A patient presenting with stable angina was successfully treated by orbital atherectomy (1.25 mm classic crown) followed by drug-eluting stent implantation. Total orbital atherectomy system (OAS) run time was 93 seconds (two passes at 80,000 rpm and three passes at 120,000 rpm). Comparisons of pre-OAS OCT images (A–C) with corresponding post-OAS optical coherence tomography (OCT) images (A’–C’) indicate the ablated areas by OAS (blue shadow).

Conclusion The recent results of OAS trials appear to be encouraging; however, further trials in a randomised fashion are still required to conclude the true value of the OAS. The necessity for sufficient lesion preparation before implantation of bioresorbable scaffolds serves as important driving forces in performing a randomised study to compare the long-term outcomes of the two atherectomy devices and balloon angioplasty in patients with severely calcified lesions. n

implantation in complex calcified coronary lesions: the randomized ROTAXUS (Rotational Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial. JACC Cardiovasc Interv 2013;6 :10–9. DOI: 10.1016/j. jcin.2012.07.017; PMID: 23266232 de Waha S, Allali A, Buttner HJ, et al. Rotational atherectomy before paclitaxel-eluting stent implantation in complex calcified coronary lesions: Two-year clinical outcome of the randomized ROTAXUS trial. Catheter Cardiovasc Interv 2015; DOI: 10.1002/ccd.26290; PMID: 26525804: epub ahead of press Kobayashi Y, Teirstein P, Linnemeier T, et al. Rotational atherectomy (stentablation) in a lesion with stent underexpansion due to heavily calcified plaque. Catheter Cardiovasc Interv 2001;52 :208–11. PMID: 11170330 Brogan WC, 3rd, Popma JJ, Pichard AD, et al. Rotational coronary atherectomy after unsuccessful coronary balloon angioplasty. Am J Cardiol 1993;71 :794–8. PMID: 8456756 Authors/Task Force, Windecker S, Kolh P, et al. 2014 ESC/ EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous

Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35 :2541– 619. DOI: 10.1093/eurheartj/ehu278; PMID: 25173339 10. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58 :e44–122. DOI: 10.1161/CIR.0b013e31823ba622; PMID: 22064601 11. Levine GN, O'Gara PT, Bates ER, et al. 2015 ACC/AHA/ SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/ AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2016;67 :1235–50. DOI: 10.1016/j. jacc.2015.10.005; PMID: 26498666 12. Barbato E, Carrie D, Dardas P, et al. European expert consensus on rotational atherectomy. EuroIntervention 2015;11 :30–6. DOI: 10.4244/EIJV11I1A6; PMID: 25982648

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Coronary 13. vom Dahl J, Dietz U, Haager PK, 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 14. Chambers JW, Feldman RL, Himmelstein SI, et al. Pivotal trial to evaluate the safety and efficacy of the orbital atherectomy system in treating de novo, severely calcified coronary lesions (ORBIT II). JACC Cardiovasc Interv 2014;7 :510–8. DOI: 10.1016/j.jcin.2014.01.158; PMID: 24852804 15. Adams GL, Khanna PK, Staniloae CS, et al. Optimal techniques with the Diamondback 360 degrees System achieve effective results for the treatment of peripheral arterial disease. J Cardiovasc Transl Res 2011;4 :220–9. DOI: 10.1007/s12265-0109255-x; PMID: 21312013 16. Madhavan MV, Tarigopula M, Mintz GS, et al. Coronary artery calcification: pathogenesis and prognostic implications. J Am Coll Cardiol 2014;63 :1703–14. DOI: 10.1016/j. jacc.2014.01.017; PMID: 24530667 17. Tomey MI, Kini AS, Sharma SK. Current status of rotational atherectomy. JACC Cardiovasc Interv 2014;7 :345–53. DOI: 10.1016/j.jcin.2013.12.196; PMID: 24630879 18. Chambers JW, Diage T. Evaluation of the Diamondback 360 Coronary Orbital Atherectomy System for treating de novo, severely calcified lesions. Expert Rev Med Devices 2014;11 :457–66. PMID: 24961517 19. Kini A, Marmur JD, Duvvuri S, et al. Rotational atherectomy: improved procedural outcome with evolution of technique and equipment. Single-center results of first 1,000 patients. Catheter Cardiovasc Interv 1999;46 :305–11. PMID: 10348127 20. Sotomi Y, Shammas NW, Suwannasom P, et al. Impact of the Orbital Atherectomy System on a Peripheral Calcified Lesion: Quantitative Analysis by Intravascular Echogenicity. JACC Cardiovasc Interv 2015;8 :e205–6. DOI: 10.1016/j. jcin.2015.06.021; PMID: 26386765 21. Sotomi Y, Shlofmitz RA, Nakatani S, et al. Impact of the orbital atherectomy system on a coronary calcified lesion: quantitative analysis by light attenuation in optical coherence tomography. EuroIntervention 2015;11 :e1. DOI: 10.4244/ EIJV11I5A110; PMID: 26390508 22. Parikh K, Chandra P, Choksi N, et al. Safety and feasibility of orbital atherectomy for the treatment of calcified coronary lesions: the ORBIT I trial. Catheter Cardiovasc Interv 2013;81 :1134–9. DOI: 10.1002/ccd.24700; PMID: 23460596 23. Bhatt P, Parikh P, Patel A, et al. Orbital atherectomy system in treating calcified coronary lesions: 3-Year follow-up in

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24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

first human use study (ORBIT I trial). Cardiovasc Revasc Med 2014;15 :204–8. DOI: 10.1016/j.carrev.2014.03.004; PMID: 24746600 Bhatt P, Parikh P, Patel A, et al. Long-term safety and performance of the orbital atherectomy system for treating calcified coronary artery lesions: 5-Year follow-up in the ORBIT I trial. Cardiovasc Revasc Med 2015;16 :213–6. DOI: 10.1016/j.carrev.2015.03.007; PMID: 25866032 Matsuo H, Watanabe S, Watanabe T, et al. Prevention of no-reflow/slow-flow phenomenon during rotational atherectomy–a prospective randomized study comparing intracoronary continuous infusion of verapamil and nicorandil. Am Heart J 2007;154 :994.e1–6. PMID: 17967610 Kume T, Okura H, Kawamoto T, et al. Assessment of the histological characteristics of coronary arterial plaque with severe calcification. Circ J 2007;71 :643–7. PMID: 17456985 Reisman M, Harms V, Whitlow P, et al. Comparison of early and recent results with rotational atherectomy. J Am Coll Cardiol 1997;29 :353–7. PMID: 9014988 Rathore S, Matsuo H, Terashima M, et al. Rotational atherectomy for fibro-calcific coronary artery disease in drug eluting stent era: procedural outcomes and angiographic follow-up results. Catheter Cardiovasc Interv 2010;75 :919–27. DOI: 10.1002/ccd.22437; PMID: 20432398 Mauri L, Reisman M, Buchbinder M, et al. Comparison of rotational atherectomy with conventional balloon angioplasty in the prevention of restenosis of small coronary arteries: results of the Dilatation vs Ablation Revascularization Trial Targeting Restenosis (DART). Am Heart J 2003;145 :847–54. PMID: 12766743 Furuichi S, Tobaru T, Asano R, et al. Rotational atherectomy followed by cutting-balloon plaque modification for drugeluting stent implantation in calcified coronary lesions. The Journal of invasive cardiology 2012;24 :191–5. Kini AS, Vengrenyuk Y, Pena J, et al. Optical coherence tomography assessment of the mechanistic effects of rotational and orbital atherectomy in severely calcified coronary lesions. Catheter Cardiovasc Interv 2015;86 :1024-32. DOI: 10.1002/ccd.26000; PMID: 25964009 Bangalore S, Vlachos HA, Selzer F, et al. Percutaneous coronary intervention of moderate to severe calcified coronary lesions: insights from the National Heart, Lung, and Blood Institute Dynamic Registry. Catheter Cardiovasc Interv 2011;77 :22–8. DOI: 10.1002/ccd.22613; PMID: 20506328 Foley DP, Pieper M, Wijns W, et al. The influence of stent length on clinical and angiographic outcome in patients

34.

35.

36.

37. 38.

39.

40.

41.

42.

undergoing elective stenting for native coronary artery lesions; final results of the Magic 5L Study. Eur Heart J 2001;22 :1585–93. PMID: 11492988 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. Chambers J, Genereux P, Lee A, Lewin J, Young C, Crittendon J, Mann M and Garrison LP. The potential cost-effectiveness of the Diamondback 360(R) Coronary Orbital Atherectomy System for treating de novo, severely calcified coronary lesions: an economic modeling approach. Therapeutic advances in cardiovascular disease 2015; PMID: 26702147: epub ahead of press. Genereux P, Madhavan MV, Mintz GS, et al. Ischemic outcomes after coronary intervention of calcified vessels in acute coronary syndromes. Pooled analysis from the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) TRIALS. J Am Coll Cardiol 2014;63 :1845–54. DOI: 10.1016/j.jacc.2014.01.034; PMID: 24561145 Instructions for use "DIAMONDBACK 360® Coronary Orbital Atherectomy System" 2015. Shlofmitz. E, Chambers. J, Moses. JW, Martinsen. B, Meraj. P, Jauhar. R and Shlofmitz. R. Temporary Pacemaker Placement Incidence with the Diamondback 360 Coronary Orbital Atherectomy System Compared to Rotational Atherectomy. J Am Coll Cardiol 2015;66 :SUPPL B. DOI:10.1016/j. jacc.2015.08.1005 Genereux P, Lee AC, Kim CY, et al. Orbital Atherectomy for Treating De Novo Severely Calcified Coronary Narrowing (1-Year Results from the Pivotal ORBIT II Trial). Am J Cardiol 2015;115 :1685–90. DOI: 10.1016/j.amjcard.2015.03.009; PMID: 25910525 Ruisi M, Zachariah J, Ratcliffe J, Lala M, Ruisi P, Huang Y, Diwan R, Daggubati R, Patel T and Kwan TW. Safety and Feasibility of the Coronary Orbital Atherectomy System via the Transradial Approach. J Invasive Cardiol 2015;27 :E252–5. PMID: 26524211 Dib N. Coronary flow reserve following orbital atherectomy and percutaneous revascularization in severely calcified coronary lesions. Available at: https://www.clinicaltrials.gov/ ct2/show/NCT02339545 (accessed 20 March 2016). Stone G. Coronary Orbital Atherectomy System Study (COAST) Available at: https://clinicaltrials.gov/ct2/show/NCT02132611 (accessed 20 March 2016).

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LE ATION.

Primary Angioplasty For Patients in Cardiogenic Shock: Optimal Management J ubin Joseph, T iffa ny Pa t ter s o n , S a t p a l A r r i , H a n n a h M c Co n k e y a n d S i m o n R Re d w o o d King’s College London British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas’ Hospital Campus, London, UK

Abstract Cardiogenic shock complicates approximately 5–10 % of all MI events and remains the most common cause of death among MI cases. Over the past few decades, the mortality rate associated with cardiogenic shock has decreased with the introduction of early revascularisation, although there are limited data for patients with triple-vessel disease and left main stem disease. In more recent years, there have been a number of advances in the mechanical circulatory support devices that can help improve the haemodynamics of patients in cardiogenic shock. Despite these advances, together with progress in the use of inotropes and vasopressors, cardiogenic shock remains associated with high morbidity and mortality rates. This review will outline the management of cardiogenic shock complicating acute MI with a smajor focus on revascularisation techniques and the use of mechanical circulatory support devices.

Keywords Cardiogenic shock, coronary intervention, mechanical circulatory support, myocardial infarction Disclosure: The authors have no conflicts of interest to declare. Received: 7 December 2015 Accepted: 11 January 2016 Citation: Interventional Cardiology Review, 2016;11(1):39–43 DOI: 10.15420/icr.2016.11.1.39 Correspondence: Jubin Joseph, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital, King’s College London, Westminster Bridge Road, London SE1 7EH, UK. E: jubin.joseph@kcl.ac.uk

Cardiogenic shock is a clinical condition of inadequate end-organ perfusion due to cardiac dysfunction (see Table 1). It most commonly occurs in the setting of acute MI with left ventricular failure (~80 % cases),1,2 but can also be caused by right ventricular infarction or late mechanical complications, such as acute mitral regurgitation or ventricular rupture (septal or free wall). Non-infarct-related cardiogenic shock is comparatively rare, and may result from decompensated valvular heart disease and arrhythmias, to name a few mechanisms. The pathophysiology of cardiogenic shock is complex. Myocardial ischaemia induces marked depression of myocardial contractility, this sets into motion a downward spiral of reduced cardiac output and hypotension, which in turn drives further myocardial ischaemia. This severe cardiac dysfunction causes tissue hypoperfusion and may eventually result in death if the vicious cycle is not adequately interrupted by timely treatment measures. In addition to the physiological impairment of myocardial function, cardiogenic shock also induces deleterious systemic responses including pathological vasodilation (after compensatory vasoconstriction), systemic inflammation with capillary leakage and impairment of the microcirculation.1,3 This review will look at the optimal management of patients with cardiogenic shock complicating acute MI, with particular focus on revascularisation therapy and the use of mechanical circulatory support devices.

Historically, MI complicated by cardiogenic shock was associated with a mortality rate of 80–90 %.5 However, with advances in coronary reperfusion techniques over the past few decades, especially with the introduction of primary percutaneous coronary intervention (PCI), the mortality rate has improved to below 50 %.4,6–12 The trend towards better outcomes may also be due to greater awareness of the need for timely treatment, improvements in the medical care of haemodynamically unstable patients as well as the use of mechanical support devices, although this has not yet been clearly demonstrated. Despite this high mortality rate, it is important to note that patients with cardiogenic shock who survive to discharge have a long-term outcome similar to that of patients without cardiogenic shock, with a good functional outcome at 1 year.13,14 This highlights the importance of improving the chance of early survival among patients in cardiogenic shock.

Management Myocardial Reperfusion There is evidence that the high mortality rates associated with cardiogenic shock have improved over time.7,9,11,15,16 This benefit is thought to be due to increased use of coronary revascularisation strategies, which, by restoring flow to the ischaemic myocardium, can limit infarct size as well as interrupt the downward spiral that characterises cardiogenic shock.7,9,15

Incidence and Prognosis of Cardiogenic Shock Cardiogenic shock complicates 5–10 % of acute MI cases, and despite advances in acute care there remains the same incidence (~60,000– 70,000 patients per year in Europe).2,4

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As such, the cornerstone of the management of cardiogenic shock complicating acute MI is prompt revascularisation, as highlighted in the Should We Emergently Revascularize Occluded Coronaries for

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Coronary Table 1: The Diagnostic Criteria of Cardiogenic Shock Cardiogenic Shock Hypotension:

compared with use at the discretion of the interventional practitioner.25 As such, current guidelines recommend use of GP IIb/IIIa inhibitors as bailout therapy for thrombotic complications during PCI and limiting their routine use during PCI for ST-segment elevation MI (STEMI).20,26

Systolic blood pressure <90 mmHg for >30 min, or Vasopressors required to achieve a blood pressure ≥90 mmHg Elevated Left Ventricular Filling Pressures: Pulmonary congestion, or Adequate or elevated filling pressures (wedge pressure >20 mmHg) Signs of impaired organ perfusion (at least one of the following):

During PCI, adjunctive anticoagulation with unfractionated heparin, low-molecular-weight heparin or direct thrombin inhibitors should be co-administered with anti-platelet therapy. With a lack of specific randomised trials in cardiogenic shock, the same recommendations apply as for other types of acute coronary syndromes.20

Altered mental status Cold, clammy skin Oliguria Increased serum lactate levels

Cardiogenic Shock (SHOCK) trial.17 Patients with cardiogenic shock were randomly assigned to initial medical stabilisation or early revascularisation (PCI or coronary artery bypass grafting [CABG] within 6 hours of randomisation and 18 hours of onset of shock). The primary endpoint (all-cause mortality at 30 days) did not differ between the initial medical stabilisation and early revascularisation treatment groups; however, there was a significant decrease in mortality rates at 3 and 6 years in patients assigned to early revascularisation.14,17,18 The number needed to save one life at 1 year by early revascularisation in comparison with initial medical stabilisation is less than eight, and this benefit remained with long-term follow-up. The SHOCK trial also demonstrated the importance of timely revascularisation, with increasing long-term mortality rate as time to revascularisation increased from 0 to 8 hours. However, the overall benefit of revascularisation in cardiogenic shock may extend past the traditional 12-hour window to potentially 54 hours post-MI and 18 hours after the onset of shock.18,19 In current European Society of Cardiology (ESC) guidelines, early revascularisation by either PCI or CABG for cardiogenic shock is recommended,20 but despite a general increase in the trend to perform early revascularisation, real-world rates remain relatively low (50–70 %).2,14,21

Anti-platelet and Anti-thrombotic Medication The clinical syndrome of cardiogenic shock impairs enteral absorption, which may result in suboptimal bioavailability of oral agents.22 In addition, patients in cardiogenic shock often require mechanical ventilation and this poses problems with oral medication (often overcome with nasogastric tube insertion and delivery of crushed tablets), which further complicates matters.23 In general, patients with cardiogenic shock should be given aspirin as is routinely recommended in acute coronary syndromes; however, administration of oral P2Y12 inhibitors should be deferred until coronary angiography, as CABG may be immediately required.20 Although not yet licensed in the UK, cangrelor (a fast-acting and rapidly reversible intravenous P2Y12 inhibitor) may prove to useful in these situations where oral anti-platelet administration may be delayed or unreliable.24 Given the abovementioned problems with oral administration of anti-platelet agents, glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors may be beneficial in the management of cardiogenic shock. Observational data suggest a potential mortality benefit with their use in treating cardiogenic shock, but one randomised trial (of only 80 patients) did not demonstrate any benefit of routine abciximab administration

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What is the Ideal Method of Early Revascularisation? Coronary reperfusion can be achieved with thrombolytic therapy (in patients with STEMI), PCI or emergency CABG. There is a paucity of randomised data assessing the efficacy of thrombolytic therapy compared with either placebo or PCI in patients who have cardiogenic shock at presentation. Studies have demonstrated some benefit of thrombolytic therapy compared with placebo, but superiority of PCI or CABG over thrombolytic therapy.18,27,28 Therefore, thrombolytic therapy is recommended only if PCI is not possible or if it is delayed (>90 min) and presenting early after symptom onset (<3 hours), followed by emergent transfer to a PCI facility.20 The prognosis of patients with cardiogenic shock is related to the procedural success of PCI and importantly, patients with cardiogenic shock are less likely to have successful PCI than patients without shock.16 Since the recruitment for the SHOCK trial (where only 37 % of patients undergoing PCI received stents) there have been many advances in PCI: first, bare-metal stents and more recently drugeluting stents have been associated with a greater likelihood of complete revascularisation, a higher incidence of Thrombolysis In MI-3 flow and improved survival rates in patient in cardiogenic shock.29–31 In the current European guidelines, infarct-related cardiogenic shock is an indication for emergency revascularisation with either PCI or CABG, if the patient has suitable coronary anatomy.26 To date, there exist no randomised clinical trials comparing PCI with CABG in patients with cardiogenic shock. In the SHOCK trial, the study protocol recommended CABG for patients with a left main coronary stenosis of ≥50 %, ≥2 total or subtotal occlusions, stenosis of >90 % in two non-infarct-related major arteries or stenosis unsuitable for PCI, as well as in patients whose PCI was unsuccessful.17 However, this decision was made on an individual basis by site investigators and PCI was often performed in patients with three-vessel disease. Among the 128 patients with cardiogenic shock receiving emergency revascularisation (63 % PCI and 37 % CABG) there was a similar mortality rate at 30 days, 1 year and 6 years regardless of the method of revascularisation.14,17,18 However, in current practice, few patients with cardiogenic shock and three-vessel disease are referred for CABG, ranging from 3.2 % to 8.8 %,32 possibly reflecting the real-world difficulties of arranging emergency CABG for patients who often present with cardiogenic shock overnight and at weekends. In summary, in patients with cardiogenic shock complicating acute MI, PCI allows prompt restoration of coronary flow, which may arrest the vicious cycle of myocardial ischaemia and reduced cardiac output. If there is likely to be a significant delay to PCI, thrombolytic therapy should be considered. Finally, urgent CABG should also be considered in the case of unsuccessful PCI, left main disease, three-vessel disease or in the presence of severe valvular disease and mechanical complications of MI.20,26

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Revascularisation of Multi-vessel Coronary Artery Disease

Figure 2: Peripheral Ventricular Assist Devices

The majority (70–80 %) of patients with cardiogenic shock complicating acute MI have multi-vessel disease, which in itself is associated with a higher mortality rate than single-vessel disease.4,33–35 As discussed above, the current evidence does not clearly identify an optimal revascularisation strategy for patients with cardiogenic shock with multi-vessel disease. There are four observational reports comparing PCI with CABG that suggest similar mortality rates;36 however, in current practice, CABG is rarely performed in patients with cardiogenic shock.2,33 Due to the lack of reliable prospective clinical data, guideline recommendations have been based on physiological principles to arrest the downward spiral of myocardial ischaemia and reduced cardiac output. In contrast to the recommendations for haemodynamically stable patients, current guidelines recommend PCI to the culprit lesion followed by PCI to critical lesions (>90 % stenosis) or those with unstable appearances (possible thrombus or lesion disruption) if there is on-going ischaemia or haemodynamic instability.20,26 The on-going prospective, multicentre CULPRIT-SHOCK trial will company culprit-vessel treatment with complete revascularisation in patients with cardiogenic shock.

Revascularisation of Left Main Stem Disease There are no current guidelines on revascularisation for patients with left main coronary artery (LMCA)-related MI complicated with cardiogenic shock. In recent years, together with the increased use of PCI for LMCA in the stable setting, PCI has become the preferred method of revascularisation for patients with LMCA-related acute coronary syndromes.37 The combined SHOCK trial and registry only include 21 patients with LMCA-related MI and there is significant treatment bias in favour of PCI (as many severely unstable patients will be unsuitable for surgical revascularisation), as such it is not possible to draw any valid conclusion from their outcomes.14,38 Given the paucity of evidence, the decision to perform CABG or PCI in patients with cardiogenic shock and LMCA disease should be made on an individual basis taking into account the clinical stability of the patient, coronary anatomy, operator experience and potential risks of either strategy.20,26

Schematic diagram to demonstrate the access sites and mechanisms of action of a) IABP, b) Impella, c) TandemHeart and d) ECMO. ECMO = extracorporeal membrane oxygenation; IABP = intra-aortic balloon pump. Reproduced from Thiele et al.52 with the permission of Oxford University Press and the European Society of Cardiology (© Copyright 2016).

in cardiogenic shock by maintaining organ perfusion while reducing myocardial oxygen demand and augmenting coronary blood flow. Historically, the intra-aortic balloon pump has been the only mechanical circulatory support device available to interventional practitioner during high risk PCI such as with a patient in cardiogenic shock.33 More recently, a number of new devices have become available, including axial flow pumps (e.g. Impella), left atrial to femoral artery bypass pumps (e.g. TandemHeart®) and new devices for the implementation of extracorporeal membrane oxygenation (ECMO) (see Figure 2).

Intra-aortic Balloon Pump The intra-aortic balloon pump (IABP) remains the most commonly used form of circulatory support in patients with cardiogenic shock. The IABP has two major components: a balloon catheter (filled with helium) and a pump console to control the balloon (see Figure 2a). It is commonly inserted via the femoral artery, and the balloon inflates with the onset of diastole (around the middle of the T-wave) and deflates at the onset of left ventricular systole (at the peak of the R-wave).41 This mechanism provides haemodynamic support by increasing diastolic perfusion pressure in the coronary arteries and reducing left ventricular afterload, thereby reducing wall tension and myocardial oxygen demand, resulting in a modest elevation in cardiac output (0.3–0.5 l/min).

Pharmacological Management There have been recent summaries on the use of inotropes and vasopressor agents in patients with cardiogenic shock,39,40 and a review of this is beyond the scope of this article. In brief, regardless of the decision to revascularise, pharmacological stabilisation of the patient in cardiogenic shock is a complex process that requires judicious use of fluids to obtain euvolaemia, vasopressors and inotropes with the aim of preventing multi-organ hypoperfusion and ultimately failure. Despite their almost ubiquitous use and clear effect on haemodynamics, there are no randomised data showing a prognostic benefit with the use of inotropes or vasopressors in the setting of cardiogenic shock. Furthermore, as catecholeamines increase myocardial oxygen consumption and vasoconstrictors may impair the microcirculation as well as tissue perfusion, their use should be restricted to the lowest possible dose for the shortest possible duration.

