ICR 9.3 by Radcliffe Cardiology

Interventional Cardiology Review Volume 9 • Issue 3 • Autumn 2014

Volume 9 • Issue 3 • Autumn 2014

www.ICRjournal.com

New Advances in Chronic Total Occlusions Nikolaos Konstantinidis, Michele Pighi, Ismail Dogu Kilic, Roberta Serdoz, Georgios Sianos and Carlo Di Mario

Bioresorbable Scaffolds Sidakpal Panaich, Theodore Schreiber and Cindy Grines

Fractional Flow Reserve Derived from Coronary Imaging and Computational Fluid Dynamics Ioannis Pantos and Demosthenes Katritsis

Evidence for Benefit of PCI for Chronically Occluded Coronary Arteries (CTO) – Clinical and Health Economic Outcomes John Rawlins, James Wilkinson and Nick Curzen

ISSN: 1756-1477

Fractional Flow Reserve Estimation in the Left Anterior Descending (Lower Panel)

Intravascular ultrasound (IVUS)guided Chronic Total Occlusion (CTO) Recanalisation

Corresponding Cross-sections of iMap and Virtual Histology Images

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

ICR9.3_FC+spine.indd All Pages

05/09/2014 09:17

Youâ&#x20AC;&#x2122;re invited to attend the scientific session on DES innovations at TCT2014

www.alvimedica.com

Alvimedica.indd 1

03/09/2014 23:36

Volume 9 • Issue 3 • Autumn 2014

www.ICRjournal.com

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

Section Editor – Structural

Section Editor – Coronary Tim Kinnaird

Darren Mylotte

University Hospital of Wales, Cardiff

Galway University Hospitals, Galway

Fernando Alfonso

Eric Eeckhout

Marko Noc

Cardiac Department,Hospital Universitario de La Princesa, Madrid

Centre Hospitalier Universitaire Vaudois, Lausanne

Andrew Archbold

Juan Granada

Jeffrey Popma

London Chest Hospital, Barts Health NHS Trust, London

CRF Skirball Research Center, New York

Beth Israel Deaconess Medical Center, Boston

Olivier Bertrand

A Pieter Kappetein

London Chest Hospital, Barts Health NHS Trust, London

Quebec Heart-Lung Insitute, Laval University, Quebec

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Elliot Smith

Lars Søndergaard

Lutz Buellesfeld

Demosthenes Katritsis

University Hospital, Bern

Athens Euroclinic, Athens, Greece

Rigshospitalet - Copenhagen University Hospital, Copenhagen

Jonathan Byrne

Ajay Kirtane

Gregg Stone

King’s College Hospital, London

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

Antonio Colombo

Didier Locca

Nicolas Van Mieghem

San Raffaele Hospital, Milan

Lausanne University Hospital, Lausanne

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Imperial College NHS Trust, London

Roxana Mehran

Renu Virmani

Mount Sinai Hospital, New York

CVPath Institute, Maryland

Carlo Di Mario

Jeffrey Moses

Mark Westwood

Royal Brompton & Harefield NHS Foundation Trust, London

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

London Chest Hospital, Barts Health NHS Trust, London

Justin Davies

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

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Michael Schmool michael.schmool@radcliffecardiology.com •

Cover image

Human heart glowing in chest 3D render CGI © janulla | shutterstock.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, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved

ICR9.3_masthead.indd 137

137

05/09/2014 11:30

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

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

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

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

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments. • Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Managing Editor formalise the working title and scope of the article. Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.ICRjournal.com.

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

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

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

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

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

138

ICR_A&S2014.indd 138

Radcliffe Cardiology

31/08/2014 12:01

MASTER Trial 1 year results:

mguard outperforms Bms & Des in stemI patients* 12-Month Update

MGuard EPS continues to show a consistent trend in lower mortality rates over time Death at 12 Months

MASTER

Cardiac Death (%)

0% vs 1.9% (P=0.06) at 30 days

BMS/DES

2.3%

MGuard

0.5%

2 1 HR: 0.20 [95% CI:0.02, 1.69] P=0.099

Time in Months

MASTER* Acute Results:

ARy PRIM InT o EnDP vED AChIE

a Significantly Superior Complete ST-Resolution (MGuard 57.8%, Control 44.7%, p = 0.008)

a Significantly Superior TIMI 3 Flow

(MGuard 91.7%, Control 82.9%, p = 0.006) MAL-078-13-01

a Zero Mortality with MGuard at 30 days (MGuard 0%, Control 1.9%, p = 0.06)

* Multicenter, Randomized Trial, 433 patients, 9 countries, 50 centers, Primary Endpoint Complete ST-Resolution, Published in JACC (Stone et. al, 2012)

™

Embolic Protection Stent CE Marked | Not available for sale in the USA MGuard Prime is an Investigational device only in the USA

InspireMD.indd 139

Embolic Protection Stent

ImprovIng ClInICal outComes for stemI patIents

04/09/2014 18:36

Contents

Foreword 144

Simon Kennon, Editor-in-Chief, ICR

Coronary Diagnosis & Imaging

145

Fractional Flow Reserve Derived from Coronary Imaging and Computational Fluid Dynamics

Ioannis Pantos and Demosthenes Katritsis

151

Intravascular Ultrasound-based Imaging Modalities for Tissue Characterisation

Andrejs Erglis, Sanda Jegere and Inga Narbute

156

Impact of Intravascular Ultrasound in Clinical Practice

Andres Vasquez, Neville Mistry and Jasvindar Singh

Adjunctive Pharmacotherapy

164

Optimum Utilisation of Novel Antiplatelet Agents in Clinical Practice Timm Bauer and Christian Hamm

STEMI

168

MGuard Embolic Protection Stent â&#x20AC;&#x201C; The Importance of Thrombus Management in ST-elevation Myocardial Infarction Primary Percutaneous Coronary Intervention

Proceedings of STEMI symposium at EuroPCR on 20â&#x20AC;&#x201C;23rd May 2014 in Paris

Katrina Mountfort, Medical Writer, Radcliffe Cardiology

Reviewed for accuracy by: Ricardo Costa, Alexandre Abizaid, Jean Fajadet, Chaim Lotan, Ran Kornowski, Dariusz Dudek, Jose PS Henriques, Giovanni Amoroso

Bioresorbable Scaffolds

175

140

ICR_contents_9.3.indd 140

Bioresorbable Scaffolds Sidakpal Panaich, Theodore Schreiber and Cindy Grines

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 09:47

ESC 2015.indd 144

04/09/2014 19:14

Contents

Drug Eluting Stents

180

Cre8™ Unique Technology in Challenging Daily Practice

Proceedings of a satellite symposium held at EuroPCR on 20th – 23rd May 2014 in Paris

Katrina Mountfort, Medical Writer, Radcliffe Cardiology

Reviewed for accuracy by: David Antoniucci, Roxana Mehran, Giuseppe DeLuca, Holger Nef, Mathias Vrolix and Ahmed Khashaba

184

Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology

Proceedings of a satellite symposium held at EuroPCR on May 20th – 23rd 2014 in Paris

Katrina Mountfort, Medical Writer, Radcliffe Cardiology

Reviewed for accuracy by: Didier Carrié, Marco Valgimigli, Gennaro Sardella, Shmuel Banai, Rafael Romaguera and Pieter Stella

CTO

142

ICR_contents_9.3.indd 142

190

Evidence for Benefit of Percutaneous Coronary Intervention for Chronically Occluded Coronary Arteries (CTO) – Clinical and Health Economic Outcomes

John Rawlins, James Wilkinson and Nick Curzen

195

Percutaneous Treatment of Coronary Chronic Total Occlusions Part 1: Rationale and Outcomes

Alfredo Galassi, Aaron Grantham, David Kandzari, William Lombardi, Issam Moussa, Craig Thompson, Gerald Werner, Charles Chambers and Emmanouil Brilakis

201

Percutaneous Treatment of Coronary Chronic Total Occlusion Part 2: Technical Approach

Alfredo Galassi, Aaron Grantham, David Kandzari, William Lombardi, Issam Moussa, Craig Thompson, Gerald Werner, Charles Chambers and Emmanouil Brilakis

208

New Advances in Chronic Total Occlusions

Nikolaos Konstantinidis, Michele Pighi, Ismail Dogu Kilic, Roberta Serdoz, Georgios Sianos and Carlo Di Mario

213

Contemporary Techniques for Coronary Chronic Total Occlusions Revascularisation: Sharing Experience in a Global World

Proceedings of a satellite symposium held at EuroPCR on May 20th – 23rd 2014 in Paris

Katrina Mountfort, Medical Writer, Radcliffe Cardiology

Reviewed for accuracy by: Heinz Joachim Büttner, Masahisa Yamane, Nicolaus Reifart, Javier Escaned, Georgios Sianos, Omer Goktekin and Roberto Garbo

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 09:48

Let’s co-create to innovate interventional cardiology!

IN T ER V EN T ION A L CA RDIOLOGY

Interventional Cardiologist

R&D Alvimedica

Alvimedica is a young, agile company devoted to developing minimally-invasive medical technologies in close cooperation with medical professionals such as yourself: physicians looking for next-level innovations in the operating room. Our ‘co-creation approach’ results in a range of products aiming to meet needs so far unmet in interventional cardiology. Certainly we can offer you worldclass DES, BMS, guidewires and diagnostic, guiding and balloon catheters. But Alvimedica also brings you the exclusive polymer-free, balloon expandable DES stent: Cre8™! Our commitment to improving interventional procedures through innovation is driven by our sincere care for patients’ quality of life and our goal to positively impact clinical outcomes. As our motto says: we want to help physicians bring their patients ‘Back to Life!’ as soon as possible, and based on safe medical practices.

www.alvimedica.com

Alvimedica.indd 143

03/09/2014 23:35

Foreword

Simon Kennon is an Interventional Cardiologist and Head of the Transcatheter Aortic Valve Implantation Programme at the London Chest Hospital, Barts Health NHS Trust, London. He trained at Manchester University, St Bartholomew’s Hospital, the London Chest Hospital and St Vincent’s Hospital, Melbourne. His research interests relate to aortic valve and coronary interventions.

his year’s third and final issue of Interventional Cardiology Review includes an excellent series of papers on chronic total occlusions. Over the last 10 years, particularly the last 5 years, this area has been transformed by the introduction of new

technologies and new techniques. Cases which would only have been considered for surgical revascularisation a decade ago are now routinely being performed percutaneously with success rates approaching 90 %. There are papers by Carlo Di Mario, Nick Curzen and an internationally recognized predominantly American group led by Emmanouil Brilakis. These papers provide concise descriptions of the new techniques and technologies as well reviewing clinical and health economic outcomes of contemporary CTO procedure. This focus on CTO interventions has, unusually, left no room for structural intervention papers but there are five high quality papers reviewing other areas of coronary intervention. There are two detailed papers on IVUS by Jasvindar Singh and Andrejs Erglis. These papers review the different IVUS technologies, their practical applications and a wealth of research data relating to them. In contrast, Demosthenes Katritsis provides an introduction to the non-invasive assessment of coronary artery stenoses by computational flow dynamics. Cindy Grines and Christian Hamm provide insightful reviews of bioresorbable scaffolds and novel antiplatelet agents respectively – both areas of where important developments are increasing the safety and efficacy of percutaneous coronary intervention. Finally, I would like to welcome Tim Kinnaird and Darren Mylotte. They have a wealth of experience from working in cardiac units in both North America and Europe. Tim and Darren have taken on editorship of the coronary and structural intervention sections respectively. I am sure we will work well together and what looks to be an excellent first issue for 2015 is already taking shape. n

144

Foreword_ICR 9.3.indd 144

05/09/2014 09:53

Coronary Diagnosis & Imaging

Fractional Flow Reserve Derived from Coronary Imaging and Computational Fluid Dynamics Ioannis Pantos1,2 and Demosthenes Katritsis1 1. Athens Euroclinic, Athens, Greece; 2. University of Athens, Greece

Abstract The assessment of functional severity of atherosclerotic stenoses in patients with coronary artery disease by invasive fractional flow reserve (FFR) measurement requires coronary artery cannulation, advancement of a wire and intravenous adenosine infusion with inherent procedure-related risk and costs. Coronary computed tomographic angiography (CCTA) and rotational coronary angiography (RA) have been recently used in conjunction with computational fluid dynamics (CFD) and image-based modelling for the determination of FFR without the need for additional imaging, modification of acquisition protocols or administration of medication. FFR derived from CCTA was demonstrated as superior to measures of CCTA stenosis severity for determination of lesion-specific ischaemia. Estimation of FFR from RA images and CFD provides a less invasive alternative to conventional FFR measurement while estimated values are in agreement with measured values. These new, combined anatomic–functional assessments have the potential to simplify the noninvasive diagnosis of coronary artery disease with a single study to identify patients with ischaemia-causing stenosis who may benefit from revascularisation.

Keywords Fractional flow reserve, computational fluid dynamics, computed tomography, rotational angiography, coronary artery disease Disclosure: The authors have no conflicts of interest to declare. Acknowledgement: Supported by a grant from the Stavros Niarchos Foundation. Received: 24 April 2014 Accepted: 15 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):145–50 Correspondence: Dr Demothenes Katritsis, Department of Cardiology, Athens Euroclinic, 9 Athanassiadou Str., 115 21 Athens, Greece. E: dkatritsis@euroclinic.gr

The functional severity of atherosclerotic coronary lesions is the single most important prognostic factor in patients with documented coronary artery disease (CAD). Assessment of the haemodynamic significance of coronary artery lesions by invasive fractional flow reserve (FFR) measurement now has an I-A indication by the European Society of Cardiology (ESC) to identify haemodynamically relevant coronary lesions when evidence of ischaemia is not available.1 FFR represents the extent to which maximal myocardial blood flow is limited by the presence of a coronary stenosis and in clinical practice FFR is defined as the ratio of distal coronary to aortic pressure at maximal vasodilation.2 FFR provides a physiologic adjunct to invasive coronary angiography, challenging the notion of coronary revascularisation need on the basis of anatomic coronary stenosis alone.3 In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study, of 1005 patients with multivessel CAD, those who underwent FFR-guided revascularisation experienced lower rates of adverse events with fewer coronary stents and lower healthcare costs, than patients undergoing angiogram-guided revascularisation.4,5 The results from FAME are in accordance with the five-year follow-up of individuals from the Deferral Versus Performance of PTCA in Patients Without Documented Ischemia (DEFER)6 study which demonstrated that amongst lesions judged angiographically “obstructive,” >50 % were haemodynamically insignificant by FFR and no benefit was observed by revascularisation. In patients with stable CAD and functionally significant stenoses, FFR-guided percutaneous coronary intervention (PCI) in combination with medical therapy, as compared with medical

Demos_FINAL.indd 145

therapy alone, decreased the need for urgent revascularisation.7 Despite these benefits, less than 10 % of PCI procedures in the UK use adjunctive intracoronary measurements, and even fewer diagnostic cases employ FFR to guide management. This is due to the various drawbacks associated with the measurement of FFR, such as the requirement of invasive cardiac catheterisation, an expensive coronary pressure wire and intracoronary or intravenous adenosine infusion which is associated with adverse effects such as AV block, bronchial hyper-reactivity, and chest pain.8,9 A clinical implication is the inadvertent revascularisation of patients with stable CAD and “innocent” lesions, who clearly do not benefit from intervention.10 Thus, a tool that could accurately and rapidly calculate FFR without the need of a pressure wire would make this physiologic index become available to a wider population. Recent advances in coronary imaging and computational fluid dynamics (CFD) enable calculation of coronary flow and pressure fields from anatomic image data.11 Novel techniques of FFR calculation have been developed based on coronary image analysis and CFD techniques which aim to provide an alternate to interventional FFR measurement by abolishing some or most of its limitations.

Computational Fluid Dynamics CFD is a general term used to account for the numerical solution of the governing equations of fluid flow (Navier-Stokes equations). These equations are solved for the unknown pressure, which varies with position and time, and for the three components (vectors) of blood velocity, each of which are functions of position and time.12 The physical properties of blood, the fluid density and the fluid viscosity, are known

145

05/09/2014 10:01

Coronary Diagnosis & Imaging Figure 1: Example of Fractional Flow Reserve derivation from computed tomography coronary angiography (FFRCT) Right Coronary Artery CT stenosis >90 % A

FFRCT Model G

Left Anterior Descending Artery CT stenosis 50–70 % D

and applied to the arterial outlets,23 or predescribed conditions are assumed.24,25 The field of CFD has made substantial progress in the past two decades, taking advantage of the availability of fast supercomputer capabilities. In terms of the application of CFD to coronary flow, the main limitations arise from ambiguities associated with inflow boundary conditions, definition of the cardiac and artery motion, etc., result in uncertainties regarding the validity of computational results.

Novel Techniques of FFR Calculation

B FFRCT 0.56 FFRCT 0.75

FFR 0.71

FFR 0.65 C

Multiplanar reformat (a, d) and straightened curved planar reformat (b, e) of a coronary computerised tomography (CT) angiogram, invasive coronary angiograms (b, e), invasive fractional flow reserve (FFR) measurements (c, f), and fractional flow reserve derived from computed tomography angiography (FFRCT) (g) of the right coronary artery and left anterior descending artery, respectively. The coronary CT angiogram demonstrates obstructive stenosis of the distal portion of the right coronary artery and the mid-portion of the left anterior descending artery (red arrows) and FFRCT values of 0.56 and 0.75 indicating ischaemia. Invasive coronary angiogram demonstrates obstructive stenoses of the right coronary and left anterior descending arteries (red ar rows) and measured FFR values, indicating ischaemia in both vessel territories. Reproduced with permission.28

when solving these equations. Although blood exhibits complex rheological properties, it can be approximated as a Newtonian fluid with a constant viscosity in large arteries. These equations were formulated as early as the 19th century, however, their solution only became possible with modern computing power and numerical methods.13 Typically, a CFD problem consists of flow in a certain vessel model which is subject to certain boundary conditions. The geometric model of the vessel is discretised into a number of smaller entities (finite volumes or finite elements), thus forming the nodes of a computational mesh, on which the unknowns are calculated. The discretisation of the governing differential equations results in systems of algebraic equations, whose solution gives the problem unknowns at the mesh nodes. In order to perform a CFD simulation of flow in a coronary vessel, a 3D description of the vessel lumen is required. Several methods have been used for this purpose, the most widely applied of which are coronary vessel reconstruction based on biplanar coronary angiography,14,15 rotational coronary angiography,16 intravascular ultrasound and biplanar coronary angiography,17 optical coherence tomography (OCT) imaging,18 3D quantitative coronary angiography19 and computed tomography coronary angiography.20,21 Boundary flow conditions also need to be specified in order to solve the blood flow problem. Boundary flow conditions are mathematical relationships between the variables of interest, e.g. flow and pressure, defined on the boundaries (entrance and exit) of the vessel model.12 Coronary flow and pressure at the coronary vessels are technically difficult to acquire both invasively and noninvasively due to the narrow lumens of the coronary vessels, the fact that they are embedded on the beating myocardium and due to the limited spatial and temporal resolution of applicable measurement techniques such as ultrasound, intravascular ultrasound and magnetic resonance imaging (MRI).22 Thus alternative methodologies are usually utilised such as methods that couple lumped parameter models of the microcirculation to the outflow boundaries,11 generic boundary conditions are developed

146

Demos_FINAL.indd 146

By taking advantage of the exceptional capabilities of modern modalities for coronary imaging coupled with CFD methodologies, various investigators have presented alternative methods of FFR calculation. In these studies the imaging modality, either a multislice computed tomography (CT) scanner,20,21,26–29 an angiography unit capable of rotational coronary angiography,16 or 3D quantitative coronary angiography (3DQCA) were employed for the acquisition of vessel models of diseased coronary arteries. On the acquired models suitable boundary conditions are applied, the blood is appropriately modelled and the incompressible Navier-Stokes equations are solved with a finite element method using CFD techniques and appropriate hardware. From the simulation results the “virtual” fractional flow reserve is calculated.

Coronary Computed Tomographic Angiography Derived FFR Coronary computed tomographic angiography (CCTA) has emerged as a noninvasive test that assesses anatomic CAD stenosis severity.30 However, CAD as determined by CCTA demonstrates a poor relationship to lesion-specific ischaemia, with the majority of high-grade stenoses detected by CCTA not being associated with ischaemia.31–34 These findings have raised concerns that widespread use of CCTA might result in excess referral of patients to ICA and unnecessary revascularisation of nonischaemic coronary lesions.35,36 Thus it would be desirable to be able to calculate the functional severity of CAD stenoses with CCTA. Computational fluid dynamics, as applied to CCTA images, provide the possibility for non-invasive quantitation of coronary blood flow, flow velocity and pressure in the major epicardial coronary arteries. A dedicated algorithm has been developed which facilitated the derivation of FFR based of CCTA (FFRCT) (HeartFlow™; HeartFlow Inc., Redwood City, CA, USA).37,38 CCTA can provide a credible coronary geometric model, including patient specific branching and pathology. Based upon this geometric information, a volumetric finite element mesh with anisotropic refinement and boundary layers is generated in order to compute numerical results. Using a proprietary algorithm the heart-vessel interaction can be defined, whereas time-varying coronary resistance for each coronary branch can be determined relative to intramyocardial pressure and microvasculature impedance. This latter component can be represented by a so-called lumped (zerodimensional) parameter model, which resembles an electric circuit, including resistive and capacitive elements. 11 The complex fluid properties of the blood are entered into the model, in order to refine the computations. The methodology of FFRCT computation is based on three key principles20: (i) the coronary supply meets myocardial demand at rest; (ii) the resistance of the microcirculation at rest is inversely but not linearly proportional to the size of the feeding vessel; (iii) the microcirculation reacts predictably to maximal hyperaemic conditions in patients with normal coronary flow. FFR can be computed from

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:01

typically acquired CCTA scans without any modification of CCTA protocols, additional image acquisition, administration of medications, or additional radiation to the patient (see Figure 1).

Figure 2: Example of Functional Assessment Before and After Revascularisation

In order to compute FFR, 3D models of the coronary tree and ventricular myocardium are reconstructed from standard coronary CT image datasets and the major epicardial vessels and plaque are segmented, luminal surfaces are identified, and visible side branches are added to the model. Blood is usually modelled as a Newtonian fluid and the incompressible Navier- Stokes equations are solved, subject to appropriate boundary conditions. Since coronary flow and pressure are unknown a priori, a method to couple lumped parameter models of the microcirculation to the outflow boundaries of the 3D model is used to represent the resistance to flow during simulated hyperaemia for each coronary branch of the segmented CT model.

Before Stenting (A)

Fractional Flow Reserve Derived from Coronary Imaging and Computational Fluid Dynamics

After Stenting (B)

CT-derived computed FFR (FFRCT)

Angiography

Invasive FFR

FFRCT 0.72 FFR 0.68

Proximal location Distal location

FFRCT 0.86

FFR 0.90

The feasibility and diagnostic performance of the method were evaluated in the Diagnosis of ischaemia-causing stenoses obtained via noninvasive fractional flow reserve (DISCOVER FLOW) study. This trial was conducted at five hospitals internationally, which prospectively enrolled 103 patients (159 lesions) who had undergone coronary CCTA.20 All patients underwent invasive angiography with FFR. Computed FFR values were found to have a very high degree of correlation with invasively measured FFR. As expected, coronary

(A) The functional significance of a stenosis of the left anterior descending (LAD) coronary artery was calculated by noninvasive fractional flow reserve (FFR) from coronary computed tomographic angiography data (FFRCT=0.72) and by FFR measurement during invasive coronary angiography (FFR=0.68). (B) Fractional flow reserve derived from computed tomography angiography FFRCT demonstrated no ischemia in the LAD after virtual stenting, with a computed value of 0.86. Invasive FFR after stent implantation was 0.90. Reproduced with permission.29

CT angiography alone showed high sensitivity of 91 % and negative predictive value (NPV) of 89 %, but comparatively low specificity of 40 % and positive predictive value (PPV) of 47 % for the identification of lesion-specific ischaemia defined as an FFR ≤0.80. By comparison, FFRCT produced sensitivity of 88 % and NPV of 92 %, similar to those of coronary CT angiography, but much higher specificity of 82 % and PPV of 74 %, resulting to an overall accuracy increase of 25%.

and distal reference areas. FFRCT is computed before and after virtual stenting thus providing not only diagnosis of lesion-specific ischaemia but additionally predicts the therapeutic benefit of coronary revascularisation (see Figure 2). FFRCT had a diagnostic accuracy of 96 % in predicting or ruling out myocardial ischaemia after stenting as defined by a post-stent FFR of >0.80 while the mean difference between FFR after stenting and FFRCT after virtual stenting was 0.02 ± 0.05.29 Thus, it appears that comprehensive planning of a revascularisation strategy and selection of the optimal target coronary lesion(s) for revascularisation is possible using this novel technology, which can provide both anatomical and functional information for each lesion before the invasive procedure.

A substudy of DISCOVER-FLOW demonstrated considerable accuracy of FFRCT for diagnosis of lesion-specific ischaemia of coronary lesions of intermediate stenosis severity (40 % to 69 %).39 A larger, prospective multicentre clinical trial, the Determination of fractional flow Reserve by anatomic computed tomographic angiography (DeFACTO) study is similarly designed to determine the diagnostic performance of FFRCT for the noninvasive assessment of lesion-specific ischaemia using invasively measured FFR as the reference standard.27 This multicentre diagnostic performance study involving 252 stable patients with suspected or known CAD observed that FFRCT demonstrated improved diagnostic accuracy versus CT alone for diagnosis of ischaemia, although the study did not satisfy its prespecified primary end point of diagnostic accuracy of greater than 70 % of the lower bound of the one-sided 95 % confidence interval. Refinements in FFR computation technology become recently available which included updated proprietary software with quantitative image quality analysis, improved image segmentation, refined physiological models, increased automation, as well as emphasis on the coronary CTA image acquisition protocol to reflect current guidelines.28 By adopting this refined methodology a recent prospective multicentre trial on 254 patients showed that FFRCT exhibits a very high diagnostic performance compared with invasively measured and high specificity of FFRCT, which was markedly better than in a previous evaluation of FFRCT.21 Moreover, compared with coronary CTA, FFRCT led to a marked reduction in false-positive results. A novel study expedited the application of FFRCT to virtual stenting for the prediction of the functional outcome of stenting prior to the invasive procedure.29 Virtual

INTERVENTIONAL CARDIOLOGY REVIEW

Demos_FINAL.indd 147

stenting is performed by modification of the computational model to restore the area of the target lesion according to the proximal

FFRCT is a promising noninvasive method for identification of individuals with ischaemia and the prediction of the functional outcome of revascularisation. These findings can be considered proof of concept of the feasibility of this novel technology and represent the first large-scale prospective demonstration of the use of computational models to calculate rest and hyperaemic coronary pressure fields from typically acquired CCTA images. The calculation of FFR from CT images requires uploading the CT scan digital imaging and communications in medicine (DICOM) image dataset to particular workstations for image analysis, geometric modelling and supercomputer computation. At present, this data is only provided as a service by a single company, which performs the image analysis, geometric modelling and supercomputer computation 20,21,26,28,29,39,40 and thus results are not generated at the clinical site. Moreover, this process currently takes several hours per exam, however iterative improvements in automation are expected reduce processing time in the near future.26 A recent investigation sought to project the potential clinical and economic consequences of using FFRCT to guide clinical management, in comparison with commonly used alternative strategies for the diagnosis and treatment of patients with known or suspected CAD and reported that use of FFRCT to select patients for invasive coronary angiography and revascularisation would result in 30 %

147

05/09/2014 10:01

Coronary Diagnosis & Imaging Figure 3: Examples of Fractional Flow Reserve Estimation in the Right Coronary Artery (Upper Panel) and Left Anterior Descending (Lower Panel) for Two Patients by Rotational Angiography

FFR (CFD) = 0.56

FFR (measured) = 0.45

FFR (measured) = 0.51

FFR (CFD) = 0.60

Two single frames (A and B) from the rotation were selected for each artery. The arrows indicate the stenosis. The angiographic data were processed for anatomic and physiological reconstruction, which is displayed in image C. The colours represent pressure (Pa) according to the scale shown. The invasively measured and estimated by computational fluid dynamics (CFD) values of fractional flow reserve (FFR) are shown for each stenosis. Reproduced with permission.16

lower costs and 12 % fewer events at one year compared with the most commonly used strategies.41 Derivation of FFRCT is hampered by certain limitations at the extraction of the vascular structures from CT images, formulation of boundary flow conditions and definition of modelling equations of flow.38 Erroneous segmentations are usually encountered in clinical practice, due to the presence of high attenuation objects such as calcified plaques or stents which produce image artefacts. Following image segmentation the entire volume occupied by the coronary artery is discretised into a large number of small elements, a process known as meshing, which allows for the solution of the blood flow problem at the location of each element. This meshing process is usually user-dependent and potentially introduces further uncertainty in blood flow modelling. Finally, realistic inflow and outflow boundary flow conditions are required to perform the CFD simulation, however blood pressure cannot be directly measured by CCTA and brachial blood pressure is often used as a surrogate for pressure in large arteries. The outlet boundary condition (which models the effect of the distal vascular system, such as small arteries, microcirculatory vessels and veins and returning blood to the heart) is difficult to determine in practice. Outlet boundaries are derived by coupling the lumped parameters, which approximate the haemodynamic conditions of the distal vascular system.42 The estimated flow distribution of each of the major coronary arteries is a consequence of the relationship between vessel size and resistance, while cardiac output is based on the measurement of myocardial mass that is derived from the cardiac CT dataset. Furthermore, the coronary venous resistance is calculated based on the assumption of mean coronary blood flow at the expense of incorporating patient-specific factors.

angiography (RA).16 The workflow has been developed to create simplified virtual models of the major epicardial arteries with or without one major side branch from a single rotational coronary angiogram. With a CFD solver and with generic boundary conditions,23 the pressure and flow solution can be calculated (see Figure 3). The estimated FFR values agree well with the measured values, with an overall average deviation from the measured values of ± 0.06. Lesions requiring PCI (measured FFR <0.80) were identified from nonsignificant lesions (measured FFR >0.80) with 97 % accuracy. This methodology does not require the induction of hyperaemic flow, additional procedure time, the hazard of passing an intracoronary wire, or additional equipment, training or cost. However, the authors acknowledge the study can be only considered as hypothesis generating since it is hampered by various limitations. The most evident being the limited patient cohort and the fact that only a limited subgroup of cases (n= 3) had an measured FFR falling between 0.75 and 0.85. In several patients with measured FFRs equal to 1.0 the calculated value varies between 0.85 and 0.95. The accuracy of the methods seems to be lesion severity dependent since for haemodynamically insignificant stenoses the calculated FFR values are more likely to be accurate whereas for most lesions with FFR <0.80, the virtual FFRs underestimates severity. Other limitations are the adoption of generic rather than patient specific boundary flow conditions and the long computational time currently required to process data. Inherent limitation is the requirement of a rotational coronary angiogram which is an invasive procedure not universally available and cumbersome to perform.

3D QCA and TIMI Frame Count Derived FFR Rotational Coronary Angiography Derived FFR A proof-of-concept, single-site study explored the feasibility of FFR estimation on 19 patients with stable coronary artery disease using CFD techniques and angiographic images acquired from rotational

148

Demos_FINAL.indd 148

A methodology for FFR computation based on 3D quantitative coronary angiography (QCA) and thrombolysis in myocardial infarction (TIMI) was recently presented.19 The methodology uses 3D QCA (QAngio® XA 3D, Medis Special BV43,44) to obtain the anatomical

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:01

Fractional Flow Reserve Derived from Coronary Imaging and Computational Fluid Dynamics

models and applies CFD subsequently, using the hyperaemic flow rate to calculate FFRQCA. To calculate flow rate, the contrast medium transport time in the reconstructed vessel was measured on hyperaemic projections using TIMI frame count. The mean volumetric flow rate (VFR) at hyperaemia was derived using the lumen volume of the reconstructed coronary tree divided by the mean transport time. The same calculation was applied to the baseline angiography, from which the baseline VFR was obtained. Coronary flow reserve (CFR) was derived by dividing the hyperaemic VFR by the baseline VFR. For the CFD part of the methodology, blood was modelled as incompressible Newtonian fluid and blood’s density and viscosity were derived using the haematocrit value of individual patients. The mean hyperaemic VFR and the mean pressure at the guiding catheter tip were applied at the inlet, whereas outflow (fully developed flow) condition was applied at the outlets. After simulation, FFRQCA was defined as the mean pressure at the outlet divided by the mean pressure at the inlet (see Figure 4). The diagnostic performance of the computed FFRQCA was assessed using wire-based FFR as reference standard on 77 vessels in 68 patients with intermediate coronary stenoses (40–70 % diameter stenosis by visual estimation). FFRQCA correlated well with FFR (r =0.81, p < 0.001), with a mean difference of 0.00±0.06 (p=0.541). Applying the FFR cutoff value of ≤0.8 to FFRQCA resulted in 18 true positives, 50 true negatives, four false positives and five false negatives.

Figure 4: Example of Fractional Flow Reserve derivation by quantitative coronary angiography (FFRQCA) A

FFR = 0.85 54 % stenosis E1

FFRQCA = 0.87

(A,B) Example of FFRQCA calculation of 54 % diameter stenosis of the RCA with a wire-based FFR measurement of 0.85. (C) 3D reconstruction of the arterial lumen. (D) Simulated pressure distribution at hyperemia and computation of FFRQCA (0.87). (E1 to E9) Consecutive angiographic image frames at hyperaemia. Reproduced with permission.19

Conclusions FFRQCA provides a more patient-specific approach than previously presented methodologies since rather than assuming that microcirculation reacts predictably to maximal hyperaemic condition, it calculates hyperaemic directly on the angiographic projections during hyperaemia. It also appears that FFRQCA is more accurate than FFRCT which, according to the investigators, can be attributed to the higher image spatial resolution of conventional coronary angiography versus coronary computed tomography angiography, as well as by the presence of downstream microcirculatory disease. Another plausible advantage of the technique is the processing time which according to the authors is less than 10 minutes, which implies that it has the potential to be adopted in clinical practice if the methodology is further optimised. Limitations of the study include its limited patient cohort and validation exclusively on de novo lesions. Another limitation of the method is that since 2D projections are used to reconstruct the 3D arterial model, vessel overlap, foreshortening and poor image quality may hamper the process.

1. 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. 2. De Bruyne B, Sarma J. Fractional flow reserve: A review: Invasive imaging. Heart 2008;94:949–59. 3. Melikian N, De Bondt P, Tonino P, et al. Fractional flow reserve and myocardial perfusion imaging in patients with angiographic multivessel coronary artery disease. JACC Cardiovasc Interv 2010;3:307–14. 4. 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. 5. 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. 6. 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. 7. 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. 8. Smits P, Thien T. Effects of adenosine on human coronary arterial circulation. Circulation 1991;84:2208–10.

INTERVENTIONAL CARDIOLOGY REVIEW

Demos_FINAL.indd 149

Comprehensive noninvasive anatomical and functional imaging would be desirable to identify patients who are likely to benefit from invasive coronary angiography and revascularisation. Advances in computational technology now permit calculation of FFR using resting CCTA, RA or QCA image data, without the need for additional radiation or medication. Early data from various studies demonstrate improved accuracy and a discriminatory ability of FFRCT to identify ischaemia-producing lesions compared with CCTA alone. FFR estimation from RA provides a less invasive alternative to conventional FFR measurement which is not widely applied yet, however early results are promising. Computation of FFRQCA allows safe and efficient assessment of the functional significance of intermediate stenosis. Acknowledging the various limitations of each technique, these combined anatomic–functional assessments have the potential to simplify the noninvasive diagnosis of coronary artery disease with a single study to identify patients with ischaemia-causing stenosis who may benefit from revascularisation. n

9. Kern MJ, Deligonul U, Tatineni S, et al. Intravenous adenosine: Continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease. J Am Coll Cardiol 1991;18:718–29. 10. Katritsis DG, Ioannidis JP. Pci for stable coronary disease. N Engl J Med 2007;357:414–5; author reply 417–8. 11. Kim HJ, Vignon-Clementel IE, Coogan JS, et al. Patient-specific modeling of blood flow and pressure in human coronary arteries. Ann Biomed Eng 2010;38:3195–209. 12. Taylor CA, Fonte TA, Min JK. Computational fluid dynamics applied to cardiac ct for noninvasive quantification of fractional flow reserve: Scientific basis. J Am Coll Cardiol 2013. 13. Meijs MF, Cramer MJ, El Aidi H, Doevendans PA. Ct fractional flow reserve: The next level in non-invasive cardiac imaging. Neth Heart J 2012;20:410–8. 14. Johnston BM, Johnston PR, Corney S, Kilpatrick D. Non-newtonian blood flow in human right coronary arteries: Steady state simulations. J Biomech 2004;37:709–20. 15. Johnston BM, Johnston PR, Corney S, Kilpatrick D. Nonnewtonian blood flow in human right coronary arteries: Transient simulations. J Biomech 2006;39:1116–28. 16. Morris PD, Ryan D, Morton AC, et al. Virtual fractional flow reserve from coronary angiography: Modeling the significance of coronary lesions: Results from the virtu-1 (virtual fractional flow reserve from coronary angiography) study. JACC Cardiovasc Interv 2013;6:149–57.

17. Bourantas CV, Kourtis IC, Plissiti ME, et al. A method for 3d reconstruction of coronary arteries using biplane angiography and intravascular ultrasound images. Comput Med Imaging Graph 2005;29:597–606. 18. Kousera CA, Nijjer S, Torii R, et al. Patient-specific coronary stenoses can be modeled using a combination of oct and flow velocities to accurately predict hyperemic pressure gradients. IEEE Trans Biomed Eng 2014;61:1902–13. 19. Tu S, Barbato E, Koszegi Z, et al. Fractional flow reserve calculation from 3-dimensional quantitative coronary angiography and timi frame count: A fast computer model to quantify the functional significance of moderately obstructed coronary arteries. JACC Cardiovasc Interv 2014;7:768–77. 20. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter discover-flow (diagnosis of ischemia-causing stenoses obtained via noninvasive fractional flow reserve) study. J Am Coll Cardiol 2011;58:1989–97. 21. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic ct angiography. JAMA 2012;308:1237–45. 22. Katritsis D, Kaiktsis L, Chaniotis A, et al. Wall shear stress: Theoretical considerations and methods of measurement. Prog Cardiovasc Dis 2007;49:307–29. 23. Westerhof N, Lankhaar JW, Westerhof BE. The arterial

149

05/09/2014 10:01

Coronary Diagnosis & Imaging windkessel. Med Biol Eng Comput 2009;47:131–41. 24. Berne R, Levy M. Cardiovasular physiology St. Louis, USA: Mosby inc. 2001. 25. Matsuo S, Tsuruta M, Hayano M, et al. Phasic coronary artery flow velocity determined by doppler flowmeter catheter in aortic stenosis and aortic regurgitation. Am J Cardiol 1988;62:917–22. 26. Yoon YE, Choi JH, Kim JH, et al. Noninvasive diagnosis of ischemia-causing coronary stenosis using ct angiography: Diagnostic value of transluminal attenuation gradient and fractional flow reserve computed from coronary ct angiography compared to invasively measured fractional flow reserve. JACC Cardiovasc Imaging 2012;5:1088–96. 27. Min JK, Berman DS, Budoff MJ, et al. Rationale and design of the defacto (determination of fractional flow reserve by anatomic computed tomographic angiography) study. J Cardiovasc Comput Tomogr 2011;5:301–9. 28. Norgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: The nxt trial (analysis of coronary blood flow using ct angiography: Next steps). J Am Coll Cardiol 2014;63:1145–55. 29. Kim KH, Doh JH, Koo BK, et al. A novel noninvasive technology for treatment planning using virtual coronary stenting and computed tomography-derived computed fractional flow reserve. JACC Cardiovasc Interv 2014;7:72–8. 30. Min JK, Shaw LJ, Berman DS. The present state of coronary computed tomography angiography a process in evolution.

150

Demos_FINAL.indd 150

J Am Coll Cardiol 2010;55:957–65. 31. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: Results from the prospective multicenter accuracy (assessment by coronary computed tomographic angiography of individuals undergoing invasive coronary angiography) trial. J Am Coll Cardiol 2008;52:1724–32. 32. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row ct. N Engl J Med 2008;359:2324–36. 33. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: A prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52:2135–44. 34. Meijboom WB, Van Mieghem CA, van Pelt N, et al. Comprehensive assessment of coronary artery stenoses: Computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008;52:636–43. 35. Lauer MS. Ct angiography: First things first. Circ Cardiovasc Imaging 2009;2:1–3. 36. Redberg RF, Walsh J. Pay now, benefits may follow-the case of cardiac computed tomographic angiography. N Engl J Med 2008;359:2309–11. 37. Serruys PW, Girasis C, Papadopoulou SL, Onuma Y. Noninvasive fractional flow reserve: Scientific basis, methods

and perspectives. EuroIntervention 2012;8:511–9. 38. Rajani R, Wang Y, Uss A, et al. Virtual fractional flow reserve by coronary computed tomography - hope or hype? EuroIntervention 2013;9:277–84. 39. Min JK, Koo BK, Erglis A, et al. Usefulness of noninvasive fractional flow reserve computed from coronary computed tomographic angiograms for intermediate stenoses confirmed by quantitative coronary angiography. Am J Cardiol 2012;110:971–6. 40. Min JK, Koo BK, Erglis A, et al. Effect of image quality on diagnostic accuracy of noninvasive fractional flow reserve: Results from the prospective multicenter international discover-flow study. J Cardiovasc Comput Tomogr 2012;6:191–9. 41. Hlatky MA, Saxena A, Koo BK, et al. Projected costs and consequences of computed tomography-determined fractional flow reserve. Clin Cardiol 2013;36:743–8. 42. Vignon-Clementel IE, Figueroa CA, Jansen KE, Taylor CA. Outflow boundary conditions for 3d simulations of nonperiodic blood flow and pressure fields in deformable arteries. Comput Methods Biomech Biomed Engin 2010;13:625–40. 43. Tu S, Xu L, Ligthart J, et al. In vivo comparison of arterial lumen dimensions assessed by co-registered threedimensional (3d) quantitative coronary angiography, intravascular ultrasound and optical coherence tomography. Int J Cardiovasc Imaging 2012;28:1315–27. 44. Tu S, Huang Z, Koning G, et al. A novel three-dimensional quantitative coronary angiography system: In-vivo comparison with intravascular ultrasound for assessing arterial segment length. Catheter Cardiovasc Interv 2010;76:291–8.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:01

Coronary Diagnosis & Imaging

Intravascular Ultrasound-based Imaging Modalities for Tissue Characterisation Andrejs Erglis,1,2 Sanda Jegere1,2 and Inga Narbute1,2 1. Insitute of Cardiology, University of Latvia, Riga, Latvia 2. Latvian Centre of Cardiology, Pauls Stradins Clinical University Hospital, Riga, Latvia

Abstract Atherosclerosis is the leading cause of cardiovascular mortality and morbidity in the developed world. Intravascular ultrasound (IVUS) is a widely used imaging modality providing complementary diagnostic information to angiography regarding the vessel wall of the coronary arteries. IVUS has been used for assessment of ambiguous angiographic lesions, evaluation of new interventional devices and in atherosclerosis progression-regression trials. However, the standard gray-scale IVUS has limited value for the accurate identification of specific plaque components. This limitation has been partially overcome by introduction of new IVUS-based imaging methods such as: virtual histology IVUS, iMAP-IVUS and Integrated Backscatter IVUS. These methods utilise the ultrasound backscatter signal to enable a more detailed characterization of plaque morphology or tissue characterization and to provide insight on the features of vulnerable plaque.

Keywords Atherosclerosis; Imaging; Ultrasonics; Radiofrequency data analysis; Tissue characterization Disclosure: The authors have no conflicts of interest to declare. Received: 2 June 2014 Accepted: 10 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):151–5 Correspondence: Andrejs Erglis, Professor, Institute of Cardiology, University of Latvia, Chief, Latvian Centre of Cardiology, Pauls Stradins Clinical University Hospital, Riga, LV1002, Latvia. E: a.a.erglis@stradini.lv

Intravascular ultrasound (IVUS) is the first catheter-based imaging modality that has been widely used in interventional cardiology.1 It creates cross-sectional images of the vessel lumen and the arterial wall and provides valuable diagnostic information to angiography regarding lumen and vessel measurements and plaque morphology. This information helps clinical decision-making in ambiguous angiographic lesions. IVUS has also been used to evaluate new interventional devices and for atherosclerosis progression-regression trials. Recently, IVUS has been used to detect vulnerable plaques. In this review, we will focus on the potential clinical and research utility of IVUS-based imaging modalities for tissue characterisation.

frequency and power of the signal differ between tissues, regardless of similarities in the amplitude. Therefore, grey-scale IVUS has limited value for the accurate identification of specific plaque components. This limitation has been partially overcome by introduction of several IVUS-based post-processing methods. Analysis of IVUS radiofrequency backscatter enables a more detailed characterisation of plaque morphology or tissue characterisation and provides insight on the features of vulnerable plaque.4 Three different mathematical methods that have been applied to IVUS RF data analysis are virtual histology IVUS, Volcano Therapeutics (Rancho Cordova, CA, USA), iMAP-IVUS, Boston Scientific Corp (Santa Clara, CA, USA), Integrated Backscatter IVUS (YD, Nara, Japan) (See Figure 1, Table 1).

Greyscale Ivus and Ivus Radiofrequency Analysis IVUS uses a miniaturised piezoelectric transducer mounted on the tip of a catheter where it produces ultrasound signals. The imaging is based on the emission, attenuation and backscattering of ultrasonic waves that are converted to electrical signals and then processed as an image. Standard greyscale IVUS allows quantitative measurements of lumen and vessel and qualitative assessment of atherosclerotic plaque. Calcified tissues are highly echogenic and thus appear as bright echoes with acoustic shadowing. Regions of low echogenicity are usually labelled as “soft” plaque. Soft plaque has high lipid content or it may also be attributable to a necrotic zone within the plaque, an intramural haemorrhage or a thrombus. Fibrous plaques have an intermediate echogenicity between soft and calcific plaques.2 Recent IVUS studies have described attenuated plaque defined as hypoechoic plaque with deep ultraouns attenuation without calcification or very dense fibrous plaque.3 The grey-scale IVUS image is formed using the envelope (amplitude) of the radiofrequency (RF) signal. However, the

Erglis_FINAL.indd 151

Virtual Histology IVUS Virtual histology (VH) IVUS is based on the spectral analysis of the raw backscattered IVUS RF data. It utilises a mathematical autoregressive model and constructs tissue maps that classify plaque into four major tissue types (fibrous, fibro-fatty, necrotic core, and dense calcium).5 VH-IVUS clinical utility ranges from predicting high-risk plaques for patients undergoing coronary angiography to predicting adverse events post percutaneous coronary intervention (PCI).6–9

Detection of High-risk Plaques Rupture of an atherosclerotic plaque is the most common pathological substrate of acute myocardial infarction (AMI). Thin fibrous cap atheroma is a precursor to plaque rupture and is associated with sudden cardiac death.10 Although the axial resolution of VH-IVUS is too low to visualise thin fibrous cap <65 μm, it can potentially identify virtual histology thin cap fibroatheroma (VH-TFCA) that is

151

05/09/2014 10:07

Coronary Diagnosis & Imaging Table 1: Similarities and differences IVUS-based imaging modalities VH Backscatter radiofrequency Autoregressive model

iMAP Fast Fourier transformation

Integrated backscatter Fast Fourier transformation

signal analysis Colour code

Fibrous: green

Fibrotic: light green

Fibrosis: light green

Fibrofatty: light green

Lipidic: yellow

Dense fibrosis: yellow

Necrotic core: red

Necrotic: pink

Lipid: blue

Dense calcium: white

Calcified: blue

Calcified: red

Ex vivo validation

The overall predictive accuracies were

The accuracies at the highest level of

The sensitivity was 100 % for

against histology

93.5 % for fibrous, 94.1 % for fibro-fatty,

confidence (75-100%) were 95 % for

calcification, 94 % for fibrosis, and 84 %

95.8 % for necrotic core, and 96.7 % for

fibrotic, 98 % for lipidic, 97 % for necrotic,

for lipid pool. The specificity was 99 %

dense calcium regions with sensitivities and

and 98 % for calcified regions25

for calcification, 93 % for fibrosis, and

specificities ranging from 72 % to 99 %36

In vivo validation of

The diagnostic accuracy to detect TCFA as

vulnerable plaque

determined by optical coherence tomography

was 86 % with sensitivity 89 %, specificity 86 %38

Limitations

• Acoustic shadowing behind the calcified tissue • Acoustic shadowing behind the calcified • It cannot show plaque composition

is expressed as fibrous of fibrofatty tissue

tissue and the wire artifact is expressed

• VH shows external elastic membrane as a grey

media stripe

as necrotic tissue • Metallic stent struts appear as dense

• VH misclassifies stent struts as calcification

with or without necrotic core

calcium without necrotic core

• Thrombus may be misclassified as fibrous

67 % for lipid pool37

behind a severe calcification and guidewire • It does not have the signal profile of metallic stent struts • Intimal hyperplasia and lipid pool have similar IB values

or fibrofatty plaque

Figure 1: Grey-scale Intravascular Ultrasound and Intravascular Ultrasound Radiofrequency Analysis A

B B’

B’’

Fibrous

Fibrotic

Fibrosis

Fibro-fatty

Lipidic

Dense fib.

Necrotic core

Necrotic

Lipidi

Dence calcium

Calcified

A. An IVUS is obtained from the vessel wall within an histology image. B. The greyscale IVUS image is formed by the envelope (amplitude) of the radiofrequency signal. C. From the backscatter radiofrequency data different types of tissue information can be retrieved: virtual histology; iMAP (D) and integrated backscattered IVUS (E). Adapted from Garcìa-Garcìa HM et al. 4

defined as >10 % confluent necrotic core on three consecutive frames and arc of necrotic core in contact with the lumen for 36 degrees along lumen circumference.11 The prevalence of VF-TFCA is higher in acute coronary syndrome than in stable angina patients.12 In the Providing regional observations to study predictors of events in the coronary tree (PROSPECT) study, 697 patients presenting with acute coronary syndrome (ACS) underwent three-vessel grey-scale and VH-IVUS after successful PCI. The three-year cumulative rate of major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction or rehospitalisation due to unstable or progressive angina) was 20.4 percent. Most events were rehospitalisation

152

Erglis_FINAL.indd 152

for unstable or progressive angina. Nearly half of these events (11.6 %) were related to non-culprit lesions. The PROSPECT study demonstrated that non-culprit lesions associated with recurrent events were frequently angiographically mild, most were VH-TFCA or were characterised by a minimal luminal area ≤ 4.0 mm2 or a plaque burden ≥ 70 %. Adverse events related to nonculprit lesions rarely developed from non-fibroatheromas, regardless of the minimal luminal area or plaque burden.6 Non-culprit lesions that had the non-fibroatheroma phenotype were associated with lower rate of future cardiovascular events than lesions with a fibroatheroma phenotype. We can speculate that VH-IVUS can predict lesion stability and defer intervention.7 In the Virtual Histology in Vulnerable Atherosclerosis (VIVA) study of 170 patients with stable angina or troponin positive ACS referred for PCI, VH-TCFA was associated with major adverse events defined as death, myocardial infarction and unplanned revascularisation.8 In line with previous studies, the European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound (ATHEROREMO-IVUS) study found that the presence of a VH-TFCA in a nonculprit coronary artery was independently predictive for the occurrence of major adverse cardiac events in stable and acute patients undergoing coronary angiography. VH-TFCA lesions were also independently associated with the composite of death or ACS only (present 7.5 % vs absent 3.0 %; adjusted hazard ratio (HR): 2.51, 95 % CI: 1.15–5.49; P = 0.021).9 Although VH-IVUS has been shown to predict major adverse cardiac events, it is unclear what treatment options might be effective in mitigating the risk associated with high-risk lesion features.