Mechanical Circulatory Support Mechanical circulatory support should be instituted in patients with cardiogenic shock who remain haemodynamically unstable despite revascularisation and inotrope therapy. 41,42 In general, mechanical circulatory support devices can potentially be of benefit

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The first randomised controlled trial comparing IABP therapy with conservative management in patients with cardiogenic shock (IABPSHOCK; n=45) found a reduction in BNP, but no change in clinical outcomes.43 This was followed with a larger trial of 600 patients with acute MI complicated by cardiogenic shock and randomised patients to either IABP or standard therapy (IABP-SHOCK II), which did not demonstrate a significant reduction in mortality rate at 30 days or 12 months (although 86.6 % of IABPs were inserted post-PCI).44 Current ESC guidelines advise against the routine use of IABP during PCI in patients with cardiogenic shock, and limit their recommendations of its use to patients with cardiogenic shock due mechanical complications of MI who are awaiting surgery.20,26

Left Atrial to Aorta Assist Devices The TandemHeart is a percutaneously inserted circulatory assist device that pumps blood extracorporeally from the left atrium to the iliofemoral arterial system via a transeptally placed atrial cannula, bypassing the left ventricle (see Figure 2b).41 By working in parallel with the left ventricle, this results in a reduction of left ventricle preload, filling pressures, wall stress and myocardial oxygen demand

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Coronary while increasing arterial blood pressure and systemic perfusion (increasing cardiac output up to 4 l/min). A retrospective analysis of patients with refractory cardiogenic shock demonstrated that the TandemHeart improved haemodynamics. 45 This was following by two small randomised controlled trials that demonstrated improved haemodynamics with TandemHeart compared with IABP, but at a cost of increased complications such as severe bleeding, limb ischaemia and arrhythmias.46,47

Left Ventricle to Aorta Assist Device The Impella is a non-pulsatile axial flow Archimedes-screw pump designed to propel blood from the left ventricle into the ascending aorta in conjunction with the left ventricle (see Figure 2c).41 This results in direct unloading of the left ventricle, an increase in forward flow associated with reduction in myocardial oxygen consumption, improvement in mean arterial pressure and reduction in pulmonary capillary wedge pressure. A number of different versions are available: the percutaneous 12-F (Impella 2.5) device and 21-F (Impella 5.0) surgical cut-down device, which provide maximal flow rates of 2.5 and 5.0 l/min, respectively. More recently, a percutaneous 14-F (Impella CP®) device provides an intermediate level of support similar to the TandemHeart (up to 4 l/min). Complications of Impella support include bleeding at the vascular access site, haemolysis and pericardial tamponade, whereas use is contraindicated in patients with severe peripheral vascular disease, presence of a mechanical aortic valve or a severely calcified aortic valve.

mechanical circulatory support device of choice and is able to provide 7 l/min of non-pulsatile flow.41 Similar to cardiopulmonary bypass circuits, V-A ECMO involves a circuit composed of a centrifugal pump, a heat exchanger and a membrane oxygenator. A venous cannula (20F) drains blood from the right atrium into a membrane oxygenator for gas exchange, and then oxygenated blood is pumped into the patient via an arterial cannula (17-F); (see Figure 2d). The main limitation of ECMO is that the retrograde flow of the peripheral arterial cannulation increases afterload, increasing myocardial oxygen demand and can precipitate pulmonary oedema. Conversely, increasing ECMO flow rates in this situation will worsen the haemodynamic situation. A number of techniques can be used to improve left ventricular emptying, including concurrent Impella usage, or venting with a pigtail catheter in the left ventricle, or creation of an atrial septal defect. Failing resolution, central ECMO can be used with direct cannulation of the left ventricle, left artery or pulmonary artery. There are non-randomised data using historical controls suggesting that ECMO use for patients with MI-related cardiogenic shock can improve survival rates.49–51 Although promising, using historical controls rather than a prospective randomised study does not account for other potential temporal advances in management. Although ECMO may improve survival of patients in cardiogenic shock, there is significant procedural morbidity; common complications include limb ischaemia, renal failure, bleeding and infection.41

Conclusion There have been a number of studies demonstrating the safety and haemodynamic benefits of Impella insertion in patients with cardiogenic shock. Recently, in the Efficacy Study of Left Ventricular Assist Device to Treat Patients with Cardiogenic Shock (ISAR-SHOCK) trial, the Impella 2.5 was associated with a greater increase in cardiac output and mean arterial pressure compared with IABP; however, the there was no difference in mortality rates between the two groups.48

Extracorporeal membrane oxygenation The most comprehensive percutaneously inserted mechanical support is provided by ECMO, which can either provide oxygenation only (veno-veno ECMO) or oxygenation with circulatory support (venoarterial [V-A] ECMO). In cases of biventricular failure, V-A ECMO is the

Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation 2008;117:686–97. doi: 10.1161/CIRCULATIONAHA.106.613596. PMID: 18250279. Jeger RV, Radovanovic D, Hunziker PR, et al. Ten-year trends in the incidence and treatment of cardiogenic shock. Ann Intern Med 2008;149:618–26. PMID: 18981487. Thiele H, Allam B, Chatellier G, et al. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J 2010;31:1828–35. doi: 10.1093/eurheartj/ehq220. PMID: 20610640. Goldberg RJ, Spencer FA, Gore JM, et al. Thirty-year trends (1975 to 2005) in the magnitude of, management of, and hospital death rates associated with cardiogenic shock in patients with acute myocardial infarction: a populationbased perspective. Circulation 2009;119:1211–9. doi: 10.1161/ CIRCULATIONAHA.108.814947. Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective, 1975 to 1988. N Engl J Med 1991;325:1117–22. PMID: 1891019. Hochman JS, Boland J, Sleeper LA, et al. Current spectrum of cardiogenic shock and effect of early revascularization on mortality. Results of an International Registry. SHOCK Registry Investigators. Circulation 1995;91:873–81. PMID: 7828316. Goldberg RJ, Gore JM, Thompson CA, Gurwitz JH. Recent magnitude of and temporal trends (1994–1997) in the incidence and hospital death rates of cardiogenic shock complicating acute myocardial infarction: the second national registry of myocardial infarction. Am Heart J 2001;141:65–72.

Redwood_FINAL.indd 42

10.

11.

12.

13.

14.

Early revascularisation remains the cornerstone of the management of patients with cardiogenic shock, although the optimal method remains unclear; patients who have the earliest revascularisation have the best outcomes. In addition to restoring myocardial perfusion, management of patients with cardiogenic shock requires haemodynamic stabilisation, predominantly through careful use of vasopressors and inotropes, which may increase myocardial oxygen demand and thereby cause worsening ischaemia. In more recent years, a number of mechanical circulatory support devices have emerged that provide promising adjuvant therapies for patients in cardiogenic shock. These will allow for angioplasty to be performed in an improved haemodynamic setting and provide a bridge to potential recovery. n

PMID: 11136488. Holmes DR, Bates ER, Kleiman NS, et al. Contemporary reperfusion therapy for cardiogenic shock: the GUSTO-I trial experience. The GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 1995;26:668–74. PMID: 7642857. Goldberg RJ, Samad NA, Yarzebski J, et al. Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 1999;340:1162–8. PMID: 10202167. Holmes DR, Berger PB, Hochman JS, et al. Cardiogenic shock in patients with acute ischemic syndromes with and without ST-segment elevation. Circulation 1999;100:2067–73. PMID: 10562262. Babaev A, Frederick PD, Pasta DJ, et al. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005;294:448–54. PMID: 16046651. TRIUMPH Investigators, Alexander JH, Reynolds HR, et al. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock: the TRIUMPH randomized controlled trial. JAMA 2007;297:1657–66. PMID: 17387132. Singh M, White J, Hasdai D, et al. Long-term outcome and its predictors among patients with ST-segment elevation myocardial infarction complicated by shock: insights from the GUSTO-I trial. J Am Coll Cardiol 2007;50:1752–8. PMID: 17964038. Hochman JS, Sleeper LA, Webb JG, et al. Early

15.

16.

17.

18.

19.

revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA 2006;295:2511–5. PMID: 16757723. Meinertz T, Kasper W, Schumacher M, Just H. The German multicenter trial of anisoylated plasminogen streptokinase activator complex versus heparin for acute myocardial infarction. Am J Cardiol 1988;62:347–51. PMID: 3046283. Zeymer U, Vogt A, Zahn R, et al. Predictors of in-hospital mortality in 1333 patients with acute myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary intervention (PCI); Results of the primary PCI registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK). Eur Heart J 2004;25:322–8. PMID: 14984921. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 1999;341:625–34. PMID: 10460813. Hochman JS, Sleeper LA, White HD, et al. One-year survival following early revascularization for cardiogenic shock. JAMA 2001;285:190–2. PMID: 11176812. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/ AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed

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20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2013;82:E1–27. doi: 10.1002/ccd.24776. PMID: 23299937. Steg PG, James SK, Gersh BJ. 2012 ESC STEMI guidelines and reperfusion therapy: Evidence-based recommendations, ensuring optimal patient management. Heart 2013;99:1156–7. doi: 10.1136/heartjnl-2013-304498. PMID: 23827860. Aissaoui N, Puymirat E, Tabone X, et al. Improved outcome of cardiogenic shock at the acute stage of myocardial infarction: a report from the USIK 1995, USIC 2000, and FASTMI French nationwide registries. Eur Heart J 2012;33:2535–43. doi: 10.1093/eurheartj/ehs264. PMID: 22927559 Součková L, Opatřilová R, Suk P, et al. Impaired bioavailability and antiplatelet effect of high-dose clopidogrel in patients after cardiopulmonary resuscitation (CPR). Eur J Clin Pharmacol 2013;69:309–17. doi: 10.1007/s00228-012-1360-0. PMID: 22890586 Van Herck JL, Claeys MJ, De Paep R, et al. Management of cardiogenic shock complicating acute myocardial infarction. Eur Heart J: Acute Cardiovasc Care 2015;4:278–97. doi: 10.1177/2048872614568294. PMID: 25624526. Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2015. doi:10.1038/nrcardio.2015.113. PMID: 26283269. Tousek P, Rokyta R, Tesarova J, et al. Routine upfront abciximab versus standard periprocedural therapy in patients undergoing primary percutaneous coronary intervention for cardiogenic shock: The PRAGUE-7 Study. An open randomized multicentre study. Acute Card Care 2011;13:116–22. doi: 10.3109/17482941.2011.567282. PMID: 21526919. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. EuroIntervention 2015;10:1024–94. doi: 10.1016/j.rec.2014.12.006. PMID: 25623431. French JK, Feldman HA, Assmann SF, et al. Influence of thrombolytic therapy, with or without intra-aortic balloon counterpulsation, on 12-month survival in the SHOCK trial. Am Heart J 2003;146:804–10. PMID: 14597928. Bates ER, Topol EJ. Limitations of thrombolytic therapy for acute myocardial infarction complicated by congestive heart failure and cardiogenic shock. J Am Coll Cardiol 1991;18:1077–84. PMID: 1894853. Antoniucci D, Valenti R, Santoro GM, et al. Systematic direct angioplasty and stent-supported direct angioplasty therapy for cardiogenic shock complicating acute myocardial infarction: in-hospital and long-term survival. J Am Coll Cardiol 1998;31:294–300. PMID: 9462570. Chan AW, Chew DP, Bhatt DL, et al. Long-term mortality benefit with the combination of stents and abciximab for cardiogenic shock complicating acute myocardial infarction. Am J Cardiol 2002;89:132–6. PMID: 11792330. Webb JG, Carere RG, Hilton JD, et al. Usefulness of coronary stenting for cardiogenic shock. Am J Cardiol 1997;79:81–4. PMID: 9024744.

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32. W hite HD, Assmann SF, Sanborn TA, et al. Comparison of percutaneous coronary intervention and coronary artery bypass grafting after acute myocardial infarction complicated by cardiogenic shock: results from the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial. Circulation 2005;112:1992– 2001. PMID: 16186436. 33. Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287–96. doi: 10.1056/ NEJMoa1208410. PMID: 22920912. 34. Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol 2003;42:1380–86. PMID: 14563578. 35. Sanborn TA, Sleeper LA, Webb JG, et al. Correlates of oneyear survival inpatients with cardiogenic shock complicating acute myocardial infarction. J Am Coll Cardiol 2003;42:1373–9. PMID: 14563577. 36. Mehta RH, Lopes RD, Ballotta A, et al. Percutaneous coronary intervention or coronary artery bypass surgery for cardiogenic shock and multivessel coronary artery disease? Am Heart J 2010;159:141–7. doi: 10.1016/j.ahj.2009.10.035. PMID: 20102880. 37. Montalescot G, Brieger D, Eagle KA, et al. Unprotected left main revascularization in patients with acute coronary syndromes. Eur Heart J 2009;30:2308–17. doi: 10.1093/ eurheartj/ehp353. PMID: 19720640. 38. Lee MS, Tseng CH, Barker CM, et al. Outcome after surgery and percutaneous intervention for cardiogenic shock and left main disease. Ann Thorac Surg 2008;86:29–34. doi: 10.1016/j.athoracsur.2008.03.019. PMID: 18573394. 39. Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation 2008;118:1047–56. doi: 10.1161/ CIRCULATIONAHA.107.728840. PMID: 18765387. 40. Unverzagt S, et al. Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome. John Wiley & Sons, Ltd, 1996. doi:10.1002/14651858.CD009669.pub2 41. Rihal CS, Naidu SS, Givertz MM, et al. 2015 SCAI/ACC/ HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care: Endorsed by the American Heart Assocation, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention*. J Am Coll Cardiol 2015;65:e7–e26. doi: 10.1016/j.jacc.2015.03.036. PMID: 25861963. 42. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–1847. doi: 10.1093/eurheartj/ehs104.

PMID: 22611136. 43. P rondzinsky R, Lemm H, Swyter M, et al. Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome. Crit Care Med 2010;38:152–60. doi: 10.1097/CCM.0b013e3181b78671. PMID: 19770739. 44. Thiele H, Zeymer U, Neumann FJ, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638–45. doi: 10.1016/S0140-6736(13)61783-3. PMID: 24011548. 45. Kar B, Gregoric ID, Basra SS, et al. The percutaneous ventricular assist device in severe refractory cardiogenic shock. J Am Coll Cardiol 2011;57:688–96. doi: 10.1016/j. jacc.2010.08.613. PMID: 20950980. 46. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005;26:1276–83. PMID: 15734771. 47. Burkhoff D, Cohen H, Brunckhorst C, O’Neill WW. TandemHeart Investigators Group. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006;152:469. e1–8. PMID: 16923414. 48. Seyfarth M, Sibbing D, Bauer I, et al. A randomized clinical trial to evaluate the safety and efficacy of a percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol 2008;52:1584–8. doi: 10.1016/j.jacc.2008.05.065. PMID: 19007597. 49. Tsao NW, Shih CM, Yeh JS, et al. Extracorporeal membrane oxygenation-assisted primary percutaneous coronary intervention may improve survival of patients with acute myocardial infarction complicated by profound cardiogenic shock. J Crit Care 2012;27:530.e1–11. doi: 10.1016/j. jcrc.2012.02.012. PMID: 22591567. 50. Sheu JJ, Tsai TH, Lee FY, et al. Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock. Crit Care Med 2010;38:1810–7. doi: 10.1097/CCM.0b013e3181e8acf7. PMID: 20543669. 51. Aissaoui N, Luyt CE, Leprince P, et al. Predictors of successful extracorporeal membrane oxygenation (ECMO) weaning after assistance for refractory cardiogenic shock. Intensive Care Med 2011;37:1738–45. doi: 10.1007/s00134011-2358-2. PMID: 21965097. 52. Thiele H, Ohman EM, Desch S, et al. Management of cardiogenic shock. Eur Heart J 2015;36:1223–30. doi: 10.1093/ eurheartj/ehv051. PMID: 25732762.

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Coronary

LE ATION.

Determining the Most Appropriate Mode of Coronary Artery Revascularisation in Patients With Diabetes Ehri n J A r m s t r o n g a n d S t e p h e n W Wa l d o Veterans Affairs Eastern Colorado Healthcare System, University of Colorado, Denver, CO, USA

Abstract Obstructive coronary artery disease is a common cause of morbidity and mortality among patients with diabetes mellitus (DM). Previous research has demonstrated that the clinical sequelae of coronary artery disease remains the most common cause of death in this population. As a result numerous observational studies and randomised clinical trials have evaluated the timing and mode of coronary artery revascularisation within this population. In this review, we survey the currently available data informing the indications and optimal method of coronary revascularisation for diabetic patients.

Keywords Diabetes, coronary artery disease, coronary artery bypass grafting, percutaneous coronary intervention Disclosure: EJA is a consultant and advisory board member to Abbott Vascular, Boston Scientific, CSI, Medtronic, Merck and Spectranetics. SWW has no conflicts of interest to declare. Received: 22 January 2016 Accepted: 24 March 2016 Citation: Interventional Cardiology Review, 2016;11(1):44–6 DOI: 10.15420/icr.2016:4:2 Correspondence: Ehrin J Armstrong, MD, MSc, VA Eastern Colorado Healthcare System, Division of Cardiology, University of Colorado School of Medicine, 12605 East 16th Avenue, 3rd Floor, Aurora, CO 80045, USA. E: ehrin.armstrong@gmail.com

Patients with diabetes mellitus (DM) have an increased prevalence of coronary artery disease (CAD) and are more likely to require coronary revascularisation than patients without DM.1 Similar to the general population, CAD remains the most frequent cause of death among patients with DM.2 As the prevalence of DM continues to rise worldwide, the appropriate management and method of revascularisation for diabetic patients will become an increasingly important clinical decision point. In this review, we discuss current data regarding the indications and optimal method of coronary revascularisation among patients with DM.

Asymptomatic Obstructive Coronary Artery Disease Among High-Risk Diabetic Patients Using CT Angiography, Following Core 64 (FACTOR 64) trial randomised patients with diabetes and no symptoms of CAD to screening coronary computed tomography angiography (CCTA) or usual care.5 After a mean follow-up of 4.0 years there was no significant difference in event rates between the screened and unscreened groups (6.2 versus 7.6 %). Randomisation to CCTA resulted in only 36 (8 %) coronary angiographies and 26 (5.8 %) coronary revascularisations. Together these two large randomised trials do not support a strategy of routine testing for CAD among asymptomatic diabetic patients.

Decision to Perform Revascularisation

Among diabetic patients with symptomatic stable CAD, the decision to pursue revascularisation with either a percutaneous or surgical approach was studied in the Bypass Angioplasty Revascularisation Investigation in Type 2 Diabetes (BARI 2D) study.6 In that trial diabetic patients with stable CAD were randomised to either optimal medical therapy with immediate percutaneous or surgical revascularisation at the discretion of the investigator or optimal medical therapy alone. At 5 years there was no difference in overall mortality between the two groups, although the rate of subsequent revascularisation in the medical therapy group was 38 % at 5 years. These results suggest that immediate revascularisation is not necessary among patients with DM and stable CAD in the absence of severe anginal symptoms, while recognising that a significant percentage of patients will eventually require revascularisation due to worsening of their symptoms. For this reason, all patients with DM and unrevascularised CAD should be closely monitored for disease progression.

As with the general population, patients with DM and CAD may present with asymptomatic ischaemia, stable angina or acute coronary syndromes. The clinical presentation and severity of symptoms significantly influences the decision to perform coronary artery revascularisation, as well as the relative timing of such a procedure. Although patients with DM have a higher prevalence of CAD, the majority of patients are asymptomatic before presenting with a myocardial infarction or other cardiovascular event.3 Numerous studies have therefore investigated the use of routine screening for CAD among diabetic patients that do not have overt symptoms. The Detection of Ischaemia in Asymptomatic Diabetics (DIAD) study investigated routine screening for coronary ischaemia using myocardial perfusion imaging among asymptomatic diabetic patients.4 During a mean follow-up of 4.8 years, the overall cardiac event rate was only 2.9 % with an event rate of 2.7 % in the screened group and 3.0 % in the unscreened group. The overall rate of revascularisation was also low at 5.5 % in the screened group and 7.8 % in the unscreened group. Similarly, the Screening For

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Approximately 30 % of patients presenting with an acute coronary syndrome (ACS) have DM and a larger percentage of patients present

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Revascularisation in Patients With Diabetes

with previously undiagnosed diabetes and/or hyperglycaemia.7,8 In large-scale clinical trials of revascularisation for ACS, patients with DM have demonstrated a similar relative benefit (and larger absolute benefit) compared to the overall clinical trial population studied.9 For this reason, diabetic patients presenting with ACS should undergo an early invasive strategy to determine the most appropriate method of revascularisation.

Method of Revascularisation A number of studies have investigated the outcomes of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI). The majority of these trials have enrolled diabetic patients with multivessel CAD and stable angina, although some studies have included patients with unstable angina or non-ST-elevation myocardial infarction (MI).10 Among patients with single-vessel or two-vessel CAD and DM, the majority of guidelines support a strategy of PCI. The exception to this may be the presence of high-grade ostial/proximal left anterior descending (LAD) coronary artery stenosis where a left internal thoracic artery to LAD bypass may provide a mortality benefit relative to angioplasty among diabetic patients. Those results are based on the BARI study, which included a large cohort of diabetic patients with multivessel CAD and at 10 years of follow-up randomisation to CABG was associated with reduced mortality and myocardial infarction compared to coronary angioplasty.11 However, that study and other smaller, contemporaneous trials utilised angioplasty or bare metal stents, making it difficult to extrapolate such findings to contemporary medical practice. In general, those trials reported overall higher rates of revascularisation with diabetic patients relative to the overall study population but no single trial was powered to examine outcomes specific to diabetic patients. Recent meta-analyses and observational studies comparing surgical and percutaneous revascularisation for isolated proximal LAD disease did not find any difference in 3-year mortality, albeit with higher rates of repeat revascularisation in patients treated with PCI (13 versus 7 %).12,13 Although these analyses were not specifically limited to diabetic patients, such studies suggest that PCI and CABG may have clinical equipoise in the setting of diabetic patients with isolated proximal LAD disease and/or proximal LAD disease with disease in second coronary artery amenable to percutaneous revascularisation. The Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) trial was a multinational, multicentre randomised trial of 1,800 patients with three-vessel or left main CAD amenable to surgical or percutaneous revascularisation who were randomised to CABG or PCI.14 The stent used in this study was the TAXUS paclitaxel drugeluting stent, which was a first-generation drug eluting stent (DES) no longer used widely in clinical practice. Relative to the overall cohort, the subgroup of patients with DM had overall higher event rates after either CABG or PCI. CABG was associated with lower 5 year major adverse cardiovascular events (MACE), but patients with a lower atherosclerotic burden assessed by the SYNTAX score had similar outcomes with PCI or CABG.15 More recently, the Randomised Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease (BEST) trial randomised 880 patients with multivessel CAD to CABG versus PCI with everolimuseluting stents.16 At short-term follow-up of 2 years, the rate of death, MI or target vessel revascularisation occurred in 11.0 versus 7.9 % of patients randomised to PCI versus CABG. At a longer-term median follow-up of

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4.6 years, these events occurred in 15.3 % of patients that underwent percutaneous revascularisation and 10.6 % of patients that underwent surgical revascularisation. These endpoints were primarily driven by an increased rate of repeat revascularisation among patients randomised to PCI, as there was no significant difference in the safety endpoint of death, MI or stroke. Approximately 40 % of the patients enrolled in the trial were diabetic, and subgroup analysis suggested that patients with DM derived significantly greater benefit from CABG relative to the nondiabetic subgroup (HR 1.07, 95 % CI [0.65–1.76] for non-diabetics, versus HR 2.24, 95 % CI [1.25–4.0] for diabetics). Consistent with the results of the BEST trial, an observational study of CABG versus PCI with everolimus-eluting stents for diabetics with multivessel disease found that PCI was associated with a similar long-term rate of death (10.5 versus 10.3 %), a lower rate of stroke (2.9 versus 3.9 %), a higher rate of MI (6.4 versus 4.1 %), and a higher rate of repeat revascularisation (22 versus 10.4 %).17 Interestingly, the higher rate of MI after PCI was not observed among patients who underwent complete revascularisation. These findings suggest that complete revascularisation with PCI in diabetic patients may result in similar long-term outcomes to CABG. The The Future REvascularization Evaluation in patients with Diabetes mellitus: optimal management of Multivessel disease trial (FREEDOM) trial specifically examined the outcomes of diabetic patients with multivessel CAD randomised to CABG versus PCI.18 At 5 years of followup, the endpoints of all-cause mortality (10.9 versus 16.3 %) and MI (6.0 versus 13.9 %) were significantly lower among patients randomised to CABG. Secondary analysis also did not find any interaction between the SYNTAX score and outcomes, suggesting that the benefit of surgical revascularisation may be independent of anatomic complexity among diabetic patients with multivessel CAD. Similar results were observed in a smaller randomised trial of Veterans (VA CARDS) with diabetes and multivessel CAD, which was terminated early due to significantly higher event rates in the group randomised to PCI.19 Although the FREEDOM and Veterans Administration Coronary Artery Revascularization in Diabetes (VA CARDS) trials provide compelling evidence for surgical revascularisation over PCI among diabetic patients with multivessel CAD, several limitations of the study populations should be considered. First, the majority of patients in the trials were low-risk for surgery and had preserved ejection fraction; whether these findings apply to patients at higher surgical risk remains uncertain. Second, first-generation DES were utilised in the majority of patients; second-generation DES, which have improved outcomes among diabetic patients, may narrow the outcomes gap among diabetic patients. Based on these results of recent studies, diabetic patients with multivessel CAD who are operative candidates should be evaluated by a multidisciplinary heart team to determine the optimal therapeutic approach, with a goal towards complete revascularisation. Given the long-term mortality benefit observed with CABG in the FREEDOM trial, patients who are younger and/or low-risk for surgery should be referred for surgical revascularisation. As stent technologies continue to evolve, future studies will continue to evaluate whether the therapeutic gap between CABG and PCI will narrow for diabetic patients.

Stent Type and Outcomes Among Patients With Diabetes Drug eluting stents (DES) are associated with significantly decreased rates of restenosis and target lesion revascularisation for both

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Coronary diabetic and non-diabetic patients. Whether specific DES types have a treatment advantage among patients with DM remains an active area of investigation. Among first generation DES, both paclitaxel eluting stents (PES) and sirolimus eluting stents (SES) were shown to reduce rates of repeat revascularisation and major adverse cardiovascular events relative to BMS in diabetic patients.20,21 In a mixed treatment meta-analysis of stent types, SES were associated with reduced rates of major adverse cardiovascular events relative to PES, suggesting that limus-eluting DES may be preferred among patients with DM.22 Two types of zotarolimus eluting stents (ZES) have been studied in diabetic patients. The initial ZES (Endeavor®, Medtronic, Inc) had a short drug elution time and was associated with higher rates of restenosis than contemporaneous stents. The subsequent Resolute® ZES (R-ZES) has a longer elution time of zotarolimus, thereby more effectively inhibiting restenosis. The R-ZES was the first DES specifically approved for use in diabetic patients. This approval was based on a predetermined performance goal of a 14.5 % 1-year rate of target vessel failure (TVF). In a large clinical trial, R-ZES in diabetic patients was associated with a significantly lower rate of TVF (7.8 %) relative to the performance goal.23 Other studies have suggested similar clinical outcomes between R-ZES and everolimus eluting stents (EES) in real-world clinical settings.24 EES are associated with reduced rates of restenosis and target lesion revascularisation relative to first-generation DES. In angiographic and intravascular ultrasound studies of EES and PES in diabetic patients, EES were associated with less neointima formation and lower rates of restenosis.25,26 Similarly, studies of EES versus SES in diabetic patients found that EES are associated with lower rates of restenosis than SES.27 In comparison, a pooled analysis of randomised studies found no difference in efficacy or safety of EES versus PES among

Tsujimoto T, Kajio H, Takahashi Y, et al. Asymptomatic coronary heart disease in patients with type 2 diabetes with vascular complications: a cross-sectional study. BMJ Open 2011;1:e000139. DOI: 10.1136/bmjopen-2011-000139; PMID: 22021872; PMCID: PMC3211053 2. Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46. PMID: 10477542 3. Dagenais GR, Lu J, Faxon DP, et al. Prognostic impact of the presence and absence of angina on mortality and cardiovascular outcomes in patients with type 2 diabetes and stable coronary artery disease: results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. J Am Coll Cardiol 2013;61:702–11. DOI: 10.1016/j.jacc.2012.11.036; PMID: 2341054; PMCID: PMC3701296 4. Young LH, Wackers FJ, Chyun DA, et al; DIAD Investigators. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:1547–55. DOI: 10.1001/jama.2009.476; PMID: 19366774; PMCID: PMC2895332 5. Muhlestein JB, Lappe DL, Lima JA, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR 64 randomized clinical trial. JAMA 2014;312:2234–43. DOI: 10.1001/jama.2014.15825; PMID: 25402757 6. BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503–15. DOI: 10.1056/ NEJMoa0805796; PMID: 19502645; PMCID: PMC2863990 7. Conaway DG, O’Keefe JH, Reid KJ, Spertus J. Frequency of undiagnosed diabetes mellitus in 559 patients with acute coronary syndrome. Am J Cardiol 2005 Aug 1;96:363–5. PMID: 16054458 8. Arnold S V, Stolker JM, Lipska KJ, et al. Recognition of incident diabetes mellitus during an acute myocardial infarction. Circ Cardiovasc Qual Outcomes 2015;8:260–7. DOI: 10.1161/ CIRCOUTCOMES.114.001452; PMID: 25901045; PMCID: PMC4439264 9. Norhammar A, Malmberg K, Diderholm E, et al. Diabetes mellitus: the major risk factor in unstable coronary artery disease even after consideration of the extent of coronary artery disease and benefits of revascularization. J Am Coll Cardiol 2004;43:585–91. PMID: 14975468 10. Armstrong EJ, Rutledge JC, Rogers JH. Coronary artery revascularization in patients with diabetes mellitus. Circulation 2013;128:1675–85. DOI: 10.1161/CIRCULATIONAHA.113.002114; PMID: 24100481; PMCID: PMC3901842

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diabetic patients, suggesting that EES may not have significant benefit compared to PES.28 Based on conflicting data with outcomes of different DES types among patients with diabetes, the recently reported Taxus Element versus Xience Prime in a Diabetic Population Taxus Element versus Xience Prime in a Diabetic Population (TUXEDO)-India) study randomised 1,830 patients with diabetes to PCI with PES or EES.29 At 1 year, patients randomised to paclitaxel had significantly higher rates of target vessel failure (5.6 versus 2.9 %) and stent thrombosis (2.1 versus 0.4 %). These results suggest that EES are significantly favoured over PES among patients with diabetes. Overall, clinical studies have demonstrated that improvements in stent design have been associated with reduced rates of target lesion revascularisation and reduced stent thrombosis among diabetic patients. Recent randomised data suggest that EES are favored over PES; other related drugs such as zotarolimus likely have a similar anti-restenotic effect. Future developments in stent technologies for treatment of diabetic patients will include clinical outcomes of bioresorbable scaffolds, which could be a useful treatment for diffuse disease or treatment of LAD disease among patients who may require future therapeutic options.

Conclusion Coronary artery disease remains highly prevalent among diabetic patients. Research has demonstrated that complete surgical revascularisation is appropriate for symptomatic patients given the lower rate of repeat revascularisations needed, though advances in percutaneous techniques and stent technologies make percutaneous revascularisation an increasingly attractive option for this population. Among currently available stents, everolimus eluting stents are associated with the lowest rates of target lesion revascularisation and stent thrombosis among diabetic patients. Future studies will evaluate newer stent design technologies in diabetic patients, including bioresorbable polymer and bioresorbable scaffold technologies. n

11. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol 2007;49:1600–6. PMID: 17433949 12. Kapoor JR, Gienger AL, Ardehali R, et al. Isolated disease of the left anterior descending artery: comparing the effectiveness of percutaneous coronary interventions and coronary artery bypass surgery. J Am Coll Cardiol Intv 2008;1:483–91. DOI: 10.1016/j.jcin.2008.07.001; PMID: 19463349 13. Hannan EL, Zhong Y, Walford G, et al. Coronary artery bypass graft surgery versus drug-eluting stents for patients with isolated proximal left anterior descending disease. J Am Coll Cardiol 2014;64:2717–26. DOI: 10.1016/j.jacc.2014.09.074; PMID: 25541122 14. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629–38. DOI: 10.1016/ S0140-6736(13)60141-5; PMID: 23439102 15. Mack MJ, Banning AP, Serruys PW, et al. Bypass versus drug-eluting stents at three years in SYNTAX patients with diabetes mellitus or metabolic syndrome. Ann Thorac Surg 2011;92:2140–6. DOI: 10.1016/j.athoracsur.2011.06.028; PMID: 21967819 16. Park SJ, Ahn JM, Kim YK, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med 2015;372:1204–12. DOI: 10.1056/NEJMoa1415447; PMID: 25774645 17. Bangalore S, Guo Y, Samadashvili S, et al. Everolimus eluting stents versus coronary artery bypass graft surgery for patients with diabetes mellitus and multivessel disease. Circ Cardiovasc Intv 2015;8:e002626. DOI: 10.1161/ CIRCINTERVENTIONS.115.002626; PMID: 26156152 18. Farkouh ME, Domanski M, Sleeper LA, et al; FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375–84. DOI: 10.1056/NEJMoa1211585; PMID: 23121323 19. Kamalesh M, Sharp TG, Tang XC, et al. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol 2013;61:808–16. DOI: 10.1016/j.jacc.2012.11.044; PMID: 23428214 20. Kirtane AJ, Ellis SG, Dawkins KD, et al. Paclitaxel-eluting coronary stents in patients with diabetes mellitus: pooled analysis from 5 randomized trials. J Am Coll Cardiol 2008;51:708–15. DOI: 10.1016/j.jacc.2007.10.035; PMID: 18279734 21. Sinning JM, Baumgart D, Werner N, et al. Five-year results of the Multicenter Randomized Controlled Open-Label Study of the CYPHER Sirolimus- Eluting Stent in the Treatment of Diabetic Patients with De Novo Native Coronary Artery Lesions (SCORPIUS) study: a German multicenter

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23.

24.

25.

26.

27.

28.

29.

investigation on the effectiveness of sirolimus-eluting stents in diabetic patients. Am Heart J 2012;163:446–53. DOI: 10.1016/j.ahj.2011.12.010; PMID: 22424016 Bangalore S, Kumar S, Fusaro M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomized trials. BMJ 2012;345:e5170. DOI: 10.1136/bmj.e5170; PMID: 22885395 Silber S, Serruys PW, Leon MB, et al. Clinical outcome of patients with and without diabetes mellitus after percutaneous coronary intervention with the resolute zotarolimus eluting stent: 2-year results from the prospectively pooled analysis of the international global RESOLUTE program. JACC Cardiovasc Interv 2013;6:357–68. DOI: 10.1016/j.jcin.2012.11.006; PMID: 23523454 von Birgelen C, Basalus MW, Tandjung K, et al. A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: the TWENTE trial. J Am Coll Cardiol 2012;59:1350–61. DOI: 10.1016/j.jacc.2012.01.008; PMID: 22341737 Grube E, Chevalier B, Guagliumi G, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the XIENCE V everolimus-eluting stent vs the TAXUS Liberte paclitaxeleluting stent in diabetic patients with de novo coronary artery lesions. Am Heart J 2012;163:867–75.e1. DOI: 10.1016/j. ahj.2012.02.006; PMID: 22607866 Otake H, Ako J, Yamasaki M, et al. Comparison of everolimusversus paclitaxel-eluting stents implanted in patients with diabetes mellitus as evaluated by three-dimensional intravascular ultrasound analysis. Am J Cardiol 2010;106:492–7. DOI: 10.1016/j.amjcard.2010.03.059; PMID: 20691306 Kim WJ, Lee SW, Park SW, et al; ESSENCE-DIABETES Study Investigators. Randomized comparison of everolimus-eluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus (ESSENCE-DIABETES): results from the ESSENCEDIABETES trial. Circulation 2011;124:886–92. DOI: 10.1161/ CIRCULATIONAHA.110.015453; PMID: 21810659 Stone GW, Kedhi E, Kereiakes DJ, et al. Differential clinical responses to everolimus-eluting and paclitaxel eluting coronary stents in patients with and without diabetes mellitus. Circulation 2011;124:893–900. DOI: 10.1161/ CIRCULATIONAHA.111.031070; PMID: 21824922 Kaul U,Bangalore S, Seth A, et al. Paclitaxel-eluting versus everolimus-eluting coronary stents in diabetes. N Engl J Med 2015;373:1709–19. doi: 10.1056/NEJMoa1510188; PMID: 26466202

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The use of the Cre8 Stent in Patients With Diabetes Mellitus D i d i e r Ca r r i é Department of Cardiology, University Hospital Rangueil, Toulouse, France

Abstract Despite improved clinical outcomes following the availability of second-generation drug eluting stents (DES), percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among patients with diabetes mellitus (DM) than among non-diabetics. The Cre8™ Amphilimus-eluting DES is polymer-free, resulting in a reduced inflammatory response and lower risk of stent thrombosis. It showed equivalent efficacy and safety in diabetic and non-diabetic populations, a unique finding among DES studies. These findings were confirmed in a real-world study called INVESTIG8. Another real-world study, pARTicip8, is ongoing. The RESERVOIR clinical trial recruited patients with diabetes mellitus and showed noninferiority of the Cre8 DES compared to an everolimus-eluting DES but showed a statistical superiority of Cre8 in diabetic patients with higher metabolic dysfunctions. The Cre8 DES is therefore a valuable option for this important patient population.

Keywords Percutaneous coronary interventions, drug eluting stent, diabetes, clinical trial Disclosure: The author has no conflicts of interest to declare. Acknowledgements: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Alvimedica. Professor Antonio Colombo (Milan, Italy) and Dr Rafael Romaguera (Barcelona, Spain), as the primary investigators of the pARTicip8 and RESERVOIR trials, respectively, have reviewed this paper for accuracy. Received: 22 January 2016 Accepted: 15 March 2016 Citation: Interventional Cardiology Review, 2016;11(1):47–50 DOI: 10.15420/icr.2016.11.1.47 Correspondence: Professor Didier Carrié, Chief of Service, Department of Cardiology, University Hospital Rangueil, 1 Avenue du Professeur Jean Poulhès, 31400 Toulouse, France. E: carrie.didier@chu-toulouse.fr

According to the International Diabetes Federation, 382 million people had diabetes in 2013, with diabetes mellitus (DM) accounting for around 90 % of all diabetes cases. By 2025 the number will rise to 592 million.1 The association between DM and cardiovascular disease is well established2 and percutaneous coronary intervention (PCI) is associated with worse clinical and angiographic outcomes among the diabetic patient population than among non-diabetics.3 Despite improvements in interventional techniques and advances in stent technology, this difference in outcomes persists. There is a greater likelihood of restenosis after PCI with drug eluting stent (DES) implantation in diabetic patients, particularly occlusive restenosis.4,5 There is also a higher risk of adverse cardiac events in diabetic patients who undergo DES implantation compared with those who undergo coronary artery bypass grafting (CABG).6–8 Second-generation DES provide superior safety and efficacy results compared with first generation DES and have been successfully used in diabetic patients,9–12 but unmet needs remain in coronary interventions in this growing patient population, leading to the hypothesis that patients with DM need a specialised DES. This article aims to review the clinical evidence in support of the Cre8™ DES in patients with DM.

The Cre8 Drug Eluting Stent The Cre8 DES is polymer-free, eliminating the disadvantages associated with durable and absorbable polymers or their breakdown products. Its drug release system (Abluminal Reservoir Technology) features reservoirs on the outer surface of the stent. These enable controlled drug elution that is directed towards the vessel wall (see Figure 1).

Carrie_FINAL.indd 47

The Amphilimus™ carrier, comprising sirolimus and an organic acid, enhances drug bioavailability. 13 Its optimised permeability allows a homogeneous distribution inside the vessel wall and a uniform action on the whole tissue, enabling an optimal balance between safety and efficacy. The effects of sirolimus are dose dependent; in diabetic patients, more sirolimus is needed to achieve the equivalent anti-proliferative action in healthy cells.14 The organic acid of the Amphilimus formulation increases the permeation of the sirolimus into the cells of diabetic patients. After drug release, a bare metal stent (BMS) remains. The Cre8 DES is covered with a bio inducer surface made of pure carbon, which is biocompatible and does not produce any late inflammatory stimuli inside the treated segment, reducing the inflammatory response and lowering the risk of stent thrombosis.

Clinical Studies Evaluating the Efficacy and Safety of the Cre8 Stent Initial clinical data in support of the efficacy of the Cre8 DES came from the International randomised comparison between DES Limus Carbostent and Taxus drug-eluting stents in the treatment of de novo coronary lesions (NEXT) clinical study, which demonstrated the noninferiority of the Cre8 DES versus a permanent-polymer paclitaxeleluting stent. The primary endpoint was 6-month angiographic in-stent late lumen loss (LLL). The most striking finding of this study was the finding that the LLL in the diabetic subgroup was comparable to that in the general study population, a finding that had not been seen with other DES.15 Following the demonstration of efficacy and safety in the NEXT clinical trial, the next steps in the Cre8 clinical

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Coronary Figure 1: Features of the Cre8 Drug Eluting Stent

development program included two real-world studies. The first was the MultIceNtric and RetrospectiVe REgiStry in ‘real world’ paTients with polymer-free drug elutInG stent CRE8 (INVESTIG8), which features diabetic and non-diabetic participants. The second is an ongoing realworld study in the diabetic population and Prove Abluminal Reservoir Technology Clinical benefit in all comers patients (pARTicip8).

Ploymer-free platform

Abluminal reservoir technology

Amphilimus™ formulation: sirolimus + organic acid

BIS: Bio inducer surface

Figure 2: RESERVOIR clinical Study – Randomisation Flow Chart 112 patients with DM receiving glucose-lowering agents randomisation

AES 56 patients 58 lesions

EES 56 patients 58 lesions

100 % angiographic success

One stent thrombosis Five refused

One death Five refused Angio FU 50 patients 52 lesions

Angio FU 50 patients 51 lesions

9 months QCA analysis

One technical issue

OCT evaluation 49 patients 51 lesions

OCT evaluation 49 patients 50 lesions

Primary endpoint

Median: 284 days

Median: 277 days

Clinical FU 56 patients

12 months

AES = amphilimus-eluting stents; DM = diabetes mellitus; EES = everolimus-eluting stents; FU = follow-up; QCA = qualitative comparative analysis; OCT = optical coherence tomography.

Figure 3: RESERVOIR Clinical Trial – Primary Endpoint (Neointimal Volume Obstruction)

Cumulative frequency (%)

Neointimal volume obstruction (%) EES 16.11 % (± 18.18)

AES 11.97 % (± 5.94)

AES = amphilimus-eluting stents; EES = everolimus-eluting stents

Carrie_FINAL.indd 48

The RESERVOIR Clinical Study Following the promising findings of the NEXT and INVESTIG8 studies, a clinical trial, the Randomised Comparison of Reservoir-based Polymer-free Amphilimus-eluting Stents (AES) versus EverolimusEluting Stents (EES) in Patients with Diabetes Mellitus (RESERVOIR) focused on patients with DM.17 A meta-analysis of 42 trials comparing sirolimus, paclitaxel, everolimus and zotarolimus-eluting DES in diabetic patients, with 22,844 patient years of follow-up, concluded that there was no increased risk of any safety outcome (including very late stent thrombosis) with any DES compared with BMS, and that the EES was the most efficacious and safe of available DES.18 The study concluded that there was an 87 % probability that EES are the most efficacious DES compared with the others and a 62 % probability that they were the least likely to develop stent thrombosis. Therefore the EES was chosen as the control treatment in the RESERVOIR study. The study population comprised patients with DM treated with glucose-lowering agents requiring PCI of a native coronary artery. Exclusion criteria included glycaemic control by lifestyle changes only, prior ST-elevation myocardial infarction (STEMI), presence of a bifurcation >2.5 mm, target vessel left main/ostial left anterior descending (LAD) artery and/or ostial left circumflex artery with indication for CABG, glomerular filtration rate <30 ml/min/1.73 m2, left ventricular ejection fraction <30 % and contraindications to dual antiplatelet therapy (DAPT) for 12 months. Patients (n=112) were randomised either to an AES (Cre8) or an EES (Xience). Angiographic follow up was performed at 9 months with qualitative comparative analysis (QCA). The primary endpoint was neointimal hyperplasia volume obstruction, as assessed by optical coherence tomography at 9 months (see Figure 2).17

100

The INVESTIG8 study had a primary endpoint of the incidence of a clinical composite endpoint (cardiac death/target vessel myocardial infarction [MI] target lesion revascularisation [TLR]) from the index procedure to 12 months. Secondary endpoints included the incidence of a clinical composite endpoint (all deaths/all MI/ any revascularisation) from the index procedure to 12 months; and the incidence of stent thrombosis from baseline procedure to 12 months, classified according to the Academic Research Consortium definition. A data sub-analysis presented at EuroPCR 2015 and not yet published indicates that at 1 year the composite endpoint was observed in 3.5 % of the non-diabetic population and 5 % of those with diabetes. Freedom from events was reported in 97.8 % of the non-diabetic study population and 95.6 % of those with diabetes. Definite and probable stent thrombosis occurred in only 0.6 % of the non-diabetic and 1.4 % of the diabetic population.16

100

Mean glycated haemoglobin (HbA1c) at baseline was 7.5 % ± 1.2 % across both treatment groups. Insulin was used for diabetes control in 21 (37.5 %) and 24 (42.9 %) patients in the Cre8 and Xience treatment groups, respectively. Before the index procedure, reference vessel diameter (RVD) was 2.69 ± 0.54 mm and 2.55 ± 0.49 mm for the Cre8 and Xience groups, respectively. The acute gain in-stent was 1.59 ± 0.40 mm

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The use of the Cre8 Stent in Patients With Diabetes Mellitus

Figure 4: Prespecified Subgroup Analysis in the RESERVOIR Clinical Trial NEOINTIMAL VOLUME OBSTRUCTION Number of lesions All

Difference (95 % CI)

101

-4.14 (-9.64–0.61)

p for interation

Stent length

>20 mm <20 mm

49 52

-6.92 (-19.93–0.5) -1.92 (-9.02–3.14)

0.376

Stent diameter

>3 mm <3 mm

55 46

-3.96 (-14.16–1.63) -3.63 (-12.51–2.24)

0.952

Target vessel

LAD non-LAD

41 60

-0.33 (-3.24–2.93) -7.46 (-17.8–0.6)

0.193

DM treatment

Insulin Oral drugs

39 62

-9.17 (-22.24–1.28) -0.59 (-3.33–2.27)

0.119

HDL

≤median >median

49 48

-5.87 (-15.37– -0.05) -1.75 (-10.61–4.66)

0.467

LDL

>median ≤median

48 49

-9.11 (-19.96– -0.09) 1.52 (-1.24–4.66)

0.054

HbA1c

>median <median

49 49

-10.62 (-22.58–=1.69) 2.20 (-1.0–5.52)

0.020

-22

AES better

EES better

AES = amphilimus-eluting stents; CI = confidence interval; EES = everolimus-eluting stents; HbA1c: glycated haemoglobin; HDL = high-density lipoprotein; LAD = left anterior descending; LDL = low-density lipoprotein.

Figure 5: RESERVOIR Trial, Secondary Endpoint (Percentage of Uncovered Struts) 3.4

3.5

0.5

2.5

2.2

2 1.5 0.9

1 0.6

0.5

Late lumen loss (mm)

All p > 0.4

3 Struts (%)

Figure 6: Late Lumen Loss in the NEXT, RESERVOIR and pARTicip8 Studies

0.4 0.3 0.2

Uncovered AES

Uncovered and malapposed

EES

AES = amphilimus-eluting stents; EES = everolimus-eluting stents

0.14 ± 0.24

NEXT (diabetic sub-group)

PARTicip8 (diabetic sub-group)

RESERVOIR

Randomised study

All-comers study

0.1 0

0.16 ± 0.13

0.12 ± 0.29

Company sponsored studies

(Cre8) and 1.54 ± 0.43 mm (Xience); in-segment was 1.22 ± 0.46 mm and 1.17 ± 0.60 mm for Cre8 and Xience groups, respectively.The primary endpoint, neointimal volume obstruction was seen in 11.97 ± 5.94 % of patients in the Cre8 group and 16.11 ± 18.18 % of patients in the Xience group (p for noninferiority = 0.0003; p for superiority = 0.22; see Figure 3). Prespecified subgroup analysis showed that the superior performance of the Cre8 was demonstrated across all subgroups. In addition, the Cre8 was statistically superior in the subgroup in which HbA1c levels were above median – see Figure 4.

DM = diabetes mellitus

In terms of secondary endpoints, the percentage of uncovered struts was similar in both patient groups (see Figure 5). The Cre8 also showed noninferiority in minimal lumen diameter and diameter stenosis. The two groups also showed similar findings in terms of

The PARTicip8 Study

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Carrie_FINAL.indd 49

Randomised study in DM Independent study

clinical events at 12 months. In addition, the LLL in the Cre8 was 0.14 ± 0.24 mm compared with 0.24 ± 0.57 mm in the Xience. The Cre8 LLL was also evaluated in the NEXT clinical study.15 Also noteworthy is the low standard deviation of the Cre8 compared with the Xience, suggesting that data from the Cre8 are highly consistent. This can be explained by the amphilimus formulation, which increases the sirolimus permeation into the cells.

The pARTicip8 clinical observational prospective study recruited 1,186 ‘real world’ patients with ischaemic myocardial symptoms related to de novo lesions in native coronary arteries,

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Coronary in 30 European sites.19 One hundred patients from a pre-specified diabetic subgroup were submitted to angiographic follow-up. The primary endpoint was a composite of cardiac death, target vessel MI and CI TLR at 6 months from the index procedure. Secondary endpoints included incidence of the endpoint at 30 days, one year and yearly up to 5 years, stent thrombosis and angiographic measurements in-stent and in-segment. PARTicip8 data presented at the Transcatheter Cardiovascular Therapeutics annual meeting in 2015 show that the primary endpoint, device oriented major adverse cardiac event (MACE) was observed in 2.0 % (95 % confidence interval [CI] [1.26 – 2.95 %]) in the overall population and 3.4 % (95 % CI [1.63 – 6.13 %]) in the diabetic population.19 Of note was the CI TLR at 6 months: 0.5 % in the overall population and 0.78 % in the diabetic subgroup. The LLL in the diabetic subgroup was 0.16 ± 0.13 mm, a similar value to those obtained in the NEXT and RESERVOIR studies (see Figure 6). At 1 year the device oriented MACE was reported in 2.8 % of the overall population and 4.7 % of the diabetic subpopulation, the CI TLR was 1 % in the overall

IDF, IDF International Diabetes Atlas 6th edition. Available at: www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf. (Accessed on 6 March 2016) Grundy SM, Benjamin IJ, Burke GL, et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134–46. PMID: 10477542 Mathew V, Gersh BJ, Williams BA, et al. Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era: a report from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2004;109:476–80. PMID: 14732749 Van Belle E, Abolmaali K, Bauters C, et al. Restenosis, late vessel occlusion and left ventricular function six months after balloon angioplasty in diabetic patients. J Am Coll Cardiol 1999;34:476–85. PMID: 10440162 Elezi S, Kastrati A, Pache J, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998;32:1866–73. PMID: 9857865 Qiao Y, Ma C, Nie S, et al. Twelve months clinical outcome of drug-eluting stents implantation or coronary artery bypass surgery for the treatment of diabetic patients with multivessel disease. Clin Cardiol 2009;32:E24–30. DOI: 10.1002/ clc.20413; PMID: 19455692 De Luca G, Schaffer A, Verdoia M, et al. Meta-analysis of 14 trials comparing bypass grafting vs drug-eluting stents in diabetic patients with multivessel coronary artery disease. Nutr Metab Cardiovasc Dis 2014;24:344–54. DOI: 10.1016/j. numecd.2013.11.002; PMID: 24373711 Li X, Kong M, Jiang D, et al. Comparing coronary artery

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10.

11.

12.

13.

population and 1.4 % in the diabetic subgroup. These findings add to the growing body of clinical data in support of the Cre8 DES and demonstrate efficacy and safety in real world use.

Conclusion Patients with DM undergoing coronary interventions remain at high risk for stent restenosis and adverse cardiovascular events despite the availability of second generation DES. Clinical trials and real-world data show that the formulation of the antiproliferative drug with an amphiphilic carrier in the Cre8 stent could result in improved efficacy in those challenging patients. The Cre8 DES has demonstrated remarkable consistency in terms of LLL across three clinical studies. The RESERVOIR clinical trial is the first study to show statistical superiority of Cre8 in diabetics patients with HbA1c >7.3 %. These data and the findings from other clinical and real-world studies, suggest a high efficacy of the Cre8 in patients with DM. A larger clinical trial is warranted to confirm these important findings. n

bypass grafting with drug-eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease: a meta-analysis. Interact Cardiovasc Thorac Surg 2014;18:347–54. DOI: 10.1093/icvts/ivt509; PMID: 24345688 Tarantini G, Nai Fovino L, Tellaroli P, et al. Optimal duration of dual antiplatelet therapy after second-generation drug-eluting stent implantation in patients with diabetes: The SECURITY (Second-Generation Drug-Eluting Stent Implantation Followed By Six- Versus Twelve-Month Dual Antiplatelet Therapy)diabetes substudy. Int J Cardiol 2016;207:168–76. DOI: 10.1016/j.ijcard.2016.01.068; PMID: 26803236 Buja P, D’Amico G, Facchin M, et al. Gender-related differences of diabetic patients undergoing percutaneous coronary intervention with drug-eluting stents: a real-life multicenter experience. Int J Cardiol 2013;168:139–43. DOI: 10.1016/j.ijcard.2012.09.049; PMID: 23103143 Tarantini G, Facchin M, Capodanno D, et al. Paclitaxel versus sirolimus eluting stents in diabetic patients: does stent type and/or stent diameter matter?: long-term clinical outcome of 2,429-patient multicenter registry. Catheter Cardiovasc Interv 2013;81:80–9. DOI: 10.1002/ccd.24445; PMID: 22511311 Buja P, Facchin M, Musumeci G, et al. Paclitaxel- and sirolimus-eluting stents in older patients with diabetes mellitus: results of a real-life multicenter registry. Catheter Cardiovasc Interv 2013;81:1117–24. DOI: 10.1002/ccd.24636; PMID: 22936398 Moretti C, Lolli V, Perona G, et al. Cre8 coronary stent: preclinical in vivo assessment of a new generation polymerfree DES with Amphilimus formulation. EuroIntervention 2012;7:1087–94. DOI: 10.4244/EIJV7I9A173; PMID: 22130128

14. Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 2010;90:367–417. DOI: 10.1152/ physrev.00003.2009; PMID: 20086080 15. Carrie D, Berland J, Verheye S, et al. A multicenter randomized trial comparing amphilimus- with paclitaxel-eluting stents in de novo native coronary artery lesions. J Am Coll Cardiol 2012;59:1371–6. DOI: 10.1016/j.jacc.2011.12.009; PMID: 22284328 16. Sardella G. The latest available data on polymer-free DES technology in diabetic patients. Presented at Euro PCR, 19–22 May 2015, Paris, France. Available at: www.pcronline.com/ Lectures/2015/The-latest-available-data-on-polymer-free-DEStechnology-in-diabetic-patients. (Accessed 25 February 2016) 17. Romaguera R, Gomez-Hospital JA, Gomez-Lara J, et al. A Randomized Comparison of Reservoir-Based PolymerFree Amphilimus-Eluting Stents Versus Everolimus-Eluting Stents With Durable Polymer in Patients With Diabetes Mellitus: The RESERVOIR Clinical Trial. JACC Cardiovasc Interv 2016;9:42–50. DOI: 10.1016/j.jcin.2015.09.020; PMID: 26762910 18. Bangalore S, Kumar S, Fusaro M, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomised trials. BMJ 2012;345:e5170. DOI: 10.1136/bmj.e5170; PMID: 22885395 19. Carrie D. Polymer-Free Cre8TM DES: Design, Current Status and Future Directions, Presented at TCT 2015 – Transcatheter Cardiovascular Therapeutics; October 11–15, 2015, San Francisco, CA.

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Coronary

Dual Antiplatelet Therapy After Drug-eluting Stent Implantation Gi u l i a M a g n a n i a n d M a r c o Va l g i m i g l i Bern University Hospital, Inselspital, Bern, Switzerland

Abstract The current guidelines for percutaneous coronary intervention use recommend dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor after drug eluting stent (DES) implantation. The optimal duration of DAPT is however area of debate. Recent clinical trials and meta-analyses suggest that the choice of DAPT duration should be tailored individually, based on the balance between ischemic and bleeding risk carried by the patient.