Use in Percutaneous Coronary Intervention Grey-scale IVUS has been used to plan and guide PCI. Recently, few studies have tested clinical utility of VH-IVUS for guidance of PCI. The Bifurcation lesion analysis and stenting (BLAST) study investigated VH-IVUS guidance for drug-eluting stent deployment in bifurcation

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:07

Intravascular Ultrasound-based Imaging Modalities for Tissue Characterisation

lesions compared to angiographic guidance alone enrolled 195 patients. Initial results showed that 30 days major adverse event rate was similar in both VH-IVUS unblinded and VH-IVUS blinded groups. Higher volumes of dense calcium and necrotic core at the side branch preintervention were contributing factors for major adverse events at 30 days.13 The long-term results have not been published yet. The Vascular evaluation for revascularisation: defining the indications for coronary therapy (VERDICT) study and Fractional flow reserve and intravascular ultrasound relationship study (FIRST) evaluated the prognostic utility of fractional flow reserve (FFR) and VH IVUS–derived parameters of atherosclerosis in intermediate coronary lesions (40–80 % angiographic diameter stenosis). There was only a modest correlation between IVUS minimum lumen area and FFR, but plaque morphology characteristics did not correlate with FFR.14,15 VH-IVUS can identify lesions that are at high-risk for causing distal embolisation or myocardial necrosis. Distal embolisation occurs in 15–70 % of patients and is associated with a poor prognosis after PCI. In a recent meta-analysis the association between plaque composition and distal embolisation after PCI was evaluated in 16 greyscale IVUS or VH-IVUS studies of 1697 patients. Pooled analysis showed that the absolute necrotic core volume, absolute and relative necrotic core areas at the minimum lumen sites were significantly greater in the embolisation group than in the no embolisation group. The other plaque components were similar in both groups.16 A previously published systematic review reported similar findings. In 9 of the 11 reviewed studies the necrotic core by itself or as a component of VH-TFCA was associated with distal embolisation.17 Two studies by Nakamura et al. and Bae et al. failed to demonstrate the association between necrotic core and distal embolisation, but a “marble”-like image, consisting of fibro-fatty and fibrous plaque, was associated with the angiographic no-reflow phenomenon during primary PCI.18,19 This can be explained by the fact that thrombus by VH-IVUS has appearance of fibrotic or fibrofatty tissue and the percentage of necrotic core could be compromised by the presence of thrombus. In a study by Hong et al. in cohort of 80 patients with stable and unstable angina necrotic core volumes and areas were significantly greater in patients with post-PCI cardiac troponin I elevation.20 The use of statins and embolic protection devices could be particularly beneficial for patients with lesions with a large necrotic core. However no trial examining embolic protection devices in high embolic risk patients has yet been published. We also cannot conclude that VH-IVUS should be used routinely in all patients undergoing PCI. VH-IVUS has not been validated to assess plaque behind stents, but it has been used to evaluate the development of neoatherosclerosis within neointimal tissues after stent implantation (See Figure 3). VH-IVUS was performed in 36 lesions more than three years after stent implantation. In-stent VH-TFCA was identiﬁed in 45.5 % of bare metal stent-treated lesions and in 18.2 % after drug eluting stent implantation (p = 0.361). There was no statistically signiﬁcant difference with regard to the in-stent tissue composition, including necrotic core and dense calcium.21

Effect of Pharmacological Intervention on Plaque Composition VH-IVUS has also been used in several studies reporting serial changes of plaque composition in patients treated with lipid lowering therapies. However IVUS-VH acquisition is electrocardiogram-gated which makes accurate co-registration of serial studies difﬁcult.

INTERVENTIONAL CARDIOLOGY REVIEW

Erglis_FINAL.indd 153

Figure 2: Corresponding Cross-sections of iMap and Virtual Histology Images A

Standard Intravascular ultrasound (IVUS) image using a 40-MHz mechanical rotating catheter (A) and a 20-MHz phased-array catheter (C). iMap shows large amounts of necrotic tissue (B), while with VH the same area is reported as fibrous or fibrofatty tissue (D).

Recently, in a substudy of the Study of coronary atheroma by intravascular ultrasound: the effect of rosuvastatin vs. Atorvastatin (SATURN) study serial VH-IVUS imaging was performed in 71 patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months.22 This study showed a decrease in fibro-fatty tissue (P<0.001), while dense calcium increased (P=0.002). There were no changes in fibrous or necrotic core tissue volumes. However, these data are inconsistent with other studies. In meta-analysis by Tian et al. 17 studies involving 2171 patients receiving statin therapy were analysed, a regressive trend was reported for necrotic core volume (mean difference: –2.1 mm3; 95 % CI: –4.7–0.5 mm3, P = 0.11) while statin therapy did not induce a significant change for fibrotic, fibro-fatty, or dense calcium compositions.23 The Synergistic effect of combination therapy with cilostazol and probucol on plaque stabilization and lesion regression (SECURE) study compared the effects of nine months of treatment with probucol and cilostazol combination therapy or cilostazol monotherapy. This study failed to demonstrate significant differences in changes in plaque volume or composition between two groups despite different impacts on lipid biomarkers.24 However, there is no clear proof of a direct connection between changes in plaque composition and clinical events.

IMAP IVUS Another IVUS RF data analysis system is the iMAP software.25 Unlike VH-IVUS, iMap uses a 40 MHz single rotational transducer and can acquire RF data continuously, while VH-IVUS data are collected with a 20 MHz electronic catheter that acquires only electrocardiogramgated data. VH-IVUS uses autoregressive modelling to analyse the IVUS RF spectrum, while iMap uses a pattern recognition algorithm on the spectra that were obtained from a fast Fourier transformation and a histology-derived database. iMAP-IVUS classifies coronary plaque into four components (ﬁbrotic, lipidic, necrotic, and calciﬁed). Like VH-IVUS, iMAP could be used to detect high risk plaques

153

05/09/2014 10:07

Coronary Diagnosis & Imaging Figure 3: Corresponding Greyscale and Virtual HistologyIntravascular Ultrasound Images One Year After Bare Metal Stent Implantation

Figure 4: Corresponding greyscale and iMAP-Intravascular Ultrasound Images One Year after Bare Metal Stent Implantation A

A. Greyscale image shows neointimal hyperplasia inside bare metal stent. B. Metallic stent struts appear as dense calcium surrounded by necrotic core.

A. Greyscale image shows neointimal hyperplasia inside bare metal stent. B. Metallic stent struts appear as dense calcium without necrotic core around them.

and predict adverse events following PCI, for example, slow flow. However it is noteworthy that in vivo comparison of iMAP and VH-IVUS tissue characterisation has reported a significant and systematic variability in plaque composition estimates (See Figure 2). iMap expressed plaque as necrotic core in poor signal areas, such as guidewire artefact or acoustic shadowing of the calcium. VH-IVUS classified acoustic shadowing as fibrous or fibrofatty tissue. VH-IVUS showed metallic stent struts as dense calcium and necrotic core, while

Integrated Backscatter IVUS

iMap showed thinner stent thickness without necrotic core around the stent (See Figures 3 and 4).26

coronary lipid volume is independent predictor of no-reflow during PCI.33 In a study of 260 patients, large lipid volume (odds ratio 1.95, 95 % confidence interval 1.14-3.33, P = 0.02) was significantly and independently associated with major adverse events defined as death, nonfatal myocardial infarction, and any repeat revascularisation during median follow-up of 1285 days after drug eluting stent implantation.34 Serial IB-IVUS studies have demonstrated that statin therapy in patients with ACS reduces plaque volume and lipid components and increases in fibrous tissue content suggesting that statin therapy is able to induce plaque morphologic changes.35

iMAP can be used for the in vivo identiﬁcation of vulnerable plaque and prediction of adverse events of PCI. In a study of 87 patients, iMAP analysis revealed that the culprit plaques in patients with ACS contained larger lipidic and necrotic components with a smaller ﬁbrous component compared to non-ACS group.27 In a study of 63 ST elevation MI patients, iMAP-IVUS imaging was performed in the culprit segment and the segment immediately proximal to the culprit lesion (non-culprit). At index procedure the culprit lesion had a higher percentage of necrotic tissue compared to the non-culprit lesions. At 10 months follow-up the proportion of necrotic tissue in the non-culprit lesion remained stable, but the percentage of lipidic tissue decreased.28 Like in studies with VH-IVUS, the necrotic plaque volume and necrotic plaque ratio by iMAP are predictors of slow flow during PCI.29 iMAP-IVUS has been used to evaluate neointimal tissue components after stent implantation. In a series of 61 lesions, iMAP-IVUS showed that neointima after drug eluting stent implantation consisted of statistically significant smaller fibrotic component, larger necrotic and calcified components compared with bare metal stent.30

1. Yock PG, Linker DT, Angelsen BA. Two-dimensional intravascular ultrasound:technical development and initial clinical experience. J Am Soc Echocardiogr 1989 Jul-Aug;2:296–304. 2. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, 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 Apr;37:1478–92. 3. Lee SY, Mintz GS, Kim SY, et al. Attenuated plaque detected by intravascular ultrasound: clinical, angiographic, and morphologic features and post-percutaneous coronary intervention complications in patients with acute coronary syndromes. JACC Cardiovasc Interv 2009 Jan;2:65–72 4. Garcìa-Garcìa HM, Gogas BD, Serruys PW, Bruining N. IVUS-based imaging modalities for tissue characterization: similarities and differences. Int J Cardiovasc Imaging 2011 Feb;27:215–24. 5. Nair A, Kuban BD, Tuzcu EM, et al. Coronary plaque

154

Erglis_FINAL.indd 154

Integrated backscatter IVUS (IB-IVUS) also uses a 40 MHz single rotational transducer.31 It analyses the RF signals by applying a fast Fourier transformation. It has been used for assessment of vulnerable plaques. IB-IVUS studies have demonstrated that culprit lesions as well as nonculprit lesions of acute coronary syndrome are significantly associated with the increase in lipid component and decrease in fibrous component compared to those with stable angina pectoris.32 The percentage of

Conclusion IVUS-based imaging modalities allow us to improve our understanding of atherosclerotic disease and vulnerable plaque. Radiofrequency IVUS analysis enables identification of patients at high risk for future cardiovascular events and adverse outcomes following PCI. It can also be used to evaluate the effect of pharmacological treatment on coronary plaque morphology. Although IVUS radiofrequency analysis is a promising tool for identification of vulnerable plaque, the limitations are unproven clinical benefit and overall cost effectiveness. More research and randomised trials are needed to answer whether or not routine IVUS radiofrequency imaging is clinically relevant. n

classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002 Oct 22;106:2200–6. 6. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J, et al; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011 Jan 20;364:226–35. 7. Dohi T, Mintz GS, McPherson JA, et al. Non-fibroatheroma lesion phenotype and long-term clinical outcomes: a substudy analysis from the PROSPECT study. JACC Cardiovasc Imaging 2013 Aug;6:908–16. 8. Calvert PA, Obaid DR, O’Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovasc Imaging 2011 Aug;4:894–901. 9. Cheng JM, Garcia-Garcia HM, de Boer SP, et al. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J 2014 Mar;35:639–47. 10. 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 May;20:1262–75. 11. García-García HM, Mintz GS, Lerman A, et al. Tissue characterization using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting. EuroIntervention 2009 Jun;5:177–89. 12. Rodriguez-Granillo GA, García-García HM, Mc Fadden EP, et al. In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol 2005 Dec 6;46:2038–42. 13. Lefevre T, Erglis A, Gil R, et al. Initial results of BLAST: bifurcation lesion analysis and stenting of thin cap fibroatheroma (TCFA/FA) as measured by VH-intravascular ultrasound – a global multicentre, prospective, randomised study. Eurointervention 2011;7(Supplement M):90(abstract). 14. Stone GW. VERDICT/FIRST: prospective, multicenter study examining the correlation between IVUS and FFR parameters in intermediate lesions. Available at: http://www.tctmd.com/ show.aspx?id=114442.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:07

Intravascular Ultrasound-based Imaging Modalities for Tissue Characterisation

15. Waksman R, Legutko J, Singh J, et al. FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study. J Am Coll Cardiol 2013 Mar 5;61:917–23. 16. Jang JS, Jin HY, Seo JS, et al. Meta-analysis of plaque composition by intravascular ultrasound and its relation to distal embolization after percutaneous coronary intervention. Am J Cardiol 2013 Apr 1;111:968–72. 17. Claessen BE, Maehara A, Fahy M, et al. Plaque composition by intravascular ultrasound and distal embolization after percutaneous coronary intervention. JACC Cardiovasc Imaging 2012 Mar;5(3 Suppl):S111–8. 18. Nakamura T, Kubo N, Ako J, Momomura S. Angiographic no-reflow phenomenon and plaque characteristics by virtual histology intravascular ultrasound in patients with acute myocardial infarction. J Interv Cardiol 2007 Oct;20:335–9. 19. Bae JH, Kwon TG, Hyun DW, et al. Predictors of slow flow during primary percutaneous coronary intervention: an intravascular ultrasound-virtual histology study. Heart 2008 Dec;94:1559–64. 20. Hong YJ, Mintz GS, Kim SW, et al. Impact of plaque composition on cardiac troponin elevation after percutaneous coronary intervention: an ultrasound analysis. JACC Cardiovasc Imaging 2009 Apr;2:458–68. 21. Kitabata H, Loh JP, Pendyala LK, et al. Intra-stent tissue evaluation within bare metal and drug-eluting stents >3 years since implantation in patients with mild to moderate neointimal proliferation using optical coherence tomography and virtual histology intravascular ultrasound. Cardiovasc Revasc Med 2014 Apr;15:149–55. 22. Puri R, Libby P, Nissen SE, et al. Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN. Eur Heart J Cardiovasc Imaging 2014 Apr;15:380–8. 23. Tian J, Gu X, Sun Y, et al. Effect of statin therapy on the

INTERVENTIONAL CARDIOLOGY REVIEW

Erglis_FINAL.indd 155

progression of coronary atherosclerosis. BMC Cardiovasc Disord 2012 Sep 1;12:70. 24. Ko YG, Choi SH, Chol Kang W, et al. Effects of Combination Therapy with Cilostazol and Probucol versus Monotherapy with Cilostazol on Coronary Plaque, Lipid and Biomarkers: SECURE Study, a Double-Blind Randomized Controlled Clinical Trial. J Atheroscler Thromb 2014 Apr 4. [Epub ahead of print] 25. Sathyanarayana S, Carlier S, Li W, Thomas L. Characterisation of atherosclerotic plaque by spectral similarity of radiofrequency intravascular ultrasound signals. EuroIntervention 2009 May;5:133–9. 26. Shin ES, Garcia-Garcia HM, Ligthart JM, et al. In vivo findings of tissue characteristics using iMap™ IVUS and Virtual Histology™ IVUS. EuroIntervention 2011 Mar;6:101–79. 27. Kozuki A, Shinke T, Otake H, et al. Feasibility of a novel radiofrequency signal analysis for in-vivo plaque characterization in humans: comparison of plaque components between patients with and without acute coronary syndrome. Int J Cardiol 2013 Aug 20;167:1591–6. 28. Trusinskis K, Juhnevica D, Strenge K, Erglis A. iMap intravascular ultrasound evaluation of culprit and non-culprit lesions in patients with ST-elevation myocardial infarction. Cardiovasc Revasc Med 2013 Mar-Apr;14:71–5. 29. Utsunomiya M, Hara H, Sugi K, Nakamura M. Relationship between tissue characterisations with 40 MHz intravascular ultrasound imaging and slow flow during coronary intervention. EuroIntervention 2011 Jul;7:340–6. 30. Tsujita K, Takaoka N, Kaikita K, et al. Neointimal tissue component assessed by tissue characterization with 40 MHz intravascular ultrasound imaging: comparison of drug-eluting stents and bare-metal stents. Catheter Cardiovasc Interv 2013 Dec 1;82:1068–74. 31. Kawasaki M, Takatsu H, Noda T, et al. Noninvasive quantitative tissue characterization and two-dimensional color-coded map

of human atherosclerotic lesions using ultrasound integrated backscatter: comparison between histology and integrated backscatter images. J Am Coll Cardiol 2001 Aug;38:486–92. 32. Ando H, Amano T, Matsubara T, et al. Comparison of tissue characteristics between acute coronary syndrome and stable angina pectoris. An integrated backscatter intravascular ultrasound analysis of culprit and non-culprit lesions. Circ J 2011;75:383–90. 33. Daidoji H, Takahashi H, Otaki Y, et al. A combination of plaque components analyzed by integrated backscatter intravascular ultrasound (IB-IVUS) and serum pregnancy-associated plasma protein A (PAPP-A) levels predict the no-reflow phenomenon during percutaneous coronary intervention (PCI). Catheter Cardiovasc Interv 2013 Nov 13. 34. Kumagai S, Takashima H, Waseda K, et al. Prognostic impact of lipid contents on the target lesion in patients with drug eluting stent implantation. Heart Vessels 2013 Oct 20. [Epub ahead of print] 35. Otagiri K, Tsutsui H, Kumazaki S, et al. Early intervention with rosuvastatin decreases the lipid components of the plaque in acute coronary syndrome: analysis using integrated backscatter IVUS (ELAN study). Circ J 2011;75(3):633–41 36. Nair A, Margolis MP, Kuban BD, Vince DG. Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation. EuroIntervention 2007 May;3(1):113–20. 37. Kawasaki M, Bouma BE, Bressner J, et al. Diagnostic accuracy of optical coherence tomography and integrated backscatter intravascular ultrasound images for tissue characterization of human coronary plaques. J Am Coll Cardiol 2006 Jul 4;48:81–8. 38. Kubo T, Nakamura N, Matsuo Y, et al. Virtual histology intravascular ultrasound compared with optical coherence tomography for identification of thin-cap fibroatheroma. Int Heart J 2011;52(3):175–9. PubMed PMID: 21646741.

155

05/09/2014 10:07

Coronary Diagnosis & Imaging

Impact of Intravascular Ultrasound in Clinical Practice Andres Va s q u e z , N e v i l l e M i s t r y a n d Ja s v i n d a r S i n g h Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, US

Abstract Intravascular ultrasound (IVUS) has expanded our understanding of atherosclerotic plaque morphology, and provides an opportunity to guide cardiovascular interventions and evaluate results. Use of this technique requires understanding of ultrasound physics, catheter differences, skills in vessel, plaque and stent quantification and knowledge of artifacts and various physiologic and pathologic findings. Optimal cardiovascular interventions should result in absence of inflow or outflow obstruction, precise geographic landing, while attaining the largest feasible luminal gain without plaque protrusion, vessel dissection or perforation and, if deployed, with complete stent expansion and apposition to the vessel wall. IVUS is safe, cost efficient and effectively optimises cardiovascular interventions. In addition, IVUS improves outcomes when used to guide coronary interventions using bare metal stents (BMS) and drug eluting stents (DES). The role of IVUS in endovascular therapy is rapidly expanding. This review will focus on the impact of IVUS in clinical practice.

Keywords Coronary artery disease, Intravascular ultrasonography, percutaneous coronary intervention Disclosure: Dr Singh is a consultant for Volcano and receives Research Grant Support from Volcano. Dr Vasquez and Dr Mistry have no conflicts of interest to declare. Received: 14 July 2014 Accepted: 23 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):156–63 Correspondence: Jasvindar Singh, Director, Cardiac Catheterization Laboratory, Barnes-Jewish Hospital, 660 South Euclid, Campus Box 8086, St. Louis, MO, 63110. E: jzsingh@dom.wustl.edu

Introduction Intravascular ultrasound (IVUS) has enhanced our understanding of atherosclerotic plaque morphology, and provides a unique opportunity to guide cardiovascular interventions and evaluate the results of these interventions. IVUS is safe, cost efficient and effective in guiding clinical decisions and cardiovascular interventions and improves outcomes when used during coronary artery stenting. Although a comprehensive IVUS overview is beyond the scope of this article, this review will focus on the impact of IVUS in clinical practice.

Intravascular Ultrasound Transducer Types and Common Artifacts Table 1 describes characteristics of some IVUS catheters. There are two different catheter types – mechanical-state or rotating transducer catheters, and solid-state or electronic array catheters. Most Volcano Corporation (Rancho Cordova, CA) catheters use electronic array technology, where multiple phased-array elements are oriented circumferentially and receive backscattered ultrasound signals which are then processed into real-time images. These catheters do not require rotation for image acquisition. Boston Scientific Corporation (Natick, MA) catheters, and catheters such as the ViewIT, Terumo Corporation (Tokyo, Japan), and HD-IVUS, Acist Medical Systems Inc. (Eden Prairie, MN), use a rotating transducer design where one rotating element captures signals with each revolution. This design requires a catheter housing and a flexible cable to rotate the transducer element. Frequent system flushing is imperative to eliminate air bubbles that may accumulate within the catheter housing creating image artifacts. A wire channel runs adjacent to the Boston Scientific transducers and may also create artifacts. Volcano catheters eliminate the wire artifact by housing the guide wire central to its transducer elements. Non-uniform rotational distortion (NURD)

156

Singh_V03_SN.indd 156

may occur during non-homogeneous transducer rotation seen in electronic array catheters, frequently due to wire bias in the presence of vessel tortuosity. Boston Scientific offers an automatic software correction to minimise NURD. Figure 1 shows various image artifacts. Available IVUS catheters used for most coronary, renal, iliac and infrainguinal arterial assessment are compatible with 5–6 French sheaths. Low frequency catheters offer an expanded imaging field at the expense of proximal image resolution and are utilised for aortic and venous imaging. High-frequency catheters offer improved image resolution but have a narrower field of imaging. The axial resolution varies among common imaging catheters: Eagle Eye® – <170 microns; Revolution™ – 50 microns; iCross™ – 43 microns and OptiCross™ – 38 microns. Near-field artifacts include ringdown and blood speckle artifacts, with the latter one clearing during saline flushing. With phased array catheters, interference can occur around the catheter creating a resonance phenomenon that leads to a long and uninterrupted echo producing a blind area or ringdown artifact. Side lobe artifacts are caused by multiple low-energy sound beams that arise from the main ultrasound beam. The receiver detects and erroneously assigns these low energy beams to the main beam parallel to the false location. They are commonly bright rounded lines displayed over hypoechoic or anechoic structures adjacent to hyperechoic structures. Vessel measurements are ideally performed with the transducer perpendicular to the vessel wall. Position artifacts caused by catheter obliquity, and vessel curvature or eccentricity may especially be of clinical significance in larger vessels. Catheter motion artifact may

05/09/2014 11:45

Impact of Intravascular Ultrasound in Clinical Practice

Table 1: Characteristics of Various Intravascular Ultrasound Catheters Catheter Volcano

Ultrasound Frequency (MHz) 20

Imaging Diameter (mm) 20

Minimum Guide Minimum Catheter Diameter Sheath (Fr) Diameter (Fr) 5 5

Distal Shaft Diameter (Fr) 3.3

Working Length (cm) 150

Wire (inch)

Comments

0.014

Solid state IVUS. Highly deliverable

Eagle Eye

plug-and-play. GlyDx hydrophilic

Platinum

coating. 3 radiopaque markers 10 mm

apart from each other. VH IVUS and

ChromaFlo imaging.

Volcano

Solid state digital IVUS. Plug and

3.4

135

0.018

Visions PV

play. ChromaFlo imaging.

0.018 Volcano

n/a

8.5

0.035

Visions PV

Solid state digital IVUS. Plug and play.

0.035 Volcano

3.3

135

0.014

Rotational IVUS. Has 150 mm

Revolution

pullback length.

Boston

Rotational IVUS. Highly deliverable

3.2

135

0.014

Atlantis

and excellent image quality. Asahi

SR Pro

Intecc drive cable and BioslideTM

Coating. 150 mm pullback length.

Distance from marker band to

transducer is 21 mm.

Boston

Rotational IVUS. Bioslide Hydrophilic

3.2

135

0.014

Scientific

Coating. Highly deliverable and

iCross

excellent image quality.

Boston

Rotational IVUS. Smallest crossing

3.15

135

0.014

Scientific

profile. Highest axial resolution

OptiCross™

(38 micron). 150 mm pullback.

Catheter Boston

3.2

135

0.018

Scientific

Rotational IVUS. Highly deliverable and excellent image quality.

Atlantis 0.018 Peripheral Imaging Catheter Boston

0.035

Rotational IVUS.

n/a

110

n/a

Rotational

Scientific Atlantis PV Peripheral Imaging Catheter Boston

Scientific IVUS. Atlantis ICE 9 mHz Boston Scientific Corporation (Natick, MA). Volcano Corporation (Rancho Cordova, CA). IVUS = Intravascular ultrasound; MHz = Mega Hertz; Fr = French; ICE= Intracardiac echocardiography.

result from forward transducer translation during vessel flushing. Axial translation may also be observed during cardiac or breathing cycle variation.

Anatomical Assessment and Intervention Guidance Various studies have demonstrated advantages of IVUS guided interventions when compared to angiography.1–12 An analysis of the Strategy and intracoronary ultrasound-guided PTCA and stenting (SIPS) trial4 noted a 60.9 % probability that IVUS was less expensive and more effective when compared to angiographic guided interventions. Similarly, Gaster et al. demonstrated decreased cost with an IVUS guided intervention strategy.5 Intravascular ultrasound confers improved

INTERVENTIONAL CARDIOLOGY REVIEW

Singh_V03_SN.indd 157

accuracy for lesion quantification (e.g. lumen, vessel wall and plaque diameter, area, length, shape and volume), and morphology assessment (e.g. aneurysms, bifurcations, ostial lesions, fibrosis and calcification patterns, filling defects, thrombus, intimal disruption, dissection and ulceration). Additionally IVUS shows the calcium distribution pattern within the vessel wall.13 IVUS is also more accurate than angiography for assessment of eccentric lesions.14 IVUS can aid in the identification of the culprit lesion in unclear cases and clarify the mechanism of Stent thrombosis (ST) or in-stent restenosis (ISR).15,16 Distal embolisation or peri-procedural myocardial infarction (MI) during interventions may be predicted with the IVUS presence of ruptured plaque and large plaque burden in acute coronary syndrome (ACS) and non-ACS

157

05/09/2014 11:45

Coronary Diagnosis & Imaging Figure 1: Common Artifacts Present During Intravascular Ultrasound Imaging A

Table 2: Basic Intravascular Ultrasound Measurements Basic Measurements External Elastic Membrane (EEM) CSA: Total vessel CSA or ‘medial’ area. It is the boundary between the echo lucent media and bright adventitia. Lumen or stent CSA Maximum and minimum lumen or stent diameter: Luminal measurement through the center of the lumen or stent.

Plaque and media (P + M) CSA (Atheroma CSA)

a- EEM CSA – Lumen CSA (no stent)

b- EEM CSA – Stent CSA (stented lesions)

Intimal hyperplasia CSA: Stent CSA – lumen CSA

Eccentricity: Maximal / mininimal P+M thickness

Plaque burden (% atheroma area)

a- Atheroma CSA / EEM CSA

Remodeling index: Lesion EEM CSA / predefined reference EEM

Area stenosis: Lesion lumen CSA / predefined reference lumen CSA

Arc of calcium: degrees of circumference covered by calcium

Lesion length: Measured using motorized transducer pullback at a fixed speed CSA: Cross sectional area; EEM: External elastic membrane.

these patient subgroups may prove beneficial. Table 2 and Figure 2 show common IVUS measurements and morphologic findings. A) Arrowhead points at a ringdown artifact. B) Image shows non uniform rotational distortion artifact. Additionally a wire artifact is signaled by the arrowhead. C) Asterisk points at blood speckle artifacts that can make it difficult to visualize intraluminal structures. This artifact can be cleared with a saline flush.

Figure 2: Basic Intravascular Ultrasound Measurements A

A) The lumen CSA is the area contained within the yellow inner circle. The EEM CSA is contained by the outer red circle. The yellow line represents the lumen diameter, and the red line represents the total vessel diameter. B) The stent CSA is the area contained within the yellow inner circle. The EEM CSA is contained by the outer red circle. The yellow line represents the stent lumen diameter, and the red line represents the total vessel diameter. C) After excluding the lumen CSA from the EEM CSA the residual area represents the atheroma CSA (Plaque and media CSA. D) The maximum luminal diameter is represented by the longer yellow line, and the minimum lumen diameter is represented by the shorter red line. The white arrows point to the borders of the near 155 degree arc of fibro-calcific plaque. CSA = cross sectional area; EEM = External elastic membrane.

patients.17 Greater attenuation angle (>180 degrees), and attenuation length >5 mm seem to be independent predictors for microvascular obstruction in ST segment elevation myocardial infarction (STEMI) patients undergoing primary PCI.18 Pre-emptive use of filter wires in

158

Singh_V03_SN.indd 158

Mechanised pullback at a stable speed allows for length calculation19 but limits dynamic interactions by the operator that are available during manual pull-back. Knowledge of the distance between IVUS catheter markers may alternatively be used to estimate length when combined with fluoroscopy (see Figures 3 and 4). Eagle Eye® Platinum Rx Digital IVUS Catheters, (Volcano Corporation, Rancho Cordova, CA) have 14 mm from transducer to its first radiopaque marker, and a total of three markers each 10 mm apart. A short tip version of the catheter is available (Eagle Eye® Platinum ST Rx Digital IVUS Catheters, Volcano Corporation, Rancho Cordova, CA). Atlantis® SR Pro Coronary Imaging Catheter (Boston Scientific Corporation, Natick, MA) has a 2.1 cm distance from marker band to its transducer. The OptiCross™ Coronary Imaging Catheter, (Boston Scientific Corporation, Natick, MA) has a 1 cm telescope marker that allows to calculate the manual pullback distance. Vessel areas of interest, (e.g. bifurcations, ostium, beginning and end of diseased vessels) can be accurately localised using the transducer marker adjacent to the imaging window. This is done by positioning the transducer at the area of interest followed by cine acquisition of the transducer marker. This marker position is compared to other adjacent fluoroscopic landmarks for future orientation. This technique allows for optimal geographic landing of interventional equipment. Gentle flushing is advised when injecting contrast during imaging for marker position evaluation, as brisk flushing may result in forward transducer translation producing a catheter motion artifact. Similarly, careful attention to catheter position is important to detect motion during cardiac or breathing cycle variation. IVUS guided PCI of native aorto-ostial, or ostial left anterior descending, left circumflex, or ramus intermedius lesions has been associated with lower rates of the composite of cardiovascular death, myocardial infarction (MI) or target lesion revascularisation (TLR) (hazard ratio [HR] 0.54, 95 % CI 0.29-0.99; p = 0.04), composite MI or TLR (HR 0.39, 95 % CI 0.18-0.83; p = 0.01) and MI (HR 0.31, 95 % CI 0.11–0.85; p = 0.02), as well as a trend towards a lower TLR rate (HR 0.42, 95 % CI 0.17-1.02; p = 0.06) compared with no IVUS.20

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:45

Impact of Intravascular Ultrasound in Clinical Practice

Figure 3: Serial Cine and IVUS Images Demonstrate the Use of Intravascular Ultrasound to Mark Structures of Interest During Coronary Interventions

Figure 4: Serial Cine and IVUS Images Demonstrate the Use of Intravascular Ultrasound to Mark Structures of Interest During Peripheral Interventions

A–B) Angiographic views show ostial LAD and LCx stenoses. C–D) The imaging window is positioned at the ostium of the C) LAD and then the D) LCx and short cine runs are obtained to mark their respective locations, using an Eagle Eye® Platinum ST Rx Digital IVUS Catheter, (Volvano Corporation, Rancho Cordova, CA). E) An IVUS image of the LCx ostium prior to intervention is shown. F) A two stent strategy is chosen and stents are positioned in accordance to the IVUS guided ostial marking. G) Post intervention G, I) cine and H) IVUS findings are shown. LAD: Left anterior descending coronary artery; LCx: Left circumflex coronary artery; IVUS: Intravascular Ultrasound.

A–B) Angiographic views show a left SCA chronic total occlusion crossed by a guidewire and an ostial LIMA stenosis in a patient with angina pectoris and a prior LIMA bypass. The imaging window is positioned at the ostium of the LIMA and C) a short cine run is obtained to mark the LIMA ostium location using an Eagle Eye® Platinum ST Rx Digital IVUS Catheter, (Volvano Corporation, Rancho Cordova, CA). D) IVUS image of the LIMA ostium is shown. E) The LIMA ostium undergoes stent deployment. F) The SCA ostium is marked and the vessel distance is calculated using the 10 mm distance between the markers of the Eagle Eye® Platinum ST Rx Digital IVUS Catheter. IVUS images of the SCA ostium are observed G) pre intervention, and H) post intervention, confirming accurate geographic stent landing. I) Final cine findings are shown. SCA: Subclavian artery; LIMA: Left internal mammary artery; IVUS: Intravascular Ultrasound.

Although not available in the US, Boston Scientific offers iMap tissue characterisation software which uses radiofrequency signal spectrum pattern recognition to characterise tissue within the plaque. 21 Boston Scientific also offers volumetric analysis software. Volcano offers virtual histology software (VH® IVUS) that identifies signal intensity and frequency variations and assigns different colours to each specified category with the goal of tissue composition characterisation, fibrous, fibro-fatty, necrotic-lipid and calcific, (see Figure 5).22 Volcano also offers ChromaFlo®; a colour flow function that highlights changes between serial frames and may assist in the identification of intraluminal filling defects (e.g. thrombus, unopposed stent struts, vessel dissection). Superficial echo attenuated plaques have been associated with advanced necrotic core containing fibroatheromas which are considered a high risk plaque pattern. 23 However, secondary non-culprit ruptures frequently seen in ACS patients with this plaque phenotype do not seem to be associated with adverse outcomes on patients treated with optimal medical therapy.24 The clinical application of non-culprit plaque characterisation is therefore unclear at this time. IVUS may clarify difficult scenarios that are uncertain by angiography, (e.g. left main coronary artery (LMCA disease), significance of inflow or outflow disease, bifurcation classification including evaluation for side branch disease), and aid in the selection of an optimal technical approach to interventions. Determining morphological characteristics associated with decreased vessel compliance, (e.g. extended arc of calcium or significant fibrosis) may assist the decision to use preemptive atherectomy.25

INTERVENTIONAL CARDIOLOGY REVIEW

Singh_V03_SN.indd 159

IVUS for BMS and DES Implantation Pre-intervention vessel size, lesion length and morphology are evaluated to select the appropriate strategy and stent size and length. Post-intervention stent landing, expansion and apposition are evaluated. Complications are excluded (e.g. malapposed or under-expanded stents, geographic miss, dissections, plaque prolapse, residual thrombus), and fine tuning performed. Figure 6 demonstrates some post intervention issues encountered during IVUS. Fluoroscopy may miss stent under-expansion, a predictor of stent thrombosis (ST) after bare metal stent (BMS) implantation.15 Fujii et al.16 identified stent under-expansion and residual reference segment stenosis as predictors of ST after sirolimus-eluting stent (SES) implantation. In addition to stent under-expansion, a higher residual disease burden at the stent edges has been associated with stent thrombosis.26 This may explain the higher rate of mIss noted by Costa et al.27 in a cohort of patients with geographic miss following SES implantation. Higher BMS ISR rates are observed with smaller minimal stent area (MSA) and longer stent length.28 A stent minimal luminal area (MLA) < 6 mm2 was observed in 28 % of BMS ISR cases. Similarly 4.5 % of these ISR cases had unrecognised mechanical complications (geographic miss, stent deformation and balloon stripping during the implantation procedure) readily detectable by IVUS.29 Everolimus eluting stents (EES) associated mechanical complications, (e.g. partial or complete stent fracture, strut fracture with overlapping stent fragments, and longitudinal deformation) have been associated with excessive

159

05/09/2014 11:45

Coronary Diagnosis & Imaging Figure 5: IVUS Images Demonstrating A) Normal and B–F) Diseased Vessel Segments A

Figure 6: IVUS Images Demonstrate Common Pathologic Findings Following Cardiovascular Interventions A

A) Stent under-expansion. B) E dge dissection is observed following coronary angioplasty. C) Stent mal-apposition is highlighted using Chroma-Flow (Volvano Corporation, Rancho Cordova, CA). IVUS: Intravascular Ultrasound.

IVUS images demonstrating A) normal and B–F) diseased vessel segments. B) A fibro-calcific plaque is shown expanding between 9 and 11 o’clock. C, E) Bulky soft plaque (fibro-fatty) and D, F) necrotic-fatty plaque examples are shown. Images E and F show virtual histology IVUS (Volvano Corporation, Rancho Cordova, CA). IVUS: Intravascular Ultrasound.

neo-intimal hyperplasia, ISR and repeat revascularisation.30 Sonoda et al.31 observed a correlation between BMS and SES MSA and long term development of ISR. Fujii et al.32 found stent under expansion (MSA < 5.0 mm2) to be associated with ISR after SES implantation. Similarly, Hong et al.33 corroborated MSA < 5.5 mm2 as an independent predictor of angiographic restenosis after SES implantation and also found a stent length > 40 mm2 to predict restenosis. A meta-analysis34 evaluating BMS and Taxus paclitaxel eluting stent (PES), observed that IVUS maximum percentage of intimal hyperplasia correlated with restenosis at nine months. Sakurai et al.35 found that residual reference vessel plaque burden and stent over-sizing relative to the reference vessel were associated with edge stenosis in a SES when compared to a BMS cohort. Liu et al.36 found residual edge plaque burden and not edge lumen area to be predictive of nine month stent edge restenosis after BMS or TAXUS PES implantation. Costa et al.27 found a high rate (66.5 %) of longitudinal and axial geographic miss following SES implantation. At one year follow-up TVR rates in the geographic miss group was 5.1 % compared to 2.5 % in the non-geographic miss group (p=0.025). There was a 3-fold increase in MI rates associated with geographic miss (2.4 % vs 0.8 %; p=0.04). The long-term health outcome and mortality evaluation after invasive coronary treatment using drug-

160

Singh_V03_SN.indd 160

eluting stents with or without the IVUS guidance study11 failed to demonstrate superiority of IVUS use to guide DES implantation using standard high pressure post-dilatation. However, the Angiography vs IVUS Optimisation (AVIO) study12 showed benefit in the postprocedure minimal lumen diameter (2.70 mm +/- 0.46 mm vs 2.51 +/- 0.46 mm; P = .0002), when using IVUS compared to angiography to optimise implantation. At 24-months follow-up no differences were observed for cumulative MACE, cardiac death, MI, target lesion revascularisation or target vessel revascularisation. The Assessment of dual antiplatelet therapy with drug-eluting stents (ADAPT-DES),37 a prospective, multicentre, non-randomised study of 8,583 consecutive patients, showed that IVUS guidance was associated with a reduction in stent thrombosis (0.6 % vs 1.0 %; HR 0.40; 95 % CI 0.21–0.73; P=0.003), MI (2.5 % vs. 3.7 % HR 0.66; 95 % CI 0.49–0.88; P=0.004), and major adverse cardiac events (cardiac death, MI, or stent thrombosis), (3.1 % vs 4.7 %; HR 0.70; 95 % CI 0.55-0.88; P=0.002) within one year after DES implantation. Larger stents, longer stents and/or higher inflation pressures were used in 74 % of IVUS guided cases. A pooled analysis of four registries included 1,670 patients with LM disease undergoing DES implantation. Thirty percent of the group underwent IVUS guided DES implantation and were compared against the non- IVUS group using a propensity score-matching method. Survival free of cardiac death, MI and TLR at three years was significantly lower in the IVUS guided group (88.7 % vs 83.6 %, p: 0.04). Similarly thrombosis was lower in the IVUS guided group (0.6 % vs. 2.2 %, p = 0.04).38 Two recent metaanalyses favour the use of an IVUS guided strategy as opposed to an angiography guided strategy for DES implantation. One meta-analysis included 26,503 patients from three randomised and 14 observational studies. IVUS-guided PCI was associated with larger, longer and more stents, and lower risk of death (OR 0.61, 95 % CI 0.48 to 0.79, p<0.001), MI (OR 0.57, 95 % CI 0.44 to 0.75, p<0.001), TLR (OR 0.81, 95 % CI 0.66 to 1.00, p=0.046), and stent thrombosis (OR 0.59, 95 % CI 0.47 to 0.75, p<0.001) after drug-eluting stent implantation.39 These results were

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:45

Impact of Intravascular Ultrasound in Clinical Practice

consistent with a meta-analysis by Jang et al.40 which encompassed 11,793 IVUS guided and 13,056 angiography guided patients from three randomised trials and 12 observational studies. In this study, the IVUS guided strategy was associated with lower rates of MACE (OR 0.79, 95 % CI 0.69 – 0.91, p: 0.001), all - cause mortality (OR 0.64, 95 % CI 0.51 – 0.81, p: 0.001), MI (OR 0.57, 95 % CI 0.42 – 0.78, p: < 0.001), TVR (OR 0.81, 95 % CI 0.68–0.95, p: 0.01) and stent thrombosis (OR 0.59, 95 % CI 0.42–0.82, p = 0.002). The achievement of optimal stent size cannot be predicted using the manufacturer’s compliance charts when using BMS or DES. The average achieved minimal stent diameter (MSD) is 75 % of the predicted MSD and 66 % of the predicted MSA when compared to IVUS measurements.41 Adequate vessel sizing is especially important when using bioresorbable vascular scaffolds.42 Scaffolds require quantitative coronary angiography or IVUS guided measurement for optimal results. An IVUS example of scaffolds as compared to stent struts is shown on Figure 7.

IVUS for Chronic Total Occlusion (CTO) Intervention Guidance IVUS for CTO interventions can assist in lowering contrast use, and improve the procedure safety. IVUS-guided controlled antegrade and retrograde subintimal tracking (CART or reverse CART) techniques are final CTO revascularisation steps that can be performed safely and effectively with IVUS guidance.43 Alternatively, transvenous IVUS-guided PCI for CTO has been described using the cardiac vein parallel to the target artery.44 The recently acquired Volcano Corporation Pioneer Plus™ Re-Entry Catheter, (Volcano Corporation, Rancho Cordova, CA) is a peripheral reentry device that uses an adjustable access needle coupled to an IVUS for real-time visualisation during CTO vessel re-entry into the distal luminal space.

IVUS Validation for Ischaemia Assessment Resistance to flow by a stenosis depends on various factors such as entrance effects, friction loss and separation loss. Vessel resistance is inversely related to the stenosis area, and directly proportional to viscosity and stenosis length. Separation loss is magnified by turbulence created by increased flow across a stenosis, and inversely related to the stenosis area and reference area of the vessel downstream to the stenosis. Additionally, the complex interaction between the vascular bed integrity, varying degrees of diffuse disease, vessel remodelling and a branching coronary tree with serial and parallel stenoses leads to complex haemodynamics that confound the use of stenosis area as an optimal single marker for stenosis significance. Fractional flow reserve (FFR) takes many of these factors into account and is the preferred invasive tool to answer what is the physiological significance of coronary stenosis. A caveat with the use of FFR that is most pronounced for left main stenosis assessment is the need to take into account the potential effect of concomitant lesions in either of its branches. A downstream flow limiting lesion will minimise the FFR significance of the left main stenosis as a result of decreased flow crossing the left main. The ultimate clinical decision lies in the conscious operator’s ability to combine various data points to obtain a final answer. Abizaid et al.45 reported a diagnostic accuracy of 92 % using an IVUS minimal lumen area (MLA) < 4.0 mm2 compared to a Doppler flow wire coronary flow reserve (CFR) of < 2.0. However, this cutoff misclassified 8.3 % of patients as either false negative or false positive (two patients with MLA > 4.0 had CFR < 2.0. and four patients with

INTERVENTIONAL CARDIOLOGY REVIEW

Singh_V03_SN.indd 161

Figure 7: IVUS Images Showing; A) Apposed Stent Struts, B) Apposed Absorb Bioresorbable Vascular Scaffolds (Abbott Vascular, Abbott Park, Illinois) A

IVUS: Intravascular Ultrasound.

MLA 4.0 or less had a CFA of 2.0 or above. NPV: 0.95 and PPV: 0.93). Similarly Nishioka et al.46 reported a diagnostic accuracy of 93 % for detecting an abnormal Thallium SPECT perfusion study using the 4.0 MLA cutoff. This study misclassified 7 % of patients (four patients with MLA > 4.0 had an abnormal SPECT study and one had an MLA of 4.0 or less and a negative perfusion study. NPV = 0.83 and PPV = 0.91. Takagi et al.47 found that most MLA values <4.0 mm2 were associated with an FFR <0.75, however, several patients with an MLA <4 mm2 still had FFR values above 0.8. In this study, regression analysis identified MLA <3.0 mm2 and area stenosis > 60 % as optimal IVUS thresholds (sensitivity 83 % and 92 %; specificity 92.3 % and 88.5 % respectively for MLA and area stenosis). In this study the combination of both criteria (MLA <3.0 mm2 and area stenosis >60 %) met an FFR <0.75 without exception. Similarly, Briguori et al.48 reported the combination of percent area stenosis and minimum lumen diameter (MLD) increased the IVUS specificity. IVUS cutoffs of area stenosis >70 %, MLD of 1.8 mm or less, MLA of 4.0 mm2 or less, and lesion length > 10 mm reliably identified lesions with an FFR < 0.75 in this study. As can be observed in these studies, although a MLA <4.0 mm2 in proximal coronary vessels other than the left main or saphenous vein grafts has been frequently associated with the presence of a physiologically significant stenosis, not every MLA <4 mm2 equates to an ischaemia inducing stenosis. Abizaid et al.49 evaluated 357 non-left main intermediate stenosis in whom intervention was deferred based on IVUS findings. At one year, the event rate of 248 lesions with a MLA of 4.0 mm2 or more was 4.4 % and TLR rate 2.8 %. No events were noted when the MLA was >6.2 mm2. However, the Physiologic and anatomical evaluation prior to and after stent implantation in small coronary vessels (PHANTOM) trial found a lack of correlation between angiography or IVUS, and FFR in patients with moderate stenosis in small coronary arteries (<2.8 mm).50 An MLA of 2.4 mm2 or above correlated with an FFR of 0.8 or higher, however the poor specificity was noted as a significant limitation by Kang et al.51 Similarly, Ahn et al.52 found a lower MLA cutoff of 2.1 mm2 to correlate with myocardial ischaemia by myocardial SPECT. This cutoff was also associated with a poor specificity (50.4 %), and a poor positive predictive value (38.6 %). Angiographic left main coronary artery stenosis assessment suffers from wide inter-operator variability.53–55 Jasti et al.56 identified an MLD of 2.8 mm and an MLA of 5.9 mm2 as the most accurate cutoffs for determining the significance of a left main stenosis. (Respectively for MLD and MLA, sensitivity 93 % and 93 %; and specificity 98 % and 95 %). Abizaid et al.57 reported an adverse event rate of 14 % in

161

05/09/2014 11:45

Coronary Diagnosis & Imaging patients who underwent angiographic and IVUS assessment of left main disease and were not referred for intervention. When stratified by IVUS MLD, the event rate was 60 % for an MLD < 2.0 mm, 24 % for an MLD 2.0 to 2.5, 16 % for an MLD 2.5 to 3.0 mm and 3 % for an MLD >3.0 mm. For any given MLD, the event rate was exaggerated in the presence of diabetes mellitus or an untreated lesion in a major vessel with >50 % diameter stenosis. Fassa et al.58 reported the mean 3.3 year follow-up results after deferral of 71 patients with LM stenosis and an MLA >7.5 mm2 and observed no significant difference in target vessel revascularisation, acute MI and death between these patients compared to a group with an MLA <7.5 mm2 who underwent revascularisation (p = 0.28). A multicentre study59 reported comparable (p = 0.3) two year event free survival rates between a group of patients with left main disease and MLA >6 mm2 that deferred intervention (87.3 % ) compared to that of patients with an MLA of 6 mm2 or less who underwent revascularisation (80.6 %). Only 4.4 % of patients in the deferred group required subsequent LMCA revascularisation, none with an infarction. Patients with a LMCA MLA <6 mm2 who did not undergo revascularisation because of operator or patient preferences had an MLA of 5–6 mm2, and 88 % of these had preserved ejection fraction. Frequently these lesions were complex, the estimated surgical risk was high, and patients had issues with dual antiplatelet therapy use or declined surgery. The two year cardiac death-free survival was 86 % (compared to 97.7 % in the deferred group; p = 0.04),

transjugular intrahepatic portosystemic shunt placement, transcaval liver biopsy, transcaval puncture of type II endoleaks and for cardiac mass biopsies.65

and survival free of cardiac death, MI, and revascularisation was 62.5 % (compared to 87.3 % in the deferred group; p = 0.02).

optical coherence tomography (OCT) catheters are on the horizon.68 Co-registration of 3D coronary angiography and IVUS or OCT will improve our understanding of complex lesions and improve our ability to deliver optimal interventional results.69 Sync Vision™ (Volcano Corporation) will use a built-in device motion indicator and combine anatomical and functional assessment using IVUS and instantaneous Wave-Free Ratio (iFR) co-registration. New transducer technology will offer advancements like increased image resolution, multi-frequency devices, real-time volumetric ultrasound imaging capability,70 and software improvements to facilitate image interpretation and increase ease of use. IVUS on guide-wires and forward-looking IVUS for use in CTOs are attractive options that may soon complement our current interventional armamentarium.

IVUS and Endovascular Interventions Literature regarding use of IVUS for endovascular interventions is scarce. Wada et al.60 reported a small case series of patients undergoing IVUS guided stent placement for subclavian artery disease. Short term results were good and long term outcomes were remarkable for absence of ISR over a 51 month median follow up. Contrast minimising strategies like the use of carbon dioxide digital subtraction and IVUS to guide interventions have been described for renal artery interventions,61 and for iliac artery CTO interventions.62 In addition to providing measurements and precisely locate key landmarks and venous branches, IVUS can identify important abnormalities (e.g. external compression, acute and chronic thrombus, fibrosis, mural wall thickening, spurs and trabeculations) that aid in the adequate execution of strategies to treat venous obstruction and bedside placement of vena cava filters.63 IVUSguided bedside placement of inferior vena cava (IVC) filters using a single puncture technique eliminates the risk of transportation, is safe, efficient and cost effective. It may be used in conjunction with pre-procedure computed tomography (CT) derived measurements to minimise filter malposition.64 IVUS has been used for direct and

1. Choi JW, Goodreau LM, Davidson CJ. Resource utilization and clinical outcomes of coronary stenting: a comparison of intravascular ultrasound and angiographical guided stent implantation. Am Heart J 2001;142:112–8. 2. Fitzgerald PJ, Oshima A, Hayase M, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation 2000;102:523–30. 3. Frey AW, Hodgson JM, Muller C, et al. Ultrasound-guided strategy for provisional stenting with focal balloon combination catheter: results from the randomized Strategy for Intracoronary Ultrasound-guided PTCA and Stenting (SIPS) trial. Circulation 2000;102:2497–502. 4. Mueller C, Hodgson JM, Schindler C, et al. Cost-effectiveness of intracoronary ultrasound for percutaneous coronary interventions. Am J Cardiol 2003;91:143–7. 5. Gaster AL, Slothuus U, Larsen J, et al. Cost-effectiveness analysis of intravascular ultrasound guided percutaneous

162

Singh_V03_SN.indd 162

Safety and Complications Strategies to prevent contrast induced nephropathy include adequate hydration and use of IVUS to guide interventions.61 IVUS has the potential to reduce radiation dose and increase procedure safety as previously discussed. As with any vessel instrumentation, IVUS carries the risk of vessel dissection, injury, perforation or total occlusion, air embolism, unstable angina, MI, haemodynamic instability, arrhythmias, limb ischaemia and death. Studies evaluating coronary IVUS have shown major complication rates ranging from 0.1 % including dissection, thrombus and ventricular arrhythmias66 to 1.1 % if spasm and guidewire entrapment are accounted for.67 Spasm has been described as frequently as in 2.9 % of cases,66 but is rarely refractory to vasodilators and device retrieval.

Future Directions Similar to Volcano’s automatised lesion assessment software (Target Assist), Boston Scientific is working on advanced lesion assessment software that will allow for automatised bookmarks and measurements for the healthier proximal and distal portions as well as the tightest portion of a lesion immediately following pullback. Hybrid IVUS and

Conclusions Intravascular ultrasound (IVUS) has brought us one step closer to the understanding of atherosclerosis, and to achieving safer and more effective interventions. IVUS improves hard outcomes during coronary stenting. This outstanding technology can help us answer clinical questions that are at times otherwise uncertain and has proven to be an invaluable tool for cardiovascular operators. Continued technological IVUS improvements and the combination with other technologies will continue to bring additional excitement to this already amazing field of medicine. n

coronary intervention versus conventional percutaneous coronary intervention. Scand Cardiovasc J 2001;35:80–5. 6. Gaster AL, Slothuus Skjoldborg U, Larsen J, et al. Continued improvement of clinical outcome and cost effectiveness following intravascular ultrasound guided PCI: insights from a prospective, randomised study. Heart 2003;89:1043–9. 7. Schiele F, Meneveau N, Vuillemenot A, et al. Impact of intravascular ultrasound guidance in stent deployment on 6-month restenosis rate: a multicenter, randomized study comparing two strategies--with and without intravascular ultrasound guidance. RESIST Study Group. REStenosis after Ivus guided STenting. J Am Coll Cardiol 1998;32:320–8. 8. Oemrawsingh PV, Mintz GS, Schalij MJ, et al. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: final results of a randomized comparison with angiographic guidance (TULIP Study). Circulation 2003;107:62–7.

9. Schiele F, Meneveau N, Gilard M, et al. Intravascular ultrasound-guided balloon angioplasty compared with stent: immediate and 6-month results of the multicenter, randomized Balloon Equivalent to Stent Study (BEST). Circulation 2003;107:545–51. 10. Mudra H, di Mario C, de Jaegere P, et al. Randomized comparison of coronary stent implantation under ultrasound or angiographic guidance to reduce stent restenosis (OPTICUS Study). Circulation 2001;104:1343–9. 11. Jakabcin J, Spacek R, Bystron M, et al. Long-term health outcome and mortality evaluation after invasive coronary treatment using drug eluting stents with or without the IVUS guidance. Randomized control trial. HOME DES IVUS. Catheter Cardiovasc Interv 2009;75:578–83. 12. Chieffo A, Latib A, Caussin C, et al. A prospective, randomized trial of intravascular-ultrasound guided compared to angiography guided stent implantation in

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:45

Impact of Intravascular Ultrasound in Clinical Practice

complex coronary lesions: the AVIO trial. Am Heart J 2012;165:65–72. 13. Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation 1995;91:1959–65. 14. Mintz GS, Popma JJ, Pichard AD, et al. Limitations of angiography in the assessment of plaque distribution in coronary artery disease: a systematic study of target lesion eccentricity in 1446 lesions. Circulation 1996;93:924–31. 15. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study. Circulation 2003;108:43–7. 16. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005;45:995–8. 17. Matsuo K, Ueda Y, Tsujimoto M, et al. Ruptured plaque and large plaque burden are risks of distal embolisation during percutaneous coronary intervention: evaluation by angioscopy and virtual histology intravascular ultrasound imaging. EuroIntervention 2013;9:235–42. 18. Shiono Y, Kubo T, Tanaka A, et al. Impact of attenuated plaque as detected by intravascular ultrasound on the occurrence of microvascular obstruction after percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2013;6:847–53. 19. Tanaka K, Carlier SG, Mintz GS, et al. The accuracy of length measurements using different intravascular ultrasound motorized transducer pullback systems. Int J Cardiovasc Imaging 2007;23:733–8. 20. Patel Y, Depta JP, Patel JS, et al. Impact of intravascular ultrasound on the long-term clinical outcomes in the treatment of coronary ostial lesions. Catheter Cardiovasc Interv June 1, 2013:[ePub ahead of Print]. 21. Sathyanarayana S, Carlier S, Li W, Thomas L. Characterisation of atherosclerotic plaque by spectral similarity of radiofrequency intravascular ultrasound signals. EuroIntervention 2009;5:133–9. 22. Nair A, Kuban BD, Tuzcu EM, et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106:2200–6. 23. Pu J, Mintz GS, Biro S, et al. Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments. J Am Coll Cardiol 2014;63:2220–33. 24. Xie Y, Mintz GS, Yang J, et al. Clinical outcome of nonculprit plaque ruptures in patients with acute coronary syndrome in the PROSPECT study. JACC Cardiovasc Imaging 2014;7:397–405. 25. Keshavarz-Motamed Z, Saijo Y, Majdouline Y, et al. Coronary artery atherectomy reduces plaque shear strains: an endovascular elastography imaging study. Atherosclerosis 2014;235:140–9. 26. Okabe T, Mintz GS, Buch AN, et al. Intravascular ultrasound parameters associated with stent thrombosis after drugeluting stent deployment. Am J Cardiol 2007;100:615–20. 27. Costa MA, Angiolillo DJ, Tannenbaum M, et al. Impact of stent deployment procedural factors on long-term effectiveness and safety of sirolimus-eluting stents (final results of the multicenter prospective STLLR trial). Am J Cardiol 2008;101:1704–11. 28. de Feyter PJ, Kay P, Disco C, Serruys PW. Reference chart derived from post-stent-implantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography. Circulation 1999;100:1777–83. 29. Castagna MT, Mintz GS, Leiboff BO, et al. The contribution of “mechanical” problems to in-stent restenosis: An intravascular ultrasonographic analysis of 1090 consecutive in-stent restenosis lesions. Am Heart J 2001;142:970–4. 30. Inaba S, Mintz GS, Yun KH, et al. Mechanical complications of everolimus-eluting stents associated with adverse events: an intravascular ultrasound study. EuroIntervention 2014;9:1301–8. 31. Sonoda S, Morino Y, Ako J, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting

INTERVENTIONAL CARDIOLOGY REVIEW

Singh_V03_SN.indd 163

stent implantation: serial intravascular ultrasound analysis from the sirius trial. J Am Coll Cardiol 2004;43:1959–63. 32. Fujii K, Mintz GS, Kobayashi Y, et al. Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent restenosis. Circulation 2004;109:1085–8. 33. Hong MK, Mintz GS, Lee CW, et al. Intravascular ultrasound predictors of angiographic restenosis after sirolimus-eluting stent implantation. Eur Heart J 2006;27:1305–10. 34. Escolar E, Mintz GS, Popma J, et al. Meta-analysis of angiographic versus intravascular ultrasound parameters of drug-eluting stent efficacy (from TAXUS IV, V, and VI). Am J Cardiol 2007;100:621–6. 35. Sakurai R, Ako J, Morino Y, et al. Predictors of edge stenosis following sirolimus-eluting stent deployment (a quantitative intravascular ultrasound analysis from the SIRIUS trial). Am J Cardiol 2005;96:1251–3. 36. Liu J, Maehara A, Mintz GS, et al. An integrated TAXUS IV, V, and VI intravascular ultrasound analysis of the predictors of edge restenosis after bare metal or paclitaxel-eluting stents. Am J Cardiol 2009;103:501–6. 37. 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 (ADAPT-DES) study. Circulation 2013;129:463–70. 38. de la Torre Hernandez JM, Baz Alonso JA, Gomez Hospital JA, et al. Clinical impact of intravascular ultrasound guidance in drug-eluting stent implantation for unprotected left main coronary disease: pooled analysis at the patient-level of 4 registries. JACC Cardiovasc Interv 2014;7:244–54. 39. Ahn JM, Kang SJ, Yoon SH, et al. Meta-analysis of outcomes after intravascular ultrasound-guided versus angiographyguided drug-eluting stent implantation in 26,503 patients enrolled in three randomized trials and 14 observational studies. Am J Cardiol 2014;113:1338–47. 40. Jang JS, Song YJ, Kang W, et al. Intravascular ultrasoundguided implantation of drug-eluting stents to improve outcome: a meta-analysis. JACC Cardiovasc Interv 2014;7:233–43. 41. de Ribamar Costa J Jr, Mintz GS, Carlier SG, et al. Intravascular ultrasound assessment of drug-eluting stent expansion. Am Heart J 2007;153:297–303. 42. Abizaid A, Costa JR Jr, Bartorelli AL, et al. The ABSORB EXTEND study: preliminary report of the twelve-month clinical outcomes in the first 512 patients enrolled. EuroIntervention 2014 Apr 29. [ePub ahead of print]. 43. Dai J, Katoh O, Kyo E, et al. Approach for chronic total occlusion with intravascular ultrasound-guided reverse controlled antegrade and retrograde tracking technique: single center experience. J Interv Cardiol 2013;26:434–43. 44. Takahashi Y, Okazaki H, Mizuno K. Transvenous IVUSguided percutaneous coronary intervention for chronic total occlusion: a novel strategy. J Invasive Cardiol 2013 Jul;25:E143–6. 45. 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. 46. Nishioka T, Amanullah AM, Luo H, et al. Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity: comparison with stress myocardial perfusion imaging. J Am Coll Cardiol 1999;33:1870–8. 47. Takagi A, Tsurumi Y, Ishii Y, et al. Clinical potential of intravascular ultrasound for physiological assessment of coronary stenosis: relationship between quantitative ultrasound tomography and pressure-derived fractional flow reserve. Circulation 1999;100:250–5. 48. Briguori C, Anzuini A, Airoldi F, et al. Intravascular ultrasound criteria for the assessment of the functional significance of intermediate coronary artery stenoses and comparison with fractional flow reserve. Am J Cardiol 2001;87:136–41. 49. Abizaid AS, Mintz GS, Mehran R, et al. Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings: importance of lumen dimensions. Circulation 1999;100:256–61. 50. Costa MA, Sabate M, Staico R, et al. Anatomical and physiologic assessments in patients with small coronary

artery disease: final results of the Physiologic and Anatomical Evaluation Prior to and After Stent Implantation in Small Coronary Vessels (PHANTOM) trial. Am Heart J 2007;153:296 e1–7. 51. Kang SJ, Lee JY, Ahn JM, et al. Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity. Circ Cardiovasc Interv 2011;4:65–71. 52. Ahn JM, Kang SJ, Mintz GS, et al. Validation of minimal luminal area measured by intravascular ultrasound for assessment of functionally significant coronary stenosis comparison with myocardial perfusion imaging. JACC Cardiovasc Interv 2011;4:665–71. 53. Cameron A, Kemp HG Jr, Fisher LD, et al. Left main coronary artery stenosis: angiographic determination. Circulation 1983;68:484–9. 54. Fisher LD, Judkins MP, Lesperance J, et al. Reproducibility of coronary arteriographic reading in the coronary artery surgery study (CASS). Cathet Cardiovasc Diagn 1982;8:565–75. 55. Lindstaedt M, Spiecker M, Perings C, et al. How good are experienced interventional cardiologists at predicting the functional significance of intermediate or equivocal left main coronary artery stenoses? Int J Cardiol 2007;120:254–61. 56. 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. 57. Abizaid AS, Mintz GS, Abizaid A, et al. One-year follow-up after intravascular ultrasound assessment of moderate left main coronary artery disease in patients with ambiguous angiograms. J Am Coll Cardiol 1999;34:707–15. 58. Fassa AA, Wagatsuma K, Higano ST, et al. Intravascular ultrasound-guided treatment for angiographically indeterminate left main coronary artery disease: a long-term follow-up study. J Am Coll Cardiol 2005;45:204–11. 59. de la Torre Hernandez JM, Hernandez Hernandez F, Alfonso F, et al. Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study. J Am Coll Cardiol 2011;58:351–8. 60. Wada T, Takayama K, Taoka T, et al. Long-term treatment outcomes after intravascular ultrasound evaluation and stent placement for atherosclerotic subclavian artery obstructive lesions. Neuroradiol J 2014;27:213–21. 61. Kawasaki D, Fujii K, Fukunaga M, et al. Safety and Efficacy of Carbon Dioxide and Intravascular Ultrasound-Guided Stenting for Renal Artery Stenosis in Patients With Chronic Renal Insufficiency. Angiology 2014 Mar 5.[ePub ahead of Print]. 62. Higashimori A, Yokoi Y. Stent implantation for chronic total occlusion in the iliac artery using intravascular ultrasoundguided carbon dioxide angiography without iodinated contrast medium. Cardiovasc Interv Ther 2013;28:415–8. 63. McLafferty RB. The role of intravascular ultrasound in venous thromboembolism. Semin Intervent Radiol 2013;29:10–5. 64. Hislop S, Fanciullo D, Doyle A, et al. Correlation of intravascular ultrasound and computed tomography scan measurements for placement of intravascular ultrasoundguided inferior vena cava filters. J Vasc Surg 2014;59:1066–72. 65. Thakrar PD, Petersen BD, Kaufman JA. Intravascular ultrasound for transvenous interventions. Tech Vasc Interv Radiol 2013;16:161–7. 66. Hausmann D, Erbel R, Alibelli-Chemarin MJ, et al. The safety of intracoronary ultrasound. A multicenter survey of 2207 examinations. Circulation 1995;91:623–30. 67. Batkoff BW, Linker DT. Safety of intracoronary ultrasound: data from a Multicenter European Registry. Cathet Cardiovasc Diagn 1996;38:238–41. 68. Li BH, Leung AS, Soong A, et al. Hybrid intravascular ultrasound and optical coherence tomography catheter for imaging of coronary atherosclerosis. Catheter Cardiovasc Interv 2012 Feb;81:494–507. 69. Carlier S, Didday R, Slots T, et al. A new method for real-time co-registration of 3D coronary angiography and intravascular ultrasound or optical coherence tomography. Cardiovasc Revasc Med 2014 Mar 19.[ePub ahead of print]. 70. Gurun G, Tekes C, Zahorian J, et al. Single-chip CMUT-onCMOS front-end system for real-time volumetric IVUS and ICE imaging. IEEE Trans Ultrason Ferroelectr Freq Control 2014;61:239–50.

163

05/09/2014 11:45

Coronary Adjunctive Pharmacotherapy

LE ATION.

Optimum Utilisation of Novel Antiplatelet Agents in Clinical Practice Timm Bauer and Christian Hamm Medical Clinic I, University of Giessen, Germany

Abstract Prasugrel and ticagrelor are two novel promising antiplatelet agents inhibiting the platelet activation via the adenosine diphosphate pathway. Both achieve a faster, more intense, and more consistent platelet inhibition than clopidogrel. Both novel antiplatelet agents have demonstrated superiority over clopidogrel in large, randomised controlled trials in patients with acute coronary syndrome (ACS). Prasugrel may be best suited for younger patients with planned percutaneous coronary intervention and large areas of myocardium at risk or diabetes mellitus who have a low risk of bleeding. The benefits of prasugrel relative to clopidogrel in ACS must be weighed against the increase in the risk of bleeding associated with its use. Ticagrelor may be the best option for patients with ACS without T elevations, elderly patients or patients managed conservatively. Vorapaxar, a new oral protease-activated-receptor 1 antagonist, may be a good option for secondary prevention in patients with stable atherosclerosis and no history of stroke.

Keywords Acute coronary syndrome, percutaneous coronary intervention, acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel, vorapaxar Disclosure: Timm Bauer received lectures fees from Daiichi Sankyo and AstraZeneca. Christian Hamm received lecture fees from AstraZeneca, Daiichi Sankyo, Sanofi Aventis and The Medicines Company. Received: 3 July 2014 Accepted: 25 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):164–7 Correspondence: Timm Bauer, University Clinic Gießen, Medizinische Klinik I, Klinikstraße 33, D-35392 Giessen, Germany. E: bauer-timm@gmx.de

Introduction

Prasugrel

Antiplatelet therapy is a cornerstone in coronary artery disease (CAD) management. Acetylsalicyclic acid (ASA) has been known for many decades to have antithrombotic efficacy. Already in the 1980’s, the ISIS-2 study demonstrated that ASA reduces mortality in acute myocardial infarction (AMI) by 23 %.1 ASA leads to irreversible inactivation of cyclooxygenase 1 and thereby blocks the formation of thromboxane A2, a potent mediator of platelet aggregation. Nevertheless, ASA is a relatively weak antiplatelet agent and only inhibits one of many pathways leading to platelet activation. Patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) remained at a substantial risk of future ischaemic events, despite the treatment with ASA.2 Only the combination of ASA with an additional antiplatelet agent could reduce the rate of cardiovascular events. 3 In the 1990’s thienopyridines were introduced. Ticlopidine and clopidogrel inhibit platelet activation by blocking the adenosine diphosphate (ADP) P2Y12 pathway. Ticlopidine, the first generation thienopyridine, was effective in reducing ischaemic events, but was associated with serious haematological toxicity. Clopidogrel, the second generation thienopyridine, replaced ticlopidine owing to its equivalent efficacy and lower haematological toxicity. During the last two decades, the utility of clopidogrel has been evaluated in several common clinical scenarios in a large number of patients. The benefits of clopidogrel in patients with stable CAD undergoing elective PCI and in patients presenting with ACS are well established.4–6 However, there are several limitations of clopidogrel, including delayed onset of action and substantial interpatient variability in platelet inhibition.7,8

Prasugrel is a third-generation thienopyridine, and like clopidogel is a prodrug and binds irreversibly at the P2Y12 receptor. However, it exhibits a few advantages over clopidogrel – a more rapid and stronger antiplatelet effect and a very low rate of non-responders. Furthermore, genetic polymorphism of cytochrome P450 do not have an impact on the efficacy of prasugrel.9 After a 60 mg loading dose prasugrel reaches maximal plasma concentration at 30 min.10 In contrast, clopidogrel has a much longer onset of action at two hours after administration of the loading dose. The active metabolite of prasugrel has an elimination half-life of ≈7 hours. Among patients undergoing PCI, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600 mg clopidogrel loading dose. Furthermore, a maintenance prasugrel dose of 10 mg/day results in a more potent and consistent inhibition of platelet activation than the standard clopidogrel maintenance doses of 75 or 150 mg/day. The Trial to assess improvement in therapeutic outcomes by optimising platelet inhibition with prasugrel – thrombolysis in myocardial infarction (TRITON–TIMI) 38 trial included more than 13,000 ACS patients with known coronary anatomy. Planned PCI also showed that prasugrel (60 mg loading dose followed by a 10 mg/day maintenance dose) compared with clopidogrel (300 mg loading dose and a 75 mg/day maintenance dose) significantly reduced the combined primary endpoint of cardiovascular death, non-fatal myocardial infraction (MI) and non-fatal stroke (9.9 vs 12.1 %; HR=0.81; P<0.001).11 Rates of cardiovascular death (2.1 % vs 2.4 %; HR=0.89; P=0.31) were not reduced by prasugrel relative to clopidogrel, whereas rates of stent thrombosis were significantly lower (1.1 % to 2.4 %; HR=0.48; P<0.001)

164

Hamm_FINAL.indd 164

05/09/2014 10:23

Optimum Utilisation of Novel Antiplatelet Agents in Clinical Practice

in the prasugrel-group. The diabetic subgroup (especially those with insulin dependent diabetes) had particular benefit from the prasugrel treatment. The relative risk reduction was 26 % in comparison to 8 % among non-diabetics. Unfortunately, this beneficial effect was accompanied by an increase of life-threatening bleeding complications (1.4 % vs 0.9 %; HR=1.52; P=0.01). Furthermore, among elderly and patients with a body weight of less than 60 kg no net clinical benefit was observed. Patients who had had a prior cerebrovascular event even had worse clinical outcomes. As a consequence, prasugrel is contraindicated in patients with prior stroke/transient ischemic attack (TIA). Its use is generally not recommended in patients aged ≥75 years or in patients with lower body weight (<60 kg). A reduced maintenance dose of 5 mg can be considered in these patients, but outcome data are not available with this dose. Although prasugrel markedly reduced ischaemic events after PCI for ACS, a major criticism of the TRITON–TIMI 38 trial was that the clopidogrel group received a 300 mg instead of a more effective 600 mg loading dose. In the Testing platelet reactivity in patients undergoing elective stent placement on clopidogrel to guide alternative therapy with prasugrel (TRIGGER-PCI) study, the efficacy of prasugrel vs clopidogrel in patients with high on-treatment platelet reactivity after elective PCI was evaluated.12 No benefit was observed with prasugrel. Prasugrel is approved in combination with ASA in ACS with or without ST elevation patients with known coronary anatomy who are planned for PCI.

related to blockage of adenosine reuptake. It usually occurs early in the course of treatment and in most cases is self-limited. Ticagrelor is approved in combination with ASA in non-ST or ST elevation ACS patients who are treated with either PCI, bypass surgery or medically. In patients with haemorrhagic stroke or patients taking medications that are strong CYP3A4 inhibitors or inducers ticagrelor is contraindicated. A major criticism of the PLATO trial was that a significant interaction between treatment effect and geographic region was seen, with an apparently smaller ticagrelor effect in North America than in other regions (e.g. East Europe). In an analysis by Mahaffey et al. a significantly higher proportion of patients in North America receiving higher ASA maintenance dose (≥300 mg/day) was identified as a possible explanation for the regional difference.15 There is no clinical data on the efficacy of ticagrelor in setting of PCI in stable CAD.

Vorapaxar Vorapaxar is an oral competitive protease-activated–receptor 1 (PAR1) antagonist that inhibits thrombin-induced platelet aggregation. In the Thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRACER) trial, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point (18.5 vs 19.9 %; HR=0.92; P=0.07) among patients with in non-ST elevation ACS.16 However, vorapaxar significantly increased the risk of moderate and severe bleeding (7.2 vs 5.2 %; HR=1.35; P<0.001), including intracranial haemorrhage (ICH) (1.1 vs 0.2 %; HR=6.45; P<0.001).

Ticagrelor Ticagrelor is not a thienopyridine, but binds also reversibly at the ADP P2Y12 receptor.9 Ticagrelor is administered orally in its active form and does not need the metabolic activation required with thienopyridines. Similar to prasugrel, ticagrelor provides faster, more intense and more consistent platelet inhibition than clopidogrel. Its bioavailability seems to be less affected by genetic factors. Ticagrelor is rapidly absorbed with a maximum plasma concentration at 1.5 hours. Due to its shorter half-life, plasma levels are maintained for only 12 hours, making a twice-a-day regimen necessary (2 x 90 mg/day). This might be beneficial in bleeding complications or planned operations like coronary artery bypass graft (CABG) surgery, but it may pose a problem for noncompliant patients. However, the ONSET/OFFSET study demonstrated that the platelet inhibition 24 hours after the last dose was equivalent in ticagrelor- and clopidogrel-treated patients.13 These data suggest that patients who miss one dose of ticagrelor and patients with maintenance clopidogrel therapy will have similar platelet inhibition at 24 hours. Ticagrelor (180 mg loading dose and a 2 x 90 mg/day maintenance dose) was compared with clopidogrel (300 mg loading dose and a 75 mg/day maintenance dose, in case of PCI additional loading with 300 mg) in the Platelet inhibition and patient outcomes (PLATO) study in patients with ACS.14 In contrast to the TRITON TIMI 38 trial, ACS-patients were included regardless of the initial treatment strategy (medically or invasive). Furthermore, inclusion of patients pretreated with clopidogrel was allowed. In the PLATO study, ticagrelor significantly reduced the combined primary endpoint of cardiovascular mortality, MI and stroke (9.8 % vs 11.7 %; HR=0.84; P<0.001) without increasing the risk of major bleeding. There were also reductions in cardiovascular, total mortality and stent thrombosis with ticagrelor. Ticagrelor has been associated with side effects such as bradycardia and dyspnoea, most likely

INTERVENTIONAL CARDIOLOGY REVIEW

Hamm_FINAL.indd 165

The Thrombin receptor antagonist in secondary prevention of atherothrombotic ischaemic events (TRA 2P) – Thrombolysis in myocardial infarction (TIMI) 50 trial was designed to evaluate the efficacy and safety of vorapaxar in reducing atherothrombotic events in patients with stable atherosclerosis treated with standard therapy.17 TRA 2P-TIMI 50 showed that vorapaxar was associated with a reduction in the composite end point of cardiovascular death, MI or stroke (9.3 vs 10.5 %; HR=0.87; P<0.001). A benefit was most apparent in patients with a history of MI and no history of stroke/transient ischaemic attack (TIA) who weighed more than 60 kg. However, vorapaxar was also associated with increased rates of moderate and severe bleeding (4.2 vs 2.5 %; HR=1.66; P<0.001), including ICH, with the latter occurring most frequently in patients with a history of stroke. On May 5, 2014, vorapaxar has received its first global approval in the USA for secondary prevention of atherothrombotic events in patients with previous MI and peripheral arterial disease. Vorapaxar must not be used in patients who have had a stroke, TIA, or ICH.

Optimum Antiplatelet Therapy in ST Elevation Myocardial Infarction (STEMI) Patients with STEMI and planned primary PCI require particularly urgent platelet inhibition and represent a group potentially benefiting most from the new antiplatelet therapies. In the STEMI cohort of the TRITON-TIMI 38 trial prasugrel significantly reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke by 32 % after 30 days (6.5 vs 9.5 %, P=0.0017).18 The absolute risk reduction was 3.0 %. In particular, benefits were seen among patients with anterior STEMI. In comparison to clopidogrel prasugrel reduced the primary endpoint in these patients by 43 % – regardless of a concomitant use of glycoprotein IIb/IIIa blockers. The

165

05/09/2014 10:23

Coronary Adjunctive Pharmacotherapy Table 1: Recommendations of the ESC and ACCF/AHA STEMI Guidelines on Novel Antiplatelet Agents in Primary PCI (Class of Recommendation, Level of Evidence) Clopidogrel Prasugrel Ticagrelor ESC IC IB IB

(preferably, when

(in clopidogrel-naive

prasugrel or ticagrelor

patients, if no history

are either not available of prior stroke/TIA,

or contraindicated)

ACCF/AHA IB

age <75 years) IB

rate of bleeding complications not related to CABG was similar in the prasugrel- and clopidogrel-group (2.4 vs 2.1 %). However, in patients with bypass surgery TIMI major bleedings occurred more often among those with prasugrel therapy (18.8 vs 2.7 %). In general, the rate of bleeding complications in the STEMI cohort was not increased – despite a use of glycoprotein IIb/IIIa blockers in 60 % of the patients. In the STEMI cohort of the PLATO trial ticagrelor reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke by 13 % (9.4 vs 10.8 %; P=0.07).19 The absolute risk reduction was 1.4 %. Ticagrelor also reduced several secondary end points, such as MI (HR=0.80; P=0.03), mortality (HR=0.82; P=0.05) and stent thrombosis (HR, 0.66; P=0.03). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76). In the Rapid activity of platelet inhibitor drugs primary PCI (RAPID) study pharmacodynamic measurements after administration of prasugrel and ticagrelor loading dose were performed.20 In terms of residual platelet reactivity there were no significant differences after two and four hours between the two agents. Surprisingly, four hours were required to achieve sufficient platelet inhibition in the majority of STEMI patients. Futhermore, morphine use was associated with a delayed activity of prasugrel and ticagrelor. Interestingly, the guidelines of the European Society of Cardiology (ESC) and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) do not completely agree on the utilisation of novel antiplatelet agents (see Table 1). The STEMI guidelines of the ESC give ticagrelor and prasugrel a IB recommendation.21 However, prasugrel should only be given in clopidogrel-naive patients, if there is no history of prior stroke/TIA and age <75 years. In general, these two novel antiplatelet agents are preferred over clopidogrel. According to the ESC guidelines clopidogrel should only be used (IC recommendation) when prasugrel or ticagrelor are either not available or contraindicated. On contrary, the ACCF/AHA STEMI guidelines do not declare superiority of ticagrelor and prasugrel over clopidogrel.22 All three agents are given a IB recommendation. In the eyes of the American task force an important shortcoming of the prasugrel and ticagrelor data is that there are no specifically designed STEMI trials and only post-hoc secondary analyses exist. In summary, prasugrel may be best suited for younger STEMI patients with large areas of myocardium at risk (e.g. anterior STEMI) or diabetes who are not planned for CABG and have a low risk of bleeding. Ticagrelor may be the best option for older patients or patients with a moderate bleeding risk and patients with a conservative strategy. Clopidogrel may rather be used in patients with a contraindication for prasugrel and ticagrelor or concomitant chronic anticoagulation therapy.

166

Hamm_FINAL.indd 166

Optimum Antiplatelet Therapy in Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) Patients with NSTE-ACS are at high risk for major adverse events and do also benefit from the new antiplatelet agents. However, NSTEACS patients tend to be older and have more co-morbidities such as chronic renal failure, and therefore there is an increased risk for bleeding complications. In the NSTE-ACS cohort of the TRITON-TIMI 38 trial prasugrel significantly reduced the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke (HR=0.82, P=0.002), but was accompanied by an increase in the rate of major bleeding complications (HR 1.40, P=0.02).23 However, in patients who met the criteria for prasugrel use recommended by the European Medicines Agency (EMEA), thus excluding patients from the analysis with prior TIA/stroke, with weight <60 kg or age ≥75 years, prasugrel was superior with regards to ischaemic events without significant differences in non-CABG major bleedings. Most recently, the Comparison of prasugrel at the time of PCI or as pretreatment at the time of diagnosis in patients with nonST elevation myocardial infarction (NSTEMI) (ACCOAST) trial has been published.24 Over 4,000 NSTEMI patients who were scheduled to undergo coronary catheterisation within 48 hours were included in this study. Patients were randomised to prasugrel (30 mg loading dose) or placebo before coronary angiography. When PCI was indicated, an additional loading dose of 30 mg prasugrel was given in the pretreatment group and a 60 mg loading dose was given in the control group. Pretreatment with prasugrel before angiography did not reduce ischaemic events (10.0 versus 9.8 %, HR=1.02; P=0.81), but was associated with more TIMI major bleeding (2.6 vs 1.4 %, HR=1.90, P=0.006). The Targeted platelet inhibition to clarify the optimal Strategy to medically managed acute coronary syndromes (TRILOGY-ACS) is also a recent study which examined the effect of prasugrel in patients not undergoing revascularisation.25 Patients were randomised in the study only after a decision for medical management without revascularisation was made. At a median follow-up of 17 months Prasugrel did not significantly reduce the primary endpoint in comparison to clopidogrel (13.9 vs 16.0 %, HR=0.91; P=0.21). The results of TRILOGY-ACS do not support extending the indication for prasugrel to medically managed patients with NSTE-ACS. There is also a post-hoc secondary analysis of the NSTE-ACS PLATO cohort. Consistent with the results in the overall population ticagrelor significantly reduced the primary endpoint (10.0 vs 12.3 %; HR=0.83; P=0.0013), cardiovascular (3.7 vs 4.9 %; HR=0.77; P=0.0.007) and total mortality (4.3 versus 5.8 %; HR=0.76; P=0.002) in patient with and without revascularisation.24 Major bleeding rate did not differ between the two treatment groups (13.4 vs 12.6 %; HR=1.07; P=0.26), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs 3.8 %; HR=1.28; P=0.0139). There is no randomised comparison of prasugrel vs ticagrelor. However, Biondi-Zoccai et al. conducted an adjusteded indirect meta-analysis comparing both agents in patients with ACS.27 Head-to-head comparison suggested similar efficacy of prasugrel and ticagrelor, but prasugrel appeared to be more benefical with regard to the occurrence of stent thrombosis, while increasing the risk of bleeding complications. There are two important advantages of ticagrelor over prasugrel in the setting of NSTE-ACS. First, according to the ESC guidelines a

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:23

Optimum Utilisation of Novel Antiplatelet Agents in Clinical Practice

P2Y12 inhibitor should be added to ASA as soon as possible,26 and ticagrelor can be given without knowledge of the coronary status. In the ACCOAST trial administration of prasugrel before coronary angiography was not associated with a net clinical benefit. Secondly, ticagrelor also improves prognosis in medically managed patients.26 The current NSTE-ACS guidelines of the ESC prefer ticagrelor and prasugrel over clopidogrel28 (see Table 2). Clopidogrel is only recommended for patients who cannot receive ticagrelor or prasugrel (IA recommendation). In contrast to the European guidelines the ACCF/AHA NSTE-ACS guidelines do not endorse prasugrel or ticagrelor over clopidogrel.29 There is only little data on the use of the novel antiplatelet agents in daily clinical practice. Randomised clinical trials usually enroll selected patient populations that may not be representative for patients seen in everyday practice. In an analysis of the Greek Antiplatelet registry (GRAPE) registry 24.1 % and 37.2 % of the patients with ACS undergoing PCI received prasugrel and ticagrelor, respectively.30 However, solid data is lacking, whether the novel antiplatelet agents also improve prognosis in an all-comer population.

Table 2: Recommendations of the ESC and ACCF/AHA NSTE-ACS Guidelines on Novel Antiplatelet Agents (Class of Recommendation, Level of Evidence) Clopidogrel Prasugrel ESC IA IB

Ticagrelor IB

(is recommended

(is recommended for

(is recommended

for patients who

P2Y12-inhibitor-naïve

for all patients

cannot receive

patients in whom

at moderate-to-high

ticagrelor or

coronary anatomy is

risk of ischaemic

prasugrel)

known and who are

events, regardless

proceeding to PCI

of initial treatment

unless there is there

strategy and

is a high risk of life-

including those pre-

threatening bleeding or

treated with

other contraindications

clopidogrel)

ACCF/AHA IB

(at the time of PCI)

Conclusions

In summary, ticagrelor may be the best option for most patients with NSTE-ACS, in particular in patients managed conservatively. Prasugrel may be best suited for younger patients with scheduled PCI and large

The two novel antiplatelet agents prasugrel and ticagrelor provide better platelet inhibition than clopidogrel. These drugs were shown to be more effective than clopidogrel in most subsets of patients with ACS, but were associated with more bleeding complications. Careful patient selection and balancing the benefits and risks

areas of myocardium at risk or diabetes mellitus who have a low risk of bleeding. Again, clopidogrel should rather be used in patients with a contraindication for prasugrel and ticagrelor or concomitant chronic anticoagulation therapy.

optimises the selection of prasugrel, ticagrelor and clopidogrel in ACS. Vorapaxar may be a good option for secondary prevention in patients with stable atherosclerosis and no history of stroke, TIA, or ICH. n

1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349–60. 2. 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;334:1084–9. 3. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999;100:1667–72. 4. Bertrand ME, Rupprecht HJ, Urban P, et al. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronarystenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–9. 5. CURE Study Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. 6. Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. 7. Serebruany VL. Plasma clopidogrel metabolites and antiplatelet “resistance”: back to the future. Thromb Res 2008;122:725–6. 8. Serebruany VL. Switching thienopyridines: hypothetical versus real risks. J Am Coll Cardiol 2008;51:775. 9. Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs 2013;73:1681–709. 10. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007;153:e9–66.e16. 11. Wiviott SD, Braunwald E, McCabe CH et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. 12. Trenk D, Stone GW, Gawaz M, et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients

INTERVENTIONAL CARDIOLOGY REVIEW

Hamm_FINAL.indd 167

Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012;59:2159–64. 13. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577–85. 14. Wallentin L, Becker RC, Budaj A, et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. 15. Mahaffey KW1, Wojdyla DM, Carroll K, et al. PLATO Investigators. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2011;124:544–54. 16. Tricoci P, Huang Z, Held C, et al. TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366:20–33. 17. Morrow DA, Braunwald E, Bonaca MP, et al. TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404–13. 18. Montalescot G, Wiviott SD, Braunwald E, et al. TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): doubleblind, randomised controlled trial. Lancet 2009;373:723–31. 19. Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP, Emanuelsson H, Finkelstein A, et al. PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010;122:2131–41. 20. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013 Apr 16;61:1601–6. 21. Steg PG, James SK, Atar D, et al. 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. 22. O’Gara PT, Kushner FG, Ascheim DD, et al. American College

of Emergency Physicians; Society for Cardiovascular Angiography and Interventions. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. J Am Coll Cardiol 2013;61:e78–140. 23. De Servi S, Goedicke J, Schirmer A, Widimsky P. Clinical outcomes for prasugrel versus clopidogrel in patients with unstable angina or non-ST-elevation myocardial infarction: an analysis from the TRITON-TIMI 38 trial. Eur Heart J Acute Cardiovasc Care. 2014 May 12. pii: 2048872614534078. [Epub ahead of print]. 24. Montalescot G, Bolognese L, Dudek D, et al. ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med 2013 Sep 12;369(11):999–1010. 25. Roe MT, Armstrong PW, Fox KA, et al. TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes. N Engl J Med 2012;367:1297–309. 26. Lindholm D, Varenhorst C, Cannon CP, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J 2014 Apr 11. [Epub ahead of print]. 27. Biondi-Zoccai G, Lotrionte M, Agostoni P, et al. Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. Int J Cardiol 2011;150:325–31. 28. Hamm CW, Bassand JP, Agewall S, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. 29. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645–81. 30. Alexopoulos D, Xanthopoulou I, Deftereos S, et al. GRAPE Investigators. Contraindications/special warnings and precautions for use of contemporary oral antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Circ J 2013;78:180–7.

167

05/09/2014 10:23

Coronary STEMI

LE ATION.

MGuard Embolic Protection Stent – The Importance of Thrombus Management in ST-elevation Myocardial Infarction Primary Percutaneous Coronary Intervention P roc eeding s of ST EMI s y m p o s i u m a t E u r o P CR o n 2 0 – 2 3 r d M a y 2 0 1 4 i n Pa r i s K a trina Mou n t f o r t , M e d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y Re vi ew ed for a c c ura c y by : R ic a rdo C o s t a , 1 A l e x a n d r e A b i z a i d , 1 J e a n Fa j a d e t , 2 Ch a i m L o t a n , 3 R a n Ko rn o w s ki, 4 Da riusz Dud e k , 5 J o s e P S H e n r i q u e s, 6 G i o v a n n i A m o r o s o 7 1. Dante Pazzanese Institute, Sao Paulo, Brazil; 2. Clinique Pasteur, Toulouse, France; 3. Hadassah-Hebrew University Hospital, Jerusalem, Israel; 4. Rabin Medical Center, Petach Tikva, Israel; 5. Department of Interventional Cardiology, Jagiellonian University, Krakow, Poland; 6. Academic Medical Centre, Amsterdam, The Netherlands; 7. Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, The Netherlands

Abstract Distal embolisation of atherothrombotic material is a frequent consequence of percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). This causes microvascular occlusions, leading to a further reduction in myocardial reperfusion. The MGuard™ embolic protection stent (EPS) features a unique polymer micronet mesh coating. When used in acute STEMI, the MGuard EPS shows significant improvement in myocardial flow and ST resolution, even in complicated clinical cases vs the standard approach with conventional bare metal or drug-eluting stents. Data from the andomised Safety and Efficacy Study of MGuard Stent After a Heart Attack (MASTER II) trial and from a real-life registry have shown the efficacy and safety of the MGuard in primary PCI. This report of the proceedings of a symposium at EuroPCR, 20–23 May 2014, Paris, France, discussed clinical trial data, as well as a number of clinical cases, illustrating the utility of the MGuard EPS in difficult situations.

Keywords ST-elevation myocardial infarction, percutaneous coronary intervention, distal thromboembolism, stent, distal embolisation, STEMI, thrombus, thrombus loaded lesion, Acute myocardial infarction, target lesion, mesh Disclosure: Dr Lotan is Medical Director for InspireMD; Dr Abizaid, Dr Henriques, Dr Dudek, Dr Costa, Dr Fajadet, Dr Kornowski and Dr Amoroso have no conflicts of interest to declare. Received: 23 June 2014 Accepted: 19 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):168–74 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. E: katsmountfort@virginmedia.com Support: The publication of this article was supported by InspireMD.

Embolisation of atherothrombotic material is a common occurrence during percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). This may lead to distal vessel occlusion resulting in impaired myocardial perfusion, which is associated with larger infarct size, incomplete ST resolution and increased mortality. Unfortunately, there is a lack of significant adjunctive devices to protect the microcirculation. A symposium was sponsored by Inspire MD

and chaired by Alexandre Abizaid, Institute Dante Pazzanese de Cardiologia (Sao Paulo, Brazil), and Jean Fajadet, Clinique Patteur, (Toulouse, France). These presentations aimed to discuss the importance of thrombus management in PCI for STEMI patients, to give an update of relevant clinical data on the performance of the MGuard™ stent in STEMI patients and to present real life examples on how this device selection can influence the outcome in STEMI patients. n

Therapeutic Alternatives for Intracoronary Thrombus – MASTER Results in Perspective Ale x a n d r e A b i z a i d 1 a n d Ch a i m L o t a n 2 1. Dante Pazzanese Institute, Sao Paulo, Brazil; 2. Hadassah-Hebrew University Hospital, Jerusalem, Israel

Dr Abizaid began by emphasising the need for therapeutic alternatives to avoid distal thromboembolism (embolisation) during highly

168

InspireMD_SatSym_FINAL.indd 168

thrombotic situations such as STEMI. The Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction

05/09/2014 10:26

MGuard Embolic Protection Stent

Figure 1: The MGuard™ Prime Embolic Protection Stent

Figure 2: Optical Coherence Tomography of MGuard™ in Acute Myocardial Infarction Showing Thrombus Entrapment Behind the Protective Net

MicroNet™

Stent Platform: • L605 CoCr • Strut Thickness: 80 µm • Sizes: Diameter 2.75–4 mm Length 8–38 mm • Guiding Catheter: 6F (ID 1.68 mm/0.007”) • Nominal Pressure: 8 atm

Advantages of technology: • Flexible structure • Minimal foreign body reaction • Does not promote thrombosis • Minimises vessel wall injury • Allows trapping of embolic materials

Figure 3: The MASTER Trial

Master Trial

433 points with ST-elevation myocardial infarction (STEMI) <12 hours of symptoms onset undergoing 1ary percutaneous coronary intervention (PCI) in 50 sites in nine countries in Europe and South America

Study (TAPAS), prospective randomised trial, aimed to determine whether aspiration of thrombotic material before stent implantation of the infarct-related coronary artery resulted in improved myocardial perfusion compared with conventional primary PCI.1 Results showed a reduction in all-cause mortality at 30 days. However, the Thrombus Aspiration during ST-segment Elevation myocardial infarction (TASTE) study (n= 7244) found that routine thrombus aspiration before PCI as compared with PCI alone did not result in a reduction in 30-day mortality.2 Even if aspiration is good, embolisation remains an ongoing issue.

The MGuard for Acute ST Elevation Reperfusion (MASTER) trial recruited 432 patients with symptoms consistent with STEMI within 12 hours of symptom onset, at 50 sites in nine countries.3 Participants were randomised to PCI with bare metal stent (BMS) or drug-eluting stent (DES), (n=216) or to PCI with MGuard (n=217). Follow-up was at 30 days, six months and one year. The primary endpoint was ST-segment resolution at 60–90 minutes. Other inclusion criteria were ≥2 mm of ST-segment elevation in ≥2 contiguous leads and PCI of a single de novo lesion with reference vessel diameter (RVD) ≥3.0 to ≤4.0 mm and length ≤33 mm (capable of being covered by a single study stent). The primary endpoint of post-procedure complete (≥70 %) ST-segment resolution was significantly higher in the MGuard stent group compared with the control group (57.8 % vs 44.7 %; difference: 13.2 %; 95 % confidence interval: 3.1 % to 23.3 %; p=0.008; see Figure 3). The MGuard EPS also showed superior rates of thrombolysis in myocardial infarction (TIMI) 3 flow (91.7 % vs 82.9 %, p = 0.006). Major adverse cardiac events (1.8 % vs 2.3 %, p=0.75) at 30 days were not significantly different between the two groups. Although the study was not powered for mortality, a trend in favour of the MGuard EPS was observed (0 % vs 1.9 %, p=0.06). A substudy, in which patients underwent magnetic resonance imaging (MRI) at five days, showed a trend towards smaller infarct size measured by delayed

INTERVENTIONAL CARDIOLOGY REVIEW

MGuard EPS N = 217

BMS or DMS N = 216 ST segment resolution ≥ 70 % (1ary endpoint)

Final TIMI 3 flow 100

100

91.7

Percentage of patients

82.9 75

75 57.8 50 44.7 25

P = 0.006 MGuard

BMS/DES

P = 0.008 MGuard

BMS/DES

Similar MACE rates at 30-day clinical follow-up (1.8 % vs 2.3 %, p = 0.75) 100

100 93

75 Percentage of patients

The MGuard™ Embolic Protection Stent (EPS) is a novel device. The EPS has evolved from the stainless steel MGuard to the L605 cobalt chromium MGuard Prime, both featuring a polyethylene terephthalate (PET) mesh with 150–180 μm aperture size, preventing the prolapse of thrombus and potential distal embolisation (see Figure 1). Case reports in patients with STEMI undergoing primary PCI have demonstrated the ability of the MGuard EPS to capture and contain (‘jail’) thrombus and atheroma behind its net, thereby preventing distal embolisation (see Figure 2).

Randomisation 1:1

Percentage of patients

• Proprietary circular knitted ultrathin , mesh made of a single PolyEthylene Terephthalate (PET) fiber • Fibre size: 20 µm • Aperture size at Expanded State: 150 µm x 180 µm

35 25

0 Primary PCI patients

TIMI 3

TIMI 3 and MBG 2/3

TIMI 3 and MBG 2/3 and STR > 70 %

enhancement with the MGuard EPS.4 At 12 months, the trend towards reduced cardiac mortality with the MGuard EPS was still seen but again did not reach statistical significance (1.0 % vs 3.3 %, p=0.092).5 No significant differences in reinfarction or stent thrombosis were seen at 12 months between the MGuard EPS and control groups. The 12-month target lesion revascularisation (TLR) rate and 13-month late loss and binary restenosis rates for the MGuard EPS was higher

169

Coronary STEMI Figure 4: Pathophysiology of no Reflow in Primary Percutaneous Coronary Intervention

than the in control group but comparable to other BMS cohorts such as in the large Harmonising Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZON) trial.4 Another subanalysis divided patients into two groups according to the measured volume of thrombus (≤ or >30 mm2). In the small thrombus group, complete resolution of ST-elevation was achieved in 66.2 % of the MGuard group vs 44.9 % of the control (p=0.02).6 In the large thrombus group, complete resolution was achieved in 54.7 % of the MGuard group vs 42.3 % of the control (p=0.02). These data suggest that the device may be successfully employed in patients with large thrombus burden.