Keywords Dual antiplatelet therapy, drug-eluting stent, myocardial infarction, stent thrombosis, tailored therapy Disclosure: GM has received grants from AstraZeneca, during the conduct of the PEGASUS TIMI-54 study. MV has received fees for serving on advisory boards from AstraZeneca and St. Jude Medical; lecture fees from AstraZeneca, The Medicines Company, Terumo Medical Corporation, St. Jude Medical, Alvimedica, Abbott Vascular and Correvio; travel support from The Medicines Company; and grant support from The Medicines Company and Terumo Medical during the conduction of the MATRIX study. Received: 30 November 2015 Accepted: 17 February 2016 Citation: Interventional Cardiology Review, 2016;11(1):51–3 DOI: 10.15420/icr.2015:17:2 Correspondence: Marco Valgimigli, MD, PhD, Bern University Hospital – Inselspital, Department of Cardiology, Freiburgstrasse 4, 3010 Bern, Switzerland. E: marco.valgimigli@insel.ch

Dual antiplatelet therapy (DAPT), defined as the use of a P2Y12 receptor inhibitor (clopidogrel, ticagrelor or prasugrel) and aspirin, is required after percutaneous coronary intervention (PCI) with drugeluting stents (DES).1 Although the use of DES has been shown to reduce the rate of restenosis as compared with bare-metal stents (BMS), there is concern that DES may be associated with a higher risk of late and very late stent thrombosis (ST),2,3 particularly after DAPT discontinuation.4 DAPT prevents thrombotic complications through a double mechanism. First, DAPT protects the stented segment from ST, which occurs as a result of inflammation during healing.5,6 Second, DAPT confers protection from atherothrombotic events occurring outside the stented segment, lowering the risk of recurrent MI.4,7 The current American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) guidelines on PCI use recommend at least 12 months of DAPT after DES implantation.8 The European Society of Cardiology (ESC) guidelines endorse 6–12 months of DAPT after DES implantation,1 and the ESC and the European Association for Cardio-Thoracic Surgery (ESC/EACTS) recommend 12 months for all patients with acute coronary syndrome (ACS) irrespective of revascularisation strategy.9 However, the optimal duration of DAPT post-DES implantation remains poorly defined. The most recent clinical trials (see Table 1) and meta-analyses in patients who underwent a PCI with stent implantation, have highlighted two key concepts: first, the hazard rate for ischaemic events is not increased with reduced (<12 months) compared with standard (12 months) or prolonged (>12 months) DAPT duration, especially with newer-generation DES10–12 and second, prolonged DAPT reduces the rate of ischaemic events at the cost of increased risk of bleeding.4,13

Valgimigli_FINAL.indd 51

Studies Evaluating Reduced Duration of Dual Antiplatelet Therapy In the Prolonging Dual Antiplatelet Treatment After Grading StentInduced Intimal Hyperplasia Study (PRODIGY) trial, consisting of a population predominantly presenting with unstable coronary artery disease, the use of DAPT for 24 months in patients who had received DES (75 %) was not significantly more effective than a 6-month clopidogrel regimen followed by aspirin monotherapy in reducing the risk of MI or cardiac death.10 However, 24 months of clopidogrel therapy resulted in a significant increase in the number of bleeding episodes, including life-threatening events. In the Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) trial, 6 months of DAPT were related to similar net clinical outcome compared with 12 months of DAPT after PCI with a DES.14 Due to a slow enrolment and low event rates, the trial was stopped prematurely after enrolment of 4,005 of the 6,000 planned. The safety of a reduced DAPT duration compared with 12-month DAPT was confirmed in a meta-analysis of 10 randomised clinical trials (n=32,287), where reduced DAPT duration regimen after PCI with DES was associated with a significant reduction in the rate of major bleeding with no significant differences in ischaemic or thrombotic outcomes.15 On the contrary, prolonged DAPT duration reduced the incidence of thrombotic complications, including ST and MI, at the cost of increased rates of major bleeding. The Zotarolimus-eluting Endeavor Sprint Stent in Uncertain DES Candidates (ZEUS) trial was the first to show that zotarolimus-eluting stent implantation followed by a reduced DAPT duration (median duration of 32 days) resulted in a lower risk of major cardiovascular events, compared with BMS, in a selected population of patients with stable coronary artery disease (SCAD) or ACS at high bleeding

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Coronary Table 1: Studies Comparing Different Durations of DAPT Therapy in Patients Undergoing DES Implantation Trial

Time at randomisation

DAPT regimens (months) Primary endpoint

(months after index PCI) ISAR-SAFE14

4,005

6 versus 12

Composite of death MI, ST, stroke or TIMI major bleeding at

PRODIGY10

2,013 (75 % DES) 1

6 versus 24

Composite of death, MI or CVA at 24 months after PCI

DAPT

9,961

12 versus 30

Definite/probable ST and MACCE defined as composite of death,

OPTIDUAL19

1,385

12 versus 48

Composite of death, MI, stroke or major ISTH bleeding at

15 months after PCI

MI or stroke at 30 months after PCI 48 months after PCI CVA = cerebrovascular accident; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; ISTH = International Society on Thrombosis and Haemostasis; MACCE = major adverse cardiac and cerebrovascular events; PCI = percutaneous coronary intervention; ST = stent thrombosis; TIMI = thrombolysis in myocardial infarction.

or thrombosis risk or at low risk of restenosis.16 Lastly, the recent Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERS FREE) trial, involving patients at high bleeding risk who underwent PCI and were treated with a reduced (1-month) DAPT duration, showed that a drug-coated stent (polymerand carrier-free biolimus A9-coated stent) was superior to BMS with respect to the primary safety (composite of cardiac death, MI and ST) and efficacy (clinically driven target-lesion revascularisation) endpoints.17

Studies Evaluating Prolonged Duration of Dual Antiplatelet Therapy The DAPT trial explored the effect of prolonged (30 months) versus 12-month DAPT (clopidogrel or prasugrel) duration in patients with ACS or SCAD at low risk of ischaemic and bleeding events and undergoing stent implantation.4 After first- or second-generation DES implantation, prolonged DAPT significantly reduce the risk of ST, cerebrovascular events and major adverse cardiovascular events. Confirming a general secondary prevention effect of DAPT, much of the benefit shown in the prolonged DAPT group came from a reduction in the rate of MI unrelated to ST. Of particular interest, it was found that overall the rate of ischaemic events increased during the 3-month period after P2Y12 inhibition discontinuation, regardless of when that occurred.4 These data are confirmed by observations from the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction (PEGASUS-TIMI 54) trial, in which patients with previous MI (39 % with previous DES implantation), enrolled after recent P2Y12 inhibitor withdrawal, were shown to be at increased risk of ischaemic events. This group derived greater benefit in terms of ischaemic risk reduction, from prolonged ticagrelor therapy plus aspirin compared with patients who had remained event-free on aspirin alone.13 Prolonged ticagrelor therapy has also been shown to reduce the rate of major cardiovascular events in patients with a history of MI, regardless of stenting history and stent type, as well as the risk of ST in patients with stents.18 In the DAPT4 and the PEGASUS-TIMI 5413 trials, the benefit in the reduced risk of ischaemic events was accompanied by an increase of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined moderate/severe bleeding and TIMI major bleeding, respectively. Furthermore, in the DAPT trial a higher mortality rate was observed in patients treated with prolonged DAPT compared with

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placebo.4 The increased non-cardiac mortality rate with extended DAPT is of uncertain significance and may be explained by an imbalance in the number of patients with cancer diagnosed before the enrolment, reflected in the higher incidence of cancer-related death observed in the prolonged-DAPT group. Consistent with the findings from the DAPT trial on ischaemic outcomes, a post-hoc analysis from the Optimal Dual Antiplatelet Therapy (OPTIDUAL) trial, showed that in patients at low risk of bleeding who underwent DES implantation, there was a trend toward fewer ischaemic events in the group randomised to prolonged (up to 48 months) DAPT therapy with clopidogrel, compared with those who stopped clopidogrel at 12 months, without increased risk of major bleeding.19

Balancing the Risks of Bleeding and Ischaemic Events Overall, these observations suggest that a 12-month DAPT period does not represent the optimal duration for all patients undergoing a DES implantation, and that the evaluation of DAPT duration should be tailored individually, considering both the bleeding and ischaemic events risk profiles of the patient.15 Individuals at low ischaemic risk, such as patients without ACS who are undergoing PCI, particularly if at high bleeding risk, may be suitable for shortened periods of DAPT, whereas prolonged DAPT (>12 months) could be of more benefit for selected patients without significant bleeding risk or at high ischemic risk, such as patients with previous MI, particularly if presenting with additional cardiovascular risk factors or recurrent ischaemic events. The risk stratification is therefore a crucial step in the decision making regarding DAPT duration. Recently, the DAPT risk score has been presented; this is the first risk score with the advantage of simultaneously assessing both the bleeding and ischaemic risk, thus identifying patients who are likely to derive harm or benefit from prolonged DAPT.20 However, this score was demonstrated in a population free of major bleeding or ischaemic events in the 12-month period of DAPT and should also be validated in other datasets.

Conclusion To further help clinicians in balancing ischaemic and bleeding risks it is necessary to carry out additional studies, as well as exploring secondary analyses of the most recent trials, to individualise the subgroups of patients that derive the greatest benefit from DAPT prolongation. Until then, clinicians should follow a personalised approach, with an ongoing risk–benefit assessment, rather than a standardised approach. n

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DAPT After DES Implantation

Authors/Task Force members, Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541–619. doi: 10.1093/eurheartj/ehu278; PMID: 25173339. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159–68. PMID: 17148711. Valgimigli M, Campo G, Gambetti S, et al. Three-year follow-up of the MULTIcentre evaluation of Single high-dose Bolus TiRofiban versus Abciximab with Sirolimus-eluting STEnt or Bare-Metal Stent in Acute Myocardial Infarction StudY (MULTISTRATEGY). Int J Cardiol 2013;165:134–41. doi: 10.1016/j. ijcard.2011.07.106; PMID: 21864917. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. doi: 10.1056/NEJMoa1409312; PMID: 25399658. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084–89. PMID: 8598866. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. PMID: 9834303. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med

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10.

11.

12.

13.

2001;345:494–502. PMID: 11519503. Levine GN, Bates ER, Blankenship JC, et al. Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–e122. doi:10.1016/j.jacc.2011.08.007. Authors/Task Force Members, Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. doi: 10.1093/ eurheartj/ehv320; PMID: 26320110. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26. doi: 10.1161/CIRCULATIONAHA. 111.071589; PMID: 22438530.s Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014;64:2086–97. doi: 10.1016/j. jacc.2014.09.008; PMID: 25236346. Cassese S, Byrne RA, Tada T, et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: A meta-analysis of randomized trials. Eur Heart J 2012;33:3078–87. doi: 10.1093/eurheartj/ehs318; PMID: 23091199. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J

14.

15.

16.

17.

18.

19. 20.

21.

Med 2015;372:1791–800. doi: 10.1056/NEJMoa1500857; PMID: 25773268. Fiedler KA, Maeng M, Mehilli J, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drugeluting stenting. Eur Heart J 2015;36:1252–63. doi: 10.1093/ eurheartj/ehu523; PMID: 25616646. Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials. BMJ 2015;350:h1618. doi: 10.1136/bmj.h1618; PMID: 25883067. Valgimigli M, Patialiakas A, Thury A, et al. Zotarolimus-eluting versus bare-metal stents in uncertain drug-eluting stent candidates. J Am Coll Cardiol 2015;65:805–15. doi: 10.1016/j. jacc.2014.11.053; PMID: 25720624. Urban P, Meredith IT, Abizaid A, et al. Polymer-free drugcoated coronary stents in patients at high bleeding risk. N Engl J Med 2015;373:2038–47. doi: 10.1056/NEJMoa1503943; PMID: 26466021. Bonaca MP, Bhatt DL, Steg PG, et al. TCT-78 efficacy of longterm ticagrelor in stented patients in PEGASUS-TIMI 54. J Am Coll Cardiol 2015;66(Suppl 15). doi:10.1016/j.jacc.2015.08.121. Helft G, Steg PG, Le Feuvre, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J 2016;37:365–74. doi: 10.1093/ eurheartj/ehv481; PMID: 26364288. Yeh RW. Individualizing treatment duration of dual antiplatelet therapy after percutaneous coronary intervention: an analysis from the DAPT Study. Abstract 20297, LBCT 3.American Heart Association 2015.

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Structural

LE ATION.

Impact of Mitral Regurgitation on Clinical Outcomes After Transcatheter Aortic Valve Implantation C roc ha n J O’ Sulliv an , D a v i d Tü l l e r, Ra i n e r Z b i n d e n a n d Fra n z R E b e r l i Department of Cardiology, Triemli Hospital, Zurich, Switzerland

Abstract Severe aortic stenosis (AS) and mitral regurgitation (MR) are the two most common valvular lesions referred for surgical intervention in Europe and frequently co-exist. In patients with both severe AS and significant MR referred for surgical aortic valve replacement (SAVR), a concomitant mitral valve intervention is typically performed if the MR is severe, despite the higher associated perioperative risk. The management of moderate MR among SAVR patients is controversial and depends on a number of factors including MR aetiology (i.e., organic versus functional MR), feasibility of repair and patient risk profile. Moderate or severe MR is present in up to one-third of patients undergoing transcatheter aortic valve implantation (TAVI), is mainly of functional aetiology and is typically left untreated. Although data are conflicting, a growing body of evidence suggests that significant MR exerts an adverse effect on both short- and long-term clinical outcomes after TAVI. Moderate or severe MR improves in just over half of patients following TAVI and recent data suggest MR is more likely to improve among patients receiving a balloon-expandable as compared with a self-expandable transcatheter heart valve.

Keywords Aortic stenosis, mitral regurgitation, aortic valve replacement, transcatheter aortic valve implantation Disclosure: FRE has received institutional grants from Abbott Vascular, Biotronik and Terumo. The other authors have no conflicts of interest to declare. Received: 29 February 2016 Accepted: 5 April 2016 Citation: Interventional Cardiology Review, 2016;11(1):54–8 DOI: 10.15420/icr.2016:11:1 Correspondence: Crochan O’Sullivan, MD, PhD, Department of Cardiology, Stadtspital Triemli, Birmendorferstrasse 497, 8063 Zurich, Switzerland. E: crochan.osullivan@triemli.zuerich.ch

Aortic stenosis (AS) is the most frequent form of valvular heart disease referred for surgery in Europe and is the second most prevalent form of valvular heart disease in the US.1,2 Conversely, moderate or severe mitral regurgitation (MR) is the most prevalent valvular disease in the US and the second most common form of valvular heart disease requiring surgery in Europe.1,2 AS and MR frequently coexist and the prevalence of both valvular lesions increases with age.2,3 While AS imposes a pressure overload on the left ventricle (LV) leading to LV concentric hypertrophy,4 MR exerts a volume overload leading to progressive LV and LA dilatation.5 Indeed, severe AS may create or even worsen MR by increasing the LV to left atrial pressure gradient thereby augmenting the regurgitant volume for any given effective regurgitant orifice.6 Both valvular lesions can lead to pulmonary hypertension and right ventricular dysfunction in isolation (severe MR more so than severe AS) but the combination of both compound the problem, resulting in hypertrophic remodeling of the pulmonary arterioles and potentially irreversibly elevated pulmonary artery pressures.7 AS is mainly caused by a degenerative inflammatory process, which is typically initiated by mechanical stress of the valve leaflets.4 Conversely, MR aetiology is more heterogeneous and may be categorised as either organic (intrinsic valve lesions) or functional (structurally normal mitral valve but deformation caused by ventricular remodelling).5 Surgical aortic valve replacement (SAVR) has traditionally been considered the gold standard treatment of severe symptomatic AS but up to one-third of patients

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with symptomatic severe AS are denied treatment owing to advanced age and co-morbidities.1,8 Several randomised clinical trials have demonstrated TAVI to be a non-inferior or even a superior alternative to SAVR in high-risk patients with severe AS.9–11 Moderate or severe MR is present in up to one-third of patients undergoing TAVI and the prevalence is even higher among certain AS subgroups such as patients with low ejection fraction, low-gradient (LEF-LG) severe AS (20–55 %).3,12 In contrast to patients undergoing SAVR, significant MR is generally left untreated among patients assigned to TAVI (see Figure 1).3 The aim of this review is to summarise the data to date regarding the effect of significant (i.e. moderate or severe) MR on clinical outcomes after TAVI.

Mitral Regurgitation Aetiology Organic MR is the most common aetiology of MR (60–70 %) and is frequently due to primary myxomatous disease, primary flail leaflets or calcification of the mitral valve apparatus.5 Mitral valve prolapse is an abnormal systolic valve movement into the left atrium (≥2 mm beyond the annular level).5 Prolapse can either be moderate (leaflet tips remain in the LV i.e. billowing mitral valve) or severe (eversion of the leaflet tip into left atrium, i.e. flail leaflet).5 The main phenotypes of mitral prolapse are diffuse myxomatous degeneration (Barlows disease) or primary flail leaflets with ruptured chordae, affecting the posterior leaflet in 70 % of cases.5 The presence of a flail leaflet almost always indicates advanced disease and surgery is required even in asymptomatic low-risk patients with preserved LV function and an LV end-systolic diameter ≥40 mm.1,13 Rarer causes of organic

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Mitral Regurgitation Post-transcatheter Aortic Valve Implantation

MR include endocarditis as well as congenital (cleft leaflet), rheumatic (acute and chronic rheumatic fever), iatrogenic (radiation/drugs) and inflammatory (lupus/anticardiolipin, eosinophilic endocardial disease, endomyocardial fibrosis) conditions.5 While organic MR is more prevalent in the general population, functional MR is more prevalent among elderly patients referred for TAVI.3 This may be related to the high prevalence of concomitant coronary artery disease (40–70 %) among severe AS patients undergoing TAVI. 14 Functional MR is usually related to ischaemia and is caused by apical and inferiorpapillary-muscle displacement due to ischaemic left-ventricular remodeling.5 Papillary-muscle displacement exerts traction on leaflets because chordae are non-extensible, which results in tethered and apically displaced leaflets (tenting). Together with annular flattening, enlargement and decreased contraction, mitral valve tenting results in coaptation loss that results in functional MR.5 It should be noted that ischaemic MR is not synonymous with functional MR since ischaemic papillary muscle rupture is classified as organic MR. Non-ischaemic causes of functional MR include cardiomyopathy, myocarditis and other non-ischaemic causes of left ventricular dysfunction.5 Carpentier proposed to classify MR into three types according to leaflet movement: type I (normal movement), type II (excessive movement) and type III (restrictive movement: IIIa – diastolic restriction; IIIb systolic restriction).5 The assessment of MR severity using echocardiography comprises qualitative (e.g. valve morphology, colour flow regurgitant jet, continuous wave signal of regurgitant jet), semiquantitative (e.g. vena contracta width, systolic pulmonary vein flow reversal) and quantitative (e.g. effective regurgitant orifice area [EROA] and regurgitant volume [R Vol]) methods.15 EROA and R vol can be calculated by either the flow convergence or the Doppler volumetric method.15 Severe primary MR is defined quantitatively as an EROA ≥40 mm2 and a R vol ≥60 ml.1,15 In secondary MR, lower thresholds of severity using quantitative methods, have been proposed (EROA ≥20 mm2 and R vol ≥30 ml) because of their prognostic value.1,15 Other criteria for severe MR are shown in Table 1. The assessment of AS severity is more complicated in the presence of significant MR owing to the fact that forward stroke volume is reduced due to the R vol « lost » in the left atrium.6 Mean transaortic gradient is directly proportional to the square of transvalvular flow meaning that even small reductions in stroke volume can result in significant reductions in the pressure gradient.16 This in turn can lead to guideline discordant mean gradient and aortic valve area values making the grading of AS severity challenging among patients with significant MR.

SAVR and Significant MR Double valve interventions are associated with a higher perioperative mortality rate compared with isolated SAVR.17,18 In the Society for Thoracic Surgeons (STS) registry, the perioperative mortality after double (mitral-aortic) valve intervention was almost three-fold higher (9.4 %) compared with isolated AVR (3.2 %).17,18 The decision to intervene on the mitral valve in the setting of severe AS depends on the severity and the aetiology of MR. In symptomatic patients with severe AS, valve replacement (conventional or percutaneous) is the treatment of choice, while in patients with severe MR, valve repair is generally favoured over replacement if feasible especially among patients with organic disease.4,5 This is mainly due to the fact that mitral valve repair is associated with lower perioperative mortality, improved survival and better preservation of post-operative LV function.1,19

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Figure 1: Severe Aortic Stenosis and Severe Organic Mitral Regurgitation

Example of a 78-year-old male patient with symptomatic severe low ejection fraction, lowgradient (LEF-LG) aortic stenosis (AS) and concomitant severe organic mitral regurgitation (MR) who underwent transcatheter aortic valve implantation (TAVI) with a 29 mm Edwards SAPIEN 3 bioprosthesis A. There was a minimal paravalvular aortic regurgitation following TAVI on transthoracic echocardiography; B. Colour flow mapping demonstrated severe MR persisting after TAVI; C. The severity was confirmed using quantitatively (effective regurgitant orifice area [EROA] = 50mm2 and regurgitant volume = 103 mL); D. A recent study reported that patients with LEF-LG) severe AS and moderate to severe MR have a three-fold higher mortality rate as compared with similar patients with mild or less MR after TAVI.12 Organic MR (as shown in the present example) is less likely to improve after TAVI as compared with functional MR.12

Table 1: Echocardiographic Criteria for the Definition of Severe Mitral Regurgitation Using an Integrative Approach Characteristics Qualitative

Mitral Regurgitation

Valve morphology

Flail leaflet/ruptured papillary muscle/large

coaptation defect

Colour flow

Very large central jet or eccentric jet adhering, swirling,

regurgitant jet

and reaching the posterior wall of the left atrium

CW signal of

Dense/triangular

regurgitant jet Other

Large flow convergence zone

Semiquantitative Vena contracta width (mm) ≥7 (>8 for biplane) Upstream vein flow

Systolic pulmonary vein flow reversal

Inflow (m/s)

E-wave dominant ≥1.5

Other

TVI mitral/TVI aortic >1.4

Quantitative Organic

Functional

EROA (mm2) ≥40

≥20

R Vol (ml/beat)

≥60

≥30

+ enlargement of

LV, LA

cardiac chambers/ vessels CW = continuous wave Doppler; EROA = effective regurgitant orifice area; LA = left atrium; LV = left ventricle; R Vol = regurgitant volume; TVI = time velocity intergral.1

For example, in the STS registry, perioperative mortality was 5.7 % for mitral valve replacement versus just 1.6 % for mitral valve repair.17 Conversely, among patients with severe functional MR of ischaemic aetiology, there appears to be no clear benefit of mitral valve repair over replacement, despite indications from earlier retrospective studies suggesting there was.20,21 A recent multicentre randomised clinical trial revealed no significant differences in left ventricular reverse remodeling or survival at 2 years among patients randomised to repair versus replacement.21 MR recurred more frequently in the

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Structural repair group, leading to more heart-failure-related adverse events and cardiovascular admissions. 21 Whether these results can be extrapolated to patients with severe functional MR undergoing SAVR is uncertain. Among patients undergoing SAVR there is a general consensus that a double-valve operation is indicated in the presence of severe MR.5 The management of moderate MR at the time of SAVR is controversial.22–24 A recent meta-analysis suggested that moderate MR left untreated during SAVR may be associated with worse early and late clinical outcomes, suggesting that double-valve intervention may be indicated in such instances.22 Barreiro et al. reported a higher mortality rate among patients with moderate MR of mainly organic aetiology (63 %) left untreated at the time of SAVR.23 Among patients with moderate functional MR undergoing SAVR, Ruel et al. observed that untreated moderate functional MR had no independent adverse effect on survival at mean follow-up of 5.4 ± 3.4 years.24 AS patients with moderate functional MR and one additional risk factor (left atrial diameter >5 cm, mean/peak gradient <40/60 mmHg or atrial fibrillation [AF]) were at increased risk for the composite outcome of heart failure symptoms, cardiac death or subsequent mitral repair or replacement (hazard ratio [HR] 2.7; p=0.004).24 In the Placement of Aortic Transcatheter Valve (PARTNER) trial, 59 of the 299 patients who underwent isolated SAVR had moderate (90.5 %) or severe (9.5 %) MR.25 As compared to patients with mild or less MR, overall mortality rate at 2 years was significantly higher among patients with moderate or severe MR (49.1 % versus 27.9 %; p<0.01). In addition, moderate or severe MR was an independent predictor of 2-year mortality in multivariate analysis (HR 1.77; 95 % confidence interval [CI] [1.17–2.68]).25 However, in a recent multicentre clinical trial randomising patients undergoing CABG with moderate functional MR of ischaemic aetiology to either CABG alone or CABG plus mitral-valve repair, the addition of mitral valve repair did not improve LV reverse remodeling as compared with CABG alone and led to more adverse events.26 The prevalence of moderate or severe MR was reduced at 1 year in the repair group and whether or not this may improve outcomes over medium- to long-term follow-up remains to be seen.26

Recently three meta-analysis studies have been published assessing the effect of moderate to severe MR on clinical outcomes after TAVI.40–42 First, Nombela-Franco performed a large meta-analysis of eight studies enrolling 8,015 patients (self-expandable valve 43 %, balloonexpandable valve 64 %, 1 % other) assessing the effect of moderate to severe MR on clinical outcomes after TAVI.40 The authors found that overall 30-day mortality rates were significantly increased in patients with moderate-to-severe MR (odds Ratio [OR] 1.49, 95 % CI [1.16–1.92]) although significant heterogeneity was observed across studies (p<0.05).40 While the impact of MR on mortality was not different between self-expandable and balloon-expandable valves in metaregression analysis (p=0.36) significant MR was more likely to improve among patients receiving a balloon expandable valve as compared with a self-expandable valve.40 Several factors were postulated to explain this observation including the possibility that the longer frame of the CoreValve™ system could mechanically interfere with the anterior mitral valve leaflet.30 However, this putative mechanism was not confirmed in a large CoreValve registry.27 The higher prevalence of post-procedural paravalvular aortic regurgitation may maintain volume overload and contribute to less MR improvement in such patients.43,44 Furthermore, CoreValve implantation is associated with a higher rate of both left bundle branch block and permanent pacemaker implantation, which may lead to LV dysynchrony and a negative effect on LV remodeling and consequently less MR improvement.45 Second, Chakravarty et al. performed a meta-analysis of eight studies (three of which were conference abstracts only) enrolling 8,927 patients assessing the impact of moderate to severe MR on outcomes after TAVI.41 The authors observed that mild or less MR was present in 77.8 % and moderate to severe MR in 22.2 % of patients.41 They observed that the presence of moderate to severe MR at baseline was associated with an increased 30-day mortality rate (relative risk [RR] 1.35; 95 % CI [1.14–1.59]; p=0.003) and that the increased mortality associated with moderate-severed MR was not influenced by MR aetiology (p=0.56).41 Finally, Sannino et al. performed a meta-analysis of 13 studies enrolling 4,839 patients undergoing TAVI and observed that all-cause mortality was increased at 30-days after TAVI (effect size -0.18, 95 % CI [-0.31– -0.04]).42

Prevalence of MR in Patients Undergoing TAVI The prevalence of moderate to severe MR among patients undergoing TAVI ranges between 2–33 % of all patients with severe AS undergoing TAVI, but among certain subgroups, such as patients with LEF-LG severe AS, the prevalence is considerably higher (20–55 %).3,12 Only a few studies have provided data on MR aetiology in patients undergoing TAVI.27–34 While organic MR is usually more frequent than functional MR in the general population, the latter is more common than the former among high-risk patients selected for TAVI.3,5 No study to date has reported the prevalence of mixed MR aetiologies (i.e. organic + functional), but it is likely to be significant.

Effect of MR on Short Term Outcomes After TAVI There are studies which suggest an increase in early mortality after TAVI among patients with significant MR at baseline27,33,35–37 and other studies that have not observed this association.12,25,38,39 The reasons for the discrepancies are due to the different definitions used to define significant MR, with some studies evaluating severe MR only,35,37 whereas others report the effect of moderate/severe MR on outcomes after TAVI.25,33,36,38,39 Many retrospective studies may be underpowered to detect differences at 30-days owing to relatively low event rates.

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Effect of MR on Mid- to Long-term Outcomes After TAVI Data from several national registries including the German, Italian, French2 and Spanish TAVI registries observed a significant association between moderate to severe MR and 1 year mortality after TAVI.27,37,46,47 In the French2 and Spanish TAVR registries, there remained only a trend toward higher mortality after adjustment for confounding variables in the multivariate analysis.37,47 Conversely, a post-hoc analysis of the PARTNER Cohort A trial found that moderate to severe MR at baseline did not affect 2-year mortality among TAVI patients (HR 1.14; 95 % CI [0.72–1.78]; p=0.58]), although it did have an impact among patients assigned to SAVR (HR 1.73; 95 % CI [1.01–2.96]; p=0.04).25 NombelaFranco reported in their meta-analysis that 1-year mortality rates were significantly increased among patients with moderate to severe MR (HR 1.32; 95 % CI [1.12–1.55]) and that the impact of MR on mortality was not different between SEV and BEV in meta-regression analysis (p=0.39).40 In the meta-analysis by Chakravarty et al., a strong association between moderate to severe MR and 1-year mortality after TAVI was observed (RR 1.24; 95 % CI [1.13–1.37]; p<0.0001).41 The investigators

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Mitral Regurgitation Post-transcatheter Aortic Valve Implantation

observed that moderate to severe residual MR after TAVI was associated with significantly increased one-year mortality (RR 1.48; 95 % CI [1.31–1.68; p<0.00001]).41 Finally, Sannino et al. found that moderate to severe MR was associated with both 1-year (effect size -0.22; 95 % CI [-0.36– -0.08]) and 2-year (effect size -0.15; 95 % CI [-0.27– -0.02]) mortality rates after TAVI in a meta-analysis enrolling 4,839 patients.42 The results were mainly derived from observational studies that were not specifically designed to assess the impact of MR on mortality. Additionally the PARTNER Cohort A & B trials were the only randomised controlled trials included in these metaanalysis and concomitant severe MR was an exclusion criteria in both PARTNER trial cohorts.9,10 There was also significant heterogeneity across studies for mortality outcome.40–42 Furthermore, the aetiology of MR (functional versus organic) was not available in the majority of studies. These are the main limiting factors for the aformentioned meta-analysis studies.

Effect on MR on Clinical Outcomes of Patients with Low Ejection Fraction, Low-gradient Severe AS Up to one in six patients undergoing TAVI present with LEF-LG severe AS and concomitant MR is present in 30–55 % of these patients.12 A recent study revealed that LEF-LG patients with moderate or severe MR had a three-fold higher rate of overall mortality at one-year (11.5 % versus 38.1 %; adjusted HR 3.27; 95 % CI [1.31–8.15]; p=0.011), as compared with LEF-LG patients with mild or less MR.12 Patients with organic MR had higher one-year mortality rates as compared with those with functional MR (adjusted HR 3.38; 95 % CI [1.32–8.67]; p=0.011).12 However, LEF-LG patients with moderate or severe MR assigned to medical therapy had a dismal prognosis independent of MR severity suggesting that TAVI should not be withheld from symptomatic patients with LEF-LG severe AS even in the presence of moderate or severe MR.12

Changes in MR Severity After TAVI In patients with severe AS and concomitant significant MR, several physiological changes occur following valve implantation that may contribute to reducing MR severity. The LV systolic pressure drops precipitously after TAVR/SAVR thereby reducing the LV-left atrial pressure gradient, leading to a reduction in MR in many patients. The late regression of concentric LV hypertrophy observed following TAVI due to a decrease in LV afterload can lead to favourable mitral valve haemodynamics.48 Furthermore, changes in LV geometry due to a reduction in LV end-diastolic volume and mitral tethering forces observed after TAVI may also lead to an improvement of functional MR (i.e. reverse remodeling).3 Nombela-Franco et al. observed that moderate to severe MR showed improvement in 51 %, no change in 47 % and worsening in 2 %.40 Reassuringly, MR appears to worsen following TAVI in only a minority of patients (2–7 %). Several studies have assessed predictors for MR improvement after TAVI. Toggweiler et al. found that an absence of AF, absence of pulmonary hypertension (pulmonary artery systolic pressure [PASP] <60 mmHg), a mean gradient ≥40 mmHg and functional (as opposed to organic) MR were predictors of MR improvement following TAVI. These findings were confirmed by Bedogni et al., who also found that absence of atrial AF, pulmonary hypertension (PASP ≤55 mmHg) and functional MR were predictive of MR improvement after TAVI. Giordana et al. and Nombela-Franco et al. observed that valve type (BEV versus SEV) was a predictor of MR improvement.34,40 Hekimian et al. observed that

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an LV ejection fraction <50 %, a LV end-systolic diameter ≥36 mm and an LV end-diastolic diameter ≥50 mm were predictors of MR improvement.32 The presence of prosthesis-patient mismatch leads to a residual gradient across the aortic valve and has been shown to be associated with a lesser regression of coexistant MR after SAVR.49–50 TAVI is associated with lower rates of prosthesis-patient mismatch and whether this translates into differences in MR improvement as compared with SAVR remains to be seen.51

Percutaneous Treatment of MR After TAVI Percutaneous mitral valve repair using the Mitraclip® (Abbot Vascular) is associated with improved outcomes compared with conservative therapy in patients with symptomatic severe MR who are deemed high risk or inoperable.52 TAVI patients who remain symptomatic due to significant MR could potentially profit from a staged percutaneous procedure to treat MR. This may be a particularly attractive option for the sub-set of patients with LEF-LG severe AS and moderate to severe MR, who tend to have a particularly high mortality after TAVI. The first description of Mitraclip device being inserted as a staged procedure after TAVI with the Edwards and CoreValve devices was in 2011.53,54 The aortic valve bioprothesis did not seem to interfere with Mitraclip implantation. There is a lack of evidence on the clinical benefits associated with this procedure in the TAVI patient population. However it seems to be technically feasible and it may be a low-risk therapeutic option for patients with significant MR who remain symptomatic after TAVI.

Management Strategy of Patients with Significant MR Undergoing TAVI The management strategy of patients with severe AS and concomitant moderate or severe MR depends on a number of factors including operative risk, MR severity, MR aetiology and likelihood of improvement. Key to decision-making is the evaluation of MR aetiology and severity by quantitative echocardiographic methods, with the use of transoesophageal echocardiography if necessary. Among low or intermediate risk patients with moderate or severe MR, patient selection is critical to identify patients in whom MR will not improve or even progress after SAVR. In such patients with a low likelihood of MR improvement (e.g. patients with severe MR due to a flail leaflet) the increased risk of a double-valve procedure may be worthwhile. Among high risk patients in whom both SAVR and TAVI are options, identification of factors associated with improvement may lead one to choose one procedure over another. Therefore, patients with a high likelihood of MR improvement after the intervention (e.g. patients with low ejection fraction and functional MR) might be selected to undergo TAVI, whereas a combined SAVR and mitral valve repair or replacement may be a more attractive option in patients with a low chance of MR improvement after TAVI. Among inoperable patients, TAVI is the best option if feasible, especially among patients with concomitant MR of functional aetiology. Among inoperable patients who remain symptomatic due to severe MR even after TAVI, percutaneous repair of the mitral valve could be considered, although data remain scarce regarding the feasibility of this approach.53–56

Conclusion Moderate to severe MR is commonly present among patients selected to undergo TAVI and is associated with an increased risk of both early and late mortality after TAVI. However, because of the limitations of the data hitherto available, it is not clear whether this association is related to the MR severity or whether MR is simply a marker of a worse prognosis. Patients with significant MR tend to have worse

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Structural baseline characteristics including poorer LV function and it may not be possible to adjust for all confounders. MR severity typically improves after TAVI in about half of patients and worsens in only a small minority of patients. In the remaining patients, MR severity remains the same. Future study areas include randomised controlled clinical trials

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Vahanian A, Ottavio A, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). The joint task force on the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012;33:2451–96. DOI: 10.1093/eurheartj/ehs109; PMID: 22922415 Nkomo VT, Gardin MJ, Skelton TN et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–11. PMID: 16980116 Nombela-Franco L, Ribeiro HB, Urena M, et al. Significant mitral regurgitation left untreated at the time of aortic valve replacement. A comprehensive review of a frequent entity in the transcatheter aortic valve replacement era. J Am Coll Cardiol 2014;63:2643–58. DOI: 10.1016/j.jacc.2014.02.573; PMID: 24681140 Carabello BA, Paulus WJ. Aortic Stenosis. Lancet 2009;373:956–66. doi: 10.1016/S0140-6736(09)60211-7; PMID: 19232707 Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation. Lancet 2009;373:1382–94. DOI: 10.1016/S01406736(09)60692-9; PMID: 19356795 Unger P, Dedobbeleer C, Van Camp G et al. Mitral regurgitation in patients with aortic stenosis undergoing valve replacement. Heart 2010;96:9–14. DOI: 10.1136/ hrt.2009.165548; PMID: 19321488 O’Sullivan CJ, Wenaweser P, Ceylan O, et al. Effect of pulmonary hypertension hemodynamic presentation on clinical outcomes in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation: Insights from the new proposed pulmonary hypertension classification. Circ Cardiovasc Interv 2015;8:e002358. DOI: 10.1161/ CIRCINTERVENTIONS.114.002358; PMID: 26156149 Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The euro heart survey on valvular heart disease. Eur Heart J 2003;24:1231–43. PMID: 12831818 Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–607. DOI: 10.1056/NEJMoa1008232; PMID: 20961243 Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. DOI: 10.1056/NEJMoa1103510; PMID: 21639811 Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590; PMID: 24678937 O’Sullivan CJ, Stortecky S, Bütikofer A, et al. Impact of mitral regurgitation on clinical outcomes of patients with low-ejection fraction, low-gradient severe aortic stenosis undergoing transcatheter aortic valve implantation. Circ Cardiovasc Interv 2015;8:e001895. DOI: 10.1161/ CIRCINTERVENTIONS.114.00189; PMID: 25657315 Ling LH, Enriquez-Sarano M, Seward JB, et al. Clinical outcome of mitral regurgitation due to flail leaflet. N Engl J Med 1996;335:1417–23. PMID: 8875918 O’Sullivan CJ, Stefanini GG, Stortecky S, et al. Coronary revascularization and TAVI: before, during, after or never? Minerva Med 2014;105:475–85. PMID: 25274461 Lancellotti P, Moura L, Pierard LA, et al. European association of echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307–32. DOI: 10.1093/ejechocard/jeq031; PMID: 20435783 O’Sullivan CJ, Praz F, Stortecky S, Windecker S, Wenaweser P. Assessment of low-flow, low-gradient, severe aortic stenosis: an invasive evaluation is required for decision making. EuroIntervention 2014;SupplU:U81–8. DOI: 10.4244/EIJV10SUA9; PMID: 25256333 O’Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: Part 2 – isolated valve surgery. Ann Thorac Surg 2009;88:S23–42. DOI: 10.1016/j.athoracsur.2009.05.056; PMID: 19559823 Rankin JS, He X, O’Brien SM, et al. The Society of Thoracic Surgeons risk model for operative mortality after multiple valve surgery. Ann Thorac Surg 2013;95:1484–90. DOI: 10.1016/j.athoracsur.2012.11.077; PMID: 23522221 Thourani VH, Suri RM, Rankin JS, et al. Does mitral valve repair offer an advantage over replacement in patients undergoing aortic valve replacement? Ann Thorac Surg 2014;98:598–604. DOI: 10.1016/j.athoracsur.2011.06.083; PMID: 21983074 Reece TB, Tribble CG, Ellmann PI, et al. Mitral repair is superior to replacement when associated with coronary

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assessing the feasibility of percutaneous management of concomitant moderate to severe MR versus medical management among patients undergoing TAVI. Such studies will require centralised core laboratories to define the precise mechanism and severity of MR using quantitative methods and standardied methods of grading MR severity. n

artery disease. Ann Surg 2004;239:671–5. PMID: 15082971; PMCID: PMC1356275 21. Goldstein D, Moskowitz AJ, Glijns AC, et al. Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med 2016;374:344–53. DOI: 10.1056/ NEJMoa1512913; PMID: 26550689 22. Harling L, Saso S, Jarral OA, et al. Aortic valve replacement for aortic stenosis in patients with concomitant mitral regurgitation: should the mitral valve be dealt with? Eur J of Cardiothorac Surg 2011;40:1087–96. DOI: 10.1016/j. ejcts.2011.03.036; PMID: 21570860 23. Barreiro CJ, Patel ND, Fitton TP, et al. Aortic valve replacement and concomitant mitral valve regurgitation in the elderly: Impact on survival and functional outcome. Circulation 2005;112:I-443–I–447. PMID: 16159860 24. Ruel M, Kapila V, Price J, et al. Natural history and predictors of outcome in patients with concomitant functional mitral regurgitation at the time of aortic valve replacement. Circulation 2006;114:I-541–I–546. PMID: 16820634 25. Barbanti M, Webb JG, Hahn RT, et al. Impact of preoperative moderate/severe mitral regurgitation on 2-year outcome after transcatheter and surgical aortic valve replacement: Insight from the Placement of Aortic Transcatheter Valve (PARTNER) trial Cohort A. Circulation 2013;128:2776–84. 26. Smith PK, Puskas JD, Ascheim DD, et al. Surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med 2014;371:2178–88. DOI: 10.1161/ CIRCULATIONAHA.113.003885; PMID: 24152861 27. Bedogni F, Latib A, Brambilla N, et al. Interplay between mitral regurgitation and transcatheter aortic valve replacement with the CoreValve revalving system: a multicentre registry. Circulation 2013;128;2145–53. DOI: 10.1161/ CIRCULATIONAHA.113.001822; PMID: 24088530 28. Tzikas A, Piazza N, van Dalen BM, et al. Changes in mitral regurgitation aftger transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;75:49–9. DOI: 10.1002/ ccd.22197; PMID: 19739261 29. Durst R, Avelar E, McCarty D, et al. Outcome and improvement predictors of mitral regurgitation after transcatheter aortic valve implantation. J Heart Valve Dis 2011;20:272–81. PMID: 21714416 30. De Chiara B, Moreo A, De Marco F, et al. Influence of CoreValve revalving system implantation on mitral valve function: an echocardiographic study in selected patients. Catheter Cardiovasc Interv 2011;78:638–44. DOI: 10.1002/ ccd.23045; PMID: 21805556 31. Samim M, Stella PR, Agostoni P, et al. Transcatheter aortic implantation of the Edwards-SAPIEN bioprosthesis: insights on early benefit of TAVR on mitral regurgitation. Int J Cardiol 2011;152:124–6. DOI: 10.1016/j.ijcard.2011.07.042; PMID: 21840071 32. Hekimian G, Detaint D, Messika-Zeitoun D, et al. Mitral regurgitation in patients referred for transcatheter aortic valve implantation using the Edwards Sapien prosthesis: mechanisms and early post-procedural changes. J Am Soc Echocardiogr 2012;25:160–65. DOI: 10.1016/j.echo.2011.10.001; PMID: 22071307 33. Toggweiler S, Boone RH, Rodès-Cabau J, et al. Transcatheter aortic valve replacement: outcomes of patients with moderate or severe mitral regurgitation. J Am Coll Cardiol 2012;59:2068–74. DOI: 10.1016/j.jacc.2012.02.020; PMID: 22483326 34. Giordana F, Capriolo M, Frea S, et al. Impact of TAVR on mitral regurgitation: a prospective echocardiographic study. Echocardiography 2013;30:250–7. DOI: 10.1111/echo.12050; PMID: 23190425 35. Rodès-Cabau J, Wegg JG, Cheung A, et al. Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience. J Am Coll Cardiol 2010;55:1080–90. DOI: 10.1016/j. jacc.2009.12.014; PMID: 20096533 36. Di Mario C, Eltchaninoff H, Moat, et al. Transcatheter Valve Treatment Sentinel Registry (TCVT) Investigators of the EUROObservational Research Programme (EORP) of the European Society of Cardiology. The 2011-12 pilot European Sentinel Registry of Transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients. EuroIntervention 2013;8:1362–71. DOI: 10.4244/EIJV8I12A209; PMID: 23256965 37. Sabatè M, Canovas S, Garcia E, et al. In hospital and midterm predictors of mortality after transcatheter aortic valve implantation: data from the TAVR National Registry 2010-2011. Rev Esp Cardiol 2013;66:949–58. DOI: 10.1016/j. rec.2013.07.003; PMID: 24774108 38. D’Onofrio A, Gasparetto V, Napodano M, et al. Impact of preoperative mitral valve regurgitation on outcomes after transcatheter aortic valve implantation. Eur J Cardiothorac Surg

2012;41:1271–6. DOI: 10.1093/ejcts/ezr236; PMID: 22219481 39. Hutter A, Bleiziffer S, Richter V, et al. Transcatheter aortic valve implantation in patients with concomitant mitral and tricuspid regurgitation. Ann Thorac Surg 2013;95:77–84. 40. Nombela-Franco L, Eltchaninoff H, Zahn R, et al. Clinical impact and evolution of mitral regurgitation following transcatheter aortic valve replacement: a meta-analysis. Heart 2015;101:1395–405. DOI: 10.1136/heartjnl-2014-307120; PMID: 26060121 41. Chakravarty T, Van Belle E, Jilaihawi H, et al. Meta-analysis of the impact of mitral regurgitation on outcomes after transcatheter aortic valve implantation. Am J Cardiol 2015;115:942–9. DOI: 10.1016/j.amjcard.2015.01.022; PMID: 25779617 42. Sannino A, Losi MA, Schiattarella GG, et al. Meta-analysis of mortality outcomes and mitral regurgitation evolution in 4,839 patients having transcatheter aortic valve implantation for severe aortic stenosis. Am J Cardiol 2014;114:875–82. DOI: 10.1016/j.amjcard.2014.06.022; PMID: 25092192 43. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA 2014;311:1503–14. DOI: 10.1001/jama.2014.3316; PMID: 24682026 44. Jerez-Valero M, Urena M, Webb JG, et al. Clinical impact of the presence of aortic regurgitation following transcatheter aortic valve replacement: insights into the degree and acuteness of presentation. JACC Cardiovasc Intv 2014;7:1022–32. DOI: 10.1016/j.jcin.2014.04.012; PMID: 25234675 45. Alizadeh A, Sanati HR, Haji-Karimi M, et al. Induction and aggravation of atrioventricular valve regurgitation in the course of chronic right ventricular apical pacing. Europace 2011;13:1587–90. DOI: 10.1093/europace/eur198; PMID: 21742681 46. Zahn R, Gerckens U, Linke A, et al. Predictors of one-year mortality after transcatheter aortic valve implantation for severe symptomatic aortic stenosis. Am J Cardiol 2013;112:272–9. DOI: 10.1016/j.amjcard.2013.03.024; PMID: 23578349 47. Van Belle E, Juthier F, Vincentelli A, et al. Does mitral regurgitation impact the outcome of TAVI procedures? Insights from the FRANCE2 Registry. TCT-92. J Am Coll Cardiol 2012;60:B29. 48. Gotzmann M, Lindstaedt M, Bojara W, Mügge A, Germing A. Hemodynamic results and changes in myocardial function after transcatheter aortic valve implantation. Am Heart J 2010;159:926–32. DOI: 10.1016/j.ahj.2010.02.030; PMID: 20435207 49. Unger P, Magne J, Vanden Eynden F, et al. Impact of prosthesis-patient mismatch on mitral regurgitation after aortic valve replacement. Heart 2010;96:1627–32. DOI: 10.1136/hrt.2010.200428; PMID: 20937750 50. Angeloni E, Melina G, Pibarot P, et al. Impact of prosthesispatient mismatch on tthe regression of secondary mitral regurgitation after isolated aortic valve replacement with a bioprosthetic valve in patients with severe aortic stenosis. Circ Cardiovasc Img 2012;5:36–42. DOI: 10.1161/ CIRCIMAGING.111.967612; PMID: 22138006 51. Clavel MA, Webb JG, Pibarot P, et al. Comparison of the hemoynamic performance of percutaneous and surgical bioprostheses for the treatment of severe aortic stenosis. J Am Coll Cardiol 2009;53:1883–91. DOI: 10.1016/j. jacc.2009.01.060; PMID: 19442889 52. Whitlow PL, Feldman T, Pedersen WR, et al. Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. J Am Coll Cardiol 2012;59:130–9. DOI: 10.1016/j.jacc.2011.08.067; PMID: 22222076 53. Barbanti M, Ussia GP, Tamburino C. Percutaneous treatment of aortic stenosis and mitral regurgitation in the same patient: first human cases description. Catheter Cardiovasc Interv 2011;78:650–5. DOI: 10.1002/ccd.23015; PMID: 21793170 54. Madder RD, Safian RD, Gallagher M, Senter SR, Hanzel GS. The first report of transcatheter aortic valve implantation and percutaneous mitral valve repair in the same patient. J Am Coll Cardiol Intv 2011;4:824. DOI: 10.1016/j.jcin.2011.05.009; PMID: 21777894 55. Rudolph V, Schirmer J, Franzen O, et al. Bivalular transcatheter treatment of high-surgical-risk patients with coexisting severe aortic stenosis and significant mitral regurgitation. Int J Cardiol 2013;167:716–20. DOI: 10.1016/j.ijcard.2012.03.060; PMID: 22459381 56. Kische S, D’Ancona G, Paranskaya L, et al. Staged total percutaneous treatment of aortic valve pathology and mitral regurgitation: institutional experience. Catheter Cardiovasc Interv 2013;82:E552–63. DOI: 10.1002/ccd.24809; PMID: 23359543

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Structural

LE ATION.

Hybrid Imaging in the Catheter Laboratory: Real-time Fusion of Echocardiography and Fluoroscopy During Percutaneous Structural Heart Disease Interventions Ja n Ba lzer, To b i a s Z e u s, Ve r e n a Ve u l e m a n s a n d M a l t e Ke l m Division of Cardiology, Pneumology and Angiology, Department of Medicine, University Hospital Duesseldorf, Duesseldorf, Germany

Abstract Percutaneous catheter-based techniques for the treatment of structural heart disease are becoming more complex, and current imaging techniques have limitations: while fluoroscopy gives poor visualisation of cardiac anatomical structures, echocardiography is limited in its ability to detect the position of catheters and devices. The EchoNavigator® (Philips) live image guidance tool is a novel system that integrates real-time echocardiography with fluoroscopic X-ray imaging, optimising the guidance and positioning of devices. Use of the EchoNavigator system facilitates improved understanding of anatomical structures while showing enhanced visualisation of catheter and device movements. Early clinical experience suggests that the technology is feasible and safe, and provides enhanced understanding of the relationship between soft tissue anatomy and catheter devices in structural heart disease. The use of the EchoNavigator system can improve the confidence of interventional cardiologists in the targeting and positioning of devices in percutaneous interventions in structural heart disease, and has the potential to reduce procedural time, reduce the dosage of contrast and radiation and increase safety in the performance of procedural steps.

Keywords Structural heart disease, multimodality imaging, percutaneous intervention, echocardiology Disclosure: JB has received fees for serving as a speaker from Philips Healthcare. All other authors have no conflict of interest to declare. Acknowlegements: Medical Media Communications (Scientific) Ltd provided medical writing and editing support to the author, funded by Philips Healthcare. Received: 19 November 2015 Accepted: 11 January 2016 Citation: Interventional Cardiology Review, 2016;11(1):59–64 DOI: 10.15420/icr.2016.11.1.59 Correspondence: Jan Balzer, Division of Cardiology, Pneumology and Angiology, Department of Medicine, University Hospital Duesseldorf, 40225 Duesseldorf, Germany. E: jan.balzer@med.uni-duesseldorf.de

Percutaneous catheter-based structural heart disease procedures are a rapidly growing area of interventional cardiology, and represent a valuable option for cardiac patients with comorbidities who are ineligible for conventional surgery as well as demonstrating excellent outcomes.1,2 Catheter-based interventions include transcatheter aortic valve implantation (TAVI),3 percutaneous mitral valve (MV) repair,4 atrial septal defect (ASD) closure, percutaneous closure of paravalvular leakages (PVL)5 and left atrial appendage (LAA) closure.6 However, these techniques may involve long procedure times and steep learning curves. During cardiac catheterisation, imaging techniques are required for intra-procedural monitoring; these include echocardiography and X-ray. Fluoroscopy is used to guide the majority of percutaneous interventions. It enables visualisation of catheters and devices but poor visualisation of cardiac anatomical structures, limiting precision in targeting soft tissue lesions in the treatment of structural heart disease.7 In addition, many experts have expressed concern about patient exposure to excess radiation in structural heart disease procedures. Ultrasound imaging using two-dimensional (2D) transesophageal echocardiography (TEE) requires neither contrast nor radiation, and provides detailed images of anatomical structures and lesions, but only provides two spatial dimensions.8 Following the development of three-dimensional (3D) echocardiography, this technique has evolved from a slow and labour-intense off-line

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reconstruction to real-time volumetric imaging, further enhancing the detection of cardiac pathology, especially valvular disease.7,9,10 The major limitation of echocardiography techniques is their limited ability to detect the position of catheters and devices, and therefore a combination of echocardiography and fluoroscopy is still required during interventions. Accurately recognising the heart structures from fluoroscopic and TEE images requires considerable training and experience, and the simultaneous use and interpretation of two imaging techniques during the procedures can be challenging, especially when manipulating and steering the catheters that carry the implant devices. In addition, structural heart disease interventions involve a multidisciplinary team, typically comprising cardiac interventionalists, cardiovascular imaging specialists and specialised nurses. The action of the interventionalist depends on the images provided by the imaging specialist.10 In particular, at the key moments of device deployment, communication between the interventional cardiologist steering the catheters, and the echocardiographer operating the 3D ultrasound equipment, is demanding. There is therefore a need for an imaging system that combines anatomical information from echocardiography with catheter and device visualisation from fluoroscopy. Such an approach requires real-time image co-registration with a sufficient overlay visualisation of both imaging modalities.11

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Structural Figure 1: Release I of the EchoNavigator ® System

Example of a transseptal puncture using release I of the EchoNavigator. The results of the co-registration process are visualised to the interventional cardiologist on a large specific display that can be divided and arranged in up to four sections at discretion of the interventionalist: (1) Free: The Free-view displays 2D and 3D TEE information that can be manipulated by the interventionalist with a sterile covered mouse on the catheter table. (2) Echo: The Echo-view demonstrates online the images from the echo machine that can only be manipulated by the echocardiographer. (3) C-Arm: The beam flow of the matrix array transducer is marked as a purple 3D sector (ie. cone) in the X-ray-view, presenting the 3D Echo information of this sector in the C-Arm-view. (4) X-ray: The X-ray-view displays the actual fluoroscopic view depending on the angulation of the gantry. For a precise co-registration of the TEE probe, the probe has to be central in this view, the correctness of the co-registration being illustrated by a green edging of the probe. Specific points of interest can be marked in the ultrasound image by the interventionalist that will automatically appear on the fluoroscopic image.