Microvascular Plugging Intravascular Thrombus

Distal Coronary Embolization

Myocardial Edema Ischemia & Reperfusion injury Hemorrhage Inflammation

Endothelial Swelling

Secondary Ischemia &Further Cell Death

Microvascular Spasm

Source: Abbate et al., 2008.11

In conclusion, among patients with STEMI undergoing emergent PCI, the MGuard EPS resulted in superior rates of restored flow (TIMI 3) and complete resolution of ST elevation, with a trend to reduced mortality compared with control groups. n

The Enemy of Primary PCI Ch a i m L o t a n Hadassah University Hospital, Jerusalem, Israel

Dr Chaim Lotan, Hadassah Medical Center (Jerusalem, Israel) discussed the clinical challenge of ‘no-reflow’ in primary PCI. Angioplasty is associated with improved epicardial flow, greater reperfusion rate and improved survival, when compared with thrombolytic therapy.7 However, despite TIMI 3 flow, optimal myocardial reperfusion is probably only achieved in one third of patients.8 This phenomenon is known as slow flow or no-reflow and characterised by ‘slow flow’ in the affected vessel and lack of contrast uptake (‘blush’) by the subtended myocardium, which is associated with a poor prognosis.9,10 The pathophysiology of no reflow is described in Figure 4.11 It is a multifactorial condition and is caused by four interacting mechanisms: ischaemic injury, reperfusion injury, distal embolisation and susceptibility of the microcirculation to

injury.12 The timing of distal embolisation varies and can affect outcomes: distal embolisation before PCI is visible in 5 % of angiograms before PCI and in 15–17% after PCI. 13,14 Thrombus composition and size is also related to outcomes. Fresh thrombus that can be aspirated typically only represents 30 % of the total thrombus load. The plaque represents 24 % and organised thrombus accounts for 47 %.15 Furthermore, angiography underestimates residual thrombus after aspiration; this can be demonstrated by optical coherence tomography (OCT).16 The MGuard EPS prevents post stenting protrusion of the remaining thrombus, commonly seen with conventional stent, as the micronet seals (“jails”) the thrombus against the vessel wall. n

STEMI Demonstrative Cases 1 Successful and Unsuccessful Techniques? Ra n Ko r n o w s k i Rabin Medical Center, Petach Tikva, Israel

Dr Ran Kornowski, Rabin Medical Center (Tel Aviv, Israel), began by stating that as of 2013, 56 % of STEMI in Israel still received aspiration, and 46 % had glycoprotein (GP) IIb/IIIa infusion during STEMI. Only around 10 % received MGuard EPS implantation during STEMI. He then presented a case of an 88-year-old man with hypertension, chronic obstructive pulmonary disease (COPD) and renal dysfunction who presented with an extensive anterior wall STEMI. The duration of chest pain before admission was 1.5 hours and door-to-balloon time was 42 minutes. Echocardiography on admission showed moderate left ventricle (LV) dysfunction, and the patient was immediately taken to the catheterisation laboratory, where he received primary PCI of an occluded mid-left anterior descending (LAD) artery with a large

170

InspireMD_SatSym_FINAL.indd 170

thrombus burden. After wiring, a large amount of thrombus was seen on the angiogram. After aspiration, a significant amount of thrombus remained without restoration of normal flow even after an additional aspiration attempt. An MGuard Prime EPS (4 x 19 mm) was therefore implanted with immediate improvement in flow after deployment. After 30s, a TIMI 2/3 flow was achieved. Prior to discharge, echocardiography showed a substantial improvement in LV function. In conclusion, this real-life case has demonstrated the utility of an MGuard EPS in an elderly patient with anterior STEMI caused by LAD occlusion by a large coronary thrombus, with limited efficacy of thrombus aspiration and anti-thrombotic regimen. n

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:26

MGuard Embolic Protection Stent

STEMI Demonstrative Cases 2 MGuard Prime EPS Optical Frequency Domain Imaging (Insights) – STEMI Yaron Almagor,1 Carlos Cafri2 and Ben Gurion3 1. Shaare Zedek Medical Center, Jerusalem, Israel; 2: Soroka University Medical Center; 3. University of Negev Beer Sheva, Israel

Dr Yaron Almagor, Shaare Zedek Medical Center (Jerusalem, Israel), presented a case that illustrated the effectiveness of the MGuard Prime in acute MI. The case was of acute anterior wall STEMI with total occlusion of the LAD. After a small balloon, the thrombus could clearly be seen using coronary OCT. Immediately after implantation of an MGuard Prime EPS, excellent reperfusion was achieved. OCT showed no thrombus protrusion. The MGuard Prime EPS showed excellent stent apposition by OCT with open side branches post stenting. He ended his presentation stating: “I never expected a result like this.” Dr Carlos Cafri, Soroka University Medical Center and Ben Gurion University of Negev (Beer Sheva, Israel), presented a case of a 58

year-old man with diabetes who had been admitted after threee hours of chest pain. An electrocardiogram (ECG) revealed ST-elevation in inferior wall leads. Angiography showed occlusion in the right coronary artery (RCA). Manual thrombus aspiration resulted in restoration of TIMI 3 flow but considerable stenosis and thrombus remained visible while the patient was still experiencing chest pain. An MGuard Prime EPS (3.5 x 18 mm) was implanted, without predilatation to avoid high pressure during implantation; a long stent was chosen to avoid dislodgement of thrombus at the distal end of the stent. The outcomes were excellent. Dr Cafri concluded that the MGuard Prime EPS allows appropriate management of seemingly impossible thrombotic situations. n

STEMI Demonstrative Cases 3 STEMI and Small Aneurysm G ra h a m Ca s s e l Milpark Hospital, Johannesburg, South Africa

Dr Graham Cassel of Milpark Hospital, Johannesburg, South Africa, presented a case of a 52 year-old male with hypertension and hypercholesteraemia, who presented one hour after the onset of severe chest pain with inferior STEMI. Angiography showed a totally occluded RCA, as well as severe stenosis in the LAD and circumflex (CX) arteries. Following thrombus aspiration, TIMI 3

flow was achieved but an aneurysm was detected in the middle of the stenosis of the RCA. An MGuard Prime EPS (4 x 28 mm) was implanted, resulting in exclusion of the aneurysm and excellent distal flow. Two weeks later, when the LAD and CX were treated percutaneously, the MGuard Prime EPS still showed excellent angiographic results. n

STEMI Demonstrative Cases 4 How Could I Treat a Bifurcation With High Thrombus Burden Despite Exhaustive Aspiration? Ra f a e l R o m a g u e ra Bellvitge University Hospital, Barcelona, Spain

Dr Rafael Romaguera of Bellvitge University Hospital, Spain, presented a case of a 49-year-old male smoker admitted with 13 hours of ongoing chest pain with signs of an inferior STEMI on the ECG. Aspirin (250 mg), clopidogrel (600 mg) and unfractionated heparin (UFH; 100 UI/kg) were administered. Coronary angiography revealed an occlusion in the distal segment of the RCA, with a large thrombus at a bifurcation. Eight rounds of aspiration were performed with two different 6F catheters. An additional wire was advanced to perform aspiration of the posterior descending artery (PDA). However, these interventions failed to restore flow. After implantation of an MGuard (2.5 x 28 mm) EPS, restoration of flow was achieved. Subsequently, side

INTERVENTIONAL CARDIOLOGY REVIEW

InspireMD_SatSym_FINAL.indd 171

branch occlusion was seen, possibly due to mechanical obstruction by the stent platform and net, or possibly due to thrombus being squeezed from the main vessel into the side branch. The PDA was rewired across the stent with an intermediate stiffness coronary wire. However, the operator was unable to advance the device through the mesh because of the angle and lack of support of a 6 Fr catheter. A 1.5 x 6 mm balloon was then advanced through an extension catheter and dilated. However, this failed to restore full flow so T-stenting with a BMS was attempted. This corrected the flow and the patient’s chest pain resolved despite a very long ischaemic time. The patient was discharged a few days later with dual antiplatelet therapy (DAPT). Concerns were

171

05/09/2014 10:26

Coronary STEMI raised about the impact of the T stenting solution combined a regular BMS and an MGuard with its dedicated mesh. Angiographic follow-up after six weeks showed TIMI 3 flow in both vessels without signs of restenosis. An OCT showed that the bifurcation was patent, with good apposition of the stent and strut coverage. Also, an improvement of

LV function was observed. In conclusion, MGuard EPS implantation at a complex bifurcation lesion was feasible and improved myocardial perfusion. Importantly, the side branch could be accessed and treated even after MGuard EPS implantation in the main vessel without compromising the acute and long-term results. n

STEMI Demonstrative Cases 5 Acute Anterior Wall Infarction Maarten Vink Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

Dr Maarten Vink, Onze Lieve Vrouwe Gasthuis (Amsterdam, The Netherlands), presented a case of a 68-year-old female with no cardiac history, although she had risk factors including smoking and family history. She was admitted following the acute onset of chest pain and received heparin, aspirin and prasugrel in the ambulance. Angiography revealed a long thrombus-containing lesion in the ostium of the LAD with impairment of flow (TIMI 1). Wiring of the lesion improved the flow and since it was important not to dislodge the thrombus, aspiration was not chosen nor was pre-dilatation.

Instead, direct stenting was performed with an MGuard Prime EPS (3.5 x 28 mm); a long stent was required to cover the thrombus. Immediately afterwards, TIMI 3 flow was achieved and the patient was symptom-free with only a minimal rise in cardiac enzymes. An ECG revealed complete ST resolution after the procedure and no apparent wall motion abnormalities at three months follow up. Dr Vink concluded that there is no need for thrombus aspiration and/or pre-dilatation if the TIMI flow is ≥1 and that the MGuard may allow achievement of fast restoration of flow with minimal use of equipment. n

What is the MGuard Role in Primary PCI Today? Dariusz Dudek Jagiellonian University, Krakow, Poland

Clinical data using the MGuard was first published in 2010.21 At that time, data from the MAGICAL trial in Krakow showed that the use of MGuard EPS implantation during primary PCI for STEMI is safe and is associated with excellent results in terms of myocardial reperfusion parameters. Importantly, no thrombus protrusion was seen with MGuard. The early safety and efficacy of the MGuard stent was maintained during the long-term follow-up (mean follow-up of 38.7 ± 3.1 months).22 In a substudy of the MASTER trial, patients were divided into two groups. Those with symptom onset to balloon time ≤3 hours when thrombus is fresh, and >3 hours. Later presentation of MI showed a bigger difference between MGuard and control in terms of rate of resolution of STEMI and percentage of patients achieving TIMI 3 flow than in earlier

172

InspireMD_SatSym_FINAL.indd 172

Figure 5: Efficacy of the MGuard Stent as a Function of Delay to Reperfusion in ST-elevation Myocardial Infarction – a MASTER Trial Substudy. 70 Rate of complete ST segment resolution (>70 %)

Dr Dariusz Dudek, Jagiellonian University (Krakow, Poland) began by presenting data that show that primary PCI caused a substantial decline of in-hospital mortality due to STEMI between 1960 and 2000.17 However, since then, STEMI mortality has plateaued at around 5 %, suggesting that additional strategies are required.18 The key goals of primary PCI are to restore epicardial flow; to prevent distal embolisation and no reflow; to improve myocardial reperfusion and to reduce infarct size. Recent studies suggest that DES are more beneficial than BMS in STEMI in terms of mortality.19 However, optimal microvascular/myocardial perfusion (TIMI 3 and myocardial blush 2/3) is often not achieved in PCI,8 with detrimental effects on longterm mortality.20

n=20 n=33

n=59

n=102 n=75

n=35 n=48 n=39

40 30 20 10 0

< 120 minutes 120–239 minutes

240–359 minutes

≥ 360 minutes

Symptoms onset to balloon time MGuard stent

Control stent

Source: Dudek et al., 201323

presentation, an effect that becomes more pronounced over time (see Figure 5).22 In conclusion, Dr Dudek recommended that use of a mesh covered stent should be an important component of the decision-making process when a STEMI patient arrives in the catheterisation laboratory and that a combination of a DES, bioresorbable vascular scaffold and mesh covered stent would be desirable. n

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:26

MGuard Embolic Protection Stent

Preliminary Results From the iMOS Prime Registry International MGuard Prime Observational Study – Acute and 30-day Results Giovanni Amoroso Onze Lieve Vrouwe Gasthuis Hospital Amsterdam, The Netherlands

Dr Giovanni Amoroso, OLVG (The Netherlands) began by outlining the advantages of the MGuard Prime EPS, and then outlined a prospective, observational registry study whose objective was to evaluate the clinical performance of the MGuard Prime EPS in ‘real world’ STEMI patients undergoing primary PCI. Inclusion criteria was STEMI diagnosis with indication for primary PCI and reference vessel diameter of 2.75–4.0 mm. Exclusion criteria were cardiopulmonary resuscitation, cardiogenic shock, excessive tortuosity or calcification of the target vessel and side branches >2.0 mm. Baseline characteristics were similar to those in the MASTER trial,3 with baseline TIMI flow of 0/1 in 71.6 % of patients. The mean symptom-toballoon time was quite long: 237.8 min; most patients were preloaded

with clopidogrel (94.8 %) and had undergone aspiration (74.2 %). Procedural success was 100%, without any problems of crossing the lesion or deploying the stent. TIMI flow of 3 was achieved in 91.8 % of patients and complete (>70 %) ST resolution in 76.1 %; these data are similar to those reported in the MASTER trial.3 At 30 days, there was a low incidence of MACE (2.2 %), without any death. In conclusion, this is the first report investigating the use of the MGuard Prime EPS in ‘real world’ patients. Results show that the MGuard Prime EPS has a good safety and efficacy profile. Twelvemonth follow-up, to assess the impact on late MACE and clinical restenosis, is ongoing. n

MASTER II – MGuard Prime Embolic Protection Stent Jose Henriques Academic Medical Center, Amsterdam, The Netherlands

Dr Jose Henriques, Academic Medical Center, (Amsterdam, The Netherlands) presented the Safety and Efficacy Study of MGuard Stent After a Heart Attack II (MASTER II) study. This aims to include 1100 patients with acute MI for >30 minutes and ≤ 12h from symptom onset with >2 mm ST elevation in ≥2 contiguous leads on baseline ECG. Exclusion criteria include left bundle branch block (LBBB), paced rhythm or other ECG abnormality interfering with assessment of ST-segment; current enrolment in another clinical trial that may interfere with the current study endpoint; a previous coronary interventional procedure of any kind within 30 days prior to the procedure; female patients of childbearing potential; subjects undergoing cardiopulmonary resuscitation; cardiogenic shock; the anticipated need for a staged procedure of a target vessel within 12 months or non-target vessel within seven days post-procedure; prior administration of thrombolytic therapy; comorbid conditions that might affect patient compliance with follow-up; concurrent medical condition with a life expectancy of <12 months and a history of cerebral vascular

accident or transient ischaemic attack within the last six months or permanent neurological deficit. A wide variety of stents may be used as control. After coronary angiography, and TIMI 2/3 has been achieved, patients are randomised to the MGuard Prime EPS or BMS/DES. Clinical follow-up is at 30 days, six months and 12 months. Extended follow-up is at two and three years. The primary endpoints are the rate of complete ST-segment resolution (>70 % resolution of the sum of ST elevations in all leads) within 60–90 minutes post-procedure, as well as a composite of allcause mortality or recurrent target vessel MI at 365 days post-procedure. Powered secondary endpoints include infarct size assessed by cardiac MRI in patients with anterior MI and proximal/mid LAD lesions, which is powered for superiority, and in-stent late lumen loss as measured by quantitative coronary angiography at 13 months; this is powered for non-inferiority. n

Summary and Concluding Remarks PCI is the optimal reperfusion modality in patients with acute STEMI and its use has resulted in improved survival in patients with cardiovascular disease. However, PCI often results in suboptimal myocardial perfusion due to embolisation of thrombus and atheromateous debris, which results in increased infarct size and mortality. The MGuard micronet mesh-covered stent prevents from distal embolisation and achieves excellent myocardial flow and

INTERVENTIONAL CARDIOLOGY REVIEW

InspireMD_SatSym_FINAL.indd 173

complete resolution of ST-elevation, even in complicated clinical cases. The clinical trials and registry studies have provided a substantial body of evidence supporting the use of MGuard in primary PCI, with the objective of improving patient outcomes. Following the introduction on MGuard, treatment of acute MI has reached a new level involving a simple device that can be used in daily practice in the catheterisation laboratory. n

173

05/09/2014 10:26

Coronary STEMI 1. Svilaas T, van der Horst IC, Zijlstra F. Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS)--study design. Am Heart J 2006;151:597 e1–e7. 2. Frobert O, Lagerqvist B, Olivecrona GK, et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med 2013;369:1587–97. 3. Stone GW, Abizaid A, Silber S, et al. Prospective, Randomized, Multicenter Evaluation of a Polyethylene Terephthalate Micronet Mesh-Covered Stent (MGuard) in ST-Segment Elevation Myocardial Infarction: The MASTER Trial. J Am Coll Cardiol 2012;. 4. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193–204. 5. InspireMD’s MGuard stent shows lower mortality rate in STEMI patients at twelve months compared to control group. Available at: http://www.inspire-md.com/site_en/inspiremdsmguard-stent-shows-lower-mortality-rate-in-stemi-patientsat-twelve-months-compared-to-control-group/; Date accessed 11 August 2014. 6. Costa RA, Lotan C, Dudek D. et al. Efficacy of embolic protection stent as a function of thrombus size in STEMI patients: a MASTER trial substudy. EuroIntervention 2013;EuroPCR Abstracts 2013. 7. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial

174

InspireMD_SatSym_FINAL.indd 174

infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20. 8. Niccoli G, Burzotta F, Galiuto L, et al. Myocardial no-reflow in humans. J Am Coll Cardiol 2009;54:281–92. 9. Jaffe R, Charron T, Puley G, et al. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention. Circulation 2008;117:3152–6. 10. Henriques JP, Zijlstra F, van ‘t Hof AW, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003;107:2115–9. 11. Abbate A, Kontos MC, Biondi-Zoccai GG. No-reflow: the next challenge in treatment of ST-elevation acute myocardial infarction. Eur Heart J 2008;29:1795–7. 12. Niccoli G, Kharbanda RK, Crea F, et al. No-reflow: again prevention is better than treatment. Eur Heart J 2010;31:2449–55. 13. Fokkema ML, Vlaar PJ, Svilaas T, et al. Incidence and clinical consequences of distal embolization on the coronary angiogram after percutaneous coronary intervention for ST-elevation myocardial infarction. Eur Heart J 2009;30:908–15. 14. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002;23:1112–7. 15. Limbruno U, De Carlo M, Pistolesi S, et al. Distal embolization during primary angioplasty: histopathologic features and predictability. Am Heart J 2005;150:102–8. 16. Gutierrez-Chico JJ, Magro M, Van Geuns RJ, et al. Persistence

of residual thrombus burden after successful primary percutaneous coronary intervention in spite of optimal angiographic result: assessment with optical coherence tomography. Eur Heart J 2010;31 (Suppl 1):Abstract no 1758. 17. Nabel EG, Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med 2012;366:54–63. 18. Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients undergoing primary PCI, N Engl J Med 2013;369:901–9. 19. Siudak Z, Dziewierz A, Rakowski T, et al. Borderline trend towards long-term mortality benefit from drug eluting stents implantation in ST-elevation myocardial infarction patients in Poland-data from NRDES registry. Catheter Cardiovasc Interv 2014;83:436–42. 20. Ndrepepa G, Tiroch K, Fusaro M, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol 2010;55:2383–9. 21. Dudek D, Dziewierz A, Rzeszutko Ł, et al. Mesh covered stent in ST-segment elevation myocardial infarction. EuroIntervention 2010;6:582–9. 22. Dudek D, Dziewierz A, Kleczyński P, et al. Long-term followup of mesh-covered stent implantation in patients with ST-segment elevation myocardial infarction. Kardiol Pol 2014;72:140–5 23. Dudek D, Abizaid A, Silber S, et al. TCT-229 Efficacy of an Embolic Protection Stent as a Function of Symptom Onset to Balloon Time in STEMI: The MASTER Trial. J Am Coll Cardiol 2013;62 (18_S1):B75.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:26

Coronary Bioresorbable Scaffolds

Bioresorbable Scaffolds Sida k pa l Pan a i c h , Th e o d o r e S c h r e i b e r a n d Ci n d y G r i n e s Department of Cardiology, Detroit Medical Center, Michigan, US

Abstract Percutaneous coronary intervention (PCI) has undergone major advances including the evolution in stent technology, from bare metal stents (BMS), to their drug eluting counterparts, to the development of bioresorbable scaffolds (BRS). The primary notion of BRS was to facilitate complete vascular healing and restore normal endothelial function following the resorption of stent scaffold while providing equivalent mechanical properties of a metallic drug eluting stents (DES) in the earlier stages. BRS provide attractive physiologic advancements over the existing DES and have shown promising results in initial clinical studies albeit with small sample sizes. Their use has been primarily restricted to patients recruited in clinical trials with limited real-world applicability. Thus, data from larger randomised control trials is awaited. The major objective of this article is to review the evidence on BRS and identify their clinical applicability in current interventional practice.

Keywords Bioresorbable scaffolds, drug eluting stents, percutaneous coronary intervention Disclosure: The authors have no conflicts of interest to declare. Received: 1 July 2014 Accepted: 15 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):175–9 Correspondence: Cindy Grines, Detroit Medical Center, Cardiovascular Institute, 311 Mack Ave, Detroit, MI 48201, US. E: cgrines@dmc.org

Percutaneous coronary intervention (PCI) is one of the most commonly performed procedures in cardiology. More recently, the limitations of rigid metallic stents have led to the development of bioresorbable scaffolds (BRS). The earliest version of bioresorbable stent developed and tested in humans in 1990 was the Igaki-Tamai stent. It featured a thermal and balloon expandable stent that showed good outcomes at six months1 as well as long-term2 with neointimal hyperplasia similar to bare metal stents (BMS). The use of heat expansion, however, limited the clinical applicability of this device due to concerns of arterial wall necrosis with consequential platelet adhesion and stent thrombosis (ST).3 The development of new generation of BRS with improving mechanical performance is believed by some to be the next evolutionary leap in interventional cardiology. The major objective of this article is to review the evidence on BRS and identify their clinical applicability in current interventional practice.

Problems With Metallic Stents and the Benefits of Bioresorbable Scaffolds In earlier days of balloon angioplasty, the adverse coronary vessel remodelling secondary to neointimal proliferation and extracellular matrix deposition as well as vessel recoil led to high restenosis rates.4,5 This early luminal loss was largely overcome by development of BMS that avoided vessel recoil and constrictive effects of vessel remodelling as well as any coronary flow impairment due to local dissections.6,7 However, the neointimal proliferative reaction to foreign body (metallic stent) resulted in greater intimal proliferation.8 The volume of neointimal proliferation was improved by introduction of drug eluting stents (DES) with anti-proliferative agents bound to stent polymers.9 Despite extensive literature on reduced revascularisation rates with DES, there have been multiple reports and safety concerns regarding occurrence of late and very late ST with DES.10 It was thought to be due to delayed and at times incomplete endothelialisation.

Grines_FINAL.indd 175

This was a result of chronic inflammation from hypersensitivity reaction to the metallic stent and/or the durable polymers, which attenuates vascular healing.11–13 The presence of drug elution and a metallic stent are also believed to interfere with endothelial function. 14,15 In addition, the persistent metallic scaffolding would subsequently limit expansive remodelling of the coronary artery. Loss of cyclic strain relief and protruding struts with resultant abnormal shear stress and strut fracture are other potential reasons for late cardiac events. The primary notion of BRS was to facilitate complete vascular healing and restore normal endothelial function while providing equivalent mechanical properties of a metallic DES in the earlier stages (see Table 1). This was confirmed in recent imaging studies that demonstrated complete scaffold resorption and positive vessel remodelling. It was further accompanied by increase in luminal dimensions (plaque regression) and improved vasomotor function on drug (acetylcholine, nitroglycerin) testing.16 The incidence of late recurrence of residual anginal symptoms is high in patients who receive metallic DES; thus future trials are being designed to study the benefit of BRS in reducing residual angina symptoms.17 The complete disappearance of stent further appears attractive in plausibly eliminating the incidence of late and very-late ST. This could possibly shorten the duration of dual antiplatelet therapy (DAPT) and consequently reduce bleeding complications. The resorption of scaffolds would also plausibly avoid any hindrance from previous metal prosthesis during future interventions including placement of a bypass graft if needed in the future. Additionally, this could avoid problems associated with poorly aligned platforms or those blocking the side-branches.3 This is especially valuable in multivessel disease requiring multiple stent implantations. Indeed, > 100 mm of stent was implanted in the Synergy between PCI with taxus and cardiac surgery

175

05/09/2014 11:23

Coronary Bioresorbable Scaffolds Table 1: Strengths and Weaknesses of Bioresorbable Scaffolds (BRS) Strengths 1. Restore normal vascular physiology including normal endothelial function, vasomotion demonstrated on drug testing and return of adaptive shear stress. 2. Late luminal enlargement demonstrated on various imaging studies. Plaque Regression.

superior vessel wall support due to better strut distribution.28 A sixmonth analysis of this device in the ABSORB Cohort B trial showed encouraging results with late luminal loss of 0.19 mm, which is comparable to many current generation DES. The MACE rate was noted to be 10 % at three years without any scaffold thrombosis. In another substudy from Cohort B trial, the circumferential neointimal tissue growth did not cause any luminal compromise between six months and two years using OCT.25

3. Potential reduction in late stent thrombosis and duration of dual anti-platelet therapy. 4. Elimination of any permanent cage with no hindrance to future interventions including bypass grafts. 5. Improved subsequent coronary imaging using multislice CT and MRI without artifacts. 6. Alleviate any patient concerns regarding permanent metal implant in their bodies. Weaknesses 1. Limited evidence in complex lesions like bifurcation lesions. 2. Thick scaffolds (>150 μm) with limited expansion. 3. Difficult delivery in heavily calcified lesions due to high profile mandating lesion preparation. 4. Accurate sizing of the stent requires imaging quantitative coronary angiography (QCA). 5. High Cost.

(SYNTAX) trial in more than one-third of the enrolled patients.18 The DES are known to produce a “blooming artifact” on coronary computed tomography (CT) angiograms that could result in underestimation of intra-stent luminal diameter due to thickened appearance of the stent struts.19,20 The BRS without any metal would thus afford the benefit of allowing better subsequent coronary imaging using multislice computerised tomography (CT) and magnetic resonance imaging (MRI) without artifacts.21 Furthermore, BRS can be intuitively thought of as drug reservoirs for local delivery due to their modifiable resorption rates.3 Lastly, bioresorbable stents would eradicate any patient concerns regarding permanent metal implant in their bodies.22

Bioresorbable Scaffolds Table 2 shows the currently available BRS being tested in clinical trials. Poly L-lactic acid (PLLA) is the most commonly used material in BRS. PLLA is metabolised into carbon dioxide and water over a period of time (12–18 months), which is subsequently phagocytosed by the macrophages.23 ABSORB Bioabsorbable Vascular Scaffold (BVS) with a PLLA backbone releasing everolimus is the most widely investigated and the only approved bio-absorbable device (for de novo coronary lesions 2.0–3.8 mm in diameter).24 ABSORB Cohort A was an openlabel, prospective study of 30 patients with single de-novo lesions, which revealed acute recoil and late loss of scaffold area (-11.8 %) as measured by intravascular ultrasound (IVUS) (corresponding angiographic in-stent loss of 0.44 mm) at six months.23 A follow-up study at two years using IVUS and optical coherence tomography (OCT) showed complete stent resorption, late luminal enlargement and absence of constrictive remodelling.25 Importantly, there was no incidence of ST at three years of follow-up and only one major adverse cardiac event (MACE) was reported at six months with no additional events at three years and five years of follow-up.26,27 Early recoil observed in the ABSORB study led to Revision 1.1 with modifications allowing for a longer duration of radial support. This iteration is believed to allow more uniform drug delivery along with

176

Grines_FINAL.indd 176

The results of the large-scale non-randomised, single-arm trial evaluating the second iteration of the ABSORB BVS (ABSORB EXTEND) in ~1000 patients with longer lesions are expected in 2015. The preliminary results from 512 enrolled patients were noted to be promising with low ischaemia driven MACE and target vessel revascularisation (TVR) rates at 4.3 % and 4.9 % respectively at 12 months.29 In another randomised, single blind trial (ABSORB II), the ABSORB BVS will be tested against the everolimus DES, XIENCE.30 The ABSORB III trial is a non-inferiority trial (n~2,250) to evaluate one-year target lesion failure powered for non-inferiority against the XIENCE DES in subjects with up to two de novo native coronary artery lesions. In a second part of this trial (ABSORB IV), additional 3,000 patients would be recruited to study the primary end-point of patient reported angina at one-year and target lesion failure between 1–5 years.17 Results from separate randomised, non-inferiority trials comparing the safety and effectiveness of the ABSORB BVS in Japanese (ABSORB JAPAN) and Chinese (ABSORB CHINA) populations to the metallic XIENCE DES in ischaemic heart disease subjects are also awaited.31,32 Few clinical studies have evaluated the efficacy of ABSORB BVS in real-world practice. BVS were met with good in-hospital outcomes in the Polish absorb registry (POLAR) in patients with acute coronary syndrome (ACS) study with no mortality, myocardial infarction (MI) or ST reported in 88 patients enrolled.33 In another non-randomised study, patients presenting with acute coronary syndrome (ACS) underwent BVS (n=150) implantation and were compared with controls receiving DES (n=103). Thirty-day and six-month MACE rates were noted to be similar between the two groups.34 BVS also showed promise with similar clinical outcomes as patients receiving DES in the PRAGUE-19 registry when used for primary PCI in ST elevation myocardial infarction (STEMI) other than calcified and tortuous lesions.35 The results of an ongoing randomised trial (ABSORB STEMI: TROFI II study) designed to compare the neointimal healing score at six months in STEMI patients treated with ABSORB BVS and XIENCE DES are awaited.36 The first Poly (iodinated desaminotyrosyl-tyrosine ethyl ester) carbonate stent or REVA stent was met with high rate of target vessel revascularisation (TLR) secondary to mechanical failures.37 A redesigned version (ReZolve) with a more robust polymer with a sheathed delivery system (limiting its use in smaller vessels) was developed, which was again modified into ReZolve2 with a lower profile and sheathless delivery system being evaluated in the ongoing pilot study of the ReZolve™ airolimus-eluting bioresorbable coronary stent (RESTORE) trial.38 Although safety and radial strength of another bioresorbable stent, the IDEAL Poly (anhydride ester) salicylic acid stent39 were demonstrated in a 12-month follow up of a small (n=11) number of patients, the neointimal suppression was deemed to be insufficient due to low dose and rapid elution of sirolimus.40 A revised version with higher dose of sirolimus and optimised stent design with thinner struts is undergoing pre-clinical trials.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:23

Bioresorbable Scaffolds

Table 2: Bioresorbable Stents Being Currently Tested in Clinical Trials Device BRS Clinical Trial Scaffold Company Material

Anti - Absorption Luminal Loss Target Vessel Outcomes proliferative Time (mm) Revascularisation (%) Drug (TVR) (%)

Kyoto

None

Igaki-Tamai

Medical

Igaki-Tamai FIM

Poly L-lactic

(n=15+50)

acid (PLLA)

Two years

Six month: 0.91 Six month: 10.5 Three year: 0.59 10 year: 28

10 year: Patients free of all-cause

mortality, cardiac

mortality, MACE: (87,

98, 50 respectively)

Abbott

BVS Revision ABSORB

Six month: 0.44 Six month: 0

Five year MACE: 3.4

Vascular

1.0

Six month: 0.19 Three year: 0

Two year MACE: 8.9

PLLA

Everolimus

Two years

Cohort A

(n=30)

One year: 3.6

MACE:

BVS Revision ABSORB

Six month*: 0.6

Six month*: 3

1.1

12 month*: 4.9

12 month*: 4.3

Cohort B

(n=101)

ABSORB

Results Awaited

EXTEND (n=800*)

ABSORB II

RCT (n=501)

ABSORB III/IV

(n ~2000/5000)

ABSORB Japan

and ABSORB

China (n~400 for

both) Elixir

DESolve

DESolve-I FIM

PLLA

Myolimus

Six month: 0.19 12 month: 0.06

12 month MACE: 0.2

Six month: 1.81 six month: 66.7

N/A

(n=15) Reva Medical Reva Stent

Reva FIM/RESORB

Poly

None

ReZolve

(n=27)

(iodinated

Sirolimus

Stent RESTORE

desaminotyrosyl

ReZolve2

(n=22)

-tyrosine

RESTORE**

ethyl ester)

Two years

12 month (n=8/22): 0.2

carbonate Biotronik

AMS-I

PROGRESS AMS

Magnesium

None

< Four months Four month: 1.08 Four month: 24

Four month MACE:23.8

DREAMS-I

(n=63)

Alloy

Paclitaxel

> Four months Six month: 0.64 One year: 45

Single MI reported

BIOSOLVE-I

Six month: 4.3

(n=46)

12 month: 7

BTI/

IDEAL Gen 1 Whisper FIM

Poly (anhydride Sirolimus

Xenogenics

IDEAL Gen 2

ester) salicylic

chronic recoil

acid

noted suppression

(n=11)

six months

No acute or

No TVR

in 12 months Insufficient neointimal

*Ongoing Trial with projected sample size; preliminary data presented from 512 patients. **Ongoing trial designed to include modification of the ReZolve stent with sheathless delivery; MACE = major adverse cardiovascular events; TVR = Target vessel revascularization; FIM = First in-man; BRS = Bioresorbable Scaffold; BVS = Bioabsorbable Vascular Scaffold. Adapted from Garg and Serruys.38

The initial iterations of non-drug eluting magnesium based absorbable scaffolds were met with disappointing results. The TVR rates were 39.7Â % at four months and 45Â % at 12 months due to both neointimal hyperplasia and recoil in the Clinical performance angiographic results of coronary stenting with absorbable metal stents (PROGRESS) AMS study.41 BIOSOLVE-I was the in-man trial to evaluate the efficacy of first paclitaxel-eluting absorbable magnesium based metal scaffold drug-eluting absorbable metal scaffold (DREAMS). It demonstrated similar TVR rates as contemporary DES and everolimus-eluting BRS though it did not match the late lumen results noted with either platform.42

The Pitfalls and Challenges Most of the existing literature on BRS is limited to their utility in simple Type A lesions. The interventionalists thus remain skeptical regarding their applicability in complex lesions more commonly encountered in real world practice. The delivery of BRS in calcified and complex lesions is relatively difficult given the stent size and strut

INTERVENTIONAL CARDIOLOGY REVIEW

Grines_FINAL.indd 177

thickness. A recent study reported higher strut malapposition with BRS used in fibrocalcific plaques.43 Additionally, the relatively lower radial strength of BRS could plausibly limit their expansion in heavily calcified lesions. Given the high profile of these scaffolds, adequate lesion preparation with rotablation or noncompliant scoring balloons might be obligatory to expand their use in complex lesions per some authors.44 Indeed, the limited expansion of BRS precludes aggressive post-dilation, which makes adequate lesion preparation and vessel sizing imperative. Improved BRS expansion has been previously noted following 1:1 balloon:vessel pre-dilation.43 The restricted distensibility of everolimus-eluting BRS may require IVUS, OCT or quantitative coronary angiography (QCA) for precise measurement of maximal distal and proximal coronary luminal reference diameters (Dmax) to accurately size the stent and thus avoid over or undersizing of the device with subsequent incomplete strut apposition.24,45 The chronic scaffold recoil noted with ABSORB Version 1.0 in Cohort A trial occurs secondary to loss of radial strength during resorption

177

05/09/2014 11:23

Coronary Bioresorbable Scaffolds and is not observed with non-absorbable DES. Likewise, the in-vivo resorption of the scaffold and its mechanical strength do not have a linear relationship.38 This might make the decline in device’s mechanical performance with minimal resorption or changes in stent mass unpredictable. Conversely, the DREAMS magnesium based scaffold showed better conformability with superior strut apposition in the BIOSOLVE-I trial though with other limitations noted above.42 The other notable limitation of polymer (PLLA) based BRS is the lack of radio-opacity, which obligates the use of radioopaque markers.

Special Populations and Future Directions Besides long calcified lesions, data is also sparse for use of BRS in treatment of in-stent restenosis (ISR). The BRS might prove attractive for ISR and avoid multiple metallic layers of scaffolds and polymers in a coronary artery thereby plausibly reducing chronic inflammation and neointimal hyperplasia.46 Likewise, clinical studies have neither included bifurcation lesions with side branches ≥ 2 mm in diameter, evaluated the “kissing balloon” technique nor is there sufficient data to recommend the use of BRS in chronic total occlusions or coronary artery bypass grafts.24 Furthermore, BRS will need critical analysis in various higher risk subgroups including diabetics, elderly as well as individuals presenting with ACS in larger sample size studies with longer prospective followups. In a propensity match analysis of ABSORB BRS (from Cohort B and Extend Trials) and everolimus DES (from SPIRIT trials), no significant difference in outcomes was noted amongst diabetic patients treated with either platform.47

scaffold should provide protection against negative remodelling for at least six months though this merits further confirmation. The current generation of DES has demonstrated improved outcomes with especially reduced rates of both late and very late ST.49 Indeed, emerging literature involving recent post-hoc analysis of pooled data from major trials demonstrated no adverse thrombotic events after earlier discontinuation of DAPT. This poses several questions for emerging technology as BRS including feasibility of designing adequately powered trials to prove the superiority of BRS over currently available DES.50 Whether BRS would further reduce DAPT requirements, lower stent fracture complications and even improve coronary vasomotor function over long term remains to be demonstrated in larger clinical and in-vivo physiological studies. Future pre-clinical studies focused on extensively studying pathophysiological underpinnings of BRS mechanisms are imperative. Furthermore, the real clinical implications of vasomotor restoration phenomenon would need further evaluation. Of note, the various physiological benefits of BRS are not expected until late (likely after first year) and thus longer follow-ups would be needed to elucidate favourable contributions over their metallic counterparts. Indeed, in a recent serial tomographic evaluation of BRS form ABSORB Cohort B, the in-scaffold loss was noted to be stable after one year in contradistinction to everolimus stent from SPIRIT II trial (increase from 0.17 mm at six months to 0.33 mm at years years).51,52 This was accompanied by significant luminal enlargement between one and three years (6.35 mm2 at one year and 6.81 mm2 at three years, p < 0.001) in case of BRS.16

Conclusion The pace of scaffold resorption can vary depending on the PLLA manufacturing process. Thus, every device needs to be tested appropriately for in-vivo biocompatibility. This is important since previously published literature has demonstrated the influence of scaffold’s molecular weight on the degree of inflammation,48 which could further influence the neointimal response. Additionally, with varying absorption times, the ideal resorption duration of scaffolding remains to be elucidated. On the basis of previously published IVUS study that showed negative vascular remodelling for up to six months8 an ideal

1. Tamai H, Igaki K, Kyo E, et al. Initial and six-month results of biodegradable poly-l-lactic acid coronary stents in humans. Circulation 2000 Jul 25;102(4):399–404. 2. Nishio S, Kosuga K, Igaki K, et al. Long-Term (>10 Years) clinical outcomes of first-in-human biodegradable poly-llactic acid coronary stents: Igaki-Tamai stents. Circulation 2012 May 15;125:2343–53. 3. Onuma Y, Serruys PW. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation 2011 Feb 22;123:779–97. 4. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987 Mar 19;316:701–6. 5. Nobuyoshi M, Kimura T, Nosaka H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988 Sep;12:616–23. 6. Luo H, Nishioka T, Eigler NL, et al. Coronary artery restenosis after balloon angioplasty in humans is associated with circumferential coronary constriction. Arterioscler Thromb Vasc Biol 1996 Nov;16:1393–8. 7. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994 Aug 25;331:496–501. 8. Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996 Sep 15;94:1247–54. 9. Sousa JE, Costa MA, Abizaid A, et al. s-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound

178

Grines_FINAL.indd 178

BRS offer an attractive theoretical advantage in absolution of late and very-late stent thrombosis. Despite promising clinical outcomes compared to existing DES, their use has been primarily restricted to patients recruited in clinical trials with strict eligibility criteria. Larger comparative trials with critical safety and efficacy analysis of newer BRS with improving designs and biomechanical properties are nearing completion. We eagerly await these results before the widespread use of BRS can be recommended, especially considering improving technology and outcomes with third generation metallic DES. n

study. Circulation 2001 Jan 16;103:192–5. 10. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007 Sep 15;370:937–48. 11. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006 Jul 4;48:193–202. 12. Stefanini GG, Kalesan B, Serruys PW, et al. Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year followup of a randomised non-inferiority trial. Lancet 2011 Dec 3;378:1940–8. 13. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008 Sep 30;52:1134–40. 14. Togni M, Windecker S, Cocchia R, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 2005 Jul 19;46:231–6. 15. Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur Heart J 2006 Jan;27:166–70. 16. Serruys PW, Onuma Y, Dudek D, et al. Evaluation of the second generation of a bioresorbable everolimus-eluting vascular scaffold for the treatment of de novo coronary artery stenosis: 12-month clinical and imaging outcomes. J Am Coll Cardiol 2011 Oct 4;58:1578–88. 17. ABSORB III Randomized Controlled Trial (RCT) (ABSORB-III) . Abbott Vascular; [cited 2014 Jun 23]; Available from: http:// www.clinicaltrials.gov/show/NCT01751906. 18. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous

coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009 Mar 5;360:961–72. 19. Mahnken AH. CT Imaging of Coronary Stents: Past, Present, and Future. ISRN Cardiol 2012;2012:139823. 20. Spuentrup E, Ruebben A, Mahnken A, et al. Artifact-free coronary magnetic resonance angiography and coronary vessel wall imaging in the presence of a new, metallic, coronary magnetic resonance imaging stent. Circulation 2005 Mar 1;111:1019–26. 21. Erbel R, Bose D, Haude M, et al. [Absorbable coronary stents. New promising technology]. Herz2007 Jun;32:308–19. 22. Ormiston JA, Serruys PW. Bioabsorbable coronary stents. Circ Cardiovasc Interv 2009 Jun;2:255–60. 23. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008 Mar 15;371:899–907. 24. Rzeszutko L, Depukat R, Dudek D. Biodegradable vascular scaffold ABSORB BVS - scientific evidence and methods of implantation. Postepy Kardiol Interwencyjnej 2013;9:22–30. 25. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet 2009 Mar 14;373:897–910. 26. Onuma Y, Serruys PW, Ormiston JA, et al. Three-year results of clinical follow-up after a bioresorbable everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB trial. EuroIntervention 2010 Sep;6:447–53. 27. Onuma Y, Dudek D, Thuesen L, et al. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:23

Bioresorbable Scaffolds

polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. JACC Cardiovasc Interv 2013 Oct;6:999–1009. 28. Okamura T, Garg S, Gutierrez-Chico JL, et al. In vivo evaluation of stent strut distribution patterns in the bioabsorbable everolimus-eluting device: an OCT ad hoc analysis of the revision 1.0 and revision 1.1 stent design in the ABSORB clinical trial. EuroIntervention 2010 Apr;5:932–8. 29. Abizaid A, Costa JR, Jr., Bartorelli AL, et al. The ABSORB EXTEND study: preliminary report of the twelve-month clinical outcomes in the first 512 patients enrolled. EuroIntervention 2014 Apr 29. 30. Diletti R, Serruys PW, Farooq V, et al. ABSORB II randomized controlled trial: a clinical evaluation to compare the safety, efficacy, and performance of the Absorb everolimus-eluting bioresorbable vascular scaffold system against the XIENCE everolimus-eluting coronary stent system in the treatment of subjects with ischemic heart disease caused by de novo native coronary artery lesions: rationale and study design. Am Heart J 2012 Nov;164:654–63. 31. A Clinical Evaluation of Absorb™ Bioresorbable Vascular Scaffold (Absorb™ BVS) System in Chinese Population ~ ABSORB CHINA RCT. Abbott Vascular; [cited 2014 Jun 23]; Available from: http://www.clinicaltrials.gov/ct2/show/ NCT01923740. 32. AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 (Absorb™ BVS) in Japanese Population (ABSORB JAPAN). Abbott Vascular; [cited 2014 Jun 23]; Available from: http://clinicaltrials.gov/show/NCT01844284. 33. Dudek D, editor POLAR ACS: bio-absorbable platform in acute coronary syndromes. euroPCR; 2013; Paris, France. 34. Simsek C, Magro M, Onuma Y, et al. Procedural and clinical outcomes of the Absorb everolimus-eluting bioresorbable vascular scaffold: one-month results of the Bioresorbable

INTERVENTIONAL CARDIOLOGY REVIEW

Grines_FINAL.indd 179

vascular Scaffold Evaluated At Rotterdam Cardiology Hospitals (B-SEARCH). EuroIntervention 2013 Sep 4. 35. Kocka V, Maly M, Tousek P, et al. Bioresorbable vascular scaffolds in acute ST-segment elevation myocardial infarction: a prospective multicentre study ‘Prague 19’. Eur Heart J 2014 Mar;35:787-794. 36. ABSORB STEMI: the TROFI II Study. ECRI bv; [cited 2014 Jun 23]; Available from: http://clinicaltrials.gov/show/ NCT01986803. 37. Pollman MJ. Engineering a bioresorbable stent: REVA programme update. EuroIntervention 2009 Dec 15;5 Suppl F:F54–7. 38. Garg S, Serruys PW. Coronary stents: looking forward. J Am Coll Cardiol 2010 Aug 31;56(10 Suppl):S43–78. 39. Jabara R, Pendyala L, Geva S, et al. Novel fully bioabsorbable salicylate-based sirolimus-eluting stent. EuroIntervention 2009 Dec 15;5 Suppl F:F58–64. 40. Jabara R. Poly-anhydride based on salicylic acid and adipic acid anhydride. EuroPCR ; 2009. 41. Erbel R, Di Mario C, Bartunek J, et al. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, non-randomised multicentre trial. Lancet 2007 Jun 2;369:1869–75. 42. Haude M, Erbel R, Erne P, et al. Safety and performance of the drug-eluting absorbable metal scaffold (DREAMS) in patients with de-novo coronary lesions: 12 month results of the prospective, multicentre, first-in-man BIOSOLVE-I trial. Lancet 2013 Mar 9;381:836–44. 43. Brown AJ, McCormick LM, Braganza DM, et al. Expansion and malapposition characteristics after bioresorbable vascular scaffold implantation. Catheter Cardiovasc Interv 2014 Jul 1;84:37–45. 44. Basavarajaiah S, Naganuma T, Latib A, Colombo A. Can bioabsorbable scaffolds be used in calcified lesions? Catheter Cardiovasc Interv 2013 Apr 16.

45. Gomez-Lara J, Diletti R, Brugaletta S, et al. Angiographic maximal luminal diameter and appropriate deployment of the everolimus-eluting bioresorbable vascular scaffold as assessed by optical coherence tomography: an ABSORB cohort B trial sub-study. EuroIntervention 2012 Jun 20;8:214–24. 46. Ielasi A, Latib A, Naganuma T, et al. Early results following everolimus-eluting bioresorbable vascular scaffold implantation for the treatment of in-stent restenosis. Int J Cardiol 2014 May 15;173:513–4. 47. Muramatsu T, Onuma Y, van Geuns RJ, et al. One-Year Clinical Outcomes of Diabetic Patients Treated With Everolimus-Eluting Bioresorbable Vascular Scaffolds: A Pooled Analysis of the ABSORB and the SPIRIT Trials. JACC Cardiovasc Interv 2014 Apr 10. 48. Lincoff AM, Furst JG, Ellis SG, et al. Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol 1997 Mar 15;29(4):808–16. 49. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012 Apr 14;379:1393–402. 50. Dauerman HL. The magic of disappearing stents. J Am Coll Cardiol 2011 Oct 4;58:1589–91. 51. Claessen BE, Beijk MA, Legrand V, et al. Two-year clinical, angiographic, and intravascular ultrasound follow-up of the XIENCE V everolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the SPIRIT II trial. Circ Cardiovasc Interv 2009 Aug;2:339–47. 52. Ormiston JA, Serruys PW, Onuma Y, et al. First serial assessment at 6 months and 2 years of the second generation of absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study. Circ Cardiovasc Interv 2012 Oct;5:620–32.

179

05/09/2014 11:23

Coronary Drug Eluting Stents

Cre8™ Unique Technology in Challenging Daily Practice P roc eeding s of a sa tellite sym p o s i u m h e l d a t E u r o PCR o n 2 0 t h – 2 3 r d M a y 2 0 1 4 i n Pa ris K a trina Mou n t f o r t , M e d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y R ev iewed for a c c ura c y b y : D a v i d A n t o n i u c c i , 1 R o x a n a M e h ra n , 2 G i u s e p p e D e L u c a , 3 Holg er Ne f, 4 M a t h i a s V r o l i x 5 a n d A h m e d K h a s h a b a 6 1. Careggi Hospital, Firenze, Italy; 2. Mount Sinai Hospital, New York, US; 3. Azienda Ospedaliera-Universitaria “Maggiore della Carità”, Novara, Italy; 4. University Hospital Giessen, Giessen, Germany; 5. Ziekenhuis Oost Limburg, Genk, Belgium; 6. Al Dorrah Heart Care Hospital.Cairo, Egypt

Abstract The use of drug-eluting stents (DES) has improved clinical outcomes in percutaneous coronary intervention (PCI) procedures. However, first-generation DES were associated with safety concerns arising from the persistence of durable polymers, including late stent thrombosis. The Cre8™ DES is a novel polymer-free stent designed to overcome these issues. In a presentation at EuroPCR 2014, two clinical cases were discussed. The first was a case of high bleeding risk; the second was the case of multivessel disease with a significant risk of stent restenosis. Together, these cases illustrated the complexity of decision-making in PCI in daily practice. In both cases, the Cre8™ DES offered a safe and effective solution to these challenging cases.

Keywords Percutaneous coronary intervention, polymer-free drug eluting stent Disclosure: The reviewers have no conflicts of interest to declare. Received: 31 July 2014 Accepted: 7 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):180–3 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. E: katsmountfort@virginmedia.com

The use of coronary artery stents was first described in 1986, and percutaneous coronary intervention (PCI) involving stenting is now routine practice. However the problem of restenosis, caused by neointimal tissue growth, led to the development of drug-eluting stents (DES), which allow controlled release of antiproliferative drugs at the arterial wall.1 The use of DES has significantly improved clinical outcomes compared to bare metal stents (BMS).2,3 But safety issues emerged with the use of DES. These were late stent thrombosis due to delayed arterial healing of the stented segment, characterised by inflammation at the stent site with uncovered stent struts.4 This is caused by the persistence of durable polymers used in first generation DES. Once the drug is fully eluted, the polymers continue to interact with the vascular endothelium. Stent technology continues to evolve, and the development of secondgeneration DES with novel or biodegradable polymer coatings and/ or bioabsorbable struts has improved the safety profile of DES.5 A symposium, chaired by David Antoniucci and Roxana Mehran, at EuroPCR

on 23rd May 2014 in Paris focussed on the Cre8™ DES (Alvimedica), a novel polymer-free stent designed to address the issues associated with early DES use (see Figure 1). The Cre8 features a polymer-free structure to reduce the risk of inflammation associated with durable polymers and the breakdown products of absorbable biopolymers. A drug delivery system, Abluminal reservoir technology, utilises a formulation of sirolimus and a fatty acid (Amphilimus™) that enhances bioavailability and drug distribution to the entire vessel wall (see Table 1). In addition, the bio inducer surface, a second-generation integral pure carbon coating, is designed to accelerate stent endothelialisation and strut coverage that reduces the risk of thrombosis. The NEXT clinical trial demonstrated the efficacy and safety of Cre8,6 and has suggested that this DES may be useful in cases with complex anatomy. This symposium aimed to demonstrate the use of Cre8 in patients with dual antiplatelet therapy constraints, to review the clinical issues related to patients undergoing PCI at high risk of restenosis and to understand PCI strategies for the above patients, through the discussion of two case studies. n

Case Presentation 1 PCI in a Patient with Dual Antiplatelet Therapy Constraints Professor Ahmed Khashaba of Ain Shams University in Cairo, Egypt, presented a case of a 45-year-old man with multiple cardiovascular (CV) risk factors; a smoker for 22 years, hypertension for five years and noninsulin-dependent diabetes for two years, with glycated

180

Cre8_SatSym_FINAL.indd 180

haemoglobin levels (HbA1c) of 7.1 percent. He also had chronic liver disease and bleeding oesophageal varices treated by endoscopic variceal ligation three weeks previously. He presented with a non-ST elevation myocardial infarction (NSTEMI). An electrocardiogram (ECG)

05/09/2014 10:39

Cre8™ Unique Technology in Challenging Daily Practice

showed an infero-lateral ST depression and T-wave changes. Troponin testing was positive, and haemoglobin (Hb) levels were 9.9, indicating anaemia. The patient appeared to have a simple lesion – varifocal stenosis in the right coronary artery (RCA) followed by a mobile small thrombus in the RCA. Several issues needed addressing regarding the treatment of this patient. The interventional strategy was the selection of stent technology; DES, BMS, bio active stent (BAS) or bioresorbable scaffold (BVS); the intra-procedural adjunctive pharmacotherapy and the post-procedural dual antiplatelet therapy (DAPT) strategy. Two interventional cardiologists were invited to discuss how they would treat this patient. Professor Giuseppe de Luca of Eastern Piedmont University in Novara, Italy, highlighted the high risk of bleeding complications in this patient. Major bleeding is an important cause of mortality in PCI procedures and is associated with a number of adverse effects, including stent thrombosis (see Figure 2). An observational cohort study found that discontinuation of DAPT was a major determinant of stent thrombosis within the first six months following treatment with DES.7 The highest negative impact of DAPT discontinuation was observed within seven days of discontinuation. For patients with high risk of bleeding complications, several potential strategies are available – balloon angioplasty, drug-eluting balloon (DEB), BMS or a pro-healing stent such as Genous or Avantgarde. In addition, the reason for DAPT cessation has an impact on cardiovascular risk. Cessation may result from discontinuation resulting from physician recommendation, interruption for surgery followed by resumption of DAPT within 14 days, or disruption due to bleeding or noncompliance. The patterns of nonadherence to anti-platelet regimens in stented patients (PARIS) registry found that the hazard ratio for stent thrombosis was 0.39 following discontinuation (p=0.137); 0.64 following interruption (p=0.664) and 2.58 following disruption (p=0.013). The early risk for stent thrombosis due to disruption was substantial – a hazard ratio of 15.94 at 0–7 days (p=<0.001). The effect was attenuated over time.8 Since this patient is therefore at high risk for stent restenosis, the Cre8 DES represents an attractive compromise between the risk of major bleeding and the risk of stent restenosis. In addition, the patient is young and may have multivessel disease, therefore an aggressive treatment strategy is warranted. Professor De Luca therefore recommended the following – pretreatment with DAPT (aspirin and clopidogrel 300 mg), PCI using a radial approach, fractional flow reserve (FFR) of the left anterior descending artery (LAD) to determine the degree of stenosis, administration of heparin, thrombectomy if required and direct stenting with Cre8, followed by postprocedural protamine and DAPT for three months. Dr Holger Nef of the University of Giessen, Germany then provided his opinion on how he would treat the patient. Firstly, he made the observation that this is not a case of 1-vessel disease, the RCA is clearly stenosed but there may be intermediate stenosis of the left coronary artery (LCA), which may not have been detected by visual assessment. Dr Nef emphasised the limitations of visual assessment – in a study in which four experienced visual interventional cardiologists compared their visual assessment of lesions to FFR measurements, the experts classified lesions correctly only in approximately 50 % of cases each.9 Dr Nef considered that we have insufficient information about the lesions and need to see more. He therefore recommended FFR in the ramus circumflex (RCX). The FAME II clinical trial indicated that

INTERVENTIONAL CARDIOLOGY REVIEW

Cre8_SatSym_FINAL.indd 181

Figure 1: Features of the Cre8™ Drug-eluting Stents

Polymer-free platform

Abluminal Reservoir Technology

Amphilimus™ Formulation: BIS: Bio Inducer Surface Sirolimus + organic acid

Table 1: Properties of the Amphilimus™ Technology Specific properties/contributions m-Tor inhibitor drug

Organic acid (Amphiphilic carrier)

• Immunosuppressant

• Sustained drug elution timing

• Anti-proliferative action

• Modulated drug bioavailability

• Anti-microbial

• Raised homogeneous drug distribution

• Inhibitor of inflammatory cell

• Enhanced drug stability

activities

Figure 2: Problems Associated with Major Bleeding Risk During Percutaneous Coronary Intervention Major Bleeding

Hypotension

Cessation of ASA/Clop

Transfusion

Ischemia

Stent Thrombosis

Inflammation

Mortality ASA = Aspirin; Clop = clopidogrel

FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, is the optimal strategy in stable coronary artery disease (CAD).10 In terms of the choice of stent, the use of a stent that is too short may damage the necrotic core, therefore intravascular imaging is needed. Two other factors should be taken into account; the patient has diabetes, a predictor of in-stent restenosis,11 and also is at a high risk of bleeding. The Zotarolimus-eluting Endeavour sprint stent in Uncertain DES candidates (ZEUS) trial, an open-label randomised clinical trial involving 1,600 individuals, aims to assess whether the use of DES, followed by DAPT, is superior to BMS.12 Outcomes at one year show that major adverse cardiac events (MACE) are lower for patients implanted with a DES compared with a BMS, with less target vessel revascularisation in the DES group and no difference in bleeding events between the two groups.13 Dr Nef recommended the following – clarification of the significance of the lesions in all vessels using FFR, use of intravascular imaging,

181

05/09/2014 10:39

Coronary Drug Eluting Stents implantation of a DES and treatment with DAPT (aspirin and ticagrelor) for as long as needed but as short as necessary, not longer than six months. Professor Khashaba returned to describe how he actually treated this patient. The major difficulty in this case was balancing the risk of bleeding against the risk of thrombosis and restenosis. The bleeding risk was calculated as a HAS-BLED score of four and a Glasgow-Blatchford gastrointestinal bleeding score of 10, indicating a high risk of bleeding. Risk factors for thrombosis/restenosis included the NSTEMI, visible thrombus, diabetes and a long atheroma. However this was in a large vessel (4 mm) with good distal vessel flow. The options were therefore balloon angioplasty, a BMS or a DES. In a patient with such a high bleeding risk, a stent needs to provide the safety of a BMS with the efficacy of a DES. The Cre8 DES (4.00 x 31 mm) was then chosen because of its decreased risk of stent thrombosis.14 The patient was kept only on aspirin because the risk of bleeding from the upper gastrointestinal tract is higher with clopidogrel. Following stent implantation, the patient did very well, with no recurrence of variceal bleeding and a correction of anaemia.

However, 15 weeks later he experienced accelerating angina and anterior dynamic T-wave changes. A lesion in the LAD was detected, and a second Cre8 DES was implanted. FFR would have given this information prior to the initial procedure. A BMS was not considered appropriate because of the evidence of disease progression and the risk of restenosis. The risk of rebleeding was now low and the decision to use clopidogrel passed by a gastroenterologist. The risk of thrombosis was high because of the unstable angina, lack of visible thrombus, diabetes and the fact that the affected vessel was small (3 mm). However, the athermoma was not very long, and a good distal vessel flow was observed. Following stent implantation, short-term DAPT was recommended for three months (clopidogrel 75 mg every other day and aspirin 81 mg/day). This regimen kept the patient’s P2Y12 reaction units (PRU) between 142–155 on serial measurements. The take-home message from this case presentation was that patients with a high risk of bleeding represent a significant challenge during PCI, even with simple lesions. n

Case Presentation 2 PCI in a Patient Undergoing PVI at High Risk of Restenosis Dr Mathias Vrolix of Ziekenhuis Oost Limburg in Genk, Belgium, presented the case of a 57-year-old female who was obese (body mass index [BMI] 31.7); other risk factors included type 2 diabetes, a familial history of cardiovascular disease (CVD) and hypercholesterolaemia (LDL 3.6 mmol/L). The patient had a recent diagnosis of breast cancer and had undergone a lobectomy six weeks previously. Nodal metastasis had been detected and chemotherapy suggested. Exercise tolerance testing (ETT) was not performed because the patient presented with unstable angina. However, nothing specific was seen on an ECG. The patient was admitted to hospital for diagnostic coronary angiography, which revealed one lesion in the RCA as well as LCA lesions in the circumflex (CX) and LAD. This patient was therefore diagnosed with 3-vessel disease and a SYNTAX score of 14. The FFR in the RCA was 0.77, in the main stem LAD was 0.71 and FFR was not performed in the CX. Professor de Luca proposed his treatment strategy. He calculated the patient’s SYNTAX score as 26, a score that would have been a clear indication for coronary artery bypass grafting (CABG) several years ago. A recent meta-analysis of 14 clinical trials found that among diabetic patients with multivessel disease and/or left main disease, CABG is superior to DES in terms of mortality.15 However, in this case, the SYNTAX score of 26 is close to the borderline (23). The patient has mostly focal, not complex lesions. The patient is relatively young and has recent cancer with metastases. These factors, together with improved stent technology and DAPT, suggest that a DES may be the appropriate strategy, and the Cre8 stent would be a good choice. The chosen approach was therefore multistep revascularisation, firstly by direct stenting of the RCA and, a few days later, stenting of the left main (LM), LAD and CX. The first step should be administration of DAPT comprising aspirin and prasugrel or ticagrelor. A radial approach should be taken. Professor de Luca recommended the following – administration of heparin and glycoprotein IIb-IIIa inhibitors (bolus) for the LM PCI, implantation of a Cre8 stent, intravascular ultrasound (IVUS) imaging, postprocedural protamine and 12 months of DAPT.

182

Cre8_SatSym_FINAL.indd 182

Dr Nef then presented his opinion. This is a case containing three clear stenosis – the RCA is highly stenosed, and stenoses are evident in the LAD and LM. Numerous studies support the use of IVUS to determine the degree of stenosis.16–20 Dr Nef recommended the use of PCI, a decision that is supported by clinical evidence – the FREEDOM trial in patients with diabetes and advanced CAD concluded that coronary artery bypass grafting (CABG) was superior to PCI in terms of rates of myocardial infarction (MI) and death from any cause.21 But that significance between the two techniques was only achieved at five years. At up to two years there was no difference between PCI and CABG.21 In view of the potentially limited life expectancy of a patient with metastatic malignancy, PCI is therefore an attractive choice. In terms of stent choice, a registry study showed that in diabetic patients, DES are associated with half the risk of restenosis compared with BMS, with similar risk of death or MI within four years in both groups.22 The ABSORB Expand trial also demonstrated the benefits of a DES in diabetic subgroups.23 In terms of stenting procedure, a simple without kissing balloon dilatation (FKBD) is recommended as this is associated with reduced use of contrast media and shorter procedure and fluoroscopy times24 Dr Nef therefore recommends a simple procedure involving one stent. The discussion returned to Dr Vrolix, who outlined how he actually treated this patient. He would have offered CABG since the patient’s life expectancy exceeded two years but the patient refused surgery. The culprit lesion was considered to be the lateral branch of the CX. The first step was peri-procedural management using femoral access and six French, aspirin 80 mg, clopidogrel 600 mg loading dose, heparin 70E/kg according to activated partial thromboplastin time (APTT). Step two was the PCI procedure for the lateral branch. A complication occurred – a fausse route in the lateral branch of the CX resulted in a dissection of the CX. The main stem and LAD were treated as follows – lesion preparation with compliant balloons, stenting of the LAD and then the main stem, 3 x 12 mm and 3.5 x 31 mm.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:39

Cre8™ Unique Technology in Challenging Daily Practice

Figure 3: Cre8™ DES – Sirolimus Distribution Inside the Vessel Wall

Figure 4: Factors to be Considered in Everyday Practice When Undergoing Percutaneous Coronary Intervention

Distribution inside the vessel wall [low] [mid] Inside vessel

[mid] Inside vessel

[high]

Blood Flow

Blood Flow Pure drug

Patient clinical history

Known PCI techniques/ experience

Formulated drug

In step three of the PCI procedure, the main stem was checked and a stent implanted in the posterior descendens RCA (DES, 2 mm, not Cre8). The lateral branch of the CX was rewired, using a Fielder XT guide wire and balloons. Stenting was impossible because of the angle of the lateral branch. A good angiographic result was seen after multiple ballooning. At six months follow-up the patient remained asymptomatic and chemotherapy was uneventful. There were no bleeding complications on DAPT, and DAPT was stopped at six months. The Cre8 DES was well suited to this complex case. Its structure provides high radial strength, a necessary consideration for use in the main stem. It can be easily positioned and has demonstrated efficacy in diabetic patients.6 It employs a fatty acid, which acts as a permeation enhancer, in its formulation. Fatty acids are used

PCI procedure

Availible Devices/ instruments/ imaging madalities

Patient clinical conditions at admission and foreseen clinical outcome

to improve transdermal and skin delivery of drugs,25 and cardiac fatty acid uptake is increased in diabetic mouse models.26 This combination of drug and permeation enhancer leads to increased drug concentration in the tissue, allowing a homogeneous distribution and a uniform action on the whole tissue (see Figure 3). n

Summary and Concluding Remarks These presentations of two very different cases – one with a high bleeding risk and the other with highly stenotic lesions in different places. These illustrate the value of case studies. Clinical trials do not discuss specific cases, but in everyday practice we need to apply clinical trial data on a one-to-one basis. No single patient fits a standard profile, and numerous factors need to be considered before undergoing PCI. These include the patient’s medical history, prognosis and clinical presentation, the available instruments, devices and imaging modalities and the experience of the cardiologist (see Figure 4). Furthermore, it can be seen that there is no consensus of opinion between experts.

1. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72. 2. Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation 2004;109:1942–7. 3. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–23. 4. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007;27:1500–10. 5. Nikam N, Steinberg TB, Steinberg DH. Advances in stent technologies and their effect on clinical efficacy and safety. Med Devices (Auckl) 2014;7:165–78. 6. 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. 7. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatmen. Circulation 2007;116:745–54. 8. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013;382:1714–22. 9. Lindstaedt M, Spiecker M, Perings C, et al. How good are experienced interventional cardiologists at predicting the functional significance of intermediate or equivocal left main coronary artery stenoses? Int J Cardiol 2007;120:254–61. 10. De Bruyne B, Pijls NH, Kalesan B, et al., Fractional flow

INTERVENTIONAL CARDIOLOGY REVIEW

Cre8_SatSym_FINAL.indd 183

The Cre8 DES could be a useful addition to the range of DES employed in complex PCI cases. Its polymer-free platform with abluminal reservoirs allow targeted and controlled drug elution. The Amphilimus formulation enhances drug bioavailability and tissue permeability for optimal safety and efficacy. Furthermore, initial clinical data have demonstrated good safety and efficacy. However, data from larger prospective trials are required to ascertain the true effectiveness of the Cre8 DES in complex lesions. n

reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367:991–1001. 11. Cutlip DE, Chhabra AG, Baim DS, et al., Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials. Circulation 2004;110:1226–30. 12. Valgimigli M, Patialiakas A, Thury A, et al., Randomized comparison of Zotarolimus-Eluting Endeavor Sprint versus bare-metal stent implantation in uncertain drug-eluting stent candidates: rationale, design, and characterization of the patient population for the Zotarolimus-eluting Endeavor Sprint stent in uncertain DES candidates study. Am Heart J 2013;166:831–8. 13. M. V, Bare metal vs. zotarolimus-eluting stent in uncertain drug-eluting stent candidates: a randomized controlled trial (ZEUS), Presented at: American College of Cardiology/i2 Scientific Session; March 31, 2014; Washington, DC. 14. Moretti C, Lolli V, Perona G, et al. Cre8 coronary stent: preclinical in vivo assessment of a new generation polymer-free DES with Amphilimus formulation. EuroIntervention 2012;7:1087–94. 15. 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. 16. Abizaid AS, Mintz GS, Abizaid A, et al. One-year follow-up after intravascular ultrasound assessment of moderate left main coronary artery disease in patients with ambiguous angiograms. J Am Coll Cardiol 1999;34:707–15. 17. Ricciardi MJ, Meyers S, Choi K, et al. Angiographically silent left main disease detected by intravascular ultrasound: a marker for future adverse cardiac events. Am Heart J 2003;146:507–12. 18. 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. 19. Fassa AA, Wagatsuma K, Higano ST, et al. Intravascular ultrasound-guided treatment for angiographically indeterminate left main coronary artery disease: a long-term follow-up study. J Am Coll Cardiol 2005;45:204–11. 20. de la Torre Hernandez JM, Lopez-Palop R, Garcia Camarero T, et al. Clinical outcomes after intravascular ultrasound and fractional flow reserve assessment of intermediate coronary lesions. Propensity score matching of large cohorts from two institutions with a differential approach. EuroIntervention 2013;9:824–30. 21. Farkouh ME, Domanski M, Fuster V. Revascularization strategies in patients with diabetes. N Engl J Med 2013;368:1455–6. 22. Stenestrand U, James SK, Lindback J, et al. Safety and efficacy of drug-eluting vs. bare metal stents in patients with diabetes mellitus: long-term follow-up in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J , 2010;31:177–86. 23. van Geuns JJ, de Jaegere, P., Diletti, R. et al. TCT-429 Shortand intermediate- term clinical outcomes after implantation of everolimus-eluting bioresorbable scaffold in complex lesions : a prospective single-arm study – ABSORB Expand trial. J Am Coll Cardiol 2013;62(suppl):B133. 24. Niemela M, Kervinen K, Erglis A, et al. Randomized comparison of final kissing balloon dilatation versus no final kissing balloon dilatation in patients with coronary bifurcation lesions treated with main vessel stenting: the Nordic-Baltic Bifurcation Study III. Circulation 2011;123:79–86. 25. Kim MJ, Doh HJ, Choi MK, et al. Skin permeation enhancement of diclofenac by fatty acids, Drug Deliv , 2008;15:373–9. 26. Chabowski A, Gorski J, Glatz JF, et al. Protein-mediated Fatty Acid Uptake in the Heart. Curr Cardiol Rev 2008;4:12–21.

183

05/09/2014 10:39

Coronary Drug Eluting Stents

Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology Proceedings of a satellite symposium held at EuroPCR on May 20th – 23rd 2014 in Paris K a trina Mou n t f o r t , M e d i c a l Wr i t e r, Ra d c l i f f e Ca r d i o l o g y R ev iewed for a c c ura c y b y : D i d i e r Ca r r i é, 1 M a r c o Va l g i m i g l i , 2 G e n n a r o S a r d e l l a , 3 Shmuel Ba n a i , 4 R a f a e l R o m a g u e ra 5 a n d Pi e t e r S t e l l a 6 1. Centre Hospitalier Universitaire Rangueil, Toulouse, France; 2. The University Hospital of Ferrara, Ferrara, Italy; 3. Policlinico “Umberto I,” “Sapienza” University, Rome, Italy; 4. Tel Aviv Medical Center, Tel Aviv, Israel; 5. Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain; 6. University Medical Centre Utrecht, The Netherlands

Abstract The use of first-generation drug-eluting stents (DES) has been associated with safety concerns such as very late stent thrombosis. Today, with the release of newer DES, there is a need for comparative studies of percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) to demonstrate their value in patients with high risk of restenosis such as diabetic patients. In a satellite symposium presented at EuroPCR 2014, the Cre8™ DES was discussed. The Cre8 device has a number of unique clinical features, including polymer-free technology, abluminal reservoir technology and bio-inducer surface that ensure effective neointima suppression and rapid endothelialisation. The efficacy of the Cre8 DES has been demonstrated in the International randomised comparison between DES Limus Carbostent and Taxus drug-eluting stents in the treatment of de novo coronary lesions (NEXT) randomised clinical study, with equivalent efficacy in the diabetic and general populations, a unique finding. Ongoing clinical studies such as Investig8 and the Tel Aviv Medical Center (TLVMC) Cre8 study have confirmed the efficacy of the device in patient populations with a high proportion of diabetic patients. The Demonstr8 randomised trial has shown almost complete Cre8 strut coverage at three months with a numerical advantage versus bare metal stent (bare metal stents [BMS] – comparator device) at one month. In addition, use of the Cre8 DES may enable a shorter duration of dual antiplatelet therapy (DAPT) following PCI. The Cre8 DES therefore represents a significant advance in stent technology and may be particularly useful in challenging clinical settings

Keywords Percutaneous coronary intervention (PCI), polymer-free drug-eluting stent, Cre8 Disclosure: The reviewers have no conflicts of interest to declare. Received: 6 August 2014 Accepted: 7 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):184–9 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. E: katsmountfort@virginmedia.com Support: The publication of the article was supported by Alvimedica.

Percutaneous coronary intervention (PCI) involving stenting is routine practice, and involves either bare metal stents (BMS) or drug-eluting stents (DES), which allow controlled release of antiproliferative drugs at the arterial wall.1 However, the persistence of durable polymers in first-generation DES led to numerous problems including inflammation, delayed arterial healing, aneurysm formation and mechanical disruption. All of which resulted in potential stent thrombosis.2 More recently, advances in technology have resulted in the emergence of DES with novel features to enhance efficacy and safety, including the Cre8™ polymer-free DES (Alvimedica). A satellite symposium, chaired by Dr Didier Carrié of Rangueil Hospital (Toulouse, France) and Marco Valgimigli of Erasmus Thoraxcenter (Rotterdam, The Netherlands), was held at EuroPCR on May 21st 2014 in Paris. The objectives of this symposium were to review clinical study data for the Cre8 DES, understand the unmet needs in DES clinical performance for PCI in everyday practice and to understand the added efficacy and safety value of the polymer DES technology.

184

Alvimedica2_SatStm_FINAL.indd 184

Dr Carrié began by introducing the Cre8 technology and reviewing published clinical data. The Cre8 DES uses a proprietary polymerfree drug release system (Abluminal Reservoir Technology), which comprises reservoirs on the outer surface of the stent. These enable controlled drug elution that is directed exclusively towards the vessel wall. The Cre8 DES utilises a formulation of sirolimus plus an organic acid, Amphilimus™, that enhances bioavailability and drug distribution to the entire vessel wall. Studies of a rabbit model show that the Cre8 DES has steady release kinetics compared to other commercially available DES (see Figure 1), reaching peak drug concentration during the first few days, 50 % drug elution in approximately 18 days, 65–75 % drug elution within 30 days and complete drug elution within 90 days.3 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. After drug release, the Cre8 could be considered a bare metal stent (BMS). Cre8 is covered with a bio-inducer surface made of pure carbon, which is

04/09/2014 19:47

Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology

Figure 1: Cre8™ Kinetic Release

Endeavor™

Overall population Cypher™

0,4

Biomatrix™

0,3 0,2

-60 %

0,5

0.14±0.36

15 Days

0.43±0.41

0,2

-72 %

0.12±0.29

0 In-stent LLL

0,3

0,1

0 Iaxus™

p<0.0002

0,4

0.34±0.40

0,1

20 0

CRE8™ * 60

p<0.0001

0,5

Xience V™

Diabetic subgroup

100 Commulative % Released

Figure 2: Six-month In-stent Lumen Loss in the NEXT Clinical Study

In-stent LLL

Cre8 (42 les, 42 pts) LLL = late lumen loss. Source: Carie 2012.

TAXUS Liberte (38 les, 33 pts) 4

* Cre8 implants in rabbit model Source: Moretti, 20123

biocompatible and does not produce any late inflammatory stimuli inside the treated segment, reducing inflammatory response and lowering the risk of device thrombogenicity. Clinical data in support of the efficacy of the Cre8 DES has been obtained from the NEXT clinical study, which enrolled 323 patients with ischaemic myocardial symptoms related to de novo lesions in native coronary arteries, in 11 European sites.4 These were randomised 1:1 to the Cre8 or the Taxus Liberté stent. The primary endpoint was six-month angiographic in-stent late lumen loss (LLL). Although the trial was a non-inferiority trial, the Cre8 demonstrated superiority over the Taxus Liberté stent. In-stent LLL was significantly lower in the Cre8 group (0.14 mm vs 0.34 mm, p non-inferiority

<0.0001, p superiority <0.0001). Clinical endpoints (cardiac death, myocardial infarction, target lesion revascularisation, and stent thrombosis) up to 12 months did not differ significantly between the two groups. The most surprising finding of this study was that the LLL in the diabetic subgroup was comparable to that obtained in the overall population, a finding that had not been seen before with DES (see Figure 2). Only one stent thrombosis was seen in each group. The study concluded that the Cre8 stent in de novo lesions showed significantly lower in-stent LLL at six months than the Taxus Liberté stent, with a trend toward better 12-month clinical safety and efficacy results. Dr Carrié ended his presentation by stating that the Cre8 unique features and initial clinical results have identified it as a possible step forward in DES development for both safety and efficacy n

Clinical Programme Update Dr Gennaro Sardella of the University of Rome (Italy) presented an update on the ongoing studies in the Cre8 clinical program, beginning with an overview of DES development. The first-generation BMS were suboptimal in terms of both efficacy and safety. The secondgeneration BMS had improved safety profiles but little improvement in efficacy was seen. The advent of the DES resulted in a substantial improvement in efficacy, but first generations of DES had safety issues. Now, with the emergence of newer DES, an optimal balance of efficacy and safety is being achieved, although efficacy in diabetics remains an unmet need. The features of the Cre8 DES that enhance its safety are the polymerfree platform, which avoids all the established drawbacks associated with the presence of polymer interface with blood flow or vessel wall; the bio-inducer surface that ensures optimal haemo-compatability vs lumen blood flow, and an abluminal reservoir that controls and directs elution to the vessel wall. The polymer-free platform, together with the amphilimus formulation of sirolimus and organic acid, enhancing drug bioavailability and permeability, contribute to the superior efficacy of Cre8. Following the demonstration of efficacy and safety in the NEXT clinical trial, the next steps in the Cre8 clinical development program are a randomised clinical trial, Demonstr8, and a real-world study in the

INTERVENTIONAL CARDIOLOGY REVIEW

Alvimedica2_SatStm_FINAL.indd 185

diabetic population, Prove Abluminal Reservoir Technology Clinical benefit in all comers patients (PARTicip8).

The Demonstr8 study The rationale for the Randomised comparison between a DES and BMS to assess neointimal coverage by optical coherence tomography (OCT) examination (Demonstr8) study5 was that millions of stable patients undergoing PCI with BMS implantation have taken one-month dual antiplatelet therapy (DAPT), followed by aspirin monotherapy to optimise safety and efficacy of PCI procedure according to European guidelines. A longer duration of DAPT is required with DES use, since incomplete endothelial stent strut coverage and malapposition is considered a predictor of stent thrombosis. Furthermore, heterogeneity of healing is commonly seen in DES.6 However, after complete drug elution, the Cre8 becomes a BMS and interacts with blood and tissue as a standard BMS. The Demonstr8 study therefore aims to show non-inferiority of the Cre8 in terms of stent strut coverage evaluated with optical coherence tomography (OCT) at three months after stent implantation compared with a well known BMS (Vision Multilink).7 It has been hypothesised that if endothelial coverage is comparable at three months, the Cre8 could be treated as a BMS at this stage; i.e. only aspirin would subsequently be needed. The study recruited 38 patients with ischaemic myocardial symptoms related to de novo lesions in native coronary arteries, in six European

185

04/09/2014 19:47

Coronary Drug Eluting Stents Figure 3: Case Example from the Demonstr8 Study Showing Complete Coverage of the Cre8 Stent, with a Thin Layer of Neointima

show that Cre8 has an excellent safety profile, with low RUTTS scores and low neointima thickness.

The PARTicip8 Trial The PARTicip8 clinical observational prospective study aims to involve around 1000 ‘real world’ patients with ischaemic myocardial symptoms related to de novo lesions in native coronary arteries, in 30 European sites.8 One hundred patients from a pre-specified diabetic subgroup will be submitted to angiographic follow up. The primary endpoint is a composite of cardiac death, target vessel myocardial infarction (MI) and clinically indicated TLR at six months. The recruitment was closed in December 2013 with an increased number of patients from the initial plan – 1250 patients.

The Investig8 Trial

sites.5 The primary endpoint was the percentage of sections with a Ratio of Uncovered to Total Stent Struts per Cross Section (RUTTS) score < 30 % at three-month non-inferior to Vision Multilink percentage of sections with RUTTS score < 30 % at one month. The 35 patients suitable for analysis have led to the evaluation of 17,000 struts in 2000 analysed sections. RUTTS scores <30 % were seen in 99.78 % of patients receiving a Cre8 DES and 99.55 % of patients receiving a BMS. In terms of secondary endpoints, OCT analysis showed superiority of the Cre8 group in terms of mean neoimtima thickness at months one and three (0.08±0.03 mm in Cre8 group vs 0.18±0.10 mm in BMS group; p<0.0001; see Figure 3). In conclusion, results to date from this study

The Multicentric and retrospective registry in real-world patients with polymer-free drug eluting stent Cre8 (INVESTIG8) study aims to collect clinical evidence of Cre8 performance from around 1,000 patients in a maximum of 15 European centres. The primary endpoint is the incidence of a composite of cardiac death, target vessel MI and clinically indicated target lesion revascularisation (TLR) at 12 months (major adverse cardiac events (MACE) at 12 months); secondary endpoints are the incidence of a composite of all deaths, all MI and any revascularisation at 12 months, as well as the incidence of stent thrombosis. Interim analysis of data from 346 patients showed that 34.68 % of the patients had diabetes and 90.8 % had target lesions classified B2 or C according to the American College of Cardiology (ACC)/ American Heart Association (AHA) classification. The results to date are extremely positive with MACE in only 4.6 % In conclusion, available data from ongoing clinical studies show that Cre8 has excellent efficacy, without compromising safety, for a broad range of patients. n

Clinical Programme Update The Tel Aviv Medical Center Cre8 Study Dr Shmuel Banai of the Tel Aviv Medical Center Israel began by summarising the current limitations of DES: the risk of late stent thrombosis and the inferior efficacy in patients with diabetes. In addition, non-homogeneous coverage of the metal struts due to breaks and cracks of the polymer may lead to inflammatory reactions in the vessel wall, promoting instant stent restenosis (ISR), as well as platelet reactivation, leading to stent thrombosis. Inflammation plays a key role in coronary development and progression in diabetic patients.9,10 In scanning electron microscopy (SEM) studies, inhomogeneous distribution of coating was recognised in all DES types examined. 11 Furthermore, balloon expansion of first and second generation DES disturbs the polymer surface and can cause detachment of microparticles.12 The clinical implication of damaged polymers may have been under-recognised and may have a substantial impact on clinical outcomes of patients receiving these stents, especially in diabetic patients. Polymer-free DES may overcome these limitations. The TLVMC Cre8 study was a prospective, single arm open label nonrandomised single-centre study and aimed to evaluate the safety

186

Alvimedica2_SatStm_FINAL.indd 186

and efficacy of the Cre8 stent in the all-comer population. The end points were death, MI, stroke, unplanned PCI and clinically driven TLR at 30 days, six and 12 months. Between Nov 2012 and Aug 2013, 215 patients were enrolled and 319 stents implanted. One-year follow-up data are available on all 215 patients. Five patients were diagnosed as non-ST elevation MI (NSTEMI), only one of which had focal in-stent restenosis in an right coronary artery (RCA) in which four Cre8 DES were implanted; in the other four patients, the nonSTEMI events were related to a new lesion in a different coronary artery. A total of nine patients underwent clinically indicated PCI. Only one required TLR, in which the lesion was successfully treated with a drug-eluting balloon. Among the remaining eight, none required PCI to the index coronary artery. These data demonstrate a very low incidence of MACE, suggesting an excellent safety profile. The very low incidence of clinically driven TLR also suggests high clinical efficacy. Dr Banai concluded by stating that polymer-free DES appear to represent a new and improved generation of DES, but that this needs to be confirmed by larger clinical trials and extended clinical experience. n

INTERVENTIONAL CARDIOLOGY REVIEW

04/09/2014 19:47

Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology

PCI in Everyday Clinical Practice: What is Still Unmet in DES Performance? Dr Marco Valgimigli of the Erasmus MC Thoraxcenter in Rotterdam, the Netherlands, began by summarising the unmet needs in DES performance. These were long-term outcomes, performance in patients with diabetes mellitus and requirement for DAPT. An observational study comparing the effectiveness of revascularisation strategies found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was an initial survival advantage among patients who underwent PCI as compared with patients who underwent coronary artery bypass grafting (CABG), but in the long-tem, the advantage switches to CABG.13 The more severe the coronary disease, the worse is the comparative effect of PCI. The results of the SYNTAX trial also showed an initial survival advantage with PCI, as long as the anatomy is not too complex.1 The FREEDOM trial reported that irrespective of complexity, CABG is superior to PCI in diabetic patients.14 However, stent technology has improved since these studies were undertaken. The SPIRIT IV trial demonstrated the benefits of the second generation DES, although all the advantages of the Xience™ stent in the first year were associated with non-diabetic patients.15 The EXCEL trial aimed to provide important information on whether the use of second-generation DES would make PCI more competitive in comparison to CABG in

elderly and frail patient population, for whom the bleeding risk is at least as high as the ischaemic risk. The current treatment paradigm is BMS + one month of DAPT or DES + long-term DAPT. However, there is no evidence from major clinical studies to support DAPT duration of more than 12 months following DES implantation.16–19 Current guidelines suggest that patients at high bleeding risk should be given a BMS followed by DAPT for 30 days. However, a safe DES followed by DAPT of short duration may be a better option. The ZEUS study, which randomised patients to a zotarolimus-eluting stent or a BMS, suggested that DAPT duration should be personalised. For example, modelled according to the patient’s clinical risk profile and not by stent type. The study found a higher risk of MI in the BMS group. A post-hoc analysis found that these MIs were largely type 1 (spontaneous MI) but also type 4b (stent thrombosis), illustrating the power of late loss inhibition in a high-risk population. Studies have demonstrated that the most important predictor of late stent thrombosis is the RUTTS score.6 Data from the Demonstr8 trial have shown that the Cre8 DES is associated with a very high percentage of struts with a RUTTS score <30 % (99.78 % of patients) indicating very good stent coverage. Hence, studies designed to prove the safety of a reduced DAPT duration after Cre8 implantation would be welcome to further understand if DAPT

a complex patient population. In 2014, enrolment in the EXCEL trial was however capped at 1900 rather than the planned 2600. No other randomised studies are currently planned or ongoing with respect to the performance of second generation DES as compared to CABG. Hence, a full understanding how newer generation DES may fill the gap to CABG in current practice, remains unmet.

duration should be driven by patients’ characteristics and not stent type as long as new generation technology DES is employed.

In terms of DAPT requirement the general consensus is that patients receiving DES should take DAPT for a minimum of 6/12 months or even more. This represents a significant disadvantage in an increasingly

In conclusion, what is unmet in DES technology is our capability to prove their value under current market conditions. There is a need for studies looking at long-term outcomes, especially in patients with diabetes. There is also a need for studies comparing the efficacy and safety of current DES with that of CABG. In addition, we need to prove that DES efficacy does not necessarily mean longer duration of DAPT. The duration of DAPT should be tailored to the patient and not to the stent. n

Cre8 in Diabetic Patients Figure 4: Durable Inflammation of Durable Polymers

0,7

BMS Polymeric DES 1° & 2° gen Fast elution Polymer-free DES

0,6 0,5 LLL (mm)

Dr Rafael Romaguera of the University of Barcelona (Spain) discussed the question of whether the Cre8 stent can make a difference to patients with diabetes. He began by examining the causes of DES failure in diabetic patients. Compared with control smooth muscle cells, those cultured under high glucose conditions require more than 10x as much sirolimus concentration to achieve similar suppression.20 Differences in vascular cell metabolism are also seen between diabetics and non-diabetics. In a basal setting, glucose and lactate account for approximately 30 % of energy, whereas 70 % of adenosine triphosphate (ATP) generation is derived from fatty acid oxidation. However, in diabetes, as glucose uptake and oxidation are impaired, the heart is coerced to use fatty acid almost exclusively for ATP generation. The Amphilimus™ technology employed in the Cre8 DES, in which the immunosuppressive drug is formulated with a long chain fatty acid, may enhance drug concentration, homogeneity and stability into the vascular cell.

0,4 0,3 0,2

Slow Elution Polymer-free DES

0,1 0

6 months

12 months

18 months

24 months

Time LLL = late lumen loss; DES = drug-eluting stents; BMS = bare metal stents. Source: Kimura,

1996, Kimura, 2002, Byrne, 2011 and Byrne, 2009.21–24

While BMS show a characteristic luminal response involving a rapid increase in LLL over the first six months, due to inflammation and followed by a levelling out,21,22 the first and second generation DES showed persistent inflammation and a continued increase in LLL after six months

INTERVENTIONAL CARDIOLOGY REVIEW

Alvimedica2_SatStm_FINAL.indd 187

(see Figure 4).23,24 Theoretically, the Amphilimus™ formulation in the Cre8 DES may represent an advantage in diabetic patients with increased fatty acid metabolism. The absence of polymer may also avoid late events

187

04/09/2014 19:47

Coronary Drug Eluting Stents related to persistent inflammation. This has been demonstrated in the clinical trial setting, where the LLL in diabetes subgroup was comparable to that obtained in the general population (see Figure 2).4 The Randomised trial comparing reservoir-based polymer-free amphilimus‐eluting stents vs everolimus-eluting stents with durable polymer in patients with diabetes mellitus (RESERVOIR) trial is a prospective, randomised-controlled, single-blind, two-arm, multicentre clinical evaluation that aims to compare the Cre8 Stent implantation to polymer-based everolimus-eluting stent in diabetic patients (n=112).

The primary endpoint is neointimal hyperplasia as determined using OCT. Secondary endpoints include percentage of uncovered struts, percentage of malapposed struts, maximum areas of obstruction and angiographic LLL.25 In summary, the PCI of patients with diabetes remains challenging, even with the second generation of DES. The Cre8 has demonstrated promising efficacy in patients with diabetes; however, the results need to be confirmed by the ongoing RESERVOIR trial, as well as future clinical trials. n

Cre8 in Non-comer Patients Professor Pieter Stella on the University Medical Centre, Utrecht, (the Netherlands) discussed non-comer or non-regular patients. Patients taking oral anticoagulant therapy have acute management issues during the PCI procedure such as choice of vascular access site and anticoagulant and antiplatelet therapy management. Longterm management issues risks of bleeding, stroke, target vessel revascularisation and stent thrombosis. Patients aged over 80 years represent a growing patient population for whom the reduction in mortality and MI rates with DES relative to BMS is particularly marked.26 Patients with DAPT issues present numerous issues, including length of treatment duration, cost, potential side effects, risk of late stent thrombosis and bleeding complications. However, 70 % of the issues associated with DAPT issues could be prevented with new stents such as Cre8 (see Figure 5).27 The stent of choice in non-comer patients according to standard practice is the BMS. However, the Cre8 offers an alternative in the form of a DES with a very safe profile, an abluminal drug, rapid but limited neo-endotheilialisation, limited neo-intima and low LL. Professor Stella considered the clinical evidence in support of the Cre8 DES and presented a case of a male patient aged 78 years, admitted for treatment of colon cancer. He presented with acute coronary syndrome with inferolateral leads on ECG. A Cre8 stent was implanted and four weeks of DAPT prescribed. The stent was examined by OCT at four weeks. OCT revealed a small neointimal layer and no uncovered struts. The patient proceeded to colon surgery and two years later had no angina, no TLR and was taking only aspirin. In terms of scientific evidence, the NEXT and Demonstr8 clinical trials have been discussed. The ReCre8

Figure 5: Principal Causative Factors of Stent Restenosis in Patients on Dual Antiplatelet Therapy

5% 11 % 28 % 14 % 6%

36 % Neoatherosclerosis

Restenosis

Uncoverd struts

Underexpansion

Malapposition

Other

Source: Byrne, 2014.

trial is an investigator initiated all comers study. It is a prospective, randomised multicentre study that aims to recruit around 2,200 patients. Patients will be randomised to the resolute integrity DES (MDT) or Cre8. The study will also investigate the use of DAPT for three months vs one month in elective PCI. Clinical follow up will be at 12 months and three years, and the primary endpoint will be all MACE. n

Summary and Concluding Remarks Dr Carrié ended the symposium by stating that there remains an unmet need for clinical data demonstrating the value of new generation DES, particularly in terms of long-term outcomes and in patients with diabetes. The NEXT clinical study has proven high Cre8 efficacy in diabetics. Ongoing clinical studies such as Investig8 and the TLVMC Cre8™ study have confirmed the efficacy of the device in all comers patients with a high proportion of diabetic patients (35 % and 38 % respectively). Ongoing evaluations will provide further

188

Alvimedica2_SatStm_FINAL.indd 188

evidence in this challenging setting. The Demonstr8 randomised trial has provided evidence in support of the excellent safety profile of the device, showing almost complete Cre8 strut coverage at three months. Single-centre experiences have suggested that Cre8 may enable a shorter duration of DAPT following stent implantation, although further studies are needed to confirm this finding. In conclusion, the unique features of the Cre8™ stent have provided high efficacy and safety in challenging clinical settings. n

INTERVENTIONAL CARDIOLOGY REVIEW

04/09/2014 19:47

Meeting the Unmet – The Cre8 Polymer-free Drug-eluting Stents Technology

1. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72. 2. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing Arterioscler Thromb Vasc Biol 2007;27:1500–10. 3. 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. 4. 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. 5. Stella P. Demonstr8 randomized trial results: Cre8: reduced anti-platelet therapy with effective DES; Presented at the EuroPCR meeting; May 21–24, 2013; Paris, France., . 6. Finn AV, Joner M, Nakazawa G, et al., Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435–41. 7. http://clinicaltrials.gov/ct2/show/NCT01543373; Optical Coherence Tomography Comparison of Neointimal Coverage Between CRE8 DES and BMS (DEMONSTRATE); date accessed 26 May 2014. 8. http://clinicaltrials.gov/ct2/show/NCT01556126; Clinical Performance of CRE8 Drug Eluting Stent in All Comer Population (PARTICIPATE); date accessed 26 May 2014. 9. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006;116:1793–801. 10. Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol 2009;53:S35–42.

INTERVENTIONAL CARDIOLOGY REVIEW

Alvimedica2_SatStm_FINAL.indd 189

11. Basalus MW, Ankone MJ, van Houwelingen GK, et al. Coating irregularities of durable polymer-based drug-eluting stents as assessed by scanning electron microscopy. EuroIntervention 2009;5:157–65. 12. Denardo SJ, Carpinone PL, Vock DM, et al. Detailed analysis of polymer response to delivery balloon expansion of drugeluting stents versus bare metal stents. EuroIntervention 2013;9:389–97. 13. Weintraub WS, Grau-Sepulveda MV, Weiss JM, et al. Comparative effectiveness of revascularization strategies. N Engl J Med 2012;366:1467–76. 14. Taggart DP. The FREEDOM trial: a definitive answer to coronary artery bypass grafting or stents in patients with diabetes and multivessel coronary artery disease. Eur J Cardiothorac Surg 2013;44:978–9. 15. Stone GW, Rizvi A, Sudhir K, et al. Randomized comparison of everolimus- and paclitaxel-eluting stents. 2-year followup from the SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) IV trial. J Am Coll Cardiol 2011;58:19–25. 16. Valgimigli M, Campo G, Monti M, et al. Short- versus longterm duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015–26. 17. Shiomi H, Kozuma K, Morimoto T, et al. Long-Term Clinical Outcomes After Everolimus- and Sirolimus-Eluting Coronary Stent Implantation: Final 3-Year Follow-Up of the Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial. Circ Cardiovasc Interv 2014;7:343–54. 18. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimuseluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22.

19. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. 20. Patterson C, Mapera S, Li HH, et al. Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling. Arterioscler Thromb Vasc Biol 2006;26:1473–80. 21. Kimura T, Abe K, Shizuta S, et al. Long-term clinical and angiographic follow-up after coronary stent placement in native coronary arteries. Circulation 2002;105:298–91. 22. Kimura T, Yokoi H, Nakagawa Y, et al. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med 1996;334:561–6. 23. Byrne RA, Kastrati A, Massberg S, et al. Biodegradable polymer versus permanent polymer drug-eluting stents and everolimus- versus sirolimus-eluting stents in patients with coronary artery disease: 3-year outcomes from a randomized clinical trial. J Am Coll Cardiol 2011;58:1325–31. 24. Byrne RA, Kufner S, Tiroch K, et al. Randomised trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis: 2-year follow-up results. Heart 2009;95:1489–94. 25. http://clinicaltrials.gov/ct2/show/NCT01710748; ReservoirBased Polymer-Free Amphilimus-Eluting Stent Versus Polymer-Based Everolimus-Eluting Stent in Diabetic Patients (RESERVOIR); date accessed 27 May 2014. 26. Bainey KR, Selzer F, Cohen HA, et al. Comparison of three age groups regarding safety and efficacy of drug-eluting stents (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am J Cardiol 2012;109:195–201. 27. Byrne RA. Stent thrombosis after drug-eluting stenting, insights from the European-wide PRESTIGE registry; presented at CRT 2014, 22–25 Feb 2014, Washington DC, US.

189

04/09/2014 19:47

Coronary CTO

Evidence for Benefit of Percutaneous Coronary Intervention for Chronically Occluded Coronary Arteries (CTO) – Clinical and Health Economic Outcomes John Rawlins,1 James Wilkinson1 and Nick Curzen1,2 1. Wessex Cardiothoracic Centre, University Hospital Southampton NHS Trust; 2. Faculty of Medicine, University of Southampton

Abstract Percutaneous revascularisation of a coronary chronic total occlusion (CTO) remains one of the technical frontiers of interventional cardiology. CTOs are common, and yet intervention is only attempted in 10 % of cases. CTO procedures are perceived to be technically challenging, lengthy, associated with significant risk and have only limited data to support the practise. Recent technical advances have dramatically increased the success rate, shortened procedural time and improved clinical outcomes. The aim of this article is to critically examine the data that supports CTO intervention, including specifically an appraisal of procedural safety, benefit and overall cost effectiveness.

Keywords Chronic total occlusions (CTO), benefits, economic outcomes Disclosure: The authors have no conflicts of interest to declare. Received: 2 July 2014 Accepted: 14 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):190–4 Correspondence: Nick Curzen, Cardiothoracic Department, University Hospital Southampton, Tremona Road, SO16 6YD. E: nick.curzen@uhs.nhs.uk

A chronic total occlusion (CTO) in a coronary artery is defined as “the presence of TIMI 0 flow within an occluded arterial segment of greater than three months standing.”1 The successful percutaneous revascularisation of CTO vessels represents one of the dominant remaining technical challenges in interventional cardiology. CTOs are common, found in between 20 %2 and 50 %3 of all patients with significant coronary artery disease (defined as a stenosis of >70 % in a single epicardial vessel). However, despite the frequency with which they are encountered, an attempt at revascularisation is made in only 10 % of cases.4 There remains a perception that CTO intervention is lengthy, costly, associated with significant risk and offers only limited clinical benefit. This is rooted in historical data demonstrating that both the procedural success and the long-term patency of CTO percutaneous coronary intervention (PCI) has been significantly lower when compared to non-CTO PCI.4 Almost certainly because of these data and reservations about CTO PCI, the culture has developed that only a minority of CTO cases are considered for angioplasty. Most patients are therefore treated with simply medical therapy, thus condemning them to ongoing angina or coronary artery bypass surgery (CABG) surgery. Whilst surgery is an effective therapy for most patients, this is a longer procedure, with higher risk, longer recovery and there are recent concerns regarding long term graft patency specifically in the context of CTO.5 The traditional technical approach to CTO PCI is progressive antegrade wire escalation strategy. This remains technically challenging and has a high failure rate even in expert hands.4 Procedures are often lengthy and associated with high radiation doses for both patient and operator, as well as large volumes of radiographic contrast. Recent technical advances, including the adoption of dissection/re-entry6 and equipment

190

Curzen_FINAL.indd 190

to enable a retrograde approach7, have significantly increased procedural success rates. In addition, the new hybrid strategies (see Figure 1) have shortened procedure time, reduced contrast load, and decreased the need for repeat procedures7,8 (see Figure 1). Despite the perceived complexity of these techniques, they can be taught extremely effectively using an experienced proctor – and adopting such an approach can significantly improve success rates.9 Despite these advances, controversy persists regarding the objective clinical value of successful CTO PCI. The aim of this article is to critically examine the data that supports contemporary percutaneous CTO intervention, specifically including an evaluation of procedural safety and cost effectiveness.

Clinical Safety A perception persists that the percutaneous treatment of coronary CTOs is associated with significant procedural and patient risk.4 This however is not reflected in the published data in the modern literature that reflects contemporary practise. In the largest published meta-analysis, examining over 18,000 patients undergoing a CTO PCI procedure from 65 studies in the era 2000–11, there was an overall rate of major adverse cardiovascular events (MACE) of 3.1 % (pooled estimate, 95 % CI:2.4 %–3.7 %).10 Specifically, the overall procedural mortality was 0.2 %, with the commonest procedural complications being perforation (2.9 %, 95 % CI: 2.2 %–3.6 %) and contrast nephropathy (3.8 %, 95 % CI: 2.4 %–5.3 %). Overall, the success rate across the cohort was 77 %, with evidence that this has improved progressively year on year during the duration of the study (see Figure 2). The authors were able to study the impact of the retrograde approach in over 886 lesions (884 patients), and reported an similar overall MACE rate (3.1 %), driven predominately by periprocedural

05/09/2014 10:48

Evidence for Benefit of Percutaneous Coronary Intervention for Chronically Occluded Coronary Arteries

an alternative strategy. This indicates that controlled dissection-reentry using Bridgepoint technology is a safe and effective technique that offers a reproducible way to facilitate procedural success in CTOs that in many cases would remain untreatable.11 However, long-term multicentre clinical outcome data remains unavailable, as do randomised controlled trials. When compared to an overall procedural mortality rate of 0.65 % for all PCI undertaken outside of ST segment elevation myocardial infarction (STEMI) (excluding cardiogenic shock)12, CTO PCI using both traditional and hybrid techniques can be considered safe. Of course, such published data is derived from a series of cohort analysis in whom the operators were expert practitioners. Given the learning curve for new CTO PCI techniques, the current recommendations advocate that CTO intervention should be undertaken by those individuals that have a specific interest in CTO intervention and who have undergone specialist training.1 There is evidence that having procedural guidance by visiting highly experienced proctors in the catheter lab significantly improves procedure success rates and shortens the learning curve9 Conceptually, however, CTO PCI (including retrograde techniques) is safe, with a low overall complication rate.

Clinical Benefits The underlying justification behind an attempt at CTO recanalisation is the relief of myocardial ischaemia in an area supplied by an occluded artery. This may manifest either as symptomatic angina/ angina equivalent, or if asymptomatic, to involve a sufficient extent of myocardium be of sufficient quantity on a non-invasive ischaemia test as to carry prognostic significance. Whilst the relief of symptoms is clear cut, the objective data to support a prognostic benefit for CTO PCI purely on the grounds of the amount of reversible ischaemia is circumstantial and derived from indirect cohort analysis rather than from prospective randomised studies. The following section will describe the data that supports CTO intervention: I. firstly, in those patients with symptomatic angina – with the goal of symptom relief, and

INTERVENTIONAL CARDIOLOGY REVIEW

Curzen_FINAL.indd 191

Dual injection

3 Yes 4

Antegrade wiring

Yes

Antegrade

1. Ambiguous proximal cap 2. Poor distal Target 3. Appropriate Collaterals

Retrograde

Lesion length <20 mm

No Antegrade dissection & re-entry

Controlled (Stingray)

Retrograde true lumen puncture

Retrograde dissection & re-entry

Wire-based

7 SWITCH STRATEGIES Algorithm summarising the Hybrid strategy for the crossing and successful treatment of Coronary chronic total occlusions. Adapted from Briilakis et al.8

Figure 2: Temporal Trends In Cumulative Angiographic Success Rates and Major Procedural Complication Rates 85

Success rate

Complication rate

80 75 70 65 60

2000–2002 (n=2766)

2003–2005 2006–2008 (n=1607) (n=6677) Publication year

2009–2011 (n=8357)

5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Complication rate (%)

The incorporation of Bridgepoint™ technology into the hybrid strategy for the treatment of CTOs has led to its adoption in CTO practice despite no large scale published data on the safety of controlled dissection re-entry using the system.11 The largest single-centre series published to date utilised the approach in 62 consecutive cases (60 patients) and have reported follow-up data for a median duration of 1.8 years. When compared to a demographically similar cohort of patients that underwent a CTO procedure over the same time scale that did not utilise Bridgepoint™ technology, overall success rates were similar to that quoted in the wider literature (Bridgepoint™ vs Non-Bridgepoint™: 74.2 % vs 75.4 %; p=0.99) and there were no significant differences in immediate procedural complication rates (Bridgepoint™ vs Non Bridgepoint™: overall complication rate 8.2 % vs 8.3 % (p=0.99); Perforation rate 1.6 % vs 3.2 % (p=0.99); vascular site complication 7.6 % vs 3.6 %: p=0.27). There was a higher (nonsignificant) rate of procedural MI reported in the Bridgepoint™ group (13.2 % vs 7.2 %, p=0.25) but the clinical impact of this remains uncertain. It is important to note, however, that within the Bridgepoint™ group, a significantly higher proportion of patients had already had one unsuccessful attempt (1.6 % vs 13.1 %; P=0.01) at CTO PCI by

Figure 1: Algorithm Summarising the Hybrid Strategy for the Crossing and Successful Treatment on Coronary Chronic Total Occlusion

Angiographic success rate (%)

MI (2.8 %), but with a lower rate of procedural mortality (0.1 %). The success rate of the retrograde approach is comparable to that of the overall cohort at 79.6 %.