Figure 2: Release II of the EchoNavigator ® System

after substantial movement of the TEE probe, the probe displays red edging. The echo view shows images that can only be manipulated by the echocardiographer. The C-arm view shows the beam flow (ie echo cone) of the matrix array transducer as a purple sector corresponding to the position of the TEE probe. Changes in the angulation, rotation or position of the TEE probe automatically appear in this view. The free view displays 2D and 3D information that may be rotated, cropped, zoomed or segmented by the interventional cardiologist by steering with a sterile covered tableside mouse. Multiplanar reconstruction (MPR) software provides tools for 3D volume segmentation along the three axes (x, y, z) in real time or during post-processing and also for quantitative analysis. Specific point of interest can be marked, and are immediately displayed on the fluoroscopic image. These marks then serve as targets to direct catheter manipulations.15 The first release (release I) of the EchoNavigator was only capable of co-registering echocardiography and fluoroscopy data (see Figure 1). The second release (release II) became commercially available in late 2014 (see Figure 2). Release II allows for real-time fusion of both imaging modalities. To date few publications have described the value of the EchoNavigator system (Philips Healthcare), a novel software solution that enables the necessary merging of echocardiographic and fluoroscopic images on the same display in real time, during interventions in structural heart disease. This paper aims to describe the initial experience with this innovative software solution using both the combination of co-registration of markers and the novel fusion imaging technology in the catheter laboratory in structural heart disease interventions. Until now only case reports have demonstrated the value of the new system (release II) during percutaneous interventions.16,17 Recently, our group demonstrated that the application of this innovative fusion imaging EchoNavigator system is effectively capable to reduce radiation exposure and fluoroscopy time both for the patient and the involved medical team.18

Advantages of Fusion Imaging in Cardiac Interventions Example of a transseptal puncture using release II of the EchoNavigator. Note how not only the markers are displayed in the X-ray image taken from the echo image information, but how the entire image information is transferred together with the marker into the X-ray image.

Fusion of Dynamic Imaging: The EchoNavigator System The EchoNavigator system is a multimodality approach that synchronises live echocardiography and fluoroscopy images in real time by a calibration algorithm that tracks the movement of the TEE probe using fluoroscopy based on the movement of the predefined ‘fingerprint’ of the TEE probe (see Figure 1).11,12 This is achieved via an image-based TEE probe localisation algorithm and a calibration procedure.13 After synchronisation of the images, the 3D TEE images automatically track and follow the movement of the fluoroscopy C-arm gantry.14 The results of the co-registration process are displayed in a form that allows the simultaneous visualisation of an X-ray image and up to three echocardiographic views. The X-ray view displays the actual fluoroscopic image. The probe must be central in this view in order to allow precise co-registration of the TEE probe. If this has been achieved, the probe displays a green edging; if not, for example,

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Another recent single-centre study performed by our group evaluated the use of the EchoNavigator software release I in 127 percutaneous interventions for structural heart disease (three paravalvular leaks, 11 atrial septal defects, 31 transapical TAVI procedures, 35 left atrial appendage occlusions, and 47 MitraClip® procedures).19 In this study, due to the fact that we worked with release I, we were only capable of transferring information from the echocardiographic image into fluoroscopy by the means of markers. A particular point of interest was designated in the echocardiographic view and then appeared in fluoroscopy. In order to control the correctness of the marker we moved the marker within the fluoroscopic image. This led to malposition of the marker within the echocardiographic image. By working with the release I of the system during several different types of structural heart disease interventions we can conclude that the information given by the markers is quite reliable, as long as the TEE probe with its 2D and 3D sector view is within the dimension of the gantry. Results of this, and other studies employing the EchoNavigator system are detailed below. Additionally the application of the new release II of the EchoNavigator and its implementation during interventions in structural heart disease is described in detail below.

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Figure 3: A) EchoNavigator速 During Transcatheter Aortic Valve Replacement Procedures. B) Use of EchoNavigator Release II During Transcatheter Aortic Valve Implantation Procedures

Figure 4: EchoNavigator速 During MitraClip速 Procedures A

B B

A: Use of the EchoNavigator Release I during Transcatheter Aortic Valve Replacement (TAVI) procedures. The hinge points of the aortic valve can be marked in the echo image and can then be transposed onto the X-ray image using the software. The gantry can then be turned into the direction in order to reach the line of perpendicularity of these three markers for proper valve implantation; B. After implantation of the Edwards bioprosthesis the exact position of the prosthesis can be seen as the radiolucent structure (white circle) within the copied echocardiographic anatomy of the aortic annulus.

Transcatheter Aortic Valve Implantation TAVI is a valuable alternative to surgery for high risk or inoperable patients with severe, symptomatic aortic stenosis.3 TEE has limited utility in peri-interventional guidance during TAVI, as general anaesthesia may be required and the probe may obstruct the optimal view. However, TEE is useful before and after valve implantation.20 The use of 3D TEE facilitates precise aortic annular sizing and exact delineation of the hinge points during valve sizing and implantation.21 In order to optimise TAVI procedural safety and effectiveness, multimodality imaging enables a precise knowledge of the anatomy of the aortic root and its surrounding structures.22 During TAVI interventions, important landmarks of the aortic root such as the leaflets, the coronary cusps, the sinotubular junction, the anatomic ventriculo-arterial junction, the aortic-mitral curtain and the virtual ring formed by the hinge points of the aortic valvar leaflets are not visible on fluoroscopy but on echocardiography. In addition, the orientation of the prosthesis is crucial for procedural success. The EchoNavigator system allows the transfer of specific echocardiographic markers onto the fluoroscopic image. This enables marking of the level of the annulus and correction of the position of the gantry to the point where all three hinge point markers derived from echocardiography create one orthogonal plane, and thus facilitating catheter guidance and prosthesis placement.16,23 It is important to generate a straight

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A: Implantation of a single MitraClip. Note the typical 3D echo view and the transfer of this information into the X-ray image. The combination of co-registration and fusion allows the transfer of certain landmarks (yellow marker: septum, red marker: crista, white marker: valve) for better orientation within the left atrium. B: Implantation of a second MitraClip. Integration of markers and 2D echo image information into the X-ray image. Note how the remaining pathology is marked within the 3D Echo image for better orientation of the target place of the second Clip within the X-ray image. (yellow marker: septum, red marker: crista, white marker: first clip, green marker: target for the second clip).

line of perpendicularity in order to reach the correct image plain for implantation of the valve.24 This can be achieved by means of the first release of the EchoNavigator (see Figure 3A). Release II of the system allows the interventionalist to virtually fuse both images and therefore transpose the echo image into the X-ray image (see Figure 3B).

Percutaneous Mitral Valve Repair With MitraClip Manoeuvring the MitraClip速 (Abbott Vascular) device during mitral valve repair is a procedure that requires precision to avoid complications such as accidental puncture of the aortic root and perforation of the left atrial wall.10 The optimum means of demonstrating the effects of the MitraClip system is visualisation of the mitral valve by 3D TEE with various offline reconstruction techniques.25 The use of 3D TEE can define the correct height above the mitral valve that is sufficient to allow movement of the delivery guide and device, information that may not be adequately provided by 2D TEE alone.26 However, while TEE allows peri-interventional evaluation of the mitral valve leaflets and annulus, as well as the subvalvular apparatus, fluoroscopy is a superior technique for determining the orientation of the guiding system and the structures of the MitraClip and its grippers. Therefore a multimodality imaging approach during the intervention is of particular value in this technique. Fusion imaging using the EchoNavigator software in percutaneous edge-to-edge repair of mitral valve regurgitation with the MitraClip

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Structural Figure 5: EchoNavigator ® Release II During Left Atrial Appendage Occlusion Procedures

Integration of echo information into the X-ray image after left atrial appendage (LAA) closure. The new release of the EchoNavigator allows for exact delineation of the LAA morphology after device implantation. The opacification of the echo overlay can be reduced in order to more or less delineate the radiolucent device position.

Figure 6: EchoNavigator ® During Closure of Interatrial Septum Defects

improved the visualisation of the complex relationship between catheter devices and anatomical structures during interventions using the MitraClip.19 Fusion imaging using the EchoNavigator system also enhances the safety of the MitraClip procedure. By enabling the interventionalist to designate three echocardiographic orientation points (interatrial septum at puncture site, crista terminalis between pulmonary vein and the LAA and the centre of the mitral valve) into the fluoroscopic image, the system reduces the risk of injury of the left atrium (see Figure 4A). Perforation of the atrial septal wall by the MitraClip can be associated with severe complications resulting in cardiac tamponade.29 In addition, when the deployment of more than one MitraClip is required, it is easy to misjudge the relative positions of the clips as a result of blooming artefacts of the echocardiographic image.30 The EchoNavigator system enables the translation of the residual pathology from the echocardiographic image into the fluoroscopic image, allowing precise implantation of multiple MitraClips (see Figure 4B).10

Treatment of Left Atrial Appendage Occlusion In non-valvular atrial fibrillation, LAA closure has been shown to be safe and effective in patients for whom systemic oral anticoagulation is contraindicated.31 This procedure involves transseptal crossing of the guiding catheter into the left atrium and the placement of the occluder into the LAA. During this procedure, perforation of the LAA wall and laceration of the pulmonary artery can lead to fatal complications.32 Precise knowledge of LAA orifice size is essential to ensure the correct sizing of LAA closure devices, and optimal catheter alignment and precise positioning of the closure device can be challenging.33 A study has demonstrated that real-time 3D TEE is more accurate than 2D TEE for the assessment of LAA orifice size.34 In addition, 3D measurements of the perimeter enable precise definition of the landing zone and correct device selection.33

The translation of echo information into the fluoroscopic image allows for safer device implantation. In this example one can reproduce the correct position of the occluder device in the echocardiographic image. The overlay image enables precise judgement of the relation between the occluder device and the delivery catheter after release of the system in real time.

enhances understanding of the morphological and functional changes during the procedure. In this procedure, the exact site of transseptal puncture within the fossa ovalis for optimal height selection of the delivery system is crucial for successful device delivery. Using the EchoNavigator system the optimal location for the transseptal puncture can be marked on the TEE images. The same marker simultaneously appears on fluoroscopy (release I, see Figure 2A) together with the echo overlay (release II, see Figure 2B), facilitating precise targeting puncture site and assuring correct crossing of the device through the interatrial septum, in particular allowing safe guidance of the clip delivery system, precise positioning of the clip delivery system and accurate alignment of the clip arms.10,11,27 One of the first studies to employ the EchoNavigator system, demonstrated its advantages in terms of facilitating transseptal puncture, understanding mitral valve anatomy, sheath exchange, clip advancement, and post-deployment visualization.28 In a study of 21 patients undergoing MitraClip interventions, the use of the EchoNavigator software was safe and feasible in all patients.12 In addition, a recent study found that the EchoNavigator software

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The EchoNavigator’s use of markers in the echocardiographic images that simultaneously appear in the co-registered X-ray images, facilitates positioning and alignment of the catheter in the LAA and the secure placement of the closure device.11,19,27 The use of markers is helpful to locate otherwise X-ray invisible LAA structures, maximize procedural safety and decrease radiation exposure for the patient and the staff.18 Markers can be placed at the LAA orifice at the level of the circumflex artery, the orifice of the left upper pulmonary vein or at the tip of the LAA.10 The 3D orientation within the LAA can often be difficult, especially due to the nature of its complex structure as described earlier by our group.35 The direct overlay of the echocardiographic 3D information before, during and after the procedure can here be very helpful to better understand the complex relationship between the device and the anatomy of the LAA (see Figure 5).

Interatrial Septum Defect Occlusion The interventional closure of defects of the interatrial septum with transcatheter techniques is used in children and adults. This procedure is safe and effective if guided using TEE alone.36 The use of TEE provides fast and complete information regarding the appropriate deployment and position of the device with regard to the surrounding structures, reducing procedure time and hence radiation exposure.37 However, good communication between the imaging operator and interventional cardiologists is crucial for

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the success of the procedure. The EchoNavigator allows easy visualisation of the defect size and catheter course. A recent study has successfully used the EchoNavigator system in ASD closure, and found that it facilitates safe device implantation (see Figure 6).19

Closure of Paravalvular Leaks Paravalvular leak (PVL) is a known complication of surgical and transcatheter valve replacement procedures and, as a result, percutaneous approaches to PVL have been developed. However, this is a particularly challenging procedure, requiring precise information about the shape and dimensions of the defect to enable selection of the appropriate type, size, and number of devices. 38 Multimodality imaging is particularly advantageous in PVL closure, providing both diagnostic and procedural guidance. 39 The use of 3D TEE enables improved spatial resolution of the defect, especially during placement of the guide wire through the defect after transseptal puncture. 38 The EchoNavigator software has been successfully employed in PVL closure procedures. It reduces procedure time, facilitating location of the lesion and evaluation of the surrounding structures.40 It also facilitates the manipulation of the guidewire through the defect.19 In addition, colour imaging fused with X-ray can be exploited to indicate the location of the leak in real time for efficient device guidance.

Summary and Concluding Remarks As a result of the ageing population and increasing technological advances, the use of percutaneous structural heart interventions is likely to increase. In order to optimise procedural efficacy and safety, accurate imaging of the three-dimensional structure of the heart is essential. Real-time fusion of imaging modalities is essential to facilitate communication between members of the intervention team and increase procedural success. The EchoNavigator system is the first software to allow the merging of echocardiographic and fluoroscopic imaging data in real time during percutaneous interventions. This can reduce procedural time, and our group also recently demonstrated that this innovative fusion imaging technology reduces radiation exposure and fluoroscopic time due to better and faster understanding of the combination of soft tissue anatomy and catheter devices, resulting in less need to X-ray during the procedure.40 18 Typically, interventional cardiologists are more familiar with fluoroscopic than ultrasound images. Information from TEE images is therefore transposed onto the fluoroscopic images. Fusion imaging using the EchoNavigator system facilitates improved understanding of anatomical structures and the spatial relation between the X-ray and ultrasound images, improved communication between imaging and interventional cardiologists, ability of the

Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366 :1696–704. DOI: 10.1056/ NEJMoa1202277 PMID: 2244347.a Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. J Am Coll Cardiol 2014;64 :172–81. DOI: 10.1016/j.jacc.2013.12.062 PMID: 25011722. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364 :2187–98. DOI: 10.1056/NEJMoa1103510 PMID: 21639811. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364 :1395– 406. DOI: 10.1056/NEJMoa1009355 PMID: 21463154. Mookadam F, Raslan SF, Jiamsripong P, et al. Percutaneous closure of mitral paravalvular leaks: a systematic review

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interventionalist to manipulate the 3D TEE images and improved confidence when positioning the interventional device and guiding interventional procedures. Target markers can be used to direct catheter access through a specific defect. With proper ‘calibration’ (ie. using three views), these markers can be very accurate. The rotation and cropping features allow assessment of the relationship of the closure device and the intra-atrial anatomy prior to and after device release. These features can reduce procedural time and increase safety in the performance of procedural steps. An increasing body of data has demonstrated the safety and efficacy of interventions performed using the system but further studies are warranted to fully assess its clinical utility. At present, although qualitative data supports the benefits of this system, there are few clinical data, and no randomized trial to establish the superiority of fusion imaging over standard techniques. Therefore, it is not yet known whether the use of fusion imaging results in increased procedural success. In conclusion, fusion imaging using the EchoNavigator system has the potential to increase the safety, accuracy and effectiveness of percutaneous interventions in structural heart disease, which we could already demonstrate during LAA closure. The system can be applied in any procedure where echocardiographic information is important or even essential for safe and efficient accomplishment. Needless to say, in patients with contraindications for TEE or bad echocardiographic image quality, the benefit of the hybrid imaging technology is limited. Prospectively the integration of various imaging modalities during interventions may even have an impact upon periprocedural success.41

Limitations This manuscript reviews our initial clinical experience using an innovative fusion imaging technology in the context of the current literature. Only few centres so far are using this technology and we tried to emphasise the cutting-edge technology of truly fusing echocardiography and fluoroscopy during structural heart disease interventions. Our review lacks information about the clinical benefit of this technology for the patient in the context of reducing procedure length or radiation dose. Data demonstrating these effects are currently missing for release II of the EchoNavigator system, but could be demonstrated for release I by our own group. Prospective randomised multi-centre studies with a larger sample size are necessary to demonstrate veritable benefits of this promising technology for the patient. Another limitation might be the fact that due to a certain learning curve the process of co-registration of the TEE probe with the gantry implements radiation and therefore might even lead to a temporary gain in radiation exposure. n

and meta-analysis. J Heart Valve Dis 2012;21 :208–17. PMID: 22645857. Matsumoto T, Kar S. Latest advances in transseptal structural heart interventions-percutaneous mitral valve repair and left atrial appendage occlusion. Circ J 2014;78 :1782–90. PMID: 25017739. Faletra FF, Pedrazzini G, Pasotti E, et al. 3D TEE during catheter-based interventions, JACC Cardiovasc Imaging , 2014;7 :292–308. DOI: 10.1016/j.jcmg.2013.10.012 PMID: 24651102. Lee MS, Naqvi TZ. A practical guide to the use of echocardiography in assisting structural heart disease interventions. Cardiol Clin 2013;31 :441–54. DOI: 10.1016/j. ccl.2013.04.004 PMID: 23931105. Tsang W, Lang RM, Kronzon I. Role of real-time three dimensional echocardiography in cardiovascular interventions. Heart 2011;97 :850–7. DOI: 10.1136/

hrt.2009.185728 PMID: 21515568. 10. Biaggi P, Fernandez-Golfin C, Hahn R, et al. Hybrid imaging during transcatheter structural heart interventions. Curr Cardiovasc Imaging Rep 2015;8 :33. PMID: 26191338. 11. Corti R, Biaggi P, Gaemperli O, et al. Integrated x-ray and echocardiography imaging for structural heart interventions. EuroIntervention 2013;9 :863–9. DOI: 10.4244/EIJV9I7A140 PMID: 24280159. 12. Sundermann SH, Biaggi P, Grunenfelder J, et al. Safety and feasibility of novel technology fusing echocardiography and fluoroscopy images during MitraClip interventions. EuroIntervention 2014;9 :1210–6. DOI: 10.4244/EIJV9I10A203 PMID: 24103772. 13. Gao G, Penney G, Ma Y, et al. Registration of 3D transesophageal echocardiography to X-ray fluoroscopy using image-based probe tracking, Med Image Anal 2012;16 :38–49. DOI: 10.1016/j.media.2011.05.003 PMID: 21624845.

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Structural 14. Housden RJ, Ma Y, Arujuna A, et al. Extended-field-of-view three-dimensional transesophageal echocardiography using image-based X-ray probe tracking. Ultrasound Med Biol 2013;39 :993–1005. DOI: 10.1016/j.ultrasmedbio.2012.12.018 PMID: 23453630. 15. Fagan TE, Truong UT, Jone PN, et al. Multimodality 3-dimensional image integration for congenital cardiac catheterization. Methodist Debakey Cardiovasc J 2014;10 :68–76. PMID: 25114757. 16. Balzer J, Zeus T, Blehm A, et al. Intraprocedural online fusion of echocardiography and fluoroscopy during transapical mitral valve-in-valve implantation. Can J Cardiol 2015;31 :364 e9–11. DOI: 10.1016/j.cjca.2014.12.011 PMID: 25677811. 17. Gonzalez Gomez A, Hernandez-Antolin R, Zamorano JL. Eco-X Ray Fusion for Transseptal Puncture. Rev Esp Cardiol (Engl Ed) 2015;68 :714. DOI: 10.1016/j.rec.2014.09.024 PMID: 25649971. 18. Jungen C, Zeus T, Balzer J, et al. Left atrial appendage closure guided by integrated echocardiography and fluoroscopy imaging reduces radiation exposure. PLoS One 2015;10:e0140386. DOI: 10.1371/journal.pone.0140386. PMID: 26465747. 19. Balzer J, Seus T, Hellhammer K, et al. Initial clinical experience using the EchoNavigator®-system during percutaneous interventions in structural heart disease. World J Cardiol 2015;7 :1–9. PMID: 26413233 20. Zamorano JL, Badano LP, Bruce, C, et al. EAE/ASE recommendations for the use of echocardiography in new transcatheter interventions for valvular heart disease. Eur Heart J 2011;32 :2189–214. DOI: 10.1093/eurheartj/ehr259 PMID: 21885465. 21. Jilaihawi H, Doctor N, Kashif M, et al. Aortic annular sizing for transcatheter aortic valve replacement using cross-sectional 3-dimensional transesophageal echocardiography. J Am Coll Cardiol 2013;61 :908–16. DOI: 10.1016/j.jacc.2012.11.055. PMID: 23449425. 22. Bloomfield GS, Gillam LD, Hahn RT, et al. A practical guide to multimodality imaging of transcatheter aortic valve replacement. JACC Cardiovasc Imaging 2012;5 :441–55. DOI: 10.1016/j.jcmg.2011.12.013 PMID: 22498335. 23. Kasel AM, Cassese S, Bleiziffer S, et al. Standardized imaging for aortic annular sizing: implications for transcatheter

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24.

25.

26.

27.

28.

29.

30.

31.

32.

valve selection. JACC Cardiovasc Imaging 2013;6 :249–62. DOI: 10.1016/j.jcmg.2012.12.005 PMID: 23489539. Gurvitch R, Wood DA, Leipsic J, et al. Multislice computed tomography for prediction of optimal angiographic deployment projections during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010;3 :1157–65. DOI: 10.1016/j.jcin.2010.09.010. PMID: 21087752. Debonnaire P, Delgado V, Bax JJ, et al. Tools & Techniques – Clinical: 3D transoesophageal echocardiography for selecting and guiding in percutaneous mitral valve repair using MitraClip. EuroIntervention 2014;10 :884–6. DOI: 10.4244/ EIJV10I7A150 PMID: 25415154. Swaans MJ, Post MC, Van den Branden BJ, et al. A complicated transseptal puncture during Mitraclip procedure: saved by 3D-TEE. Eur J Echocardiogr 2011;12 :E45. DOI: 10.1093/ejechocard/jer228 PMID: 22048982. Gafoor S, Schulz P, Heuer L, et al. Use of EchoNavigator, a novel echocardiography-fluoroscopy overlay system, for transseptal puncture and left atrial appendage occlusion. J Interv Cardiol 2015;28 :215–7. DOI: 10.1111/joic.12170 PMID: 25676602. Gafoor S, Franke J, Bertog S, et al. TCT-131 Use Of A Novel Echo-fluoroscopy Overlay System For Percutaneous Mitral Valve Intervention. J Am Coll Cardiol 2013;62 (18_S1):B42. Tamburino C, Ussia GP, Maisano F, et al. Percutaneous mitral valve repair with the MitraClip system: acute results from a real world setting. Eur Heart J 2010;31 :1382–9. DOI: 10.1093/ eurheartj/ehq051. PMID: 20299349 PMCID: PMC2878966. Kische S, Nienaber C, Ince H. Use of four MitraClip devices in a patient with ischemic cardiomyopathy and mitral regurgitation: “zipping by clipping”. Catheter Cardiovasc Interv 2012;80 :1007–13. DOI: 10.1002/ccd.23431 PMID: 22120912. Reddy VY, Mobius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61 :2551–6. DOI: 10.1016/j.jacc.2013.03.035 PMID: 23583249. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for

33.

34.

35.

36.

37.

38.

39.

40. 41.

prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374 :534–42. DOI: 10.1016/S0140-6736(09)61343-X PMID: 19683639. Perk G, Biner S, Kronzon I, et al. Catheter-based left atrial appendage occlusion procedure: role of echocardiography. Eur Heart J Cardiovasc Imaging 2012;13 :132–8. DOI: 10.1093/ ejechocard/jer158 PMID: 21903725. Nucifora G, Faletra FF, Regoli F, et al. Evaluation of the left atrial appendage with real-time 3-dimensional transesophageal echocardiography: implications for catheter-based left atrial appendage closure. Circ Cardiovasc Imaging 2011;4 :514–23. DOI: 10.1161/ CIRCIMAGING.111.963892 PMID: 21737601. Sommer M, Roehrich A, Boenner F, et al. Value of 3D TEE for LAA Morphology. JACC Cardiovasc Imaging 2015;8 :1107–10. DOI: 10.1016/j.jcmg.2014.07.030 PMID: 26381771. Schubert S, Kainz S, Peters B, et al. Interventional closure of atrial septal defects without fluoroscopy in adult and pediatric patients. Clin Res Cardiol 2012;101 :691–700. DOI: 10.1007/s00392-012-0445-1 PMID: 22454137. Balzer J, van Hall S, Rassaf T, et al. Feasibility, safety, and efficacy of real-time three-dimensional transoesophageal echocardiography for guiding device closure of interatrial communications: initial clinical experience and impact on radiation exposure. Eur J Echocardiogr 2010;11 :1–8. DOI: 10.1093/ejechocard/jep116 PMID: 19755469. Kliger C, Eiros R, Isasti G, et al. Review of surgical prosthetic paravalvular leaks: diagnosis and catheter-based closure. Eur Heart J 2013;34 :638–49. DOI: 10.1093/eurheartj/ehs347 PMID: 23117162. Kliger C, Al-Badri A, Wilson S, et al. Successful first-in-man percutaneous transapical-transseptal Melody mitral valve-inring implantation after complicated closure of a para-annular ring leak. EuroIntervention 2014;10 :968–74. DOI: 10.4244/ EIJV10I8A164 PMID: 25540082. Gonzales-Gomez AZ JL. Imaging during transcatheter interventions for valvular disease. EMJ Cardiol 2014;2 :54–60. Kliger C, Jelnin V, Sharma S, et al. CT angiographyfluoroscopy fusion imaging for percutaneous transapical access. JACC Cardiovasc Imaging 2014;7 :169–77. DOI: 10.1016/j. jcmg.2013.10.009 PMID: 24412189.

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Hypertension

LE ATION.

Interventional Therapies for Resistant Hypertension: A Brief Update L i s a B ra n d o n a n d Fa i s a l S h a r i f Department of Cardiology, University Hospital Galway, Galway, Ireland

Abstract Resistant hypertension remains a clinical challenge with few management options beyond maximisation of medications. Catheterbased renal artery denervation (RDN) was proposed in 2009 as a possible therapy for resistant hypertension and early feasibility trials caused excitement among cardiologists and antihypertensive specialists, showing remarkable and sustained blood pressure reductions. In 2014, enthusiasm for RDN dampened following the SYMPLICITY 3 trial results, which showed no statistically significant difference in blood pressure between the intervention and control arms. However, hope remains for the improved management of resistant hypertension; procedural understanding, technological advancements and alternative targets – such as baroreceptor activation therapy and arteriovenous shunts – may aid the identification of those patients for whom specific interventional therapies will be effective.

Keywords Resistant hypertension, interventional therapy, renal artery denervation, baroreceptor activation therapy, arteriovenous shunting Disclosure: The authors have no conflicts of interest to declare. Received: 20 December 2015 Accepted: 17 February 2016 Citation: Interventional Cardiology Review, 2016;11(1):64–9 DOI: 10.15420/icr.2016:3:1 Correspondence: Faisal Sharif, Department of Cardiology, University Hospital Galway, Newcastle Road, Galway, H91 YR71, Ireland. E: faisal.sharif@nuigalway.ie

Resistant hypertension remains a serious clinical burden despite significant advances in cardiology and healthcare. Hypertension is a chronic condition without any available cure, with significant associated morbidity and mortality, and necessitates lifelong use of medications. It is multifactorial in origin, associated with genetics, lifestyle factors and the metabolic syndrome. Resistant hypertension is defined as “blood pressure that remains above target (usually 140/90 ) despite the use of three classes of antihypertensives, one being a diuretic, or requiring four medications to control blood pressure.”1 Refractory hypertension is the term to describe the 10 % of these patients that remain uncontrolled despite maximal medication use (four or more drugs) while attending a hypertensive specialist. The incidence and prevalence of resistant hypertension remains unclear as there are no direct studies to evaluate this. Extrapolation of data from large scale antihypertensive trials suggests a prevalence of 10–20 %.2,3 It is likely that this is increasing on analysis of medication prescriptions and in the setting of obesity and an ageing population. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)4 showed 27 % of participants were on three or more medications and only 49 % were controlled on one or two medications. Diagnosis of resistant hypertension can be difficult to confirm. Variables such as secondary causes of hypertension must be excluded, alongside other possibilities including white coat hypertension, nonadherence to treatment, diet and lifestyle measures and medication use that may be contributing, such as steroids, oestrogen, etc. Resistant hypertension remains a serious clinical unmet need as this patient population is exposed to a three-to-five-fold higher risk of cardiovascular events5 including ischaemic heart disease, congestive heart failure, stroke, chronic renal failure and peripheral vascular disease. The role for invasive management strategies, alongside medications, is a growing

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area of interest as a possible solution for this patient profile. Current invasive strategies that have been tried include: 1. Catheter-based renal artery denervation (RDN) 2. Barorecepter activation therapy 3. Arteriovenous shunts

Renal Artery Denervation Background and Pathophysiology In the early 1900s the importance of sympathetic hyperactivity and comprised primarily of sympathectomy in hypertension was recognised. Various procedures were trialled including subdiaphragmatic bilateral resection of the splanchnic nerves with superior lumbar sympathectomy and often included adrenalectomy or renal decapsulation. Sustained improvements in blood pressure were seen but treatment was limited by serious side effects including surgical complications, hypotension and automonic dysfunction. With the discovery of thiazide diuretics these procedures became redundant in the late 1950s.6,7 In recent years observational evidence from kidney transplantation suggested that diseased kidney removal reduces blood pressure further.8 The pathophysiology of hypertension explains the interest in RDN. Essential hypertension is a complex multifactorial condition with interplay between the central and peripheral nervous systems, heart, vasculature and kidneys. The kidneys have norepinephrine releasing sympathetic efferent and afferent nerves running in the adventitia of the renal artery. Efferent renal nerve stimulation causes upregulation of renin secretion, increases sodium absorption in the distal tubule and vasoconstriction, all contributing to increased water retention and hypertension. Stimulation of sensory afferent renal nerves leads to increased sympathetic activity via signals to the central nervous system, causing vasoconstriction and increased cardiac output.

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Hypertension Norepinephrine spillover was investigated to assess the theory of increased renal sympathetic activity contributing to hypertension. Renal venous concentration of norepinephrine was significantly higher in people with hypertension in comparison to controls and was reduced following renal nerve removal.9,10 Muscle sympathetic nervous activity can also be utilised to test the activity of the sympathetic nervous system being elevated in people with hypertension. Experimental work in animals suggested that RDN has a plausible role in hypertension, as rats with bilateral renal sympathetic denervation showed delayed onset of hypertension with attenuated severity.11 The concept of catheter-based RDN was introduced in 2009. It was a reinvention of an old concept with further understanding of the pathophysiology, alongside clinical observation in renal transplantation and animal models, suggesting that it may have a very real and exciting role in the treatment of hypertension.

Clinical Trials for Renal Artery Denervation SYMPLICITY-112 was the first in-human feasibility and safety study for RDN, published in The Lancet in 2009. Primary endpoints included safety and blood pressure reduction. There were 153 patients, all deemed treatment resistant, taking more than three antihypertensives with an average office blood pressure of 175/98. The Symplicity™ Renal Denervation catheter (Medtronic) was used with a single electrode tip requiring between four and eight ablations of 2 minutes in a circumferential fashion along the renal artery. This showed sustained 4-, 12- and 36-month reductions in office blood pressure measurements with few procedural complications,13 thus confirming safety. SYMPLICITY-214 was a multicentre, randomised, controlled, clinical trial, following the promising success of the first trial, published in The Lancet in 2010. Investigators used the same catheter as the previous trial and followed similar methodology with addition of a control arm. There were 106 patients with resistant hypertension, on an average of five antihypertensives, randomised in a 1:1 fashion to RDN or medication, with crossover allowed at 6 months. Results showed a significant and sustained reduction in office blood pressure measurements at 6 months with a mean reduction of 33/11 mmHg in those treated with RDN and few procedural complications.15 Of note, only 20 RDN patients had 24-hour ambulatory blood pressure monitoring (ABPM) in whom blood pressure reductions were less pronounced, with a mean difference of 11/7 mmHg from controls. EnligHTN™ was a non-randomised, unblinded, clinical trial,16 evaluating the St Jude Medical catheter device for RDN, similar to SYMPLICITY-1, being the first in-human use of the device. The trial had 46 patients with resistant hypertension, using three or more antihypertensives for a sustained period, office systolic blood pressure >160 mmHg, alongside confirmatory 24-hour ABPM. Primary efficacy endpoints mirrored that of SYMPLICITY-1, showing sustained office blood pressure reductions at 1, 3, 6 and 18 months, with a good safety profile. ABPM showed an average reduction of 10/5 mmHg at 6 months, below the average 26/10 mmHg reduction of office recordings.17 SYMPLICITY-318 was a prospective multicentre, randomised, doubleblinded trial, with 535 patients evaluated, assigned in a 2:1 fashion to undergo RDN with the Symplicity Medtronic catheter or renal angiography alone, a sham procedure. Primary efficacy endpoints looked at office blood pressure measurements at 6 months, and secondary endpoints included ambulatory recordings. Primary

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safety endpoints looked at major adverse events. This trial showed no statistically significant difference in baseline blood pressures, both office and ambulatory, in both groups at 6 months, which was contradictory to the previous trials. There was no significant safety difference thus confirming procedure safety.

Post-hoc Analysis of Negative Trials Multiple analyses have been undertaken to explain this trial being negative in the setting of two prior strongly positive trials. The earlier trials were unblinded and primarily feasibility and safety trials, creating a bias. In SYMPLICITY-3, there was more extensive screening of the population prior to trial entry for secondary causes, and definite diagnosis of resistant hypertension requiring a 24-hour ambulatory monitor. Patient characteristics showed a higher demographic of AfricanAmericans than earlier trials, a higher proportion of obese patients and usage of aldosterone antagonists. Operator experience may have played a role, given the wider scale of the trial. Also the addition of the placebo intervention may have contributed to a Hawthorne effect where patients in both arms are aware they are being closely observed and modify their behaviour in response to this scrutiny. Post-trial analysis published in the European Heart Journal19 revealed that 39 % of patients underwent medication changes during the trial, despite strict criteria in place to reduce this, as patients were supposed to be on maximally tolerated doses before entering the trial. From a procedural aspect, there was significant variability in the number of ablation attempts per patient, between one and 26. Partial denervation may result from too few ablations with significant sustained blood pressure reductions noted when >14 ablations are done. Additionally it appears necessary to ablate in all four quadrants of the renal artery, as in-depth analysis reveals that this contributes to greater blood pressure reductions. These issues may give guidance and provide hope to future trials. However it remains a sobering outcome for the previously exciting development of RDN.

Current Renal Denervation Technologies There are a number of different catheters designed and in development for RDN. The ideal catheter should be safe, easily delivered to the renal artery, effective in a reproducible fashion with minimal operator variability, cause little local trauma to the tissue and facilitate as short a procedure time as possible. There is significant design variability in the attempt to address these all needs. Anatomic variations are also an issue for successful RDN, as anatomy must be favourable for the procedure. Typically, the renal artery must be ≥4 mm in diameter, ≥20 mm in length, with absence of significant atherosclerosis, previous angioplasty, fibromuscular dysplasia or accessory arteries. Femoral access is required, along with a baseline renal angiogram.

Radiofrequency Ablation Catheters SYMPLICITY – Medtronic The largest trial to date, SYMPLICITY-3, was carried out by Medtronic with the sole use of their device, the Symplicity flex catheter. This is a radiofrequency-based catheter, compatible with 6 Fr and 8 Fr introducer sheaths via the femoral artery, passed over-the-wire, with a single unipolar electrode at the tip to create spot lesions using radiofrequency ablation. The device has a handle to flex and rotate the tip of the catheter in the renal artery. It generates a temperature of 75 degrees. At least four ablations per artery are recommended, 2 minutes per ablation, preferably in a circumferential helical fashion with at least 5 mm between lesions. Good wall contact is crucial. Medtronic

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has a further device in progress, Symplicity Spyral™, which has a spiral shape with four unipolar electrodes activated simultaneously, allowing a more rapid and easier procedure with better spot lesion location ensuring adequate ablation. This reduces potential operator error.

EnligHTN™ St Jude Medical St Jude Medical designed the first EnligHTN multi-electrode radiofrequency RDN system. This is passed via an 8 Fr sheath with a 8 Fr guiding catheter used to engage the renal artery. It has a nitinol basket design available in two sizes, 16 mm and 18 mm, allowing 4-point contact per catheter placement, activating each individual electrode in 90 second segments. This aims to increase procedural success with a more predictable ablation pattern and less catheter manipulation. Individual electrodes can be turned on and off. The generator reaches 75 degrees for transmural ablation. Two rounds of ablation are recommended, a total of eight ablation lesions per artery.

Vessix™ Boston Scientific Boston Scientific’s Vessix RDN system is a balloon-based system with an over-the-wire technique. This requires an 7 Fr introducer sheath, passing a guidewire to the renal artery, facilitating delivery of the Vessix noncompliant balloon, available in 4–7 mm diameter balloons. The balloon is inflated to 3 atm, and contrast administered to ensure apposition to the wall and occlusion of the artery. Once inflated the device activates 4, 6, or 8 bipolar electrodes (depending on balloon size), delivering temperatures of 68 degrees to the vessel wall via a temperature controlled algorithm, over 30 seconds. In most cases one cycle is sufficient, longer arteries may require two cycles. The single-arm, multicentre, Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter (REDUCE-HTN) trial in 2013 of 150 patients confirmed safety and sustained blood pressure reductions.20,21

OneShot Covidien Covidien acquired the OneShot RDN system from Maya Medical in 2012, which consists of an irrigated noncompliant radiofrequency balloon catheter with a unipolar spiral electrode. The catheter is advanced over an 0.014 inch wire via a 7 Fr or 8 Fr sheath, inflated to 1 atm and has eight tiny irrigation holes allowing cooling of the vessel at the time of ablation. This mitigates overheating, vessel damage and thrombus formation. Balloons are available in 5–7 mm and the spiral shape allows a single 2-minute treatment per artery. Their first in-human trial was the Renal Hypertension Ablation system (RHAS) trial.22 This consisted of eight patients and showed no procedural complications with a sustained drop in blood pressure at 6 months. This was followed up by the Rapid Renal Sympathetic Denervation for Resistant Hypertension (RAPID) trial,23 enrolling 50 patients and meeting primary safety endpoints and sustained blood pressure reductions at 6 and 12 months. In January 2014 Covidien ceased development of their RDN system, with cessation of the RAPID II trial, due to the slower then expected growth in the market.

Ultrasound-based Catheters Paradise® ReCor Medical

ReCor Medical introduced the Paradise system, a new concept in the field of RDN being the first ultrasound-based catheter, instead of radiofrequency ablation. This design consists of a circumferential balloon catheter, available in 6 mm or 8 mm, delivered to the renal artery over-the-wire via a 6 Fr guiding catheter. The balloon has a cylindrical piezoelectric ultrasound transducer, which emits circumferential high

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frequency sound waves over 30 seconds, generating heat to induce nerve injury. It is recommended to target three different spots per artery. The balloon allows cooled fluid to circulate during ultrasound transmission, thus reducing endothelial damage and protecting from overheating. The REDUCE trial was the first in-human trial of 15 patients, proving device safety with reduction in office-based blood pressure readings at 6 months. The follow-on REALISE24 and ACHIEVE trials were small, non-randomised trials with similar results.

Chemical-based Catheters Peregrine System™ Infusion Catheter, Ablative Solutions A new area of interest is in the field of chemical RDN with ethanol. Concerns with radiofrequency ablation regarding the possibility of incomplete and inconsistent RDN contributing to negative trials results has been raised. Circumferential burns and adequate depth can be difficult to obtain and few people have renal arteries >4–5 cm to allow adequate burns per artery. The Peregrine infusion catheter was developed by Ablative solutions to deliver micro doses of the known neurolytic ethanol to the adventitia by placing three 0.008-inch needles through the media and injecting 0.3–0.6 ml of ethanol. This was shown in animal studies to reduce renal norepinephrine levels and histology assessment revealed successful circumferential artery injury with evidence of permanent nerve damage. The first in-human study commenced in 2013 with 18 patients treated alongside 17 swine.25 There were no procedural complications and minimal patient discomfort. Six-month blood pressure reductions were significant at 23/14 mmHg. Further clinical evaluation is ongoing to assess the potential value and clinical role chemical ablation may have for resistant hypertension.

The Future Trials remain ongoing to evaluate the role of radiofrequency ablation. Boston Scientific are currently undertaking the Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension (REDUCE-HTN:REINFORCE) trial and believe variables in medications and high-risk patients clouded results of previous investigations. Medtronic are conducting trials with their Spyral device on and off medications including a sham procedure. Certainly, the initially promising field has slowed down in the setting of negative outcomes from SYMPLICITY-3 but there are lessons to be learned. A first-generation device was used with significant operator and procedure variability. More recent devices with multiple electrodes may increase procedural success from a complete denervation perspective and subsequently clinical outcomes. Thermal ablation RDN catheters have shown excellent safety profiles, largely due to controlled thermal energy to the renal blood vessels. Better penetration into the adventitia either through optimal catheter contact or higher energy is required to achieve nerve deactivation. Anatomically, information from the IVY trial in preclinical models has shown better response when the side branch and main trunk are ablated, instead of the main trunk and the side branches alone. It is now advocated that more dense innervation is present in the distal renal artery and side branches, and better clinical outcomes can be achieved by distal ablations. This is contrary to the earlier belief of ostial ablations. The role of ultrasound and chemical ablation with ethanol warrants further evaluation and may lead to more positive clinical outcomes. A current limiting factor in RDN is the lack of awareness of procedural success at the time of intervention. There is no confirmatory method to ensure the renal nerves have been successfully ablated. Research

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Hypertension into peripheral markers may permit overcoming this obstacle in the future. There remains a population of patients who are likely to be more adrenergic driven then others and may benefit more from RDN then others. These patients deserve to be identified, given the serious mortality and morbidity associated with uncontrolled hypertension.

Baroreceptor Activation Therapy Baroreceptor activation therapy (BAT) is another exciting investigational area for an interventional role in treatment of hypertension. This was also initially evaluated in the 1950s and 1960s, prior to the development of the wide array of antihypertensive medications currently available. At that time electrical stimulators were used to activate the afferent pathway of the baroreceptor reflex to treat angina initially, then hypertension.26,27 However they were limited by procedural complications, surpassed by medications and became a defunct procedure. Current understanding of the pathophysiology allows attention to be drawn back to a possible role for carotid body stimulation in hypertension. Baroreceptors are located at the carotid sinus, at the level of the bifurcation of the carotid artery and the aortic arch. Stretch mechanoreceptors are activated by pressure in the arterial wall and information transmitted via the glossopharyngeal nerve to the nucleus tractus solitarus in the medulla of the central nervous system. There, it is integrated with other afferent and cortical inputs and efferent pathways are modulated to regulate blood pressure with alteration of sympathetic or parasympathetic activation of the heart, vasculature and kidneys as appropriate. Activation of baroreceptors in the setting of high blood pressure causes upregulation of the parasympathetic system while hypotension and reduced baroreceptor stimulation activates the sympathetic nervous system. Previously, it was thought that the baroceptor reflex has only a short-term role in blood pressure regulation to protect from extremes. However animal studies and human observational studies suggest it also has a longer term role with possible resetting of response levels, in the setting of prolonged hypertension.28

6-month blood pressure reduction in treatment versus controls, but did have a significant sustained response at 12 months. It confirmed BAT efficacy and long-term device safety. Short-term procedural adverse events did not reach target endpoint with 9.2 % of patients sustaining nerve injury, 4.4 % had surgical complications and 2.6 % had respiratory complications. Long-term data suggests favourable regression of left ventricular hypertrophy and significant reductions in cardiac dimensions following BAT.31

Barostim Neo™ CVRx Inc CVRx Inc has developed a second-generation device, the Barostim neo system. It is smaller with a longer lasting battery and only one electrode being implanted into the right carotid sinus. Previous trials have suggested that unilateral stimulation may be sufficient to achieve a chronic BP response.32 The initial XR-1 Verification Study33 of 30 patients showed average blood pressure reduction was 26 mmHg systolic and 12 mmHg diastolic at 6 months and 43 % of patients had SBP <140 mmHg. The neo PIVOTAL trial of 310 patients with the new device is currently underway. BAT is also being investigated for use in heart failure as a reduction in sympathetic activity is postulated to have beneficial effects haemodynamically. A recent study has shown improvements in functional capacity, quality of life and proBNP in patients with New York Heart Association class III heart failure and this area is undergoing further active investigation. The role of RDN alongside BAT is not yet understood. It is possible that they may have a complimentary role in the setting of resistant hypertension, or perhaps one is superior to the other. Studies in dogs show further reduction in blood pressure with BAT following RDN. Both treatments reduce blood pressure and renin levels and BAT reduces systemic levels of norepinephrine. RDN only reduces renal venous levels of norepinephrine. Six patients who had the Barostim neo device placed in the initial trial had previously undergone RDN and had an average blood pressure reduction of 21/11 mmHg, suggesting BAT has a role in non-responders to RDN. Given advancements remain underway in both fields and we have not yet reached a time when a head-to-head comparison would be feasible.

Devices

The Rheos System ® Hypertension Therapy System, CVRx Inc CVRx Inc developed the first device for baroceptor stimulation, the Rheos system, with first implantation in 2005. This requires surgical insertion with bilateral electrodes being tested intra-operatively to ensure correct positioning and activation of the right and left carotid sinus with leads connecting the electrodes to a generator device, placed usually in the right infraclavicular area. It is activated one month after implantation, animal studies suggest earlier activation interferes with skin healing. It electrically activates the carotid sinus to simulate hypertension in the central nervous system and downregulate the sympathetic nervous system. Two feasibility trials initially assessed the Rheos system, the Device Based Therapy of Hypertension Trial (DEBUT) in Europe and US Feasibility trial enrolling 61 patients.29 Two-year follow-up showed a sustained reduction in baseline blood pressure of systolic 30 mmHg and diastolic 15 mmHg, with reduced use of antihypertensive medications. The Rheos PIVOTAL trial30 was a follow-on double-blind study with 181 patients having device activation at month 0 (one month after surgery) and 84 having activation at month 6 (7 months after surgery). The trial met three out of five endpoints, failing to show a significant

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Arteriovenous Shunts Patients with advanced chronic obstructive pulmonary disease underwent studies of arteriovenous (AV) shunt creation with the theory to improve oxygenation, cardiac output and functional capacity. Large and unexpected blood pressure reductions were noted34 suggesting that this may be a treatment option for resistant hypertension. Creating a shunt reduces total systemic vascular resistance by moving blood into the high capacity venous system, thus reducing blood pressure. Rox Medical developed The Coupler, a paperclip size device inserted angiographically between the iliac artery and vein, creating a 4-mm shunt. The Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (ROX CONTROL HTN)35 trial published in the Lancet in 2015 evaluated 83 patients with resistant hypertension. Of the 83 patients, 44 underwent implantation of a Coupler device alongside medication and 39 continued on medical treatment. Patients who received the Coupler device had significant blood pressure reductions with a systolic blood pressure drop of 26.9 mmHg versus 3.7 mmHg in the control arm and 24-hour ABPM drop of 13.5 mmHg versus 0.5 mmHg in controls. Ten patients in the active arm had prior unsuccessful RDN, with good response to AV shunt treatment.

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There were 25 procedure or device related complications, two were serious and all resolved without consequences. However, 28.6 % of patients experienced issues with lower limb edema 2–9 months following the procedure and were diagnosed with iliac vein stenosis proximal to the anastomosis. Eleven patients required venoplasty and stenting and one required just venoplasty. Concerns also exist regarding the potential for high output cardiac failure and lack of a sham procedure in this trial. However, further studies need to be undertaken to fully evaluate the role AV shunt creation may play in the treatment of resistant hypertension, and to elucidate the patients that would benefit most from this procedure in the future.

Conclusion Resistant hypertension remains a serious unmet need, prompting the current vogue of research into an intervention to improve clinical outcomes for this patient population. RDN initially appeared to be a very successful adjuvant to medication in the treatment of resistant hypertension, but this excitement was tempered with SYMPLICITY-3. The

6. 7.

8. 9.

10.

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12.

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2013 ESH/ESC Guidelines for the management of arterial hypertension. Blood Press 2014;23:3-16. DOI: 10.3109/08037051.2014.868629; PMID: 24359485 Persell SD. Prevalence of resistant hypertension in the United States, 2003–2008. Hypertension 2011;57:1076–80. doi: 10.1161/HYPERTENSIONAHA.111.170308; PMID:21502568. de la Sierra A, Segura J, Banegas JR, et al. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension May;57:898–902. DOI: 10.1161/ HYPERTENSIONAHA.110.168948; PMID: 21444835. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;18;288:2981–97. PMID: 12479763. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012;125:1635–42. DOI: 10.1161/ CIRCULATIONAHA.111.068064; PMID: 22379110; PMCID: PMC3343635. EV Allen. Sympathectomy for Essential Hypertension. Circulation 1952;6:131–40. PMID: 14936210 Smithwick RH, Thompson J. Splanchnicectomy for essential hypertension. Results in 1266 cases. J Am Med Assoc 1953;474:473–4. Hausberg M, Kosch M, Harmelink P, et al. Sympathetic nerve activity in end-stage renal disease. Circulation 2002;106:1974–9. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension 2009;54:690–7. DOI: 10.1161/ HYPERTENSIONAHA.108.119883; PMID: 19720958. Esler M, Jennings G, Korner P, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 1988;11:3–20. PMID: 2828236. Abramczyk P, Zwoliñska A, Oficjalski P, et al. Kidney denervation combined with elimination of adrenal-renal portal circulation prevents the development of hypertension in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1999;26:32–4. PMID: 10027067. Krum H, Schlaich M, Whitborne R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373:1275–81. DOI: 10.1016/S0140-6736(09)60566-3; PMID: 19332353. Esler MD, Krum H, Sobotka PA, et al. Catheter-based renal sympathetic denervation for resistant hypertension: durability

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14.

15.

16.

17.

18.

19.

20. 21.

22.

23.

24.

addition of a sham procedure and rigorous controls found no clinical benefit from the procedure, but did prove safety. This was a strong blow to the field and has dampened enthusiasm, however clinical trials remain ongoing and researchers have returned to the drawing board to understand and answer many questions regarding the role of RDN. We believe that RDN can reduce blood pressure in the right patient phenotype and if the device is used appropriately, especially in terms of anatomical placement of catheters and number of ablations. Baroreceptor activation therapy may also have a future role for these patients, however the current device is too invasive and requires vascular surgical cut down in an operating theatre. Further iteration and complete percutaneous implantation may see an important clinical role for this therapy. Other targets under evaluation include targeted splanchnic denervation and carotid body ablation. An interventional procedure with sustained blood pressure reduction resulting in improved clinical outcomes would be a very welcome addition to the cardiology field in the management of resistant hypertension. n

of blood pressure reduction out to 24 months. Hypertension 2011;57:911–7. DOI: 10.1161/HYPERTENSIONAHA.110.163014; PMID: 21403086. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension: A randomised controlled trial. Lancet 2010;4376:1903–9. DOI: 10.1016/S0140-6736(10)62039-9; PMID: 21093036. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation 2012;126:2976–82. DOI: 10.1161/ CIRCULATIONAHA.112.130880; PMID: 23248063. Worthley SG, Tsioufis CP, Worthley MI, et al. Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial. Eur Heart J 34:2132–40. DOI: 10.1093/eurheartj/eht197; PMID: 23782649; PMCID: PMC3717311. Worthly SG, Tsioufis CP, Worthley MI, et al. St. Jude medical study of EnligHTN I renal denervation system: 18-month data. In: Proceedings of the 25th Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium, San Francisco, CA, USA; October 2013. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–401. DOI: 10.1056/NEJMoa1402670; PMID: 24678939. Kandzari DE, Bhatt DL, et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015;36:219–27. DOI: 10.1093/eurheartj/ehu441. PMID: 25400162; PMCID: PMC4301597. Schofer, Joachim, MD REDUCE-HTN PCR 2013. Sievert H, Schofer J, Ormiston J, et al. Renal denervation with a percutaneous bipolar radiofrequency balloon catheter in patients with resistant hypertension: 6-month results from the REDUCE-HTN clinical study. EuroIntervention 2015;10:1213–20. DOI: 10.4244/EIJY14M12_01; PMID: 25452197. Ormiston J, Watson T, van Pelt N, et al. First Report of the 6-Month First in Human results of the OneShot™ Renal Denervation System: The RHAS Study. J Am Coll Cardiol 2012;60:B62. Verheye S, Ormiston J, Bergmann MW, et al. Twelve-month results of the rapid renal sympathetic denervation for resistant hypertension using the OneShotTM ablation system (RAPID) study. EuroIntervention 2015;10:1221–9. DOI: 10.4244/ EIJY14M12_02; PMID: 25452198. Montalescot G, Cluzel P, Pathak A, et al. Preliminary safety and efficacy results from the REALISE trial: REnAL

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

denervatIon by ultraSound transcatheter Emission. J Am Coll Cardiol 2013;62:B40–B40. DOI:10.1016/j.jacc.2013.08.853. Fischell TA, Fischell DR, Ghazarossian VE et al. Next generation renal denervation: chemical “perivascular” renal denervation with alcohol using a novel drug infusion catheter. Cardiovasc Revasc Med 2015;16:221–7. DOI: 10.1016/j. carrev.2015.04.008; PMID: 25979565. Bilgutay AM, Lillehei CW. Surgical treatment of hypertension with reference to baropacing. Am J Cardiol 1966;17:663–7. PMID: 5934985 Bilgutay AM, Lillehei CW. Surgical treatment of hypertension with reference to baropacing. Am J Cardiol 1966;17:663–7. PMID: 5934985. Thrasher TN. Arterial baroreceptor input contributes to long-term control of blood pressure. Curr Hypertens Rep 2006;8:49–254. PMID: 17147924 Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex Activation Therapy Lowers Blood Pressure in Patients With Resistant Hypertension. JACC 2011;58:765–73. DOI: 10.1016/j. jacc.2011.06.008; PMID: 21816315. Bakris GL, Nadim MK, Haller H, et al. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: Results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens 2012;6:152–8. DOI: 10.1016/j. jash.2012.01.003; PMID: 22341199. de Leeuw PW, Alnima T, Lovett E, et al. Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension 2015;65:187–92. DOI: 10.1161/HYPERTENSIONAHA.114.04492; PMID: 25331845. Hoppe UC, Brandt MC, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens 2012;6:270–6. DOI: 10.1016/j.jash.2012.04.004; PMID: 22694986. Faul J, Schoors D, Brouwers S, et al. Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension. J Vas Surg 2014;59:1078–83. DOI: 10.1016/j.jvs.2013.10.069; PMID: 24484754. Lobo MD, Sobotka PA, Stanton A, et al. Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study). Lancet 2015;385:1634–41. DOi: 10.1016/S0140-6736(14)62053-5; PMID: 25620016.