Temporal trends in cumulative angiographic success rates and major procedural complication rtates, presenting according to study publication year. Reproduced from Patel et al. with kind permission of the American College of Cardiology Foundation.10

II. secondly in patients with demonstrable ischaemia on a noninvasive test (who may be asymptomatic) – in whom the document goal is to improve prognosis.

Symptomatic Angina Numerous studies have demonstrated that successful CTO intervention is effective at reducing angina.13,14 Specifically, in patients with clear angina symptoms (CCS 3–4), successful CTO intervention is associated with an early improvement in angina frequency, physical limitation and quality of life (QoL),14 when compared to those patients in which CTO recannulisation was unsuccessful. However, amongst patients who have minimal symptoms of angina (defined in one study as having an angina frequency score of <100 and termed asymptomatic), only modest non-signifiant improvements in both angina frequency and QoL were noted after successful PCI. Amongst this group, there were no significant differences noted in angina frequency or QoL score if the PCI procedure was successful or not, along with no differences in 30-day mortality (see Figure 2).14 There remains no long-term systematic follow-up data

191

05/09/2014 10:48

Coronary CTO Figure 3: Effect of Procedural Success on Adjusted Health Status Outcomes Among Patients Without (Asymptomatic) and with (Symptomatic) Pre-procedural Angina Asymptomatic

or preventing ventricular arrhythmia’s in patients who do not have manifest angina. There are ongoing trials in this area that are due to report in 2016–17 (see below).

Prognostic Impact

SAQ Angina frequency

4.3 (-5.4, 13.9)

SAQ Physical limitation

6.3 (-5.0, 17.6)

SAQ Quality of life

8.5 (-3.7, 20.7)

Symptomatic SAQ Angina frequency

10.3 (-0.8, 21.3)

SAQ Physical limitation

15.9 (5.1, 26.7)

SAQ Quality of life

27.3 (16.5, 38.0) -40

-20

The identification of ischaemia in patients with coronary artery disease (CAD) is likely a key determinant of prognosis.19 Furthermore, reducing the overall ischaemic myocardial burden (i.e. effective re-vascularisation) is effective at long-term improvment prognosis.13,20,21 Contemporary data looking specifically at non-invasive measures of ischaemia suggest that in symptomatic patients with demonstrable ischaemia of greater than 10 % of viable myocardium, a reduction in ischaemic burden by more than 5 % is associated with a significant improvement in overall mortality, as well as a reduction in the incidence of MI.22 This effect is marked most amongst patients who have the greatest ischaemic burden pre-revascularisation.22 It could be inferred, that in patients with at least one CTO and demonstrable ischaemia on a non-invasive test, revascularisation may be of significant clinical benefit.

Effect of procedural success Variables used in this model included age, sex, prior MI, hypertension, hyperlipidaemia, diabetes, smoking status, prior CABG, number of diseased vessels, ejection fraction, preprocedural creatinine, B-blocker, calcium channel blocker, and nitrate use. Data expressed as point estimate of change in outcome from baseline to follow-up with 95% confidence intervals. Reproduced from Grantham et al. by kind permission of the American Heart Association.14

Figure 4: Markov Model for Comparing Chronic Total Occlusions-Percutaneous Coronary Intervention (CTO-PCI) with Optimal Medical Treatment in Patients With Chronic Stable Angina

CTO PCI

Chronic stable Angina with CTO

OMT • CABG • Death

Successful Unsuccessful

Peri-procedural complications • Arterial complications • Tamponade • Myccardial infarction • Death • CABG • Death

• CVA • Death

Post-procedural state • Stent thrombosis* • Myccardial infarction • TVR (PCI or CABG) • Death

*= Risk of stent thrombosis only pertains to patients post successful CTO-PCI. CABG = coronary artery bypass graft; CVA - Cerebrovascular accident (stroke); OMT = optimal medical therapy; TVR - Target vessel revascularisation. Reproduced from Gada et al. by kind permission of the British Cardiovascular Society.27

to assess the overall impact on mortality/prognosis in this cohort of asymptomatic patients. In addition to the improvement in symptoms, successful CTO intervention can lead to demonstrable improvements in left ventricular function,15–17 and a reduction in ventricular arrhythmias18 when completed in patients with impaired left ventricular systolic function. In addition, a number of observational studies have demonstrated a reduction in the need for coronary bypass surgery in those patients who have undergone a successful CTO PCI procedure.1 All these data were derived from patients who presented with symptomatic angina. By contrast, there are, at present, no specific data to support CTO revascularisation with the aim of improving left ventricular function

192

Curzen_FINAL.indd 192

In patients with a CTO, an ischaemia burden of more than 12.5 % on myocardial perfusion scanning was associated with a greater probability of a successful reduction in ischaemia (greater than 5 % improvement noted in 34.7 % with mild ischaemia vs 86.7 % in severe ischaemia P<0.001) following successful CTO intervention with a sensitivity and specificity of 80 % respectively. Paradoxically, amongst this group of 301 patients, those with a low ischaemia burden before CTO intervention (less than 6.25 %), were more likely to have a increase in ischaemia post PCI.23 This maybe due to restenosis, loss of collateral circulation, loss of side branches, or progression of coronary artery disease in other territories. Further evidence that the presence and extent of ischaemia is a determining factor in defining patient prognosis can be derived from examining outcomes after an attempt at PCI. Overall, incomplete revascularisation is associated with worse clinical outcomes when compared to patients in whom complete revascularisation has been achieved.21 The presence of a CTO is a predictor of incomplete revascularisation in those patients treated with PCI. For example, in a cohort of over 11,000 PCI patients treated in the DES era, 69 % (n=7795) were incompletely revascularised. These individuals had a higher mortality rate at 18 months (adjusted HR 1.23, 95 % CI 1.04–1.45), that increased if greater than two vessels (including a CTO) remained unrevascularised (HR 1.44 95 % CI 1.14–1.82, adjusted survival 94.9 % vs 92.9 % p=0.002). Hence, within the context of symptomatic angina, successful CTO intervention which leads to complete revascularisation (and relief of underlying ischaemia) may offer a substantial mortality benefit.20 It is also important to appreciate that CABG is not certain to produce complete revascularisation. For example, in the Syntax trial CTO subset, successful bypass grafting to an occluded arterial segment occurred in only 69 %, with complete revascularisation (in the context of a CTO) being achieved in only 49 %24, albeit by a very strict definition. Interpretation of these data requires care, of course. There remains a paucity of a large scale randomised trial data that specifically addresses the outcomes after successful ischaemia-driven CTO intervention. The bulk of data currently available to support CTO interventional practice is derived from registries that compare patients in whom CTO intervention has been successful with those in whom it

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:48

Evidence for Benefit of Percutaneous Coronary Intervention for Chronically Occluded Coronary Arteries

has not. For example, when comparing 582 successful CTO procedures with 282 cases in which revascularisation was not achieved, Jones et al. report a 12.7 % decrease in mortality at five years.25 A metaanalysis of data available up until 2010, including over 7,000 patients across 13 studies found a 3.2 % lower mortality with successful CTO intervention13 (14.3 % vs 17.5 % OR 056, 95 % CI 0.43–0.72). In addition, a significantly lower rate of CABG was observed (OR 0.22, 95 % CI 0.17–0.27), but no differences in MI or other major adverse cardiac events were noted. Overall, successful CTO intervention does appear to offer a prognostic advantage, but only when compared to those in whom a CTO procedure was unsuccessful. These data provide circumstantial evidence at best: a randomised trial of CTO PCI versus optimal medical therapy (OMT) with an intention-to-treat analysis is required for definitive proof of benefit.

therapy. However, utilising a Markov model examining a hypothetical cohort of 10,000 patients (see Figure 3), Gada et al. have constructed a detailed analysis of the relative cost benefits of CTO intervention in patients with CCS class III-IV angina. Based on a mean age of 60 years, with a procedural success rate (68 %) and overall complication rate derived from contemporary published literature and based upon costs derived from CTO procedures conducted in an outpatient setting, the authors were able to calculate cost benefit model over a five-year period.27 They concluded that a successful CTO PCI strategy incurred higher costs than optimal medical therapy ($31,512 vs $27,805), but accumulated more quality-adjusted lifeyears (QALYs). Overall, CTO-PCI appeared to be cost effective, with a ratio of $9,505/QALY, which is well below the accepted conventional threshold of $50,000/QALY.

The reasons behind the difference between successful and unsuccessful CTO PCI remain undefined. Certainly, the differences observed can only partly be explained by adverse events in the unsuccessful PCI arms, the rates of which are broadly similar across reported data.13 The observed prognostic benefit may relate partly to a reduction in ischaemia driven arrhythmia,18 and possibly improved outcome amongst patients who go on to have an acute myocardial infarction of a non-CTO artery, on the basis of the “double jeopardy” theory. This was demonstrated in one large series of over 3,200 STEMI

With the addition of further variables, including the costs of a repeat CTO procedure that increased the overall procedure success rate to 80 %, the cost per QALY rose to $14,047/QALY, which is still dominant.

patients where the presence of a CTO, distinct from the culprit artery, was an independent predictor of 30-day mortality (HR 3.6, 95 % CI 2.6– 4.7; p<0.01). In those alive at 30 days, the presence of a CTO remains a predictor of overall five year mortality.26 To summarise, although the current data are encouraging, Despite these favourable indicators, CTO interventional practice is still lacking a large scale randomised trial to formally demonstrate prognostic benefit for the procedure. However, to answer this criticism, two large scale randomised trials comparing CTO intervention with optimal medical therapy are ongoing, EURO-CTO and DECISIONCTO, both of whom are still recruiting and due to report in 2017 & 2018 respectively.

Cost Effectiveness As is detailed above, objective evidence from properly conducted randomised trials that CTO intervention decreases mortality is not available at present. As such, a formal assessment of cost effectiveness of CTO intervention versus medical therapy is difficult. Indeed, CTO PCI in the majority of cases is only offered to those patients who continue to be symptomatic despite optimal medical

1. Sianos G, Werner GS, Galassi AR, et al. Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club. EuroIntervention 2012;8:139–45. 2. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlu-sions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol 2012;59:991–7. 3. Christofferson RD, Lehmann KG, Martin GV, et al. Effect of chronic total coronary occlusion on treatment strategy. Am J Cardiol 2005;95:1088–91. 4. Grantham JA, Marso SP, Spertus J, et al. Chronic total occlusion angioplasty in the United States. JACC Cardiovasc Interv 2009;2:479–86. 5. Widimsky P, Straka Z, Stros P, et al. One-year coronary bypass graft patency: a randomized comparison between off-pump and on-pump surgery angiographic results of the PRAGUE-4 trial. Circulation 2004;110:3418–23. 6. Werner GS, Schofer J, Sievert H, et al. Multicentre experience with the Bridge-Point devices to facilitate recanalisation of chronic total coronary occlusions through controlled subintimal re-entry. EuroIntervention 2011;7:192–200. 7. Joyal D, Thompson CA, Grantham JA, et al. The retrograde

INTERVENTIONAL CARDIOLOGY REVIEW

Curzen_FINAL.indd 193

Importantly, however, the cost calculations are based on procedures conducted in a single centre between 2010–11. This is before the more widespread adoption of technology such as the Corsair® microcatheter and the Crossboss™ dissection re-entry system. The use of these technologies demonstrably increases the overall rate of procedure success6,7, but they are associated with a increase in overall procedural cost. This may be balanced with a reduced need for a second CTO-PCI procedure and reduced rate of target lesion revascularisation (TLR) but data is not available to fully establish true cost effectiveness of these technical advances in CTO revascularisation.

Conclusions CTO intervention remains a technically challenging process, but recent advances in technology and technique have increased procedural success rates and safety. Despite the complexity of the hybrid CTO techniques, these are readily teachable to experienced PCI operators with an interest in CTO. However, given the learning curve for these technically challenging techniques, it is clear that CTO PCI should be concentrated on a relatively few specialist operators. In patients with significant angina, CTO intervention is proven to be highly effective at relief of symptoms. This is likely to be cost effective – even allowing for increases in procedural costs associated with newer hybrid strategies. In patients with demonstrable ischaemia in a territory supplied by an occluded vessel, CTO intervention is likely to offer prognostic benefit but this has not yet been confirmed in a large scale randomised trial. n

technique for reca-nalization of chronic total occlusions: a step-by-step approach. JACC Cardiovasc Interv 2012;5:1–11. 8. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79. 9. Sharma V, Ntatsios A, Harcombe A, Smith W. Impact of proctoring and new techniques on suc-cess rates for operators undertaking percutaneous intervention of chronic total occlusions. Heart 2013;99:A39. 10. Patel V, Brayton K, Tamayo A, et al. Angiographic Success and Procedural Complications in Patients Undergoing Percutaneous Coronary Chronic Total Occlusion Interventions. J Am Coll Cardiol Intv 2013;6:128–36. 11. Mogabgab O, Patel VG, Michael TT, et al. Long-term outcomes with use of the CrossBoss and stingray coronary CTO crossing and re-entry devices. J Invasive Cardiol 2013;25:579–85. 12. Peterson ED, Dai D, DeLong ER, et al. Contemporary mortality risk prediction for percutaneous coronary intervention: results from 588,398 procedures in the National Cardiovascular Data Registry. J Am Coll Cardiol 2010;55:1923–32. 13. Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of

chronic total occlusions: a sys-tematic review and metaanalysis. Am Heart J 2010;160:179–87. 14. Grantham JA, Jones PG, Cannon L, Spertus JA. Quantifying the early health status benefits of successful chronic total occlusion recanalization: Results from the FlowCardia’s Approach to Chronic Total Occlusion Recanalization (FACTOR) Trial. Circ Cardiovasc Qual Outcomes 2010;3:284–90. 15. Kirschbaum SW, Baks T, van den Ent M, et al. Evaluation of left ventricular function three years after percutaneous recanalization of chronic total coronary occlusions. Am J Cardiol 2008;101:179–85. 16. Melchior JP, Doriot PA, Chatelain P, et al. Improvement of left ventricular contraction and re-laxation synchronism after recanalization of chronic total coronary occlusion by angioplasty. J Am Coll Cardiol 1987;9:763–8. 17. Cheng AS, Selvanayagam JB, Jerosch-Herold M, et al. Percutaneous treatment of chronic total coronary occlusions improves regional hyperemic myocardial blood flow and contractility: insights from quantitative cardiovascular magnetic resonance imaging. JACC Cardiovasc Interv 2008j;1:44–53. 18. Nombela-Franco L, Mitroi CD, Fernández-Lozano I, et al.

193

05/09/2014 10:48

Coronary CTO Ventricular arrhythmias among im-plantable cardioverterdefibrillator recipients for primary prevention: impact of chronic total coro-nary occlusion (VACTO Primary Study). Circ Arrhythm Electrophysiol 2012k;5:147–54. 19. Longman K, Curzen N. Should ischemia be the main target in selecting a percutaneous coro-nary intervention strategy? Expert Rev Cardiovasc Ther 2013b;11:1051–9. 20. Valenti R, Migliorini A, Signorini U, et al. Impact of complete revascularization with percutane-ous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J 2008c;29:2336–42. 21. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascu-larization of patients with multivessel coronary artery disease: a meta-analysis

194

Curzen_FINAL.indd 194

of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol 2013d;62:1421–31. 22. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Re-vascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008e;117:1283–91. 23. Safley DM, Koshy S, Grantham JA, et al. Changes in myocardial ischemic burden following percutaneous coronary intervention of chronic total occlusions. Catheter Cardiovasc Interv 2011f;78:337–43. 24. Thompson C. Percutaneous revascularisation of coronary chronic total occlusions: the new era begins. JACC

Cardiovasc Interv 2010;3(2):152–4. 25. Jones DA, Weerackody R, Rathod K, et al. Successful recanalization of chronic total occlusions is associated with improved long-term survival. JACC Cardiovasc Interv 2012d;5:380–8. 26. Claessen BE, van der Schaaf RJ, Verouden NJ, et al. Evaluation of the effect of a concurrent chronic total occlusion on long-term mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009l;2:1128–34. 27. Gada H, Whitlow PL, Marwick TH. Establishing the costeffectiveness of percutaneous coro-nary intervention for chronic total occlusion in stable angina: a decision-analytic model. Heart 2012m;98:1790–7.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:48

Coronary CTO

Percutaneous Treatment of Coronary Chronic Total Occlusions Part 1: Rationale and Outcomes Alfredo Ga la ssi, 1 Aa ron Gran t h a m , 2 D a v i d Ka n d z a r i , 3 Wi l l i a m L o m b a r d i , 4 I s s a m M o u s s a , 5 C ra ig T hompson, 6 Gera l d We r n e r, 7 Ch a r l e s Ch a m b e r s 8 a n d E m m a n o u i l B r i l a k i s 9 1. University of Catania, Catania, Italy; 2. Saint Luke’s Mid America Heart Institute and University of Missouri Kansas City, Missouri, US; 3. Piedmont Heart Institute, Atlanta, Georgia, US; 4. University of Washington, Seattle, US; 5. Mayo Clinic, Jacksonville, Florida, US; 6. Boston Scientific, Natick, Massachusetts, US; 7. Klinikum Darmstadt, Darmstadt, Germany; 8. Penn State University College of Medicine, Hershey, Pennsylvania, US; 9. VA North Texas Healthcare System and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, US

Abstract Coronary chronic total occlusions (CTOs) are commonly encountered in patients with coronary artery disease. Compared to patients without coronary CTOs, those with CTO have worse clinical outcomes and lower likelihood of complete coronary revascularisation. Successful CTO percutaneous coronary intervention (PCI) can significantly improve angina and improve left ventricular function. Although currently unproven, successful CTO PCI might also reduce the risk for arrhythmic events in patients with ischaemic cardiomyopathy, provide better tolerance of future acute coronary syndrome, and possibly improve survival. Evaluation by a heart team comprised of both interventional and non-interventional cardiologists and cardiac surgeons is important for determining the optimal revascularisation strategy in patients with coronary artery disease and CTOs. Ad hoc CTO PCI is generally not recommended, so as to allow sufficient time for (a) discussion with the patient about the indications, goals, risks, and alternatives to PCI; (b) careful procedural planning; and (c) contrast and radiation exposure minimisation. Use of drug-eluting stents is recommended for CTO PCI, given the lower rates of angiographic restenosis compared to bare metal stents.

Keywords Percutaneous coronary intervention, chronic total occlusions, outcomes Disclosure: Dr Grantham: educational grants from Abbott Vascular, Medtronic, Asahi-Intecc, BridgePoint Medical; speakers bureau, consulting fees and travel support from Abbott Vascular, BridgePoint Medical and Boston Scientific; CTO Scientific Advisory Board Boston Scientific, Banyan medical systems, Vascular solutions, Terumo; founding member of a web-based CTO-PCI education initiative called CTOFundamentals.org. All funds are paid to Saint Luke’s Cardiovascular Consultants or the Saint Luke’s Hospital Foundation. Dr Kandzari: Boston Scientific (advisory board/board member, grants or research support); Abbott Vascular (grants or research support); Micell Technologies (consultant); Medtronic (advisory board/board member, grants or research support); Dr Lombardi: BridgePoint Medical (stock owner or shareholder); BridgePoint Medical (consultant, advisory board/board member; Dr Thompson: employee, Boston Scientific; Dr Werner: speaker for ASAHI Intecc, Abbott Vascular, Biosensors, Terumo; principal investigator of a randomised trial on the benefit of CTO PCI vs medical therapy conducted by the EURO CTO Club sponsored by ASAHI Intecc and Biosensors; Dr Brilakis: consulting/speaker honoraria from St Jude Medical, Terumo, Janssen, Sanofi, Asahi, Abbott Vascular, Boston Scientific; research support from Guerbet; spouse is an employee of Medtronic. Dr Galassi, Dr Moussa and Dr Chambers have no conflicts of interest to declare. Acknowledgement: The authors would like to thank Ms Sheila Agyeman for her invaluable effort in coordinating the manuscript creation process. Received: 14 April 2014 Accepted: 10 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):195–200 Correspondence: Emmanouil Brilakis, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Division of Cardiology (111A), 4500 S. Lancaster Rd, Dallas, TX, US 75216. E: esbrilakis@gmail.com

Section A Coronary Chronic Total Occlusions – Prevalence and Pathophysiology A chronic total occlusion (CTO) is defined as a completely occluded coronary artery with no antegrade flow (thrombolysis in myocardial infarction [TIMI] 0 flow) for at least three months.1 CTOs are present in 15–30 % of patients undergoing coronary angiography.2–5 In a Canadian prospective registry of 14,439 patients undergoing coronary angiography a CTO was present in 18.4 % of all patients with significant coronary artery disease (CAD).2 Approximately 1/3–1/26,7 of patients undergoing CTO percutaneous coronary intervention (PCI) have had a prior acute myocardial infarction (MI). This suggests acute onset of the occlusion, whereas in the remaining patients gradual development of CTO from high-grade lesions likely occurred.

BRILAKIS_Rationale_FINAL.indd 195

The basic histopathologic feature of a CTO is a proximal cap of the occlusion. This is often fibrotic or calcified and may provide considerable resistance to wire advancement during CTO PCI. Distal to the proximal cap and along the occlusion length follows a segment of loose fibrous tissue or organised thrombus, with various extent of calcification.8,9 In several of these lesions, residual channels may be observed that are not visible under angiography. In addition, microchannels may appear during the CTO’s consolidation process, however these are mostly located in the adventitia with extremely tortuous courses and do not generally traverse the entire occluded segment.10 A recent autopsy study of 95 CTO lesions from 82 patients reported frequent negative remodelling of the CTO body (more frequent with longer duration of the occlusion), very rare presence of microchannels and more frequent tapering of the distal cap as compared with the proximal cap (79 % vs. 50 %, P<0.0001).11

195

05/09/2014 10:51

Coronary CTO Table 1: Rentrop and Werner Classification of Coronary Collateral Circulation Rentrop Classification15 (Developed for Occluded and Non-occluded Arteries) 0 no filling of collateral vessels 1

filling of collateral vessels without any

epicardial filling of the target artery

partial epicardial filling by collateral vessels

of the target artery

complete epicardial filling by collateral

vessels of the target artery (In CTOs,

Rentrop 3 is prevalent in 85% of lesions)

Collateral Connection Grade13 CC0 no continuous connection CC1

threadlike continuous connection

CC2

side branch–like connection (≥0.4 mm)

CC3

>1 mm diameter of direct connection (not included in the

original description)

Section B Clinical Presentations and Timing of Intervention Clinical Presentation The symptoms attributable to CTOs are no different than those of non-total occlusions. Patients may report characteristic angina or anginal equivalents, including dyspnoea and fatigue. CTO symptoms are by definition chronic and may sometimes be minimised through accommodation and denial. Stable angina is present in many patients with CTO. Data from the FlowCardia’s approach to chronic total occlusion recanalisation (FACTOR) trial22 suggests that two thirds of the patients referred for the trial (which required symptoms and/or abnormal stress testing) had angina, that significantly impaired their quality of life (QoL). Dyspnoea is the most common anginal equivalent among patients with CTO. Safley et al.23 compared 98 patients with single-vessel CTO with 687 patients undergoing non-CTO PCI and reported similar alleviation in both dyspnoea and angina.

CTO = chronic total occlusion.

Collaterals are interarterial connections that provide blood flow to a vascular territory whose original supply vessel is obstructed. Thus, the integrity of the myocardium supplied by the obstructed vessel may be preserved, or to a certain degree impaired, but would not become necrotic. Collaterals develop through arteriogenesis, i.e. the recruitment of preformed and preexisting interarterial connections, which is driven mainly by shear forces along the pressure gradient that develops when the native vessel is occluded.12 The functional assessment of collaterals revealed that, in patients without well-developed preexisting collateral connections, collaterals require between 2–12 weeks to fully develop their functional capacity.13 The collateral supply provides a perfusion pressure in the range of 30–40 mm Hg at the occluded territory, a pressure that leads to the functional reduction of distal vessel size, which then leads to the underestimation of the vessel dimensions during a recanalisation procedure.14 The most widely used angiographic grading system for collaterals (described by Rentrop et al. in 1985) does not actually rate the collaterals themselves but rather their effect in filling the occluded arterial segment15. Recently, a grading of collateral connections was introduced specifically for CTOs, which can help plan the retrograde approach13,16 (see Table 1). Collateral function can develop to a similar functional level in patients with prior MI and large akinetic territories, as in patients with preserved regional function, i.e. viability is not required for collateral development.17 The direct assessment of collateral function shows that the functional competence of collaterals in CTOs is limited, even in patients without a prior Q-wave MI. During a standard stress protocol with systemic infusion of adenosine, the coronary flow velocity and pressure changes distal to an occlusion (after CTO crossing but before stent implantation) were well below the cut-off values for assessing the functional reserve in non-occlusive coronary obstructions, i.e. a fractional flow reserve (FFR) above 0.75. Therefore, even well-developed collaterals do not prevent ischaemia during exercise.18–20

Numerous patients with CTO have been identified after presenting with other culprit lesions (46 % of patients with CTO presented with an acute coronary syndrome (ACS) in the Canadian Multicentre CTO Registry).2 Among patients presenting with ST-segment elevation acute myocardial infarction, approximately 10 % also have a CTO.2 The same study showed that 13 % of the CTO patients were asymptomatic or had minimal angina (Canadian classification angina class 0 and/or 1).2 The decision to revascularise the CTO in these patients depends on the indications discussed in section C. A careful search should be conducted for residual symptoms of myocardial ischaemia such as poor progression in cardiac rehabilitation, activity avoidance, residual dyspnoea, fatigue and angina, as well as residual ischaemic burden.

Timing of CTO-PCI In most patients CTO-PCI should be performed electively and not ad hoc.24 Separating diagnostic angiography and CTO-PCI allows for a detailed discussion with the patient about the indications, goals, risks, and alternatives (such as medical therapy and coronary artery bypass graft surgery) to PCI. Risks that are more specific to CTO PCI warrant discussion. These include the risk of radiation injury, perforation, tamponade and donor vessel injury. There is controversy on whether CTO PCI provides clinical benefit to asymptomatic patients, which should be discussed with the patient (section C, part 6).25 Finally, adequate pre-procedural planning, which is critical to maintaining high procedural success, is more challenging when performed on an ad hoc basis. On rare occasions, the clinical situation may force ad hoc CTO PCI. An example would be a patient who presents with an ACS due to a severely degenerated saphenous vein graft (SVG) with no option for embolic protection. Native vessel CTO-PCI might be preferable and required if the patient cannot be stabilised with medical therapy.26

Section C Outcomes after CTO Interventions

Collaterals will regress once the native artery that was replaced by the collaterals is revascularised.21 This process starts immediately after re-establishing antegrade flow with immediate loss of collateral conductance and lasts for many months after the revascularisation procedure.

196

BRILAKIS_Rationale_FINAL.indd 196

CTO PCI can improve angina and left ventricular (LV) function. Although registry data are promising, the potential role of CTO PCI to decrease the risk for ventricular arrhythmias, improve tolerance of subsequent ACS and improve survival has not yet been demonstrated.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:51

Percutaneous Treatment of Coronary Chronic Total Occlusions Part 1: Rationale and Outcomes

Angina In a meta-analysis of six observational studies27–32 that evaluated angina post-CTO PCI, patients undergoing successful PCI experienced a significant reduction in recurrent angina during a six-year follow-up compared with patients undergoing unsuccessful PCI (odds ratio, 0.45; 95 % confidence interval, 0.30 to 0.67).33

demonstrated better outcomes for patients who underwent successful vs failed CTO PCI after primary PCI for acute ST-segment elevation MI.49 The ongoing Evaluating XIENCE V® and left ventricular function in percutaneous coronary intervention on occlusions after ST-elevation myocardial infarction (EXPLORE) trial is assessing whether PCI of a CTO in a non-infarct-related artery within one week from primary PCI can improve LV dimensions and function.

LV Dysfunction Left ventricular systolic function has been demonstrated to improve after CTO PCI in patients with baseline LV dysfunction,34–42 while no change in ejection fraction can be expected when the baseline LV function is normal.42 Left ventricular function improvement is dependent on the maintenance of CTO target vessel patency37,38 and on the viability of the perfused myocardial territory,39,40 therefore an assessment of left ventricular viability should be performed in case of left ventricular dysfunction. Theoretically, an improvement in LV function should improve heart failure symptoms, but this has not yet been demonstrated. A magnetic resonance imaging study of 170 consecutive patients with coronary CTO revealed prior myocardial infarction by late gadolinium enhancement in 86 %, a much higher proportion that previously recognised, although only 25 % of patients had Q waves on their electrocardiogram.43

Survival

Ventricular Arrhythmias

Completeness of Coronary Revascularisation and Outcomes

Ischaemia may predispose to ventricular arrhythmias. Among 162 patients with ischaemic cardiomyopathy who received an implantable cardioverter defibrillator, 44 % had at least one CTO.44 During a median follow-up of 26 months, the presence of CTO was associated with higher ventricular arrhythmia and mortality rates (p<0.01).44 The preventive effect of CTO revascularisation on subsequent arrhythmias remains to be shown.

Patients with incomplete coronary revascularisation have worse clinical outcomes compared to those with complete revascularisation.60 Research in this area has been hampered by the lack of universal definition of complete revascularisation. Anatomic definitions often require revascularisation of all stenotic vessels whereas functional definitions usually require revascularisation of ischaemic myocardial territories only.61 The presence of a CTO has been one of the major reasons for incomplete revascularisation, 62 suggesting (but not proving) that providing complete revascularisation by recanalising the CTOs could improve clinical outcomes.63,64 The presence of moderate or severe ischaemia is associated with worse clinical outcomes in patients with65 or without66–68 a CTO. In a study of 301 patients who underwent myocardial perfusion imaging before and after CTO PCI, a baseline ischaemic burden of >12.5 % was optimal in identifying patients most likely to have a significant decrease in ischaemic burden post-CTO PCI, suggesting that the highest benefit of CTO PCI is more likely to be achieved in patients with significant baseline myocardial ischaemia.69

Tolerance of Future ACS The presence of a CTO has been associated with worse outcomes in patients presenting with ACS, possibly due to the greater extent of myocardial injury during the initial ACS presentation.45 Among 3,277 patients with acute ST-segment elevation myocardial infarction treated with primary PCI, the presence of a CTO was an independent predictor for 30-day mortality (hazard ratio (HR), 3.6; 95 % confidence intervals (CI), 2.6–4.7; p<0.01), a stronger predictor than multivessel disease (HR, 1.6; 95 % CI, 1.2–2.2; p=0.01). Among patients who survived at least 30 days, the presence of a CTO (but not multivessel disease without CTO) remained a strong predictor of death (HR, 1.9; 95 % CI, 1.4–2.8, p<0.01).46 Similar results were obtained from the 3,283 patients who participated in the Harmonising outcomes with revascularisation and stents in acute myocardial infarction (HORIZONS-AMI) trial, where 8.6 % had a CTO in a non-infarct-related artery.45 A CTO in a non-infarct-related artery was an independent predictor of both 0- to 30-day mortality (HR 2.88; 95 % CI, 1.41–5.88; p=0.004) and 30-day to three-year mortality (HR 1.98; 95 % CI 1.19–3.29; p=0.009), while multivessel disease without a CTO was associated with higher early (0- to 30-day) (HR 2.20; 95 % CI, 1.00–3.06; p=0.049) but not late (30-days to three years) mortality.45 A similar adverse impact of CTO was observed in patients with ST-segment elevation acute myocardial infarction presenting with cardiogenic shock47 and in a series of patients with non-ST segment elevation acute coronary syndromes.48 A small retrospective study

INTERVENTIONAL CARDIOLOGY REVIEW

BRILAKIS_Rationale_FINAL.indd 197

There are no published, randomised controlled trials comparing CTO PCI with medical therapy or with surgical revascularisation. However, there are several observational studies that have consistently shown better survival among patients who underwent successful vs failed CTO PCI. In a meta-analysis of 13 observational studies7,27–32,50–55, mortality over a weighted mean follow-up of six years was 14.3 % among 5,056 patients with successful CTO recanalisation compared with 17.5 % among 2,232 patients with failed CTO recanalisation (odds ratio [OR] 0.56; 95 % CI, 0.43–0.72).33 Similar results were observed in two more recent studies56,57 but no difference was observed in a third study.58 In a large, single-centre, retrospective study, a mortality benefit was only observed among patients in whom the CTO target vessel was the left anterior descending artery.59

Ongoing Clinical Trials To date no randomised-controlled clinical trials of CTO PCI vs medical therapy or coronary artery bypass graft surgery have been reported. Importantly, the Open artery trial (OAT) was not a CTO trial, as it included patients within 30 days from acute myocardial infarction.2 Two clinical trials comparing CTO PCI with optimal medical therapy (OMT) are ongoing.70 The Drug-eluting stent implantation vs optimal medical treatment in patients with chronic total occlusion (DECISIONCTO, http://clinicaltrials.gov/show/NCT01078051) trial is evaluating whether compared to OMT, CTO PCI will reduce the composite endpoint of all cause death, myocardial infarction, stroke and any revascularisation at three years after randomisation. The European study on the utilisation of revascularisation vs optimal medical therapy for the treatment of chronic total coronary occlusions (EURO-CTO) trial (http://clinicaltrials.gov/ct2/show/NCT01760083) is randomising patients to CTO PCI with biolimus-eluting stent implantation and OMT vs OMT alone and has as primary endpoints the

197

05/09/2014 10:51

Coronary CTO QoL at 12 months and the composite of death or non-fatal myocardial infarction during a follow-up of 36 months. Finally, the Evaluating Xience V and left ventricular function in percutaneous coronary intervention on occlusions after ST-elevation myocardial infarction (EXPLORE) trial (http://www.exploretrial.com/) is randomising 300 patients presenting with ST-segment elevation acute myocardial infarction and a CTO in a non-infarct vessel to either CTO PCI within seven days of presentation or standard medical therapy. The study’s primary endpoint is left ventricular ejection fraction and end-diastolic volume, measured using cardiac magnetic resonance imaging at four months.

Section D

While these findings further support the safety and efficacy of DES following CTO recanalisation, they also have implications regarding procedural technique. For example, restenosis in the entire treated segment after recanalisation occurs nearly twice as often beyond the stent margins than in-stent. Therefore, DES treatment of the entire segment exposed to pre-dilatation angioplasty may yield greater reductions in restenosis and subsequent TLR than with balloon angioplasty alone or in combination with bare metal stents.83,87 Nevertheless, percutaneous revascularisation of CTOs is routinely associated with more extensive stent placement. As a consequence, it is unclear whether the improvement in restenosis is offset by a potentially higher risk of thrombotic occlusion, by complications associated with stent fracture or by acquired late malapposition.83,88

Stent Selection Clinical Rationale for Drug-eluting Stents in Percutaneous Revascularisation of Coronary Occlusions The appeal of drug-eluting stents (DES) for improving long-term vessel patency following CTO recanalisation is related not only to the success of DES in other complex lesion morphologies, but also to the clinical inadequacies of bare metal stents in sustaining restenosisfree patency in this particular lesion subset.71 As an example, in the Total occlusion study of Canada 1 (TOSCA-1) trial, rates of restenosis and re-occlusion six months after bare metal stent revascularisation exceeded 50 % and 10 %, respectively.72 The failure to achieve or sustain patency after CTO recanalisation has been associated with an impairment in the regional and global left ventricular systolic function, recurrent angina and target vessel revascularisation, and a greater need for late bypass surgery.73 Therefore, improving long-term, restenosis-free patency in coronary occlusions may have a potentially significant clinical impact.

Contemporary DES Trials in CTO Revascularisation In the randomised Primary stenting of totally occluded native coronary arteries (PRISON) II trial (N=200), treatment with sirolimus-eluting stents (SES) was associated with statistically significant reductions in angiographic restenosis at six months (in-stent, 36 % versus 7 %, p<0.0001), reocclusion at six months (13 % versus 4 %, p<0.04) and repeat revascularisation at one year (21 % versus 5 %, p<0.0001).74 At five years, the benefit of SES was sustained, demonstrating significant reductions in target lesion revascularisation (TLR, 30 % versus 12 %, p=0.001) and major adverse cardiac events, despite a greater number of cases of definite or probable stent thrombosis (ST).75 Similar clinical and angiographic benefit using first-generation DES has been supported in non-randomised studies.76–84 Among the 200 CTO patients treated with SES in the prospective Approaches to chronic occlusions with sirolimus-eluting stents/total occlusion study of coronary arteries-4 (ACROSS/TOSCA-4) trial, the three-year rate of TLR and ST remained favourable at 10.9 % and 1.0 %, respectively, with no occurrences of ST beyond one year.83 However, stent fracture was associated with higher restenosis rates. The growing clinical trial experience with DES in CTO revascularisation has also enabled meta-analyses of angiographic and clinical outcomes.85,86 Among 17 studies evaluating SES and/or paclitaxeleluting stents (PES) against bare metal stents in CTO revascularisation, treatment with DES was associated with a significant reduction in angiographic restenosis (odds ratio (OR) 0.15; 95 % CI, 0.08–0.26) and repeat revascularisation (OR 0.13; 95 % CI, 0.06–0.26), with a similar long-term incidence of death, myocardial infarction and ST.85

198

BRILAKIS_Rationale_FINAL.indd 198

The question as to whether disparities in angiography and clinical outcome arise in more complex lesion morphologies is an issue of ongoing study and is especially relevant to coronary total occlusions. At present, at least five comparative trials of SES and PES in CTOs have been performed.89 In general, these studies have been limited by their small study populations, which limit statistical comparisons – variability in trial design and limited clinical and angiographic follow-up. The demonstration of differences in clinical outcomes across the individual trials has been less consistent. More recently, the PRISON III trial randomised 300 CTO patients to receive either SES or two different zotarolimus-eluting stents, Endeavor and Resolute, Medtronic CardioVascular (Santa Rosa, CA).90 Compared with SES, the primary endpoint of in-segment late lumen loss at the eight-month angiographic follow-up was significantly higher with Endeavor but similar with Resolute. Given the overall small sample size, the clinical outcomes did not vary statistically according to the DES assignment. Additional studies have evaluated everolimus-eluting stents (EES) compared with PES,91,92 reporting lower angiographic and clinical restenosis with EES. In the Non-acute coronary occlusIon treated by everolimus eluting stent (CIBELES) randomised trial that compared SES with EES (N=207), the nine-month in-stent late loss (primary endpoint, 0.13 ± 0.69 mm EES versus 0.29 ± 0.60 mm SES, p=0.12) and angiographic restenosis were similar between the stent types.93,94 At 12 months, TLR and ST were numerically, but not significantly, higher among SES-treated patients. In a recent meta-analysis, compared with first-generation DESs, second-generation DESs were associated with lower incidence of death (odds ratio [OR], 0.37; 95 % confidence intervals [CI], 0.15-0.91), target vessel revascularisation (OR, 0.59; 95 % CI, 0.40-0.87), binary angiographic restenosis (OR, 0.68; 95 % CI, 0.46-1.01) and reocclusion (OR, 0.35; 95 % CI, 0.17–0.71), but similar incidence of myocardial infarction (OR, 0.45; 95 % CI, 0.10–1.95) and stent thrombosis (OR, 0.34; 95 % CI, 0.07–1.59).95 Additional studies evaluating EES in CTO revascularisation are forthcoming and include the Angiographic evaluation of the everolimus-eluting stent in chronic total occlusions (ACE CTO, clinicaltrials.gov identifier NCT01012869) and the evaluation of the XIENCE PRIME™ LL and XIENCE Nano™ everolimus eluting coronary stent coronary stents, performance, and technique in chronic total occlusions (EXPERT CTO, NCT01435031).

Section E Clinical Summary and Recommendations The aim of revascularisation in CTOs is to improve symptoms and/or prognosis, thus recanalisation attempt of a CTO should be considered

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:51

Percutaneous Treatment of Coronary Chronic Total Occlusions Part 1: Rationale and Outcomes

in the presence of symptoms or objective evidence of viability/ ischaemia in the territory of the occluded artery. In the 2011 American College of Cardiology/American Heart Association PCI guidelines, CTO PCI carries a class IIA recommendation: “PCI of a CTO in patients with appropriate clinical indications and suitable anatomy is reasonable when performed by operators with appropriate expertise”. 96 The 2010 European Society of Cardiology state that “similar to nonchronically occluded

vessels, revascularisation of CTO may be considered in the presence of angina or ischaemia related to the corresponding territory”.97 In the 2012 statement on Appropriate Use Criteria for Coronary Revascularisation, coronary revascularisation was given a lower level recommendation compared with patients with 1–2 vessel CAD without a CTO in 5 of 18 assessed clinical scenarios.25 It is the authors’ opinion that the presence of a CTO should not have an impact on the revascularisation decision, as long as appropriate expertise in CTO PCI is locally available. n

The authors support the following summary statements and specific recommendations regarding indications and performance of CTO PCI: 1. Compared to patients without coronary CTOs, those with CTO have worse clinical outcomes and lower likelihood of complete coronary revascularisation. 2. Successful CTO PCI can significantly improve angina and improve left ventricular function. Although currently unproven, successful CTO PCI might also reduce the risk for arrhythmic events in patients with ischaemic cardiomyopathy, provide better tolerance of future acute coronary syndrome and possibly improve survival. 3. Patients with an ischaemia-causing culprit CTO lesion who either (a) have had prior coronary artery bypass graft surgery and patent left internal mammary graft to the left anterior descending artery or (b) have single vessel coronary artery disease with a right coronary artery CTO are best treated with CTO PCI than with coronary artery bypass graft surgery. 4. Evaluation by a heart team comprised of both interventional and non-interventional cardiologists and cardiac surgeons is important for determining the optimal revascularisation strategy in patients with coronary artery disease and CTOs. 5. Ad hoc CTO PCI is generally not recommended, so as to allow sufficient time for (a) discussion with the patient about the indications, goals, risks, and alternatives to PCI; (b) careful procedural planning; and (c) contrast and radiation exposure minimisation. 6. Use of drug-eluting stents is recommended for CTO PCI, given the lower rates of angiographic restenosis compared to bare metal stents.

1. Di Mario C, Werner GS, Sianos G, et al. European perspective in the recanalisation of Chronic Total Occlusions (CTO): consensus document from the EuroCTO Club. EuroIntervention 2007;3:30–43. 2. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol 2012;59:991–7. 3. Christofferson RD, Lehmann KG, Martin GV, et al. Effect of chronic total coronary occlusion on treatment strategy. Am J Cardiol 2005;95:1088–91. 4. Kahn JK. Angiographic suitability for catheter revascularization of total coronary occlusions in patients from a community hospital setting. Am Heart J 1993;126:561–4. 5. Jeroudi OM, Alomar ME, Michael TT, et al. Prevalence and management of coronary chronic total occlusions in a tertiary veterans affairs hospital. Catheter Cardiovasc Interv 2013:published online before print. 6. Galassi AR, Tomasello SD, Reifart N, et al. In-hospital outcomes of percutaneous coronary intervention in patients with chronic total occlusion: insights from the ERCTO (European Registry of Chronic Total Occlusion) registry. EuroIntervention 2011;7:472–9. 7. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience. J Am Coll Cardiol 2001;38:409–14. 8. Katsuragawa M, Fujiwara H, Miyamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993;21:604-11. 9. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29:955–63. 10. Munce NR, Strauss BH, Qi X, et al. Intravascular and extravascular microvessel formation in chronic total occlusions a micro-CT imaging study. JACC Cardiovasc Imaging 2010;3:797–805. 11. Sakakura K, Nakano M, Otsuka F, et al. Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft. Eur Heart J 2013. 12. Schaper W, Schaper J. 2004. Arteriogenesis. Norwell, Massachusetts, USA: Kluwer Adademic Publishers. 13. Werner GS, Ferrari M, Heinke S, et al. Angiographic assessment of collateral connections in comparison with invasively determined collateral function in chronic coronary occlusions. Circulation 2003;107:1972–7. 14. Galassi AR, Tomasello SD, Crea F, et al. Transient impairment of vasomotion function after successful chronic total occlusion recanalization. J Am Coll Cardiol 2012;59:711–8. 15. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol 1985;5:587–92. 16. Surmely JF, Katoh O, Tsuchikane E, et al. Coronary septal collaterals as an access for the retrograde approach in the

INTERVENTIONAL CARDIOLOGY REVIEW

BRILAKIS_Rationale_FINAL.indd 199

percutaneous treatment of coronary chronic total occlusions. Catheter Cardiovasc Interv 2007;69:826–32. 17. Heil M, Schaper W. Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res 2004;95:449–58. 18. Werner GS, Figulla HR. Direct assessment of coronary steal and associated changes of collateral hemodynamics in chronic total coronary occlusions. Circulation 2002;106:435–40. 19. Werner GS, Fritzenwanger M, Prochnau D, et al. Determinants of coronary steal in chronic total coronary occlusions donor artery, collateral, and microvascular resistance. J Am Coll Cardiol 2006;48:51–8. 20. Sachdeva R, Agrawal M, Flynn SE, et al. The myocardium supplied by a chronic total occlusion is a persistently ischemic zone. Catheter Cardiovasc Interv 2014 Jan 1;83(1):9–16. 21. Zimarino M, Ausiello A, Contegiacomo G, et al. Rapid decline of collateral circulation increases susceptibility to myocardial ischemia: the trade-off of successful percutaneous recanalization of chronic total occlusions. J Am Coll Cardiol 2006;48:59–65. 22. Grantham JA, Jones PG, Cannon L, Spertus JA. Quantifying the early health status benefits of successful chronic total occlusion recanalization: Results from the FlowCardia’s Approach to Chronic Total Occlusion Recanalization (FACTOR) Trial. Circ Cardiovasc Qual Outcome s 2010;3:284–90. 23. Safley DM, Grantham J, Jones PG, Spertus J. Heatlh Status benefits of angioplasty for chronic total occlusions - an analysis from the OPS/PRISM studies. J Am Coll Cardiol 2012;59:E101–E101. 24. Blankenship JC, Gigliotti OS, Feldman DN, et al. Ad hoc percutaneous coronary intervention: a consensus statement from the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2013;81:748–58. 25. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 Appropriate use criteria for coronary revascularization focused update: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, American Society of Nuclear Cardiology, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2012;59:857–81. 26. Brilakis ES, Banerjee S, Lombardi WL. Retrograde recanalization of native coronary artery chronic occlusions via acutely occluded vein grafts. Catheter Cardiovasc Interv 2010;75:109–13. 27. Angioi M, Danchin N, Juilliere Y, et al. [Is percutaneous transluminal coronary angioplasty in chronic total coronary occlusion justified? Long term results in a series of 201 patients]. Arch Mal Coeur Vaiss 1995;88:1383–9. 28. Drozd J, Wojcik J, Opalinska E, Zapolski T, Widomska-Czekajska T. Percutaneous angioplasty of chronically occluded coronary arteries: long-term clinical follow-up. Kardiol Pol 2006;64:667– 73; discussion 674. 29. Finci L, Meier B, Favre J, et al. Long-term results of successful and failed angioplasty for chronic total coronary arterial occlusion. Am J Cardiol 1990;66:660–2. 30. Ivanhoe RJ, Weintraub WS, Douglas JS Jr, et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions.

Primary success, restenosis, and long-term clinical follow-up. Circulation 1992;85:106–15. 31. Olivari Z, Rubartelli P, Piscione F, et al. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol 2003;41:1672–8. 32. Warren RJ, Black AJ, Valentine PA, et al. Coronary angioplasty for chronic total occlusion reduces the need for subsequent coronary bypass surgery. Am Heart J 1990;120:270–4. 33. Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of chronic total occlusions: a systematic review and metaanalysis. Am Heart J 2010;160:179–87. 34. Melchior JP, Doriot PA, Chatelain P, et al. Improvement of left ventricular contraction and relaxation synchronism after recanalization of chronic total coronary occlusion by angioplasty. J Am Coll Cardiol 1987;9:763–8. 35. Danchin N, Angioi M, Cador R, et al. Effect of late percutaneous angioplastic recanalization of total coronary artery occlusion on left ventricular remodeling, ejection fraction, and regional wall motion. Am J Cardiol 1996;78:729–35. 36. Van Belle E, Blouard P, McFadden EP, et al. Effects of stenting of recent or chronic coronary occlusions on late vessel patency and left ventricular function. Am J Cardiol 1997;80:1150–4. 37. Sirnes PA, Myreng Y, Molstad P, et al. Improvement in left ventricular ejection fraction and wall motion after successful recanalization of chronic coronary occlusions. Eur Heart J 1998;19:273–81. 38. Piscione F, Galasso G, De Luca G, et al. Late reopening of an occluded infarct related artery improves left ventricular function and long term clinical outcome. Heart 2005;91:646–51. 39. Baks T, van Geuns RJ, Duncker DJ, et al. Prediction of left ventricular function after drug-eluting stent implantation for chronic total coronary occlusions. J Am Coll Cardiol 2006;47:721–5. 40. Kirschbaum SW, Baks T, van den Ent M, et al. Evaluation of left ventricular function three years after percutaneous recanalization of chronic total coronary occlusions. Am J Cardiol 2008;101:179–85. 41. Cheng AS, Selvanayagam JB, Jerosch-Herold M, et al. Percutaneous treatment of chronic total coronary occlusions improves regional hyperemic myocardial blood flow and contractility: insights from quantitative cardiovascular magnetic resonance imaging. JACC Cardiovasc Interv 2008;1:44-53. 42. Werner GS, Surber R, Kuethe F, et al. Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion. Am Heart J 2005;149:129–37. 43. Choi JH, Chang SA, Choi JO, et al. Frequency of myocardial infarction and its relationship to angiographic collateral flow in territories supplied by chronically occluded coronary arteries. Circulation 2013;127:703–9. 44. Nombela-Franco L, Mitroi CD, Fernandez-Lozano I, et al. Ventricular arrhythmias among implantable cardioverterdefibrillator recipients for primary prevention: impact of chronic total coronary occlusion (VACTO Primary Study). Circ Arrhythm Electrophysiol 2012;5:147–54. 45. Claessen BE, Dangas GD, Weisz G, et al. Prognostic impact of a chronic total occlusion in a non-infarct-related artery in patients with ST-segment elevation myocardial infarction:

199

05/09/2014 10:51

Coronary CTO 3-year results from the HORIZONS-AMI trial. Eur Heart J 2012;33:768–75. 46. Claessen BE, van der Schaaf RJ, Verouden NJ, et al. Evaluation of the effect of a concurrent chronic total occlusion on long-term mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:1128–34. 47. Hoebers LP, Vis MM, Claessen BE, et al. The impact of multivessel disease with and without a co-existing chronic total occlusion on short- and long-term mortality in ST-elevation myocardial infarction patients with and without cardiogenic shock. Eur J Heart Fail 2013;15:425–32. 48. Gierlotka M, Tajstra M, Gasior M, et al. Impact of chronic total occlusion artery on 12-month mortality in patients with non-ST-segment elevation myocardial infarction treated by percutaneous coronary intervention (from the PL-ACS Registry). Int J Cardiol 2013;168:250–4. 49. Yang ZK, Zhang RY, Hu J, et al. Impact of successful staged revascularization of a chronic total occlusion in the noninfarct-related artery on long-term outcome in patients with acute ST-segment elevation myocardial infarction. Int J Cardiol 2013;165:76–9. 50. Aziz S, Stables RH, Grayson AD, et al. Percutaneous coronary intervention for chronic total occlusions: improved survival for patients with successful revascularization compared to a failed procedure. Catheter Cardiovasc Interv 2007;70:15–20. 51. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992–2002. Eur Heart J 2005;26:2630–6. 52. de Labriolle A, Bonello L, Roy P, et al. Comparison of safety, efficacy, and outcome of successful versus unsuccessful percutaneous coronary intervention in “true” chronic total occlusions. Am J Cardiol 2008;102:1175–81. 53. Noguchi T, Miyazaki MS, Morii I, et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Determinants of primary success and long-term clinical outcome. Catheter Cardiovasc Interv 2000;49:258–64. 54. Prasad A, Rihal CS, Lennon RJ, et al. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: a 25-year experience from the Mayo Clinic. J Am Coll Cardiol 2007;49:1611–8. 55. Valenti R, Migliorini A, Signorini U, et al. Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J 2008;29:2336–42. 56. Jones DA, Weerackody R, Rathod K, et al. Successful recanalization of chronic total occlusions is associated with improved long-term survival. JACC Cardiovasc Interv 2012;5:380–8. 57. Mehran R, Claessen BE, Godino C, et al. Long-term outcome of percutaneous coronary intervention for chronic total occlusions. JACC Cardiovasc Interv 2011;4:952–61. 58. Jolicoeur EM, Sketch MJ, Wojdyla DM, et al. Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions. Catheter Cardiovasc Interv 2012;79:603–12. 59. Safley DM, House JA, Marso SP, et al. Improvement in survival following successful percutaneous coronary intervention of coronary chronic total occlusions: variability by target vessel. JACC Cardiovasc Interv 2008;1:295–302. 60. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol 2013;62:1421–31. 61. Gossl M, Faxon DP, Bell MR, et al. Complete versus incomplete revascularization with coronary artery bypass graft or percutaneous intervention in stable coronary artery disease. Circ Cardiovasc Interv 2012;5:597–604. 62. Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact ofi incomplete angiographic revascularization on clinical outcomes and Its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll

200

BRILAKIS_Rationale_FINAL.indd 200

Cardiol 2013;61:282–94. 63. Hannan EL, Wu C, Walford G, et al. Incomplete revascularization in the era of drug-eluting stents: impact on adverse outcomes. JACC Cardiovasc Interv 2009;2:17–25. 64. Genereux P, Palmerini T, Caixeta A, et al. Quantification and impact of untreated coronary artery disease after percutaneous coronary intervention: the residual SYNTAX (Synergy Between PCI with Taxus and Cardiac Surgery) score. J Am Coll Cardiol 2012;59:2165–74. 65. Galassi AR, Werner GS, Tomasello SD, et al. Prognostic value of exercise myocardial scintigraphy in patients with coronary chronic total occlusions. J Interv Cardiol 2010;23:139–48. 66. Hachamovitch R, Rozanski A, Shaw LJ, et al. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. Eur Heart J 2011;32:1012–24. 67. Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283–91. 68. Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900–7. 69. Safley DM, Koshy S, Grantham JA, et al. Changes in myocardial ischemic burden following percutaneous coronary intervention of chronic total occlusions. Catheter Cardiovasc Interv 2011;78:337–43. 70. Garcia S, Abdullah S, Banerjee S, Brilakis ES. Chronic total occlusions: patient selection and overview of advanced techniques. Curr Cardiol Rep 2013;15:334. 71. Brilakis ES, Kotsia A, Luna M, et al. The role of drug-eluting stents for the treatment of coronary chronic total occlusions. Expert Rev Cardiovasc Ther 2013;11:1349–58. 72. Buller CE, Dzavik V, Carere RG, et al. Primary stenting versus balloon angioplasty in occluded coronary arteries: the Total Occlusion Study of Canada (TOSCA). Circulation 1999;100:236–42. 73. Stone GW, Kandzari DE, Mehran R, et al. Percutaneous recanalization of chronically occluded coronary arteries: a consensus document: part I. Circulation 2005;112:2364–72. 74. Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions. Circulation 2006;114:921–8. 75. Van den Branden BJ, Rahel BM, et al. Five-year clinical outcome after primary stenting of totally occluded native coronary arteries: a randomised comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions (PRISON II study). EuroIntervention 2012;7:1189–96. 76. Ge L, Iakovou I, Cosgrave J, et al. Immediate and mid-term outcomes of sirolimus-eluting stent implantation for chronic total occlusions. Eur Heart J 2005;26:1056–62. 77. Hoye A, Tanabe K, Lemos PA, et al. Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions. J Am Coll Cardiol 2004;43:1954–8. 78. Werner GS, Krack A, Schwarz G, et al. Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents. J Am Coll Cardiol 2004;44:2301–6. 79. Nakamura S, Muthusamy TS, Bae JH, et al. Impact of sirolimus-eluting stent on the outcome of patients with chronic total occlusions. Am J Cardiol 2005;95:161–6. 80. Buellesfeld L, Gerckens U, Mueller R, et al. Polymer-based paclitaxel-eluting stent for treatment of chronic total occlusions of native coronaries: results of a Taxus CTO registry. Catheter Cardiovasc Interv 2005;66:173–7. 81. Abizaid A, Chan C, Lim YT, et al. Twelve-month outcomes

with a paclitaxel-eluting stent transitioning from controlled trials to clinical practice (the WISDOM Registry). Am J Cardiol 2006;98:1028–32. 82. Lotan C, Almagor Y, Kuiper K, et al. Sirolimus-eluting stent in chronic total occlusion: the SICTO study. J Interv Cardiol 2006;19:307–12. 83. Kandzari DE, Rao SV, Moses JW, et al. Clinical and angiographic outcomes with sirolimus-eluting stents in total coronary occlusions: the ACROSS/TOSCA-4 (Approaches to Chronic Occlusions With Sirolimus-Eluting Stents/Total Occlusion Study of Coronary Arteries-4) trial. JACC Cardiovasc Interv 2009;2:97–106. 84. Galassi AR, Tomasello SD, Costanzo L, et al. Long-term clinical and angiographic results of Sirolimus-Eluting Stent in Complex Coronary Chronic Total Occlusion Revascularization: the SECTOR registry. J Interv Cardiol 2011;24:426–36. 85. Saeed B, Kandzari DE, Agostoni P, et al. Use of drug-eluting stents for chronic total occlusions: a systematic review and meta-analysis. Catheter Cardiovasc Interv 2011;77:315–32. 86. Colmenarez HJ, Escaned J, Fernandez C, et al. Efficacy and safety of drug-eluting stents in chronic total coronary occlusion recanalization: a systematic review and metaanalysis. J Am Coll Cardiol 2010;55:1854–66. 87. Werner GS, Schwarz G, Prochnau D, et al. Paclitaxeleluting stents for the treatment of chronic total coronary occlusions: a strategy of extensive lesion coverage with drug-eluting stents. Catheter Cardiovasc Interv 2006;67:1–9. 88. Hong MK, Mintz GS, Lee CW, et al. Incidence, mechanism, predictors, and long-term prognosis of late stent malapposition after bare-metal stent implantation. Circulation 2004;109:881–6. 89. Jang JS, Hong MK, Lee CW, et al. Comparison between sirolimus- and Paclitaxel-eluting stents for the treatment of chronic total occlusions. J Invasive Cardiol 2006;18:205–8. 90. Suttorp MJ, Laarman GJ. A randomized comparison of sirolimus-eluting stent implantation with zotarolimus-eluting stent implantation for the treatment of total coronary occlusions: rationale and design of the PRImary Stenting of Occluded Native coronary arteries III (PRISON III) study. Am Heart J 2007;154:432–5. 91. Valenti R, Vergara R, Migliorini A, et al. Comparison of everolimus-eluting stent with paclitaxel-eluting stent in long chronic total occlusions. Am J Cardiol 2011;107:1768–71. 92. Valenti R, Vergara R, Migliorini A, et al. Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion. J Am Coll Cardiol 2013;61:545–50. 93. Moreno R, Garcia E, Teles RC, et al. A randomised comparison between everolimus-eluting stent and sirolimuseluting stent in chronic coronary total occlusions. Rationale and design of the CIBELES (non-acute Coronary occlusion treated by EveroLimus-Eluting Stent) trial. EuroIntervention 2010;6:112–6. 94. Moreno R, Garcia E, Teles R, et al. Randomized comparison of sirolimus-eluting and everolimus-eluting coronary stents in the treatment of total coronary occlusions: results from the chronic coronary occlusion treated by everolimus-eluting stent randomized trial. Circ Cardiovasc Interv 2013;6:21–8. 95. Lanka V, Patel VG, Saeed B, et al. Outcomes With FirstVersus Second-Generation Drug-Eluting Stents in Coronary Chronic Total Occlusions (CTOs): A Systematic Review and Meta-Analysis. J Invasive Cardiol 2014;26:304–10. 96. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI 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. Catheter Cardiovasc Interv 2012;79:453–95. 97. Wijns W, Kolh P, Danchin N, et al. 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). Eur Heart J 2010;31:2501–55.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:51

Coronary CTO

Percutaneous Treatment of Coronary Chronic Total Occlusion Part 2: Technical Approach Alfredo Ga la ssi, 1 Aa ron Gran t h a m , 2 D a v i d Ka n d z a r i , 3 Wi l l i a m L o m b a r d i , 4 I s s a m M o u s s a , 5 C ra ig T hompson, 6 Gera l d We r n e r, 7 Ch a r l e s Ch a m b e r s 8 a n d E m m a n o u i l B r i l a k i s 9 1. University of Catania, Catania, Italy; 2. Saint Luke’s Mid America Heart Institute and University of Missouri Kansas City, Missouri, US; 3. Piedmont Heart Institute, Atlanta, Georgia, US; 4. University of Washington, Seattle, US; 5. Mayo Clinic, Jacksonville, Florida, US; 6. Boston Scientific, Natick, Massachusetts, US; 7. Klinikum Darmstadt, Darmstadt, Germany; 8. Penn State University College of Medicine, Hershey, Pennsylvania, US; 9. VA North Texas Healthcare System and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, US

Abstract Dual injection is recommended for nearly all chronic total occlusion (CTO) percutaneous coronary intervention (PCI) to determine the optimal crossing strategy and guide wire advancement into the distal true lumen. Strategies that provide enhanced guide catheter support (such as long sheaths, large-bore guiding catheters, use of guide catheter extensions, and anchor techniques) are important for maximising the success rate and efficiency of CTO PCI. Use of a microcatheter or over-the-wire balloon is strongly recommended in CTO PCI for enhancing the penetrating power of the guidewire, enabling change in tip shape and allowing guidewire change (stiff CTO guidewires are not optimal for crossing non-occluded coronary segments). Adherence to a procedural strategy that standardises CTO technique and facilitates procedural success is recommended. Such a strategy would permit stepwise decision-making for antegrade and retrograde methods; inform guidewire selection; and incorporate alternative approaches for instances of initial failure. Given the paucity of long-term outcomes with use of novel crossing techniques (antegrade dissection/re-entry and retrograde), antegrade wire escalation is the preferred CTO crossing technique, if technically feasible. Using measures to minimise radiation exposure (including but not limited to use of 7.5 frames per second fluoroscopy and use of low magnification) and contrast administration is recommended. CTO PCI is best performed at centres with dedicated CTO PCI experience and expertise. Use of crossing difficulty prediction tools, such as the J-CTO score, can facilitate the selection of cases with a high likelihood of quick crossing that can be attempted at less experienced centres.

Keywords Percutaneous coronary intervention, chronic total occlusions, complications, outcomes Disclosure: Dr Grantham: educational grants from Abbott Vascular, Medtronic, Asahi-Intecc, BridgePoint Medical; speakers bureau, consulting fees and travel support from Abbott Vascular, BridgePoint Medical and Boston Scientific; CTO Scientific Advisory Board Boston Scientific, Banyan medical systems, Vascular solutions, Terumo; founding member of a web-based CTO-PCI education initiative called CTOFundamentals.org. All funds are paid to Saint Luke’s Cardiovascular Consultants or the Saint Luke’s Hospital Foundation. Dr Kandzari: Boston Scientific (advisory board/board member, grants or research support); Abbott Vascular (grants or research support); Micell Technologies (consultant); Medtronic (advisory board/board member, grants or research support); Dr Lombardi: BridgePoint Medical (stock owner or shareholder); BridgePoint Medical (consultant, advisory board/board member; Dr Thompson: employee, Boston Scientific; Dr Werner: speaker for ASAHI Intecc, Abbott Vascular, Biosensors, Terumo; principal investigator of a randomised trial on the benefit of CTO PCI vs medical therapy conducted by the EURO CTO Club sponsored by ASAHI Intecc and Biosensors; Dr Brilakis: consulting/speaker honoraria from St Jude Medical, Terumo, Janssen, Sanofi, Asahi, Abbott Vascular, Boston Scientific; research support from Guerbet; spouse is an employee of Medtronic. Dr Galassi, Dr Moussa and Dr Chambers have no conflicts of interest to declare. Acknowledgement: The authors would like to thank Ms Sheila Agyeman for her invaluable effort in coordinating the manuscript creation process. Received: 14 April 2014 Accepted: 10 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):201–7 Correspondence: Emmanouil S. Brilakis, MD, PhD, VA North Texas Health Care System, The University of Texas Southwestern Medical Center at Dallas, Division of Cardiology (111A) 4500 S. Lancaster Rd, Dallas, TX, US 75216. E: esbrilakis@gmail.com

Section A Techniques for Chronic Total Occlusions Revascularisation Access Route, Guiding Catheter Selection and Contralateral Injection The femoral approach is the preferred access route by most operators. However, the radial approach might be chosen because of severe peripheral vascular disease, operator’s preference or for contralateral injection. The guiding principle of access selection is that operators should use access routes that support their typical and optimal technique.1 The relative merits of potentially larger sheath/guide sizes (femoral) can be weighed against the reduction in vascular

Brilakis_Technique_FINAL.indd 201

complications and improved patient comfort (radial). 2,3 Both are acceptable. When femoral access is used, long (45 cm) sheaths can overcome iliac tortuosity and increase guide catheter support. Guiding catheter size is usually limited to six French (occasionally seven French) from the radial approach, compared with standard eight or seven French sheaths and guides used in transfemoral CTO PCI. Good passive support with coaxial alignment is crucial, especially in complex CTO procedures. Although the choice of the guiding catheter shape is generally dictated by personal experience, it is important to be willing to search for a guide with optimal back-up support rather than

201

05/09/2014 10:56

Coronary CTO accepting one with merely satisfactory support. The radial operator should be familiar with active guide manipulation to augment the support, and all operators should be versed in balloon anchoring and mother-and-child techniques to improve support when needed.4 When the distal vessel is filled by retrograde collaterals, the ipsilateral collaterals can have their flow impaired after wire and catheter advancement, resulting in a collateral or preferential collateral shift to the retrograde collaterals during the procedure. Therefore, in order to achieve the best diagnostic angiography (i.e. to fill the entire collateral bed), contralateral injection should be performed at the start of the procedure, if any visible contralateral collaterals are present. Operators from the EuroCTO Club have used contralateral injection in 62 % of cases in their personal series,5 whereas dual injection was used in 78 % of cases in a more recent North American series.6 Dual injection is best performed using low-magnification, so that the entire coronary tree is visualised without panning. Careful study of the collaterals not only provides important information in choosing the most appropriate collateral, but will also alert the operator to the risk for ischaemia and haemodynamic or electrical instability if the wired collateral becomes occluded. Careful and detailed review of the angiogram is critical for creating a primary and alternative CTO treatment strategies to optimise the efficacy, efficiency and safety of

to overcome any hard, calcified or fibrotic segments of the occlusion and then quickly change to soft polymer/hydrophilic wires to continue tracking along the occluded segment and complete the crossing of the CTO.7,15 Balloons or catheters should never be advanced over a wire unless it is certain that the wire is in the structure of the vessel, as wire perforations at the body of CTO are usually benign but can be catastrophic if larger equipment is advanced outside the vessel. Moreover, the CTO crossing wires should be exchanged once they access the distal true lumen for workhorse safer wires, as distal perforation of small vessels can cause delayed tamponade.16 Parallel Wire Technique This technique is applied when the first wire enters the false lumen. The first wire is left in place, and a second wire is passed parallel to the first wire aiming for the distal true lumen. Following this approach, the first wire keeps the dissection channel closed and serves as a marker for advancing and redirecting a second wire, which is selected for greater stiffness and control to overcome lesion resistance.17 Occasionally, three or more wires are used. Use of the parallel wire technique can reduce the need for multiple antegrade contrast injections, given that the first wire serves as a marker. Improved guidewires and modern re-entry techniques have reduced the need for parallel wiring in many programs.

the procedure.7 Anticoagulation during CTO PCI is best achieved with unfractionated heparin because it can be reversed with protamine in case of perforation and also allows titration of the anticoagulant effect (an activated clotting time of >350 seconds is recommended by many operators during retrograde CTO PCI to minimise the risk of donor vessel and guide thrombosis).8 As with all PCI, preloading with a P2Y12 ADP receptor inhibitor is important to reduce the risk of acute stent thrombosis and peri-procedural myocardial infarction.

Prediction of CTO Crossing Difficulty Predicting the difficulty of CTO crossing with a guidewire is important for case selection and procedural planning. The Multicentre CTO Registry of Japan (J-CTO) score is determined by assigning one point to each of five variables (previously failed lesion, blunt type of entry, calcification, bending, and occlusion length). Patients are classified into four difficulty groups: easy (J-CTO score of 0), intermediate (score of one), difficult (score of two), and very difficult (score of ≥3). The J-CTO score correlated well with the probability of successful guidewire crossing within 30 min (87.7 %, 67.1 %, 42.4 %, and 10.0 %, respectively)9 and was recently validated in an independent single-centre Canadian cohort.10 In a large retrograde CTO PCI series the only predictors of procedural failure were corkscrew tortuosity of the collateral channel and nonvisibility of the collateral connection with the recipient vessel.11

Antegrade Approach Antegrade recanalisation of CTOs has been and remains the most common approach worldwide.12–14 Single-wire Techniques (Modern Step-up/step-down) Very soft tapered polymeric wires are currently the initial wire choice in most CTO procedures. In approximately 40 % of cases, these wires will cross the occlusion by taking advantage of small, invisible channels or by tracking relatively soft tissue.5 The current trend in antegrade recanalisation is to rapidly step-up to stiff, spring-coil, tapered wires

202

Brilakis_Technique_FINAL.indd 202

Techniques with Subintimal Tracking The original Subintimal tracking and re-entry (STAR) technique introduced by Colombo et al.18 involves fashioning an “umbrellahandle-shaped” bend at the tip of a hydrophilic wire once the wire is within the dissection flap. Force is then applied to this tip and evenly distributed over a large surface area and along the length of the umbrella-handle in order to break through the sub-endothelial layer, thereby creating a communication between the false lumen and the true lumen. In theory, the looped “knuckle wire” follows the subintimal path to a point where the dissection can no longer be propagated, thereby achieving re-entry. The limitations of this method include unpredictability of the re-entry location and inability to prospectively control the major side branches proximal to the re-entry site, which can result in poor outflow and high re-occlusion rates, often >50 %.19,20 In order to simplify the original STAR technique and to make it more widely applicable, Carlino et al. introduced the contrast-guided STAR technique,21 which consists of gently injecting contrast into the subintimal space via an over-the-wire balloon or microcatheter or by employing the “microchannel technique”22 where contrast is injected with the aim of enlarging and connecting the microchannels that already exist within the occluded vessels. Galassi et al.23 further refined the STAR technique by proposing the “Mini-STAR” variant that uses very soft polymeric guidewires, the Fielder family of wires, Asahi Intecc (Nagoya, Japan). By forcing this type of wire with support from a microcatheter, a J-tip shape is automatically created within the occlusion, allowing for “mini subintimal tracking” and the creation of significantly smaller subintimal spaces. Finally, the limited antegrade subintimal tracking (LAST) technique, introduced by Dr Thompson and Dr Lombardi, is a similar technique designed for refractory anatomies. It uses a stiff, polymer-jacketed wire or a stiff, nonjacketed, penetration wire to redirect to the distal true lumen after facilitating device advancement with the knuckle wire technique.24 Wire-based subintimal tracking techniques, irrespective of the method

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:56

Percutaneous Treatment of Coronary Chronic Total Occlusion Part 2: Technical Approach

chosen, are best applied only as a bail-out to refractory antegrade and retrograde procedures in well-selected patients. Device-Assisted Antegrade Dissection/Re-entry The primary mode of failure when recanalising a chronically occluded vessel is entrapment of the guidewire and support equipment within the subintimal/subadventitial space and the inability to return into the distal true lumen. Recent technologies, “CrossBoss™” catheter, Stingray™ balloon and Stingray™ re-entry guidewire, Boston Scientific, (Natik, MA) have addressed this limitation and have provided a reproducible and systematic method for successfully gaining re-entry into the coronary lumen. The CrossBoss catheter is a metal-braided, over-the-wire, support catheter with a 1-mm rounded distal tip, which can be used to support standard guidewire manipulation or can be advanced using rapid rotation, with or without the wire lead. Without the wire lead, this catheter can cross into the distal true lumen of approximately 40 % of lesions.25 Alternatively it can enter into a side branch (which is important to recognise to avoid perforation) or cross within the subintimal space. This device’s relative safety and minimal perforation risk and the change in technique to a wire-skill independent model make it attractive for CTO crossing.25 If the CrossBoss catheter reaches a subintimal position, or if a standard wire strategy leads to subintimal wire entrapment, coronary re-entry can be systematically achieved with the Stingray coronary re-entry technologies (Boston Scientific). The Stingray balloon is a 1 mm thick, over-the-wire, balloon catheter with three exit ports (one distal and two 180°, diametrically opposed, side ports). When the balloon is inflated, it effectively wraps the artery with an exit port that is always directed towards the adventitia and an exit port that is always directed towards the lumen. Using fluoroscopy, operators can select the lumen port with the dedicated Stingray re-entry wire and achieve distal lumen control. Occasionally, subintimal wire entry can cause subintimal haematoma that can compress the distal true lumen, requiring aspiration through an over-the-wire balloon or microcatheter for decompression to enable distal true lumen re-entry (subintimal transcatheter withdrawal [STRAW] technique). For operators with access to these technologies and techniques, the need for the aforementioned parallel wire or wire-based re-entry methods is low. These technologies have been highly successful and have had low complication rates, even in early experiences and in refractory cases.25,26 The Retrograde Approach In 2005, Katoh et al. pioneered the modern era of retrograde CTO recanalisation,27 by introducing the following new techniques – targeted septal or epicardial collateral crossing, retrograde lesion crossing and management of the subintimal space through the use of balloon dilation for connecting antegrade and retrograde channels.8 Currently, retrograde procedures account for 15–34 % of all CTO PCI procedures in European and USA registries.5,28–30 These methods require access to the distal CTO vessel from a collateral (or occasionally bypass graft) vessel with successful placement of a support catheter.31 Retrograde Wire Crossing Retrograde wire crossing indicates lesion crossing in the distal to proximal cap direction with successful true lumen access to the proximal vessel.8 The standard approach after successful retrograde wire manipulation includes placing the wire and then the microcatheter into the antegrade guide catheter and then exchanging for a long wire to be externalised from the antegrade guide.32 The externalised wire,

INTERVENTIONAL CARDIOLOGY REVIEW

Brilakis_Technique_FINAL.indd 203

such as the ViperWire™ Advance (CSI, St Paul Minnesota), R350, Vascular Solutions (Minneapolis, Minnesota), RG3 (Asahi Intecc) is then used as the interventional platform to complete the PCI procedure.33 It is important for the retrograde guidewire to remain covered by a microcatheter to protect the collateral vessel from injury and to pay careful attention to guide movement to prevent guide-induced donor vessel injury. Kissing Wire Technique This technique combines the antegrade and retrograde approaches,34 although CTO penetration is achieved from the antegrade route. If the CTO lesion is relatively soft, the retrograde wire can be advanced easily, with the operator stopping the wire half way through the lesion. If the tip nears the CTO proximal cap, the operator can aim the tip towards the antegrade guide wire. Eventually, the antegrade and retrograde guide wires meet or “kiss”. This technique is generally used to reduce the use of contrast and to eliminate any potential ambiguity regarding the course of the vessel, thus making advancement of the antegrade wire safer. After crossing with the antegrade wire, the balloon catheter is advanced into the occlusion and dilatation is performed. The kissing wire technique is rarely performed by experienced retrograde operators, as the reverse controlled antegrade and retrograde tracking and dissection [CART], as described below) technique provides a more consistent method for connecting the channels in refractory cases. Knuckle Technique35 In this technique a dissection of the subintimal space is created by forming a loop in the retrograde wire, which is then advanced into the occluded segment. For this technique, soft hydrophilic wires are preferred, especially if there is good support from the retrograde microcatheter, for example the Corsair channel dilator (Asahi Intecc). However, an antegrade stiff wire is generally required in order to pass through the dissected lumen created by the knuckle wire. After crossing with the antegrade wire, PCI is performed as per usual fashion.36 CART Technique37 The principle of this technique is to create a subintimal dissection with limited extension only at the CTO site, thereby facilitating antegrade wire crossing. In practice, this involves exchanging the microcatheter for a balloon catheter after septal collateral dilation with a Corsair catheter or a small balloon (however, epicardial collaterals should never be dilated). This balloon catheter is advanced retrograde into the lesion and overlapped with the antegrade equipment. Dilation with an appropriately sized balloon will typically create a connection between the antegrade and retrograde spaces, which can be subsequently wired. The main disadvantages of this method include the need to pass the wire into an often small and diffusely diseased distal lumen and the inability to effectively use intravascular ultrasound to optimise the strategy. Reverse CART Technique The principle behind this technique is the same as that of the CART technique, except that the connected space is created with antegrade balloon dilation (after overlapping with the retrograde catheter), thereby facilitating the crossing of the occlusion with the retrograde wire. Currently, this is the dominant technique in the retrograde CTO approach.29 The optimal wire position for reverse CART is when both the antegrade and retrograde guidewire are located within the subintimal space. The most common reason for failure of this technique is use of undersized balloons, that can be prevented by using intravascular ultrasound for optimal balloon sizing and positioning.38

203

05/09/2014 10:56

Coronary CTO Section B

Figure 1: Hybrid Algorithm for Chronic Total Occlusion Percutaneous Coronary Intervention

Treatment of Lesions Resistant to Dilation

Dual Catheter Angiography Yes Antegrade Yes Wire escalation

No Fail

No 1. Clear proximal cap 2. Good Distal Target 3. Lenght <20 mm

Dissection Reentry (crossboss-stingray)

Retrograde Yes

Wire escalation

No Fail

Fail Dissection Reentry (reverse CART)

Dissection Reentry (reverse CART) Fail Dissection Reentry (crossboss-stingray)

CART = controlled antegrade and retrograde tracking and dissection

The most common current methods for successfully completing a retrograde CTO PCI procedure are the “true” wire crossing with externalisation and the reverse CART with wire externalisation. The kissing wire technique, the knuckle technique (without adjunctive reverse CART) and the classic CART technique are included for review completeness but are rarely performed at present.29 Hybrid Strategy for CTO PCI Contemporary antegrade, retrograde and dissection and re-entry techniques are complementary and necessary for the full spectrum of CTO PCI. Exploring sequential CTO crossing options can increase success, shorten procedural time and reduce radiation exposure. The CTO expert operator needs broad skillsets, versatility and flexibility to accommodate the wide range of anatomic scenarios for chronic occlusion that will be present in patients with strong indications for revascularisation.39 While significant variability exists with many operators with respect to procedural approaches, the “hybrid method” for CTO PCI represents an effort to standardise initial and provisional technique selection based on patient anatomy (see Figure 1).7 The implementation of the hybrid method requires skillset development in optimal wire manipulation, dissection/re-entry strategies and retrograde techniques. The development and adoption of only one or two of these skillsets will ultimately limit the experienced operator who wishes to approach all patients with appropriate indications for revascularisation. Failure to develop all three skillsets will likely lead to the dilemma of underutilisation of revascularisation in subgroups of patients who may derive the greatest benefit from these techniques. Development of a CTO PCI Program Successfully developing a CTO PCI program requires several steps; developing consensus among cardiologists (interventional and noninvasive), cardiac surgeons and hospital administrators regarding the rationale for CTO revascularisation; ensuring appropriate patient selection with individualised consideration of the risk/ benefit; obtaining CTO-specific didactic and hands-on training by experienced CTO operators; and establishing a quality assurance program with accountability of procedural results and acute and long-term clinical outcomes.40 The importance of the “heart team” that enables collaborative work between cardiac surgeons and cardiologists in making coronary revascularisation decisions for patients with complex coronary artery disease including CTOs, cannot be overemphasised.41

204

Brilakis_Technique_FINAL.indd 204

Although less common than failure to cross a CTO lesion with a guidewire, occasionally a coronary lesion cannot be crossed with a balloon or cannot be dilated with a balloon. It is important to confirm that the guidewire is in the vessel architecture or in the distal true lumen before proceeding with any over-the-wire catheter or before applying various dilation strategies. The vessel architecture can usually be determined by observing calcium deposits or other signs of the vessel outline moving or “dancing” in sync with the interventional guidewire. The distal true lumen can be determined by contralateral angiography. For cases in which a balloon cannot cross the lesion, the initial step is to advance a small (1.2–1.5 mm in diameter) balloon as deep as possible into the lesion to modify the proximal cap. When using small balloons, it is important to use longer length balloons (15–20 mm) because the largest profile of these balloons is at the mid shaft marker and the balloon tip will often penetrate the occlusion and stop at the marker. At this point, the balloon can be inflated to high pressure (14–16 atm) to determine if the lesion can be crossed from proximal to distal. If this fails, the next maneuver is to intentionally rupture the small balloon so as to modify the morphology of the proximal vessel/cap. If this fails to enable crossing then either a Corsair catheter, Asahi Intecc, (Nagoya, Japan) for more tortuous or less calcified lesions, or the Tornus catheter (Asahi Intecc) for more calcified lesions with shorter proximal stumps can be used.42 This is followed by maneuvers that can increase guide catheter support, such as use of guide catheter extensions43 or anchor techniques.4 Occasionally, a FineCross (Terumo, Somerset, New Jersey) or Valet (Volcano, Rancho Cordova, California) catheter may be able to cross lesions that the Corsair and Tornus catheters could not. The catheters can be rotated to facilitate their passage, as this will reduce friction within the vessel. If these maneuvers fail then more aggressive techniques, such as the use of coronary laser,44 rotational atherectomy,45 and the Crosser catheter, FlowCardia Inc. (Bard, Peripheral Vascular, Tempte, AZ)46 can be employed. Rotational atherectomy and the Crosser catheter can be used even when the wire is not in the distal lumen but still in the vessel architecture. Small burrs (usually 1.25 mm and no larger than 1.5 mm) can be used to modify the proximal vessel architecture, which may allow the base of operations (i.e. the over-the-wire catheter) to be moved to a more advantageous location. However, rotational atherectomy requires exchanging the guidewire, which can be accomplished by exchanging through an over-the-wire balloon or microcatheter. In situations where the distal true lumen has not been reached, the last 2 cm of the radiopaque wire tip can be removed prior to placement in the artery, thereby providing further reach with the burr (part of the radiopaque portion of the wire should be preserved to prevent the burr from going off the guidewire). Alternatively, the wire can be looped further down the vessel prior to atherectomy. Rotational atherectomy in the subintimal space should only be attempted by very advanced CTO operators. Similarly, there are several strategies for lesions resistant to balloon dilation, such as high pressure inflation of non-compliant balloons (with or without buddy wires), the use of cutting balloons or the AngioSculpt (AngioScore, Fremont, CA), the use of the Tornus catheter (Asahi Intecc), rotational atherectomy, and laser.47

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:56

Percutaneous Treatment of Coronary Chronic Total Occlusion Part 2: Technical Approach

If all of these techniques fail to achieve balloon crossing and/or balloon dilation of the lesion then success can often be achieved by recrossing the lesion within the subintimal space either in the antegrade direction using a prolapsed guide wire or CrossBoss catheter with re-entry of the true lumen prior to major branches,48 or using a retrograde approach with retrograde dissection and re-entry to go around the non-crossable or non-dilatable lesion.

Section C Use of Adjunctive Devices Multislice Computed Tomography and Intravascular Ultrasonography Intravascular ultrasonography can facilitate the recanalisation of stumpless CTO lesions by revealing the entry point of the occlusion when the occlusion site is angiographically unrecognisable due to its smooth entrance into the adjacent side branch. Moreover, intravascular ultrasonography can facilitate the repositioning of a guidewire in the event of an inadvertent subintimal passage and enable the selection of an optimal balloon size when reverse CART is performed.38

Table 1: Percutaneous Coronary Intervention Guideline Recommendations for Contrast-Induced Acute Kidney Injury Class I • Patients should be assessed for risk of contrast-induced acute kidney injury before PCI. • Patients undergoing cardiac catheterisation with contrast media should receive adequate preparatory hydration. • In patients with chronic kidney disease (creatinine clearance <60 cc/min), the volume of contrast media should be minimised. Class III: No Benefit Administration of N-acetyl-L-cysteine is not useful for the prevention of contrast-induced acute kidney injury. Taken from 2011 ACC/AHA/SCAI guidelines. ACC = American College of Cardiology; AHA = American heart association; SCAI = Society for Cardiovascular Angiography and Interventions

Table 2: Radiation Dose Management in Percutaneous Coronary Intervention I. Pre-Procedure A. Radiation Safety Program in the Cardiac Catheterisation Laboratory

1. Dosimeter use, shielding, training/education

B. Imaging Equipment with Operator Knowledge in Use

Multislice computed tomography can provide a detailed characterisation of the amount of calcification, tortuosity and length of the occluded segment, which can facilitate the procedural planning and estimation of the probability of successful PCI. Moreover, 3D reconstruction of the coronary anatomy and its integration with 2D fluoroscopy images during CTO PCI may help identify the best angiographic projection and provide a directional guide for the “missing segment” in the angiography.49

Section D CTO PCI Complications

1. On-screen dose assessment (Ka,r, PKA)

2. Dose saving: “fluoroscopy store” function, adjustable pulse and

frame rate, virtual collimation, last image hold.

C. Pre-procedure dose planning a. Assess patient and procedural issues including patient size and lesion(s) complexity. Examine patient’s back before starting re-attempt CTO PCI procedures. D. Informed Patient with appropriate Consent II. Procedure A. Limit fluoroscopy – step on pedal only when looking at screen B. Limit cine – use “fluoroscopy store” function when high quality imaging is not required, for example to document balloon and stent inflation

Complications during CTO PCI can be either acute or occur during long-term follow-up. Acute CTO PCI complications can be classified as coronary artery-related, (such as coronary occlusion, coronary perforation, and equipment loss or entrapment); cardiac non-coronary (such as periprocedural myocardial infarction, arrhythmias, and tamponade); and non-cardiac (such as vascular access complications, systemic embolisation, contrast-induced nephropathy, allergic reactions, and radiation-induced injury).16 A number of complications (such as donor vessel dissection or thrombosis) are specific to CTO interventions.16

C. Limit magnification, frame rate (7.5 frames per second is preferred), and

A meta-analysis of 65 studies with 18,061 patients undergoing CTO PCI reported a low incidence of acute complications. These were death 0.2 % (95 % CI: 0.1 % to 0.3 %); emergent coronary artery bypass grafting 0.1 % (95 % CI: 0.0 % to 0.2 %); stroke <0.01 % (95 % CI: 0.0 % to 0.1 %); MI 2.5 % (95 % CI: 1.9 % to 3.0 %); Q-wave MI 0.2 % (95 % CI: 0.1 % to 0.3 %); coronary perforation 2.9 % (95 % CI: 2.2 % to 3.6 %); tamponade 0.3 % (95 % CI: 0.2 % to 0.5 %); and contrast nephropathy 3.8 % (95 % CI: 2.4 % to 5.3 %).50 Given the low frequency of emergency coronary artery bypass grafting, the authors believe that surgical backup is not essential for CTO PCI programs, provided there is a tested plan for urgent transfer to a facility with cardiac surgery in case of complications. However, the performance of CTO PCI at facilities without on-site surgery is discouraged unless performed by an operator with considerable experience in CTO PCI and at a laboratory that has immediately available all interventional equipment needed for CTO PCI and for the management of potential complications.

B. Patient and referring physician notification for high doses

INTERVENTIONAL CARDIOLOGY REVIEW

Brilakis_Technique_FINAL.indd 205

steep angles D. Use collimation and filters to fullest extent possible E. Vary tube angle when possible to change skin area exposed F. Position table and image receptor appropriately: the patient should be placed as far possible from the X-ray tube and the image intensifier as close as possible to the patient G. Keep patient and operator body parts out of field of view H. Maximise shielding and distance from x-ray source for all personnel I. Manage and monitor dose in real time from the beginning of the case III. Post Procedure A. Document radiation dose in records (fluoroscopy time, Ka,r, PKA) 1. Ka,r >5 Gy, chart document; inform patient; arrange follow up 2. When Ka,r >10 Gy, qualified physicist should calculate skin dose

3. Peak Skin Dose > 15, contact risk management (sentinel event)

C. Adverse skin effects should be referred to appropriate consultant

Although coronary perforations are common in CTO PCI (27.6 % in one series15), most perforations are related to localised wire exit sites from the vessel architecture and limited to angiographic evidence of contrast staining. In the above meta-analysis of CTO complications the risk of perforation was 2.9 % but the risk of tamponade only 0.3 %.50 There are three main perforation types. The first is main vessel perforation, which may require implantation of a covered stent. The second is distal wire perforation and the third is collateral vessel perforation, which may require coil embolisation. 16 The availability of equipment for perforation management (covered

205

05/09/2014 10:56

Coronary CTO stents and coils) and familiarity with their use is important for every CTO PCI program. Contrast induced nephropathy (CIN), which was recently termed contrast induced acute renal injury (CI-ARI), is a well-recognised complication of invasive procedures using iodinated contrast agents. Patients at highest risk are those with baseline impaired renal function and diabetes. Mehran et al. developed a risk score for development of contrast nephropathy that includes eight variables (hypotension, intra-aortic balloon pump, congestive heart failure, chronic kidney disease, diabetes, age >75 years, anaemia and volume of contrast).51 CIN/CI-ARI is a contrast-dose dependent phenomenon.52 Laskey et al. determined that a contrast volume to creatinine clearance ratio >3.7 significantly increased the risk of CIN/CI-ARI in PCI patients.53 The use of this ratio to identify patients undergoing PCI who will benefit from less contrast and closer follow-up may improve care. Table 1 lists the recent 2011 ACC/AHA/ SCAI PCI guidelines for CIN/CI-ARI.41

required in 47.9 % of 74 patients treated with the contrast-guided STAR technique.56 In a single-centre study of 170 patients undergoing CTO PCI patients in whom the CrossBoss and Stingray devices were used (n=60) had similar long-term outcomes with 110 patients treated with other crossing strategies, in spite of its use in higher complexity cases.57 There are no published, long-term, outcome data on the use of the mini-STAR and LAST techniques (20). Similarly, only one of the 20 studies that examined the outcomes of patients treated with the retrograde approach provided long-term outcomes.20 The incidence of major adverse cardiac events in 24 patients during a median follow-up of 10.3 months was 18 %.58 Obtaining additional long-term data will be critical for assessing the comparative effectiveness of the various CTO crossing strategies.

Over the long-term, CTO interventions can be complicated by in-stent restenosis, stent thrombosis and coronary aneurysm formation. The use of drug-eluting stents significantly reduces the risk of restenosis (as described in part 1) without increasing the risk of stent thrombosis.54 The risk of coronary aneurysm formation and

Given that CTO PCI may expose patients to significant amounts of radiation, those patient should undergo careful follow-up to diagnose radiation-induced skin injury.59 The fluoroscopy time should not be used as the sole method for measuring radiation exposure because fluoroscopy time does not include cine imaging. Therefore, fluoroscopy time in and of itself is not a useful descriptor of the patient radiation dose. Total air kerma at the interventional reference point (Ka,r, Gy) is the procedural cumulative air kerma (X-ray energy delivered to a volume of air) at the interventional reference point and is used to monitor deterministic skin effects. No observable

their management has been poorly studied. Among 560 patients undergoing CTO PCI in Japan, aneurysms were observed in 7.3 % of those where retrograde intervention was performed vs 2.6 % of those where antegrade intervention was performed.55 There is limited information on the long-term outcomes of the novel dissection/ re-entry and retrograde techniques.20 Target lesion revascularisation was required at five months for 52 % of 31 patients treated with the STAR technique,18 whereas target vessel revascularisation was

effects are present with Ka,r, <2 Gy while effects may occur at >5 Gy, with significant skin injury possible at >15 Gy. In clinical practice, much higher doses could be tolerated before radiation skin injury occurs if multiple imaging angles are used, as this would produce smaller, single-site, peak skin doses than would occur if the X-ray source were stationary. Table 2 outlines a comprehensive approach to patient dose management that should be standard practice in all interventional laboratories, especially those performing CTO PCI.59 n

Section E Summary and Recommendations Specific recommendations regarding CTO PCI technique are as follows: 1. Dual injection is recommended for nearly all CTO PCI to determine and retrograde methods, inform guidewire selection and incorporate the optimal crossing strategy and guide wire advancement into the alternative approaches for instances of initial failure. distal true lumen. 5. Given the paucity of long-term outcomes with use of novel crossing 2. Strategies that provide enhanced guide catheter support (such as techniques (antegrade dissection/re-entry and retrograde), antegrade long sheaths, large-bore guiding catheters, use of guide catheter wire escalation is the preferred frontline CTO crossing technique, if extensions, and anchor techniques) are important for maximising the technically feasible. success rate and efficiency of CTO PCI. 6. Using measures to minimise radiation exposure (including but not 3. Use of an over-the-wire system is strongly recommended in CTO PCI for limited to use of 7.5 frames per second fluoroscopy and use of low enhancing the penetrating power of the guidewire, enabling change in magnification) and contrast administration is recommended. tip shape and allowing guidewire change (stiff CTO guidewires are not 7. CTO PCI is best performed at centres with dedicated CTO PCI optimal for crossing non-occluded coronary segments). experience and expertise. Use of crossing difficulty prediction tools, 4. Adherence to a procedural strategy (Figure 1) that standardises CTO such as the J-CTO score,9 can facilitate the selection of cases with technique and facilitates procedural success is recommended. Such a high likelihood of quick crossing that can be attempted at less a strategy would permit stepwise decision making for antegrade experienced centres.

1. Rinfret S, Joyal D, Nguyen CM, et al. Retrograde recanalization of chronic total occlusions from the transradial approach; early Canadian experience. Catheter Cardiovasc Interv 2011;78:366–74. 2. Hamon M, Mehta S, Steg PG, et al. Impact of transradial and transfemoral coronary interventions on bleeding and net adverse clinical events in acute coronary syndromes. EuroIntervention 2011;7:91–7. 3. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69:73–83.

206

Brilakis_Technique_FINAL.indd 206

4. Di Mario C, Ramasami N. Techniques to enhance guide catheter support. Catheter Cardiovasc Interv 2008;72:505–12. 5. Galassi AR, Tomasello SD, Reifart N, et al. In-hospital outcomes of percutaneous coronary intervention in patients with chronic total occlusion: insights from the ERCTO (European Registry of Chronic Total Occlusion) registry. EuroIntervention 2011;7:472–9. 6. Michael TT, Mogabgab O, Fuh E, et al. Application of the “hybrid approach” to chronic total occlusion interventions: a detailed procedural analysis. J Interv Cardiol 2014;27:36–43. 7. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79.