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Simulation Training

Simulator Training in Interventional Cardiology A b h i s h e k J o s h i a n d A n d r e w Wra g g Barts and The London NHS Trust, Bart’s Heart Centre, St Bartholomew’s Hospital, London, UK

Abstract Simulator training in interventional cardiology is becoming a central part of early career acquisition of technical and non-technical skills. Its use is now mandated by national training organisations. Haptic simulators, part-task trainers, immersive environments and simulated patients can provide benchmarked, reproducible and safe opportunities for trainees to develop without exposing patients to the learning curve. However, whilst enthusiasm persists and trainee-centred evidence has been encouraging, simulation does not yet have a clear link to improved clinical outcomes. In this article we describe the range of simulation options, review the evidence for their efficacy in training and discuss the delivery of training in technical skills as well as human factor training and crisis resource management. We also review the future direction and barriers to the progression of simulation training.

Keywords Simulation, training, part-task, immersive, haptic, human factors Disclosure: The authors have no conflicts of interest to declare. Received: 12 September 2015 Accepted: 26 November 2015 Citation: Interventional Cardiology Review, 2016;11(1):70–3 DOI: 10.15420/icr.2016.11.1.70 Correspondence: Andrew Wragg, Department of Cardiology, Bart’s Heart Centre, St Bartholomew’s Hospital, West Smithfield, EC1A 7BE, UK. E: andrew.wragg@bartshealth.nhs.uk

Simulator training provides the opportunity to acquire and practise technical skills in a safe, controlled and reproducible environment without the risk of harming patients. Although there is no evidence to prove that patient outcomes are worse if trainees undertake interventional procedures, there is an inevitable concern that procedures may not be as safe or successful if undertaken by doctors in training.1,2 Experiential training in the workplace exposes patients to the theoretical risks of the learning curve of trainees, especially in the radial era.3 Further, as catheter laboratory (cath lab) scheduling time is precious, having trainees undertaking procedures that inevitably take longer can be difficult to justify when the focus is on lab efficiency. Simulator training has the potential to offer focussed training opportunities that allow both the time and space to develop interventional skills.4 These skills can then be analysed and critiqued without any risk of patient harm or impact on the cath lab schedule. Enthusiasm for simulation training has increased dramatically over recent years because advances in technology have allowed the delivery of authentic simulated training opportunities. Despite a broad body of evidence supporting the use of simulation in medicine, there are still some concerns when this evidence is extrapolated to less studied specialties.5 Simulation training enhances learning, especially when used alongside traditional, apprentice models of training, and it is now increasingly recognised in cardiology and interventional training programs.6,7 In interventional cardiology the evidence and experience of simulation continues to grow, although presently there are no studies that have documented a positive effect on patient outcomes. As mentioned, many healthcare settings have restricted the weekly working hours for doctors in training due to an increasing demand on

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cath lab schedules.8,9 Institutions are becoming risk averse and often limit training opportunities through fear that patient outcomes might be lowered when procedures are undertaken by doctors in training.1 These two factors reduce exposure to practical procedures thus weakening the skills and experience of future specialists. Experience is an essential component of becoming an independent operator. Solutions are therefore required to enhance and increase training opportunities and simulation is one of the most useful practical options. Supervised simulated training experiences away from the bedside in a controlled, authentic environment will allow trainees to explore and develop techniques and consolidate their learning without exposing patients to risk, as has been seen in other medical specialties.

The Role of Simulation in Other Medical Specialties Simulation is a long established form of medical training.10 The early cardio-pulmonary resuscitation dolls are a simple but effective way of delivering the core elements of resuscitation training by providing a safe environment to practise and rehearse tasks, algorithms and also create opportunities to receive feedback on performance.11–13 Simulation is a central part of resuscitation training and there is a large body of evidence to suggest that a number of metrics, from processes to patient outcomes, are positively affected through simulation of a simple, repeatable clinical scenario.12 Simulated laparoscopic and endovascular surgery reproduce some of the technical skills in interventional cardiology, delivering the opportunity to simulate a complex, multi-step procedure, and using screen-based representations of the procedure rather than direct visualisation of the operative field. Virtual reality simulators have been shown to improve patient outcomes in reallife laparoscopic surgery14 and reduce procedural error.15 Part-task simulators have been used to focus on single steps in the process.

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A multitude of simulated procedures are now available across multiple commercial platforms, ranging from basic diagnostic angiography through to complex coronary interventions. Specific packages also exist for more complex structural interventions, including atrial septal defect (ASD) closure and transcatheter aortic valve implantation (TAVI). Numerous simulators are also available for training in trans-thoracic and trans-oesophageal echocardiography, cardiac rhythm device implantation and testing.

Part-task Training Simulators Although many cardiologists have seen or experienced the ‘Immersive’ cath lab simulators, there is still a role for simulators that allow the learning of specific single technical skills. Rather than simulate an entire procedure or clinical encounter, the constituent components of the task can be simulated and rehearsed, so-called part-task training (PTT). There is some evidence, primarily from psychological literature, that PTT improves the rate of skill acquisition when properly integrated into a learning framework,16–18 although there is less specific evidence for medical procedures. Arterial and venous access and closure lend themselves well to this format of training as they are discrete steps in interventional practice. A number of low and high fidelity simulators exist to aid these part-tasks, which can simulate pulsatile arterial blood flow for vascular access training. More sophisticated simulators allow practise of the Seldinger technique for vascular access19,20 and numerous simulators are available for training on vascular closure devices.

Cardiac Catheter Laboratory Simulators Most cardiology interventions are highly complex, multi-step procedures and the technical skills that underpin them need to be learnt in an authentic environment. Sophisticated cath lab simulators are now available that combine hardware user interfaces with simulator software with the aim of providing high fidelity representations of real life practice, providing both visual and haptic (or tactile) feedback for the operator. As well as part-task simulations of individual parts of a procedure, modern simulators can provide immersive exposure and training in an entire clinical encounter. A library of simulated cases provides context and clinical background for trainees with the opportunity to administer medications or other therapies before undertaking a simulated procedure. Sensors detect the manipulation of real world tools (such as catheters and wires) in the simulator and translate these into movements of virtual objects on screens integrated into authentic fluoroscopic images. Tools can also return haptic or touch-based feedback to operators using either passive resistance to movement, or active motorised movement of the tool. These are felt by the operator as changes in the resistance to the movement of the tool. Simulators also allow control of the virtual fluoroscopy C-arm and display physiological data, which can be manipulated during the procedure through either by administration of drugs, or the success or otherwise of the procedure. Some systems allow other ways to view the simulated vascular system, particularly through the use of 3D rendered models, allowing better understanding in the anatomy. After the procedure is completed there are scoring systems that provide detailed technical feedback on the procedure, including unsafe catheter manoeuvres and inappropriate wire placement.

Does Simulation Improve Training in Medicine? Despite the extensive selection of simulators available, what is the evidence that simulation is beneficial to trainees or indeed their future patients? Although there is widespread acceptance of simulation as a training modality across many medical and surgical specialties,21–24

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it is important that the evidence behind it is understood. There still remain empirical questions about the relevance and efficacy of simulation despite what is now a large body of evidence. In cardiology there are studies of efficacy although many cardiologists always want more. Studies on the effects of simulator training tend to be small and are extremely heterogeneous in the techniques simulated, the design of the educational intervention and the measured outcomes. However, a large meta-analysis pooled data from 609 studies of simulation in training for medical procedures in an attempt to gauge the potential impact of simulation training across medicine.5 This meta-analysis included studies of colonoscopy, laparoscopic surgery, suturing, emergency resuscitation, physical examination and team leadership amongst a vast range of topics. Studies of endovascular procedural training accounted for 10 studies. All included studies compared simulation training with no intervention; 66.5 % were pre-test/post-test studies and 22.5 % were a randomised, two-group design. Overall, 32,556 trainees were included and strong effects were seen for improvements in broad knowledge and skills categories in studies with objectively measured outcomes. More modest effects were seen in the small number of trials (n=32) reporting direct patient outcomes. A second meta-analysis looked specifically at patient outcomes after simulator training across a heterogeneous group of medical skills.25 Fifty studies were included and the analysis found improvements in reported patient outcomes when compared to no intervention. Whilst these data are encouraging for the general principle of improved outcomes with simulation, they are often drawn from small, singlecentre studies with short follow-up periods. Further, whilst there is a general trend for simulation to improve outcomes compared with no intervention, no specific feature of simulation has been positively correlated with improvement in practice. It is therefore not clear how simulator training improves these measured outcomes, nor whether this robustly translates to improved patient outcomes. However, as cardiologists we can be over focused on seeking hard evidence for changes in important clinical end points before we embrace new technology. Most established training opportunities and structures were never submitted to the rigours of a randomised trial and we should accept that the face value and authenticity of modern simulators is strong and perhaps not be over preoccupied on wanting definitive evidence of clinical benefit.

Transferring to the Catheter Laboratory: Evidence in Interventional Cardiology? What is the evidence for the impact of simulation training in interventional cardiology? There are three studies investigating simulation training and transfer of skills to cardiac angiography procedures.26–29 A singlecentre trial based in Toronto enrolled 27 cardiology trainees over the course of one year (2011–12), and assessed their baseline technical proficiency in the ‘real-life’ catheter laboratory through two, observed and supervised femoral diagnostic angiograms.29 Trainees were scored using technical and global performance scores. They were then block-randomised by year of clinical training to the control arm, who continued their usual, clinical training and the intervention arm. The intervention arm received between two and eight hours of mentored simulator training until a specific competence marker (being able to complete a full angiogram independently) was achieved. Trainees in the intervention arm also had full access to the simulator equipment for a week. At the end of the one-week intervention, trainees were again assessed on the performance of two femoral angiograms, with a second technical and global score calculated.

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Simulation Training The authors report a clear improvement in technical performance score over the training period for those in the simulator arm and no such improvement for those in the control arm. Statistically significant improvement was seen for global performance scores in both simulator and control groups. There was a greater effect on technical scores for those trainees with little prior experience. Although the study design had limitations, such as problems with effective randomisation and study group imbalance (there were more experienced operators in the simulation arm of the trial), the results are encouraging and prove that simulation does improve clinical skills. It would be easy to suggest that the control trainees might have achieved the same results if given an additional eight hours of training time in the real cath lab, but this was not the reason for the study. As previously described, the benefit of simulation training is to re-create authentic training experiences in a risk averse training landscape that is often short of enough real opportunities. More recently, a prospective, single-centre study from Chicago measured the performance of 14 early interventional trainees before and after a three-hour training session with one hour of didactic teaching and two hours of simulator training.28 Trainees demonstrated significant improvements in their scores on an investigator-designed checklist for quality in diagnostic coronary angiography. This included appropriate consent, safety and sterile technique, description of placement of sheath (the simulator used does not include arterial puncture), correct exchange of catheter over wire and engagement and imaging of left and right coronary system. The trainees also demonstrated reduced fluoroscopy time and total procedure time but did not use significantly less contrast or better wire technique in the real world cath lab. Trainees themselves felt the exercise to be valuable. The marked improvement in technical and non-technical skills from less than one day of training is encouraging, although the authors do not report which skills drive the significant improvement. This study also shows improvement in outcomes that could be directly related to patient outcomes. The authors may be criticised for using their own checklist to assess progression, rather than an externally validated measure, but no standardised measurement exists to date. The two studies demonstrate some benefit to trainees, if not patients, from simulator training, however not all of the evidence in cardiology is positive. A retrospective cohort study from Stockholm provides another direct assessment of the transfer of skills from simulator to cardiac catheterisation.30 The study identified 58 novices who began training during the study period, 20 % of whom attended an angiography simulator course. These trainees were enrolled in a two-day course comprising six hours of supervised simulator training and six hours of lectures. The simulator was also available out of course time for practice. Registry data for the outcomes of these operators as they progressed in their careers was collected and analysed. The study therefore collects patient-centred data per operator, including contrast dose received, fluoroscopy time and complication rates. Surprisingly, trainees who were enrolled in the simulator course appeared to perform less well than those who had only ‘real-life’ training. Fluoroscopy times were longer for simulator trained operators and learning curves for these participants showed a slower reduction in screening times. Course attendees had a higher rate of vascular complications. It is very tempting to draw conclusions about the potentially negative consequences of some simulation training. However, this data may relate to the course design and delivery and as a retrospective analysis the results are likely to be confounded by numerous other variables. Regardless, the

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study does emphasise the point that simulation training needs to be authentic, delivered in a formal, structured manner and ensure that it does not allow the delegates to acquire potentially harmful approaches to procedures, one being over confidence. Without good guidance and high fidelity training, bad habits can easily translate into clinical practice.

Are Randomised Studies to Prove the Benefits of Simulation Training Needed? An important question to consider when reviewing the data for educational interventions is whether the study design, adapted from medical trials of therapeutics and interventions, is the right way to measure educational impact and change in practice. Educationalists have multiple tools for assessing educational interventions that generally rely on the endpoint of a real clinical outcome.31 Whilst it is instinctively attractive to cardiologists to measure definable endpoints, the process of taking measurable outcomes and comparing them across groups may not capture the entire benefits of an educational intervention. Specifically, it is unlikely to be possible to accurately assess or measure trainees’ use of reflection after training, or the effects of increased or reduced confidence on performance. On the other hand, the selfreported measures from trainees of their learning outcomes tend to be subject to reporting biases and may reflect intention but not necessarily action. Regardless, across medicine, and to a lesser degree cardiology, there is now strong evidence to show that simulation has an important role to play in training and it is arguable that further trials focused on clinical endpoints may not be appropriate or necessary.

Beyond Screening Time – Human Factors Training and Crisis Resource Management The real clinical benefits of simulation may lie in human factors training. Despite the authentic nature of modern interventional simulators, the training is often delivered in a classroom environment which is completely different from a real cath lab. In addition to the focussed development of technical skills, the role of simulation in medical training has been used to train for rare events, and to train in non-technical or ‘human’ factors. This has been extensively used, an example being in cardiac arrest management where Advanced Life Support32 is used extensively in aviation. This type of training is best delivered in an immersive environment that brings together an authentic scenario with a real team grappling with difficult clinical problems supported by high fidelity simulation equipment. The study of crisis resource management (CRM) requires the development of communication, teamwork, leadership, situational judgement and decision-making skills.33 Simulated situations again appear to provide a safe and controlled environment with the opportunity for structured feedback to improve performance. Human factors training often constitutes a team of trainees working in a simulated medical environment with a developing clinical scenario driven by trainers who either control the environment or directly interact with trainees as part of the clinical team or as patients.34 Training sessions can be viewed live by other trainees or recorded as a video and replayed to trainees to allow reflection and analysis. Given the frequently acute nature of interventional cardiology, the need to be able to manage rare events and complications the benefits of improving CRM skills appear clear. This type of immersive cath lab training is being increasingly used to allow individuals and teams to work more effectively together in emergency situations and when unexpected, potentially life-threatening events or complications can occur. Most research in this field is led by anaesthetic, emergency and critical care medical teams. A systematic review of the literature on

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CRM training included over 80 studies. Most of the studies focused on either a change in the trainees’ perspective or performance during the simulation. However, nine publications had study designs that reported either changes in real clinical practice or in actual patient outcomes after CRM training had been completed. These endpoints included mortality, resuscitation time or perinatal outcomes.33 These studies documented beneficial changes in clinical practice as well as improvement in patient outcomes, including resuscitation time and length of hospital stay. Most studies reported a clear change in practice after simulated scenario training, and patient outcome measures, including one study which showed an improvement in mortality after perinatal cardiac arrest. Although many of these studies were small and single-centre with a risk of bias, the conclusions are encouraging and would support the more widespread use of this type of immersive simulation. The use of actors or real patients in simulator situations is conceptually attractive and can access a complex web of conscious and unconscious professional responses. These include empathy, communication, clinical judgment and decision making.35 It is clear that the use of actors as patients improves the transferability of simulator training to clinical practice, as the simulated situation carries the extra import of a patient-centred approach.

Accessibility and Cost High fidelity simulators and immersive training environments are expensive. The investment required to acquire simulation hardware is significant and there has been a demand from training bodies to see demonstrable benefits from simulator training before purchasing the devices, some costing in excess of £90,000. Due to the increasing

1. Jones DA, Gallagher S, Rathod K, et al. Clinical outcomes after myocardial revascularization according to operator training status: cohort study of 22,697 patients undergoing percutaneous coronary intervention or coronary artery bypass graft surgery. Eur Heart J 2013;34 :2887–95. DOI: 10.1093/eurheartj/eht161. PMID: 23677845. 2. Barbash IM, Minha S, Gallino R, et al. Operator learning curve for transradial percutaneous coronary interventions: implications for the initiation of a transradial access program in contemporary US practice. Cardiovasc Revasc Med 2014;15 :195–9. DOI: 10.1016/j.carrev.2014.03.001. PMID: 24746598. 3. Looi JL, Cave A, El-Jack S. Learning curve in transradial coronary angiography. Am J Cardiol 2011;108 :1092–5. DOI: 10.1016/j.amjcard.2011.06.009. PMID: 21798498. 4. Fox KF. Simulation-based learning in cardiovascular medicine: benefits for the trainee, the trained and the patient. Heart 2012;98 :527–8. DOI: 10.1136/heartjnl-2011-301314. PMID: 22337950. 5. Cook DA, Hatala R, Brydges R, et al. Technology-enhanced simulation for health professions education: a systematic review and meta-analysis. JAMA , American Medical Association 2011;306 :978–88. DOI: 10.1001/jama.2011.1234. PMID: 21900138. 6. Harold JG, Bass TA, Bashore TM, et al. ACCF/AHA/SCAI 2013 update of the clinical competence statement on coronary artery interventional procedures: a report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Compete. Circulation 2013;128 :436–72. DOI: 10.1161/CIR.0b013e318299cd8a. PMID: 23658439. 7. Fox K, Bradbury K, Curran I, et al. Working Group Report on Simulation Based Learning August 2011. 2011;(August). 8. Iglehart JK. Revisiting duty-hour limits--IOM recommendations for patient safety and resident education. N Engl J Med 2008;359:2633–5. DOI: 10.1056/NEJMp0808736. PMID:19052119. 9. Moonesinghe SR, Lowery J, Shahi N, et al. Impact of reduction in working hours for doctors in training on postgraduate medical education and patients’ outcomes: systematic review. BMJ 2011;342(mar22_1):d1580. DOI: 10.1136/bmj.d1580. PMID: 21427046. 10. Cooper JB, Taqueti VR. A brief history of the development of mannequin simulators for clinical education and training. Qual Saf Health Care 2004;13 Suppl 1:i11–8. PMCID: PMC1765785. PMID:15465949. 11. Perkins GD. Simulation in resuscitation training. Resuscitation 2007;73 :202–11. PMID: 17379380. 12. Mundell WC, Kennedy CC, Szostek JH, Cook DA. Simulation

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positive evidence and the demand for simulation to fill the training gap, an increasing number of training centres have purchased the simulators. Perhaps not unexpectedly, access to simulation training is variable at present. In the UK for example, not all trainees have access to simulators locally although there are national programmes run by the British Cardiac Society that offer structured training programs to all trainees. Access to simulation is also variable in Europe.7

Conclusion Simulator training has now been widely accepted as an important tool for procedural training and is seen as an important future development for interventional cardiology training programmes across the world. The BCS, ESC and AHA are all incorporating simulator training into their respective curricula and it is worth reflecting that other, more traditional, learning methods have been accepted in medicine without satisfying the rigorous demands of demonstrating a statistical benefit in a clinical outcome study. In addition to its clear face value, there actually is an increasing body of evidence across medicine, not just in cardiology, to support the use of simulation and its further roll out. Currently, access to simulators is variable and significant investment in equipment and trainer time will be required to improve access for all trainees in the future. Beyond the acquisition of technical and procedural skills, it is likely that the greatest benefit of simulator training will be to improve team-working and awareness of human factors in the often highly pressured cath lab environment. Training for rare events is another potential benefit. Simulator training provides a safe and flexible range of opportunities to practice technical and nontechnical skills, and its use is likely to grow and be of great benefit to cardiologists of the future, and their patients. n

technology for resuscitation training: a systematic review and meta-analysis. Resuscitation 2013;84 :1174–83. DOI: 10.1016/j.resuscitation.2013.04.016. PMID: 23624247. 13. Perkins GD, Kimani PK, Bullock I, et al. Improving the efficiency of advanced life support training: a randomized, controlled trial. Ann Intern Med 2012;157 :19–28. DOI: 10.7326/0003-4819-157-1-201207030-00005. PMID: 22751757. 14. Seymour NE, Gallagher AG, Roman SA, et al. Virtual reality training improves operating room performance: results of a randomized, double-blinded study. Ann Surg 2002;236 :458–63; discussion 463–4. PMID: 12368674. PMCID: PMC1422600. 15. Gallagher AG, Seymour NE, Jordan-Black J-A, et al. Prospective, randomized assessment of transfer of training (ToT) and transfer effectiveness ratio (TER) of virtual reality simulation training for laparoscopic skill acquisition. Ann Surg 2013;257 :1025–31. DOI: 10.1097/SLA.0b013e318284f658. PMID: 23426342. 16. Goettl BP, Shute VJ. Analysis of part-task training using the backward-transfer technique, PMID: 11541091. 17. Sülzenbrück S, Heuer H. Effective part-task training as evidence of distinct adaptive processes with different time scales. PLoS One Public Library of Science 2013;8:e60196. Epub 2013 Mar 27. DOI: 10.1371/journal.pone.0060196. PMID: 23544133. PMCID: PMC3609823. 18. Wickens CD, Hutchins S, Carolan T, Cumming J. Effectiveness of part-task training and increasing-difficulty training strategies: a meta-analysis approach. Hum Factors 2013;55 :461–70. PMID: 23691838. 19. Luboz V, Zhang Y, Johnson S, et al., ImaGiNe Seldinger: first simulator for Seldinger technique and angiography training. Comput Methods Programs Biomed 2013;111 :419–34. DOI: 10.1016/j.cmpb.2013.05.014. PMID: 23787028. 20. Luboz V, Hughes C, Gould D, et al. Real-time Seldinger technique simulation in complex vascular models. Int J Comput Assist Radiol Surg 2009;4 :589–96. DOI: 10.1007/s11548-0090376-0. PMID: 20033335. 21. Fairhurst K, Strickland A, Maddern G. The LapSim virtual reality simulator: promising but not yet proven. Surg Endosc 2011;25 :343–55. DOI: 10.1007/s00464-010-1181-0. PMID: 20614142. 22. Hishikawa S, Kawano M, Tanaka H, et al. Mannequin simulation improves the confidence of medical students performing tube thoracostomy: a prospective, controlled trial. Am Surg 2010;76:73–8. PMID: 20135944. 23. Snyder CW, Vandromme MJ, Tyra SL, Hawn MT. Retention of colonoscopy skills after virtual reality simulator training by independent and proctored methods. Am Surg 2010;76 :743–6. PMID: 20698383.

24. Kneebone R. Simulation in surgical training: educational issues and practical implications. Med Educ 2003;37 :267–77. PMID: 12603766. 25. Zendejas B, Brydges R, Wang AT, Cook DA. Patient outcomes in simulation-based medical education: a systematic review. J Gen Intern Med 2013;28 :1078–89. DOI: 10.1007/s11606-0122264-5. PMID: 23595919. PMCID: PMC3710391. 26. De Ponti R, Marazzi R, Ghiringhelli S, et al. Superiority of simulator-based training compared with conventional training methodologies in the performance of transseptal catheterization. J Am Coll Cardiol 2011;58 :359–63. DOI: 10.1016/j.jacc.2011.02.063. PMID: 21757112. 27. De Ponti R, Marazzi R, Doni LA, et al. Simulator training reduces radiation exposure and improves trainees’ performance in placing electrophysiologic catheters during patient-based procedures. Heart Rhythm 2012;9 :128–5. DOI: 10.1016/j.hrthm.2012.04.015. PMID: 22516184. 28. Schimmel DR, Sweis R, Cohen ER, et al. Targeting clinical outcomes: Endovascular simulation improves diagnostic coronary angiography skills. Catheter Cardiovasc Interv 2015 Jul 21 [Epub ahead of print]. DOI: 10.1002/ccd.26089. PMID: 26198625. 29. Bagai A, O’Brien S, Al Lawati H, et al. Mentored simulation training improves procedural skills in cardiac catheterization: a randomized, controlled pilot study. Circ Cardiovasc Interv 2012;5 :672–9. DOI: 10.1161/CIRCINTERVENTIONS.112.970772. PMID: 23048053. 30. Jensen UJ, Jensen J, Olivecrona G, et al. The role of a simulator-based course in coronary angiography on performance in real life cath lab. BMC Med Educ 2014;14 :49. DOI: 10.1186/1472-6920-14-49. PMID: 24621310. PMCID: PMC3995776. 31. McGaghie WC, Issenberg SB, Petrusa ER, Scalese RJ. Effect of practice on standardised learning outcomes in simulationbased medical education. Med Educ 2006;40 :792–7. PMID: 16869926. 32. Isenberg DL, Bissell R. Does advanced life support provide benefits to patients?: A literature review, Prehosp Disaster Med 2005;20 :265–70. PMID: 16128477. 33. Boet S, Bould MD, Fung L, et al. Transfer of learning and patient outcome in simulated crisis resource management: A systematic review. Can J Anesth 2014;61 :571–82. DOI: 10.1007/ s12630-014-0143-8. PMID: 24664414. PMCID: PMC4028539. 34. Scrivener R. Human factors – what are they? 2014. Available at: http://bit.ly/1Q1M3eI (accessed 4 December 2014) 35. Kneebone R, Nestel D, Wetzel C, et al. The human face of simulation: patient-focused simulation training. Acad Med 2006;81 :919–24. PMID: 16985358.

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