8. Brilakis ES, Grantham JA, Thompson CA, et al. The retrograde approach to coronary artery chronic total occlusions: a practical approach. Catheter Cardiovasc Interv 2012;79:3–19. 9. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. 10. Nombela-Franco L, Urena M, Jerez-Valero M, et al. Validation of the J-chronic total occlusion score for chronic total occlusion percutaneous coronary intervention in an independent contemporary cohort. Circ Cardiovasc Interv 2013;6:635–43.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:56

Percutaneous Treatment of Coronary Chronic Total Occlusion Part 2: Technical Approach

11. Rathore S, Katoh O, Matsuo H, et al. Retrograde percutaneous recanalization of chronic total occlusion of the coronary arteries: procedural outcomes and predictors of success in contemporary practice. Circ Cardiovasc Interv 2009;2:124–32. 12. Grantham JA, Marso SP, Spertus J, et al. Chronic total occlusion angioplasty in the United States. JACC Cardiovasc Interv 2009;2:479–86. 13. Morino Y, Kimura T, Hayashi Y, et al. In-hospital outcomes of contemporary percutaneous coronary intervention in patients with chronic total occlusion insights from the J-CTO Registry (Multicenter CTO Registry in Japan). JACC Cardiovasc Interv 2010;3:143–51. 1. Rinfret S, Joyal D, Nguyen CM, et al. Retrograde recanalization of chronic total occlusions from the transradial approach; early Canadian experience. Catheter Cardiovasc Interv 2011;78:366–74. 2. Hamon M, Mehta S, Steg PG, et al. Impact of transradial and transfemoral coronary interventions on bleeding and net adverse clinical events in acute coronary syndromes. EuroIntervention 2011;7:91–7. 3. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69:73–83. 4. Di Mario C, Ramasami N. Techniques to enhance guide catheter support. Catheter Cardiovasc Interv 2008;72:505–12. 5. Galassi AR, Tomasello SD, Reifart N, et al. In-hospital outcomes of percutaneous coronary intervention in patients with chronic total occlusion: insights from the ERCTO (European Registry of Chronic Total Occlusion) registry. EuroIntervention 2011;7:472–9. 6. Michael TT, Mogabgab O, Fuh E, et al. Application of the “hybrid approach” to chronic total occlusion interventions: a detailed procedural analysis. J Interv Cardiol 2014;27:36–43. 7. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5:367–79. 8. Brilakis ES, Grantham JA, Thompson CA, et al. The retrograde approach to coronary artery chronic total occlusions: a practical approach. Catheter Cardiovasc Interv 2012;79:3–19. 9. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. 10. Nombela-Franco L, Urena M, Jerez-Valero M, et al. Validation of the J-chronic total occlusion score for chronic total occlusion percutaneous coronary intervention in an independent contemporary cohort. Circ Cardiovasc Interv 2013;6:635–43. 11. Rathore S, Katoh O, Matsuo H, et al. Retrograde percutaneous recanalization of chronic total occlusion of the coronary arteries: procedural outcomes and predictors of success in contemporary practice. Circ Cardiovasc Interv 2009;2:124–32. 12. Grantham JA, Marso SP, Spertus J, et al. Chronic total occlusion angioplasty in the United States. JACC Cardiovasc Interv 2009;2:479–86. 13. Morino Y, Kimura T, Hayashi Y, et al. In-hospital outcomes of contemporary percutaneous coronary intervention in patients with chronic total occlusion insights from the J-CTO Registry (Multicenter CTO Registry in Japan). JACC Cardiovasc Interv 14. Sianos G, Werner GS, Galassi AR, et al. Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club. EuroIntervention 2012;8:139–45. 15. Rathore S, Matsuo H, Terashima M, et al. Procedural and in-hospital outcomes after percutaneous coronary intervention for chronic total occlusions of coronary arteries 2002 to 2008: impact of novel guidewire techniques. JACC Cardiovasc Interv 2009;2:489–97. 16. Brilakis ES, Karmpaliotis D, Patel V, Banerjee S. Complications of chronic total occlusion angioplasty. Interventional Cardiology Clinics 2012;1:373–89. 17. Mitsudo K, Yamashita T, Asakura Y, et al. Recanalization strategy for chronic total occlusions with tapered and stiff-tip guidewire. The results of CTO new techniQUE for STandard procedure (CONQUEST) trial. J Invasive Cardiol 2008;20:571–7. 18. Colombo A, Mikhail GW, Michev I, et al. Treating chronic total occlusions using subintimal tracking and reentry: the

INTERVENTIONAL CARDIOLOGY REVIEW

Brilakis_Technique_FINAL.indd 207

STAR technique. Catheter Cardiovasc Interv 2005;64:407–11; discussion 412. 19. Valenti R, Vergara R, Migliorini A, et al. Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion. J Am Coll Cardio l 2013;61:545–50. 20. Michael TT, Papayannis AC, Banerjee S, Brilakis ES. Subintimal dissection/reentry strategies in coronary chronic total occlusion interventions. Circ Cardiovasc Interv 2012;5:729–38. 21. Carlino M, Godino C, Latib A, et al. Subintimal tracking and re-entry technique with contrast guidance: a safer approach. Catheter Cardiovasc Interv 2008;72:790–6. 22. Carlino M, Latib A, Godino C, et al. CTO recanalization by intraocclusion injection of contrast: the microchannel technique. Catheter Cardiovasc Interv 2008;71:20–6. 23. Galassi AR, Tomasello SD, Costanzo L, et al. Mini-STAR as bail-out strategy for percutaneous coronary intervention of chronic total occlusion. Catheter Cardiovasc Interv 2012;79:30-40. 24. Lombardi WL. Retrograde PCI: what will they think of next? J Invasive Cardiol 2009;21:543. 25. Whitlow PL, Burke MN, Lombardi WL, et al. Use of a novel crossing and re-entry system in coronary chronic total occlusions that have failed standard crossing techniques: results of the FAST-CTOs (Facilitated Antegrade Steering Technique in Chronic Total Occlusions) trial. JACC Cardiovasc Interv 2012;5:393–401. 26. Werner GS, Schofer J, Sievert H, et al. Multicentre experience with the BridgePoint devices to facilitate recanalisation of chronic total coronary occlusions through controlled subintimal re-entry. EuroIntervention 2011;7:192–200. 27. Surmely JF, Tsuchikane E, Katoh O, et al. New concept for CTO recanalization using controlled antegrade and retrograde subintimal tracking: the CART technique. J Invasive Cardiol 2006;18:334–8. 28. Thompson CA, Jayne JE, Robb JF, et al. Retrograde techniques and the impact of operator volume on percutaneous intervention for coronary chronic total occlusions an early U.S. experience. JACC Cardiovasc Interv 2009;2:834–42. 29. Karmpaliotis D, Michael TT, Brilakis ES, et al. Retrograde coronary chronic total occlusion revascularization: procedural and in-hospital outcomes from a multicenter registry in the United States. JACC Cardiovasc Interv 2012;5:1273–9. 30. Michael TT, Karmpaliotis D, Brilakis ES, et al. Procedural Outcomes of Revascularization of Chronic Total Occlusion of Native Coronary Arteries (from a Multicenter United States Registry). Am J Cardiol 2013;112:488–92. 31. El Sabbagh A, Patel VG, Jeroudi OM, et al. Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: A weighted meta-analysis of 3482 patients from 26 studies. Int J Cardiol 2014:174:243-8. 32. Tsuchikane E, Katoh O, Kimura M, et al. The first clinical experience with a novel catheter for collateral channel tracking in retrograde approach for chronic coronary total occlusions. JACC Cardiovasc Interv 2010;3:165–71. 33. Galassi AR, Tomasello SD, Costanzo L, Tamburino C. Retrograde approach for chronic total occlusion percutaneous revascularization. Interventional Cardiology 2010;2:391–403. 34. Hsu JT, Tamai H, Kyo E, et al. Traditional antegrade approach versus combined antegrade and retrograde approach in the percutaneous treatment of coronary chronic total occlusions. Catheter Cardiovasc Interv 2009;74:555–63. 35. Galassi AR. 2010. Coronary Interventions for Chronic Total Occlusions; Galassi’s Tips and Tricks: Alpha. 36. Kimura M, Katoh O, Tsuchikane E, et al. The efficacy of a bilateral approach for treating lesions with chronic total occlusions the CART (controlled antegrade and retrograde subintimal tracking) registry. JACC Cardiovasc Interv 2009;2:1135–41. 37. Sianos G, Barlis P, Di Mario C, et al. European experience with the retrograde approach for the recanalisation of coronary artery chronic total occlusions. A report on behalf of the euroCTO club. EuroIntervention 2008;4:84–92. 38. Rathore S, Katoh O, Tuschikane E, et al. A novel modification of the retrograde approach for the recanalization of chronic total occlusion of the coronary arteries intravascular ultrasound-guided reverse controlled antegrade and retrograde tracking. JACC Cardiovasc Interv 2010;3:155–64. 39. Thompson CA. Percutaneous revascularization of coronary

chronic total occlusions: the new era begins. JACC Cardiovasc Interv 2010;3:152–4. 40. Karmpaliotis D, Lembo NJ, Brilakis ES, Kandzari DE. Percutaneous Chronic Total Occlusion Revascularization Program Development, Resource Utilization, and Economic Outcomes. Intervent Cardiol Clin 2012;1:391–5. 41. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/ SCAI 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. Catheter Cardiovasc Interv 2012;79:453–95. 42. Fang HY, Lee CH, Fang CY, et al. Application of penetration device (Tornus) for percutaneous coronary intervention in balloon uncrossable chronic total occlusion-procedure outcomes, complications, and predictors of device success. Catheter Cardiovasc Interv 2011;78:356–62. 43. Luna M, Papayannis A, Holper EM, et al. Transfemoral use of the GuideLiner catheter in complex coronary and bypass graft interventions. Catheter Cardiovasc Interv 2012;80:437–46. 44. Shen ZJ, Garcia-Garcia HM, Schultz C, et al. Crossing of a calcified “balloon uncrossable” coronary chronic total occlusion facilitated by a laser catheter: a case report and review recent four years’ experience at the Thoraxcenter. Int J Cardiol 2010;145:251–4. 45. Pagnotta P, Briguori C, Mango R, et al. Rotational atherectomy in resistant chronic total occlusions. Catheter Cardiovasc Interv 2010;76:366–71. 46. Galassi AR, Tomasello SD, Costanzo L, et al. Recanalization of complex coronary chronic total occlusions using high-frequency vibrational energy CROSSER catheter as first-line therapy: a single center experience. J Interv Cardiol 2010;23:130–8. 47. Lindsey JB, Banerjee S, Brilakis ES. Two “buddies” may be better than one: use of two buddy wires to expand an underexpanded left main coronary stent. J Invasive Cardiol 2007;19:E355–8. 48. Michael TT, Banerjee S, Brilakis ES. Subintimal distal anchor technique for “balloon-uncrossable” chronic total occlusions. J Invasive Cardiol 2013;25:552–4. 49. Magro M, Schultz C, Simsek C, et al. Computed tomography as a tool for percutaneous coronary intervention of chronic total occlusions. EuroIntervention 2010;6 Suppl G:G123–31. 50. Patel VG, Brayton KM, Tamayo A, et al. Angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 18,061 patients from 65 studies. JACC Cardiovasc Interv 2013;6:128–36. 51. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393–9. 52. Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13–9. 53. Laskey WK, Jenkins C, Selzer F, et al. Volume-to-creatinine clearance ratio: a pharmacokinetically based risk factor for prediction of early creatinine increase after percutaneous coronary intervention. J Am Coll Cardiol 2007;50:584–90. 54. Saeed B, Kandzari DE, Agostoni P, et al. Use of drug-eluting stents for chronic total occlusions: a systematic review and meta-analysis. Catheter Cardiovasc Interv 2011;77:315–32. 55. Tanaka H, Kadota K, Hosogi S, et al. Mid-term angiographic and clinical outcomes from antegrade versus retrograde recanalization for chronic total occlusions. J Am Coll Cardiol 2011;57:E1628. 56. Godino C, Latib A, Economou FI, et al. Coronary chronic total occlusions: mid-term comparison of clinical outcome following the use of the guided-STAR technique and conventional anterograde approaches. Catheter Cardiovasc Interv 2012;79:20–7. 57. Mogabgab O, Patel VG, Michael TT, et al. Long-Term Outcomes With Use of the CrossBoss and Stingray Coronary CTO Crossing and Re-Entry Devices. J Invasive Cardiol 2013;25:579–85. 58. Lee NH, Seo HS, Choi JH, et al. Recanalization strategy of retrograde angioplasty in patients with coronary chronic total occlusion -analysis of 24 cases, focusing on technical aspects and complications. Int J Cardiol 2010;144:219–29. 59. Chambers CE, Fetterly KA, Holzer R, et al. Radiation safety program for the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2011;77:546–56.

207

05/09/2014 10:56

Coronary CTO

New Advances in Chronic Total Occlusions Nik ola os Kons t a n t i n i d i s, 1,2 M i c h e l e P i g h i , 1 I s m a i l D o g u K i l i c, 1 R oberta Se r d o z , 1 G e o r g i o s S i a n o s 2 a n d Ca r l o D i M a r i o 1 1. National Institute for Health Research (NIHR) Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom; 2. 1st Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece

Abstract Coronary chronic total occlusions (CTOs) still represent the greatest technical challenge that interventional cardiologists face. CTOs remain seriously undertreated with percutaneous techniques, far below their prevalence. One reason for the low uptake was the suboptimal CTO percutaneous coronary intervention (PCI) success rates over a long period of time. During the last years, dedicated groups of experts in Japan, Europe and United States fostered the development and standardisation of modern CTO recanalisation techniques, along with providing focused training and proctorship worldwide. As a result, dedicated operators achieved success rates far beyond 90 %, while coping with lesions of increasing complexity. A series of studies, mainly retrospective and observational in nature, explored the prognostic impact of CTO PCI, revealing that successful lesion recanalisation is related to improved patient outcome and anginal status; further evidence from randomised trials is on the way. The following review reports on the most recent advances in the field of CTO recanalisation, in an attempt to promote a more balanced approach in patients with chronically occluded coronary arteries and encourage more operators to cope with these inherently complex lesions.

Keywords Coronary chronic total occlusion (CTO), retrograde approach, collateral circulation, prognostic benefit, J-CTO, subintimal space, true lumen re-entry Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: Nikolaos Konstantinidis is grateful to the Hellenic Society of Cardiology for the 2013 research grant. Received: 8 May 2014 Accepted: 10 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):208–12 Correspondence: Carlo Di Mario, NIHR Cardiovascular BRU, Royal Brompton Hospital, Sydney Street, London SW3 6NP. E: c.dimario@rbht.nhs.uk

Coronary chronic total occlusions (CTOs) are identified in up to one third of patients with coronary artery disease referred for nonurgent coronary angiography,1,2 with an incidence increasing with age.3 Conceptually, you may argue that the motivation to reopen a totally blocked artery is not as strong as for subocclusive lesions, that have the potential to progress and cause acute events. The evidence for coronary chronic occlusions goes into the opposite direction, suggesting that when viability and ischaemia are present reopening a coronary CTO yields a greater benefit than reopening subocclusive lesions. Data from mainly retrospective and observational series relate successful CTO recanalisation with improved survival, improvement in anginal status and left ventricular function, increased exercise tolerance and decreased need for coronary artery bypass grafting (CABG).4–8 CTOs still represent the most complex lesion subset that interventional cardiologists face. Lesions with severe tortuosities, calcifications or large bifurcations present technical challenges, but the success rate in expert hands remains far above 95 %.9 With the exception of dedicated centres applying new strategies, the success rate of CTO PCI was over long period of time in the range of 60-70 %,5 considerably lower than the success rate in non-occlusive coronary artery disease. Restenosis and reocclusion were also high before the introduction of Drug eluting stents (DES).10 The perception that CTOs are challenging lesions with a low success rate, limited scope for revascularisation and questionable

208

DiMario_FINAL.indd 208

impact on patient outcome led to underutilisation of percutaneous recanalisation, with the majority of lesions left to medical therapy or referred for surgical revascularisation. No more than 10 % of all CTOs have been treated with percutaneous techniques over a long period of time.1,3,11–14 The following review reexamines the evidence leading to this conservative attitude and reports the advances in the treatment of CTOs, promoting a more balanced and proactive approach in patients suffering of this often highly disabling condition.

Definition A chronic total occlusion is defined as a complete interruption of antegrade coronary flow (thrombolysis in myocardial infarction [TIMI-0] flow) of greater than three months standing.15 The long persistence of the occlusion implies the development of collateral circulation and this leads to opacification of the occluded distal vessel during injection in most cases. The pattern of distal filling – anterograde or with flow coming retrograde from the distal vessel – clarifies whether we are dealing with a real occlusion or a functional subocclusive lesion. Occasionally, non-intralesional bridging collaterals may give antegrade flow to the vessel beyond the occlusion. The careful examination of the occlusion in multiple views delineates the extraluminal course of these collaterals. Intraluminal channels are demonstrated pathologically in the majority of cases and may play a role in facilitating wire crossing16,17; yet they mostly remain

05/09/2014 10:59

New Advances in Chronic Total Occlusions

below the resolution of angiography (100 µm) and, by definition, have no continuity throughout the occluded segment or they violate the TIMI-0 criterion.18 The second criterion of CTO definition, occlusion duration, is more difficult to assess. Three levels of certainty are commonly used; occlusion duration angiographically confirmed, clinically confirmed and undetermined.15 A previous angiographic study confirming the presence of the CTO for more than three months is available in less than 30 % of cases, if you exclude high volume CTO centres receiving patients after previous attempts. A history of an acute coronary event or of a sudden change in symptoms can be used as a clinical surrogate in the absence of angiographic confirmation. A greater than three months duration is also assumed when there is a clear angiographic pattern compatible with total occlusion in the absence of recent symptom deterioration or with new symptoms clearly caused by an acute lesion in a different culprit artery.

with ‘difficult’ – J-CTO score equal or greater than 3 – lesions having a 73.3 % success rate and demanding a prolonged time for crossing.22 Technical progress and the introduction of the retrograde approach have certainly modified these percentages, probably cancelling the importance of some of these factors and shifting the field from lesion-related to collateral circulation-related predictive factors of failure. The presence and quality of the collaterals, their continuity and tortuosity, their location in the septum or in the epicardium, the angle of the collateral anastomosis with the CTO vessel become important factors if a retrograde strategy is considered.23 Non-invasive imaging, in particular coronary multi-slice computed tomography (MSCT), can help delineate the characteristics of the CTO, by definition invisible because not opacified. With coronary MSCT the occluded segment can be better delineated, calcium more reliably detected and quantified, the tortuosity and vessel path followed, the true length of the lesion better defined.

Rationale and Indications to CTO Recanalisation Prevalence and Occlusion Characteristics The frequency of CTOs depends on the type of patients studied with an incidence ranging between 10 and 30 % of all coronary angiograms.1,2 More recent reports tend to show a lower incidence, possibly explained by the universal use of primary angioplasty and early revascularisation in acute coronary syndromes. Still, silent ischaemia or presence of atypical symptoms misinterpreted at the time of the acute event account for the consistent persistence of CTOs in 18.4 % of patients even in the most recent series.1 You may expect that in patients with acute coronary syndromes CTOs are less frequent. In reality, even in patients with acute ST segment elevation myocardial infarction (STEMI), the incidence is 13 %.19 Interestingly, this subgroup of patients has a particularly poor immediate and long term prognosis. The presence of a CTO in a non-infarct-related artery was found to be a strong and independent predictor for both early mortality (within 30 days after STEMI) and late mortality (from 30 days to five years after STEMI).19,20 Inability to provide collaterals to the occluded vessel and, vice versa, acute impairment of preexisting collaterals from the acutely occluded vessel to the CTO jeopardising a large myocardial territory are possible explanations of this phenomenon, which also explains the prognostic benefit of recanalising CTOs. Far greater prevalence of CTOs, exceeding 50 % of cases,1 are identified in the subgroup of patients restudied after coronary artery bypass graft (CABG) implantation. Since interventions in degenerated bypass grafts have frequent embolic complications and poor long term durability, the recanalisation of the CTO in the native vessel is an appealing but often technically challenging alternative.21 Lesion characteristics play an important role in the likelihood of a successful recanalisation. Morino et al. introduced a lesion-related difficulty grading tool, the J-CTO score, based on a large series of anterograde recanalisations in Japan.22 Length greater than 20 mm, presence of a greater than 45 degrees bend within the occlusion, presence of intralesional calcification, delineation of a stump at the proximal end are four angiographic parameters shown to influence the percentage and time requested for anterograde recanalisation. With the addition of a fifth non-angiographic parameter derived from the clinical history, a previous failed attempt, it is possible to calculate the J-CTO score attributing to each of these parameters one point. ‘Easy’ lesions with a score of 0–1 had a success rate of greater than 90 % (97.8 % and 92.3 % respectively) and required a short time for wire crossing in most cases. Success progressively falls with an increased score

INTERVENTIONAL CARDIOLOGY REVIEW

DiMario_FINAL.indd 209

Relief of symptomatic ischaemia and angina and improvement of prognosis are the ultimate goals of CTO revascularisation. Borgia et al. documented that successful CTO PCI is related to improved angina-related quality of life (QoL).24 A number of retrospective reports and prospective registries have demonstrated that successful CTO revascularisation leads to enhanced left ventricular function tests and exercise tolerance, decreased need for CABG and improved survival and decreased cardiac mortality or complications in case of future acute events.4,5,7,19,20,25–28 Multicentre randomised trials, such as the EuroCTO trial, have been launched to further elucidate the prognostic impact of CTO revascularisation.15 In anticipation of the study results, the indications to revascularisation of CTOs should not differ from the indications to revascularisation of subocclusive lesions and can be defined based on a potential improvement of prognosis. The dimension of the occluded artery and the presence of other critically narrowed arteries weigh heavily in the decision to revascularise a CTO. Evidence of ischaemia and viability in the territory supplied by the occluded vessel, accompanied in most cases by anginal symptoms or anginal equivalents, should be confirmed.15 Imaging techniques are most suitable to define viability and ischaemia. Magnetic resonance imaging (MRI) can provide objective evaluation of pharmacologically-induced wall motion changes, precisely assessing myocardial fibrosis, perfusion29 and viability. Subendocardial extent of the late gadolinium enhancement smaller than 50 % of the wall thickness with MRI and reversible perfusion deficit greater than 10 % of the total myocardial mass with myocardial nuclear perfusion are currently used as gold standards for viability and prognostically relevant ischaemia. Patients with poorly controlled anginal symptoms with medical therapy may also have indications to revascularisation.30 A prerequisite to meet this indication is the optimisation of the dose and type of drugs, starting from beta-blockers, and the demonstration of objective evidence of ischaemia. Secondary causes of angina, such as anaemia or hyperthyroidism must be appropriately corrected. In theory, indications to surgery or angioplasty are based on the same criteria and the decision between one or the other is purely technical. Surgical revascularisation may be favoured in the presence of left main coronary artery disease, complex triple vessel disease (especially in patients with insulin-dependent diabetes, severe left ventricular dysfunction or chronic renal insufficiency), occluded proximal left anterior descending artery and multiple CTOs with a relatively low anticipated success rate.31 In practice, surgical

209

05/09/2014 10:59

Coronary CTO Figure 1: Intravascular Ultrasound (IVUS)-guided Chronic Total Occlusion (CTO) Recanalisation A

4 1

2 1

A: Stumpless proximal left anterior descending (LAD) occlusion at the takeoff of a sizeable first Diagonal branch (D1). B: Right coronary artery (RCA) providing retrograde flow to the occluded LAD via tortuous epicardial collaterals. C: Gaia Second wire (Asahi Intecc, Japan) supported by a Corsair microcatheter (Asahi Intecc, Japan) at the assumed proximal cap of the occlusion. IVUS catheter (Eagle Eye Platinum ST Catheter, Volcano, USA) in D1 identifying the proximal CTO cap; the wire is not visualised and retrieved. D: Following IVUS guided puncture of CTO proximal cap, an IVUS pullback from the D1 (vessel relatively parallel to the occluded proximal LAD) confirms the intra-CTO site of the wire from distal to proximal part (numbers 1 to 4) of the occlusion (arrows). E: Final angiographic result after a 2.5x38 mm and a 2.25x23 mm everolimus eluting stents implantation.

Figure 2: Anterograde Recanalisation Using the Parallel Wire Technique G

A: Right coronary artery (RCA) chronic total occlusion (CTO); blunt proximal stump and bifurcation at the site of CTO. B: Contralateral contrast injection revealing CC241 septal and epicardial collaterals from the left anterior descending (LAD) coronary artery. C: Bilateral contrast injection with the distal vessel opacified indicating a short and straight occluded segment. D: To prevent dislodgment of the guiding catheter while pushing wire and microcatheter through the occlusion, a 2.5x20 mm balloon is inflated in an atrial branch proximal to the occlusion (anchoring technique). The wire (Fielder XT, Asahi Intecc, Japan) made progress through the body of the occlusion but clearly appears to have deflected from the target. E: A Confianza Pro 12 wire (Asahi Intecc, Japan) supported by a Corsair microcatheter (Asahi Intecc, Japan) is advanced parallel to the Fielder XT wire left in place and steered towards the distal end of the occlusion. F: Successful chronic total occlusion (CTO) crossing; dissection at the site of the occlusion after predilatation. G: Final angiographic result after implantation of 3.5x38 mm and 3.0x38 mm everolimus eluting stents. There is no residual stenosis and (thrombolysis In myocardial infarction [TIMI]) flow is normal.

indications are rarely given if there is no involvement of the proximal left anterior descending coronary artery. The decisions should be taken in an open discussion among clinicians, interventionalists and cardiac surgeons. Data from large national registries (British Cardiovascular Interventional Society (BCIS), Swedish Coronary Angiography and Angioplasty Registry (SCAAR), American College of Cardiology (ACC) Dynamic registry) suggest underutilisation of PCI for CTO, limited to 5-6 % of all the revascularisation procedures and far below its prevalence.12,32 The preference given to surgery is probably not justified because recent trials show that more than 30 % of occlusions initially scheduled for bypass implantation were not grafted because of poor distal vessel quality and the occlusion rate of vein grafts, the most frequently used conduits for right and left circumflex coronary arteries, remains suboptimal and in some series in excess of 50 %.

Technique of CTO Recanalisation with Angioplasty Complete coronary occlusions have been approached by pioneers such as Kaltenbach and Reifart in Frankfurt or Hartzler and Rutherford in Kansas City more than 30 years ago, when the materials were often

210

DiMario_FINAL.indd 210

inadequate and the reocclusion rate prohibitive.33,34 The introduction of laser wires and of various devices that expected to improve success rates led to a revival in enthusiasm for CTO treatment in the early nineties. It also fostered the use of methods due to become standard, such as bilateral contrast injection for visualisation of the distal occluded vessel and assessment of the collateral circulation. However it was only in the last decade that the utilisation of percutaneous CTO recanalisation became more widespread thanks to the availability of dramatically improved wires and dedicated microcatheters, and the introduction of DES drastically reducing late failure.15 Much effort has been put forth to develop techniques to tackle these complex lesions and provide operators with strategies to optimise their success rate. The increase of success rate from 50–60 % to 80–90% of all CTOs attempted does not tell the full story because many CTO lesions routinely attempted in the last years were not even considered before, except by very few highly committed operators.35 Opening complex CTOs still remains a challenge requiring a certain learning curve before the operator becomes familiar and can be highly effective, while simultaneously keeping the procedure safe. An active CTO programme with specific proctorship and guided training are indispensable elements for a centre to obtain

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:59

New Advances in Chronic Total Occlusions

Figure 3: Retrograde Recanalisation with a Reverse Controlled Antegrade Retrograde Subintimal Tracking (CART) Technique A

K A: Proximal right coronary artery (RCA) chronic total occlusion (CTO) with tapered stump. B: Contralateral injection revealing retrograde filling of the distal vessel via septal collaterals. C: Selective contrast injection through a Corsair microcatheter (Asahi Intecc, Japan) better delineates the course of the septal collaterals. D: A mid continuous septal collateral (Werner CC1 [41]) is selected and crossed with a Sion wire (Asahi Intecc, Japan). E: Corsair microcatheter advanced into the distal true lumen over the Sion wire; selective contrast tip injection confirms intraluminal position. F: Bilateral contrast injection through the antegrade guiding catheter (GC) and the Corsair delineating the occlusion’s length. G: Antegrade wiring of the occlusion with a Gaia second wire. H: Bilateral wiring of the occlusion with a Gaia second wire antegrade and an Ultimate wire (Asahi Intecc, Japan) retrograde, both supported by Corsair microcatheters. I: Antegrade balloon dilatations enlarging the subintimal space to facilitate retrograde wire crossing (reverse CART technique). J: Guideliner™ (Vascular Solutions, Inc., Minneapolis, Minnesota) facilitated retrograde wire (Ultimate) crossing; the Corsair is advanced over the wire through the Guideliner in the antegrade GC and the externalisation of an RG3 wire (Asahi Intecc, Japan) allows antegrade insertion of balloons and stents. K: Final angiographic result after implantation of 4.0 x18 mm, 3.5x33 mm and 3.0x33 mm everolimus eluting stents.

the success rates reported above and a minimal number of 50 CTOs per year is considered essential for an operator to maintain competence.15,36 In that direction, crucial was the rapid development of dedicated CTO PCI equipment, such as long sheaths to optimise back-up support, over-the-wire microcatheters for wire support and frequent reshaping

and allowing anterograde completion of the procedure (see Figure 3). Second generation DES have been shown to reduce restenosis and reocclusion, while experienced operators have high thresholds for treating proximal or distal disease outside the occluded segment, often due to become less prominent and not flow limiting with

and exchange, wires of escalating stiffness with high steerability and tapering. Balloon anchoring for active support and trapping of wires within guiding catheters to facilitate removal of long microcatheters are useful adjunctive techniques common to contemporary CTO PCI.15 Stumpless occlusions may benefit from identification of the proximal end of the occlusion with MSCT before the procedure and intravascular ultrasound during the procedure (see Figure 1). At present, CTO recanalisation strategy depends on two important parameters – coronary anatomy and operator experience both with antegrade and retrograde techniques. For operators experienced in all CTO techniques, anatomy dictates the strategy. Antegrade approach is successful in most cases and should be attempted first in the majority of the occlusions. Although a retrograde approach is needed only in a minority of lesions and collateral crossing can be very time consuming and unpredictable even in the best hands, greater than 80–90 % success rates are unattainable without the addition of 15–20 % retrograde success in lesions failed anterogradely or with no anterograde options (true ostial occlusions, unidentified stump, ambiguous track).37

the growth of the vessel after flow restoration. Recently Brilakis et al. codified a strategy of initial selection and rapid switching from antegrade to retrograde approach should the initial strategy fail based on lesion characteristics and response, developing an unconventional use of rapid wire progression in the subintimal space knuckling it against the occlusion.39 The incidence of complications remains low when these procedures are performed by experienced operators and high volume laboratories, despite the long procedural duration and use of multiple aggressive wires and catheters.40 Wire exits are the norm in these procedures and are uneventful if promptly recognised and addressed. Drainage of pericardial tamponade and sealing of perforations with covered stents or microcoils are very rarely required but can be life-saving and the operator should be familiar with their use.

In case the antegrade wire cannot be advanced through the occlusion and appears to deflect to a subintimal position, a second wire can be directed towards the distal true lumen using the first as a marker (parallel wire technique) (see Figure 2). If the wire remains in the subintimal space for a longer track distal wire reentry can be attempted guided by ultrasound or using a dedicated flat balloon with lateral ports for wire exit (Sting-Ray™, Boston Scientific, USA).38 Katoh established the modern era of retrograde CTO recanalisation, guiding the development of dedicated microcatheters (Corsair®, Asahi Intecc, Japan) and delicate highly steerable wires (Sion, Fielder XT-R, Asahi Intecc, Japan) for use of tortuous septal and epicardial collaterals to probe the occlusion retrogradely, joining anterograde and retrograde wires with balloon inflation in the occlusion9. The externalisation of a long 330 cm 0.010 inch (0.26 mm) diameter RG3 wire (Asahi Intecc, Japan) after retrograde crossing post reverse controlled antegrade retrograde subintimal tracking (CART) became the final step in most of these complex procedures, providing excellent back-up support

INTERVENTIONAL CARDIOLOGY REVIEW

DiMario_FINAL.indd 211

Conclusion Thanks to increasing operator experience and development of more sophisticated techniques, CTO PCI is currently achieving high technical and procedural success rates and serves as an efficient alternative to the established approach of these complex lesions (medical therapy or surgery). The high incidence of CTO requires good clinical judgment in the selection of the lesions in need of recanalisation. Recent guidelines have corrected the mistakes from the misinterpretation of trials exploring the clinical benefit of universal recanalisation of recent occlusions after STEMI (Occluded Artery Trial(OAT) trial), responsible for inappropriate restrictions in the use of PCI for these lesions.30 Further technical development is needed to facilitate and simplify the revascularisation techniques, making them both safer and more standardised and predictable. Operator’s ability and centre’s experience play a key role in achieving final success, still highly variable from less than 70 % when bilateral injection, modern dedicated wires and retrograde recanalisation are not used to 80–90 % in an increasing number of high volume dedicated centres. Further evidence, ideally from randomised studies, of clinical benefit of these inherently complex procedures may encourage operators and centres to engage in this challenging endeavour. n

211

05/09/2014 10:59

Coronary CTO 1. Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol 2012;59:991–7. 2. Kahn JK. Angiographic suitability for catheter revascularization of total coronary occlusions in patients from a community hospital setting. Am Heart J 1993;126(3 Pt 1):561–4. 3. Cohen HA, Williams DO, Holmes DR, Jr., et al. Impact of age on procedural and 1-year outcome in percutaneous transluminal coronary angioplasty: a report from the NHLBI Dynamic Registry. Am Heart J 2003;146:513–9. 4. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992–2002. Eur Heart J 2005;26:2630–6. 5. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience J Am Coll Cardiol 2001;38:409–14. 6. Ivanhoe RJ, Weintraub WS, Douglas JS, Jr., et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Primary success, restenosis, and long-term clinical follow-up. Circulation 1992;85:106–15. 7. Werner GS, Surber R, Kuethe F, et al. Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion. Am Heart J 2005;149:129–37. 8. Serruys PW, Hamburger JN, Koolen JJ, et al. Total occlusion trial with angioplasty by using laser guidewire. The TOTAL trial. Eur Heart J 2000;21:1797–805. 9. Rathore S, Katoh O, Tuschikane E, et al. A novel modification of the retrograde approach for the recanalization of chronic total occlusion of the coronary arteries intravascular ultrasound-guided reverse controlled antegrade and retrograde tracking. JACC Cardiovasc Interv 2010;3:155–64. 10. Dzavik V, Buller CE, Devlin G, et al. Angiographic and clinical outcomes of drug-eluting versus bare metal stent deployment in the Occluded Artery Trial. Catheter Cardiovasc Interv 2009;73:771–9. 11. Abbott JD, Kip KE, Vlachos HA, et al. Recent trends in the percutaneous treatment of chronic total coronary occlusions. Am J Cardiol. 2006;97:1691–6. 12. Anderson HV, Shaw RE, Brindis RG, et al. A contemporary overview of percutaneous coronary interventions. The American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR). J Am Coll Cardiol 2002;39:1096–103. 13. Srinivas VS. Contemporary Percutaneous Coronary Intervention Versus Balloon Angioplasty for Multivessel Coronary Artery Disease: A Comparison of the National Heart, Lung and Blood Institute Dynamic Registry and the Bypass Angioplasty Revascularization Investigation (BARI) Study. Circulation 2002;106:1627–33. 14. Williams DO, Holubkov R, Yeh W, et al. Percutaneous Coronary Intervention in the Current Era Compared With 1985-1986 : The National Heart, Lung, and Blood Institute Registries. Circulation 2000;102:2945–51. 15. Sianos G, Werner GS, Galassi AR, et al. Recanalisation of Chronic Total coronary Occlusions: 2012 consensus

212

DiMario_FINAL.indd 212

document from the EuroCTO club. EuroIntervention 2012;8:139–45. 16. Srivatsa S, Holmes D, Jr. The Histopathology of Angiographic Chronic Total Coronary Artery Occlusions N Changes in Neovascular Pattern and Intimal Plaque Composition Associated with Progressive Occlusion Duration. J Invasive Cardiol 1997;9:294–301. 17. Katsuragawa M, Fujiwara H, Miyamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993;21:604–11. 18. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol 1997;29:955–63. 19. Claessen BE, van der Schaaf RJ, Verouden NJ, et al. Evaluation of the effect of a concurrent chronic total occlusion on longterm mortality and left ventricular function in patients after primary percutaneous coronary intervention. JACC Cardiovasc Interv 2009;2:1128–34. 20. Moreno R, Conde C, Perez-Vizcayno MJ, et al. Prognostic impact of a chronic occlusion in a noninfarct vessel in patients with acute myocardial infarction and multivessel disease undergoing primary percutaneous coronary intervention. J Invasive Cardiol 2006;18:16–9. 21. Konstantinidis N, Sianos G. Post-coronary Artery Bypass Grafting – Degenerated Saphenous Vein Graft Intervention, or Native Vessel Coronary Chronic Total Occlusion Recanalisation? Interventional Cardiology 2012;7:66–70. 22. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. 23. Rathore S, Katoh O, Matsuo H, et al. Retrograde percutaneous recanalization of chronic total occlusion of the coronary arteries: procedural outcomes and predictors of success in contemporary practice. Circ Cardiovasc Interv 2009;2:124–32. 24. Borgia F, Viceconte N, Ali O, et al. Improved cardiac survival, freedom from MACE and angina-related quality of life after successful percutaneous recanalization of coronary artery chronic total occlusions. Int J Cardiol 2012;161:31–8. doi: 10.1016/j.ijcard.2011.04.023. Epub Jul 1. 25. Olivari Z, Rubartelli P, Piscione F, et al. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol 2003;41:1672–8. 26. Hannan EL, Racz M, Holmes DR, et al. Impact of completeness of percutaneous coronary intervention revascularization on long-term outcomes in the stent era. Circulation 2006;113:2406–12. 27. Valenti R, Migliorini A, Signorini U, et al. Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion. Eur Heart J 2008;29:2336–42.

28. van der Schaaf RJ, Vis MM, Sjauw KD, et al. Impact of multivessel coronary disease on long-term mortality in patients with ST-elevation myocardial infarction is due to the presence of a chronic total occlusion. Am J Cardiol 2006;98:1165–9. Epub 2006 Aug 31. 29. Baks T, van Geuns RJ, Duncker DJ, et al. Prediction of left ventricular function after drug-eluting stent implantation for chronic total coronary occlusions. J Am Coll Cardiol 2006;47:721–5. 30. Task Force M, Montalescot G, Sechtem U, 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. 31. Stone GW, Reifart NJ, Moussa I, et al. Percutaneous recanalization of chronically occluded coronary arteries: a consensus document: part II. Circulation 2005;112:2530–7. 32. Delewi R, Hoebers LP, Ramunddal T, et al. Clinical and procedural characteristics associated with higher radiation exposure during percutaneous coronary interventions and coronary angiography. Circ Cardiovasc Interv 2013;6:501–6. 33. Kahn JK, Hartzler GO. Retrograde coronary angioplasty of isolated arterial segments through saphenous vein bypass grafts. Cathet Cardiovasc Diagn 1990;20:88–93. 34. Kaltenbach M, Hartmann A, Vallbracht C. Procedural results and patient selection in recanalization of chronic coronary occlusions by low speed rotational angioplasty. Eur Heart J 1993;14:826–30. 35. Syrseloudis D, Secco GG, Barrero EA, et al. Increase in J-CTO lesion complexity score explains the disparity between recanalisation success and evolution of chronic total occlusion strategies: insights from a single-centre 10-year experience. Heart 2013;99:474–9. 36. Thompson CA, Jayne JE, Robb JF, et al. Retrograde techniques and the impact of operator volume on percutaneous intervention for coronary chronic total occlusions an early U.S. experience. JACC Cardiovasc Interv 2009;2:834–42. 37. Sianos G, Barlis P, Di Mario C, et al. European experience with the retrograde approach for the recanalisation of coronary artery chronic total occlusions. A report on behalf of the euroCTO club. EuroIntervention 2008;4:84–92. 38. Whitlow PL, Burke MN, Lombardi WL, et al. Use of a novel crossing and re-entry system in coronary chronic total occlusions that have failed standard crossing techniques: results of the FAST-CTOs (Facilitated Antegrade Steering Technique in Chronic Total Occlusions) trial. JACC Cardiovasc Interv 2012;5:393–401. 39. Brilakis ES, Grantham JA, Rinfret S, et al. A percutaneous treatment algorithm for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2012;5(4):367–79. 40. Morino Y, Kimura T, Hayashi Y, et al. In-hospital outcomes of contemporary percutaneous coronary intervention in patients with chronic total occlusion insights from the J-CTO Registry (Multicenter CTO Registry in Japan). JACC Cardiovasc Interv 2010;3:143–51. 41. Werner GS, Ferrari M, Heinke S, et al. Angiographic assessment of collateral connections in comparison with invasively determined collateral function in chronic coronary occlusions. Circulation 2003;107:1972–7.

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 10:59

Coronary CTO

Contemporary Techniques for Coronary Chronic Total Occlusions Revascularisation: Sharing Experience in a Global World P roc eeding s of a sa t ellite sym p o s i u m h e l d a t E u r o PCR o n M a y 2 0 t h – 2 3 r d 2 0 1 4 i n Pa ris K a trina Mou n t f o r t , M e d i c a l Wr i t e r, R a d c l i f f e Ca r d i o l o g y Re vi ew ed for a c c ura c y by : Heinz Joa c h i m B ü t t n e r, 1 M a s a h i s a Ya m a n e, 2 N i c o l a u s Re i f a r t , 3 Ja v i e r E s can e d , 4 Georg ios Si a n o s, 5 O m e r G o k t e k i n 6 a n d Ro b e r t o G a r b o 7 1. Universitaets-Herzzentrum Freiburg, Bad Krozingen, Germany; 2. Sayama Hospital, Saitama, Japan; 3. Main Taunus Kliniken, Bad Soden, Germany; 4. Clinico San Carlos University Hospital, Madrid, Spain; 5. AHEPA University Hospital, Thessaloniki, Greece; 6. Bezmialem Vakıf University, Istanbul, Turkey; 7. Ospedale San Giovanni Bosco, Torino, Italy

Abstract Chronic total occlusions (CTO) are the most challenging lesions treated by interventional cardiologists. A symposium at EuroPCR 2014 discussed factors influencing the success of percutaneous intervention (PCI) in CTO. Current treatment paradigms suggest that one or two vessel disease should be treated by PCI while three-vessel disease requires surgery if complete revascularisation cannot be achieved with PCI. In patients with CTO and multi-vessel disease timing is key, and evidence of ischaemic burden and expected completeness of revascularisation is required before PCI is undertaken. Other factors affecting procedural success include the available equipment and expertise of the operator. Flexiblity in strategy selection is also important as it is frequently necessary to switch strategies during the procedure. The presentation included two live cases that illustrated the complexity of this procedure.

Keywords Coronary artery disease, chronic total occlusion, percutaneous intervention Disclosure: The reviewers have no conflicts of interest to declare. Received: 14 August 2014 Accepted: 21 August 2014 Citation: Interventional Cardiology Review, 2014;9(3):213–5 Correspondence: Katrina Mountfort, Medical Writer, Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. E: katsmountfort@virginmedia.com

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

Introduction and Objectives A symposium, chaired by Dr Heinz Joachim Büttner of Freiburg-Bad Krozingen (Germany) and Dr Masahisa Yamane of St Luke’s International Hospital (Tokyo, Japan) took place at EuroPCR, Paris on May 23rd, 2014. Its objectives were as follows: to learn how to improve the success of percutaneous intervention (PCI) in chronic total occlusion (CTO) by matching techniques to anatomical and clinical characteristics; to improve procedural skills in CTO and complex PCI by sharing experience with established operators during transmitted live cases; to understand why bioabsorbable polymer or polymer-free sirolimuseluting stents can improve long-term benefit in patients undergoing complex and CTO PCI and how to use imaging modalities to facilitate CTO recanalisation. Chronic total occlusions remain the most challenging lesions treated by interventional cardiologists. Approximately 30 % of all coronary angiograms in patients with coronary artery disease (CAD) show a CTO.1 These represent around 24 % of the patient population treated by PCI and 22 % of those treated by coronary artery bypass graft (CABG) according to the Synergy between PCI with Taxus™ and

Alvimedica3_CTO_V03.indd 213

cardiac surgery (SYNTAX) study. The majority of patients with CTO (56 %) are denied PCI and sent to surgery (see Figure 1).2 Successful recanalisation of a CTO is a strong independent predictor for reduced long-term mortality in patients with three vessel disease (3VD) but not with 1+2VD.3 In patients with multi-vessel disease and ST-elevation myocardial infarction (STEMI) undergoing primary PCI in the Harmonising outcomes with revascularisation and stents in acute myocardial infarction (HORIZONS-AMI) trial, a CTO in a non -infarctrelated artery was an independent predictor of early mortality. The presence of a CTO in a non-IRA was also an independent predictor of increased late mortality up to three years.4 A meta-analysis of randomised clinical trials and observational studies suggested that complete revascularisation is the optimal strategy in both CABG and PCI in patients with multi-vessel disease.5 Despite the improving success rates of PCI in CTO, they are still inferior compared to non-occlusive CAD. There is a great diversity in the complexity of the CTO lesion and the J-CTO (Multicenter CTO Registry of Japan) score has been developed as a model to stratify

213

05/09/2014 11:09

Coronary CTO Figure 1: The SYNTAX study – Proportion of Chronic Total Occlusions in Patients Selected for Percutaneous Intervention of Coronary Artery Bypass Graft

24 %

97.8 100 90 80 70 60 50 40 30 20 10 0 Risk groups: Easy

92.3

88.4 73.3

Final GW success %

56 %

Figure 2: Guidewire Manipulation Time and Success Rates for Different Multicenter CTO Registry of Japan Scores

22 %

>90 min 60–90 min 30–60 min =<30 min Intermediate

Difficult

Very difficult

J-CTO score:

>=3

PCI = Percutaneous Intervention; CAGBI = coronary artery bypass graft. Source: Serruys, 2009.2

Patient number 494

130

138

135

the complexity and predict expected success rates. According to that model there are four difficulty groups: easy (J-CTO score of 0), intermediate (score of 1), difficult (score of 2) and very difficult (score of ≥ 3), (see Figure 2).6 Score points were determined by assigning one point in the presence and zero in the absence of each of the following angiographic characteristics: calcification, intra CTO bending, blunt stump, occlusion length >20 mm and a previously failed lesion. Guidewire manipulation time and success rates for different J-CTO

J-CTO = Multicenter CTO Registry of Japan; GW = Guidewire. Source: Morino, 2011.6

Recanalisation techniques include the anterograde (single wire, parallel wire, intravascular ultrasound [IVUS] navigated, and their variations), the retrograde that require collateral crossing, CTO entering, wire (re)entry beyond CTO via reverse CART (controlled antegrade and retrograde tracking (CART), direct wire crossing kissing wire and their variations, and the dissection re-entry techniques that

scores are shown in Figure 2.

they can be used both antegrade and retrograde. n

Syntax PCI

Syntax CABGI

CABGI Registry

Adequate Patient Selection is Key to Ensure Success and Benefit of Coronary CTO PCI

In terms of predicting patient benefıt, the Euro CTO recommendations state that we should treat patients with CTO as any other CAD patients, provided the operator ıs experienced enough and that that the expected success rates are ın the range of 80 %. In a metaanalysis of CTO recanalisation, successful attempts were associated with symptomatic relief.8 Ischaemic burden is also reduced following PCI of CTO, and the decrease is greater at higher ischaemic burden. Conversely, in patients wıth a lower ischaemic burden, the treatment benefıt was less consıdering the presence of potential complıcations and treatment costs related to the procedures.9 It has been suggested that in the setting of CTO, we should select patients for PCI with ischaemic burden >10 % of myocardium, to achieve certain benefit.9 Individual patient data should be always taken into account. In multi-vessel disease and CTO, it is necessary to determine which lesion causes the symptoms, and also to obtain evidence of ischaemic burden and expected completeness of revascularisation. In the SYNTAX trıal ıncomplete revascularisation is associated with an increased rate

214

Alvimedica3_CTO_V03.indd 214

Figure 3: MACCE Event Rate in Complete (CR) and Incomplete Revascularisation (ICR) of CTO PCI (Total Occlusions) (n=286) 50 Estimated Event Rate (%)

Dr Gerald Werner from the Darmstadt Hospital (Germany) discussed the importance of patient selection in the PCI of coronary CTOs. Several questions should be addressed in the assessment of whether a patient with CTO will benefit from PCI. Is the patient symptomatic in terms of angina, dyspnoea or exercise limitation? Is there evidence of a prior MI? Accordıng to the EuroCTO club consensus document, recanalization of CTOs is ındıcated ın symptomatıc patıents that have no hıstory of prevıous MI. In case of prevıous MI viability should be documented ın the area provıded by the occluded artery and the myocardium at risk should be more than 10 %.7

Log=rank p=value 0.024 ICR: 39.9 %

40 30

CR: 26.6 %

20 10 0

365

730

1095

1460

MACCE (Days) MACCE = major cardiac and cerebrovascular events. Source: Farooq, 2013.

of major cardiac and cerebrovascular events (MACCE, see Figure 3) and the presence of CTOs is an ımportant contributor to the ıncomplete revascularısatıon.10 The residual SYNTAX score ıs an angıographıc tool that can quantıtate the level of the completeness of revascularisation. A residual SYNTAX Score exceeding eight was associated with high mortality (35.3 % all-cause mortality at five-years, p<0.001).11 Current treatment paradigms suggest that one or two vessel disease favours PCI while three-vessel disease requires surgery if complete revascularisation cannot be achieved with PCI. So, what if we can achieve complete revascularisation? This needs to be built into the guidelines. The strategy of the EuroCTO club in multi-vessel disease with CTO, is a staged procedure for non-CTO first, with the goal of complete revascularisation. n

INTERVENTIONAL CARDIOLOGY REVIEW

05/09/2014 11:09

Contemporary Techniques for Coronary Chronic Total Occlusions Revascularisation

Ensuring Procedural Safety and Good Long-term Results in Complex PCI Procedures Dr Nicolaus Reifart from Frankfurt, Germany, gave a presentation focussing on CTO and complex PCI procedures. Before undertaking PCI, all risks need to be addressed, and other options such as optimal medical therapy should be considered. Case selection should also be tailored to level of experience of the operator. Dr Reifart suggested that a level C operator is one who has undertaken less than 500 PCIs and should only undertake PCI of simple lesions and simple bifurcations. A level B operator has undertaken 500–1000 PCIs and can therefore attempt more complex procedures such as complex bifurcations, moderate calcified lesions and some cases of CTO. Only a level A operator, i.e. one who has performed more than 1000 PCIs, including 300 CTO, might undertake complex cases such as long and highly calcified lesions and complex CTOs including retrograde. If a level C operator attempts a level A task, he/she is less likely to be successful and may cause harm to the patient. Other considerations for procedural safety are the use of premedication and the amount of contrast used. The volume of dye used in a PCI procedure should not exceed 4–6 x the glomerular filtration rate (GFR).

and total occlusion of the right coronary artery (RCA). His SYNTAX score was 30. The LAD was treated fırst and the RCA was deferred for a second procedure performed lıfe durıng the meetıng. A PCI procedure of the RCA was undertaken, with the aim of implanting the Coracto™ sirolimus-eluting stent wıth bıodegradable polymer. The right femoral access approach was taken using a 7 Fr guidıng catheter for the donor artery and the right radial artery usıng a 6 Fr guıdıng catheter for the occluded artery. The CTO length was 10-15 mm with presence of some calcification. A procedural plan was presented: if one approach failed the next would be tried. An antegrade approach was initially used, with a plan to shift to retrograde if needed. During the procedure, the antegrade wire entered the subintimal space, and the wire could not cross to the distal true lumen, necessitating the retrograde approach to achıeve fınal success. Two Coracto™ sirolimus elutıng stents were successfully implanted wıth a very good final result.

Live case from Instituto Cardiovascular / Hospital Clínico San Carlos - Madrid, Spain

In terms of procedural time, completion within 60 min in 90 % of cases is expected. It is important to prepare for complications such as pericardial effusion. Finally, stent selection is important; the operator must decide which stent type and size is appropriate for the patient and the lesion. Contemporary DES should be considered for all CTO procedures.

Case 2: LAD CTO in single-vessel disease. Operators: Javier Escaned, Luis Nombela-Franco

Live Case from Instituto Cardiovascular/ Hospital Clínico San Carlos – Madrid, Spain

A PCI procedure of the LAD was undertaken, with the aim of implanting the Cre8 amphilimus polymer free elutıng stent. The procedure started with the use of IVUS to guide the puncture of the proximal cup wıth contemporary CTO guidewires. The procedure was not conceded during dedicated transmission tıme and continued further, but later had to be abandoned for a second attempt in the future. n

Case 1: RCA CTO in multi-vessel disease. Operators: George Sianos, Antonio Fernandez-Ortiz A case was presented of a 78 year-old man with hypertension, effort angina over the last month and resting chest pain. He had a severe calcified lesion in the proximal left anterior descending artery (LAD)

This case was a 63 year-old man with a single-vessel CTO. The coronary angiogram showed occlusion of the LAD at a bifurcation of a large fırst diagonal branch.

Take-home Message Dr Yamane concluded the session by emphasising the key messages. Patients with CTO and significant ischemia are at risk of MACE and have a clear indication for PCI. In terms of CTO and multi-vessel disease, timing is important, and much depends on whether complete revascularization can be achieved, the available equipment and expertise of the operator. It is important to be strict in terms of activated clotting time (ACT) monitoring and to be flexible 1. Aziz S, Ramsdale DR. Chronic total occlusions--a stiff challenge requiring a major breakthrough: is there light at the end of the tunnel? Heart 2005;91 Suppl 3:iii42–8. 2. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72. 3. Toma A, Gick M, Ferenc M, et al. Extent of coronary artery disease and prognostic effect of recanalisation success after percutaneous intervention for chronic total coronary occlusions. Eur Heart J 2013;34 (Abstract Supplement), 220. 4. Claessen BE, Dangas GD, Weisz G, et al. Prognostic impact of a chronic total occlusion in a non-infarct-related artery in patients with ST-segment elevation myocardial infarction: 3-year results from the HORIZONS-AMI trial. Eur Heart J 2012;33:768–75.

INTERVENTIONAL CARDIOLOGY REVIEW

Alvimedica3_CTO_V03.indd 215

in strategy selectıon; it is frequently necessary to switch strategies durıng the procedure. Safety and long-term outcomes should always be the priority in any procedure. In terms of stent selection, once the vessel is open in a CTO, it is essential to use thin-strut biodegradable polymer or polymer free drug-eluting stents (DES) that exert low-restenosis rates, as restenosis rates are still high in CTO patients. n

5. Garcia S, Sandoval Y, Roukoz H, et al. Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. J Am Coll Cardiol 2013;62:1421–31. 6. Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv 2011;4:213–21. 7. Sianos G, Werner GS, Galassi AR, et al. Recanalisation of chronic total coronary occlusions: 2012 consensus document from the EuroCTO club. EuroIntervention 2012;8:139–45. 8. Joyal D, Afilalo J, Rinfret S, Effectiveness of recanalization of chronic total occlusions: a systematic review and metaanalysis. Am Heart J 2010;160:179–87.

9. Safley DM, Koshy S, Grantham JA, et al. Changes in myocardial ischemic burden following percutaneous coronary intervention of chronic total occlusions. Catheter Cardiovasc Interv 2011;78:337–43. 10. Farooq V, Serruys PW, Garcia-Garcia HM, et al. The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial. J Am Coll Cardiol 2013;61:282–94. 11. 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.

215

05/09/2014 11:09

CIT2015 Ad.indd 216

04/09/2014 19:05

PCR_216x303_HR.indd 1

04/09/2014 19:10

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

AN INTERACTIVE LIVE CASE COLLABORATION BETWEEN

LIVE FROM THE HAMMERSMITH

NEXT LIVE CASE - Clinical Utilisation of Fractional Flow Reserve in Multi-Vessel Disease

LIVE WEBCAST on Monday 13th October 2014 14:30-15:30 GMT (15:30-16:30 CET; 9:30-10:30AM EST, 6:30-7:30AM PST)

PROVISIONAL AGENDA • Introduction to the ethos of Live from the Hammersmith

Performed by

• Outline for the live case broadcast

Dr. Justin E Davies

• Importance of FAME 3, Syntax in multi-vessel disease assessment

Consultant Cardiologist

in changing patient demographics

Imperial College NHS Trust

• Introduction of patient case • FFR set up at the Hammersmith • Essentials for good measurement • ABC of measurement (normalisation, nitrates, and measurement) • Measurements and Treatment • Review of Case - how FFR changed practice in context of Syntax • Session Ends

live case hammersmith.indd 1

05/09/2014 11:24