ICR 8.1 by Radcliffe Cardiology

Interventional Cardiology Review Volume 8 • Issue 1 • Spring 2013

Volume 8 • Issue 1 • Spring 2013

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Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review Heleen MM van Beusekom et al

Coronary Chronic Total Occlusion Recanalisation – Current Techniques and Approaches Vijay S Ramanath and Craig A Thompson

Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve Willem IM Willaert and Isabelle Van Herzeele

Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Unprotected Left Main Disease – A Review Edward McNulty

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Volume 8 • Issue 1 • Spring 2013

Publishing

Editorial Board Fernando Alfonso

Raimund Erbel

Jeffrey W Moses

Professor of Cardiology, West-German Heart Centre, University Duisburg-Essen

Professor of Medicine, Columbia University Medical Center

Tatiana Losinska

Instituto Cardiovascular, Hospital Universitario Clínico “San Carlos”, Ciudad Universitaria, Madrid

David Antoniucci

Ted Feldman

Production

Director, Cardiac Catheterization Laboratory Evanston Hospital

Marko Noc

Managing Editor Jonathan McKenna

Designer

Craig Young

Publication Manager Liam O’Neill

Publisher

David Ramsey

Editorial Contact Jonathan McKenna jonathan.mckenna@radcliffepublishing.com

Head, Division of Cardiology, Careggi Hospital

Gerald Barbeau Institut de cardiologie et de pneumologie, Hopital LAVAL

Olivier F Bertrand Assistant Professor, Laval University, Quebec City

Lutz Buellesfeld HELIOS Heart Center Siegburg

Circulation Contact

Antonio Colombo

david.ramsey@radcliffepublishing.com

Clinical Professor of Medicine, New York University

Commercial Contact

Alberto Cremonesi

liam.oneill@radcliffepublishing.com

Department of Vascular and Endovascular Surgery, University of Siena

David Ramsey

Liam O’Neill

Cover image Micrograph of blood vessel © Pan Xunbin | shutterstock.com

Alain Cribier Head, Department of Cardiology, University Hospital Charles Nicolle, Rouen

Bernard De Bruyne Interventional Cardiology Review acknowledges the support of the following companies in the publication of this edition:

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Accumetrics ACIST Medical Systems Alvimedica Balton Medtronic

Wim J van der Giessen Jeffrey J Popma Thoraxcenter, Erasmus University Medical Center, Rotterdam

Juan F Granada Assistant Professor of Medicine, Columbia University Medical Center

A Pieter Kappetein Thoraxcenter, Erasmus University Medical Center, Rotterdam

Ajay J Kirtane Assistant Professor of Clinical Medicine, Columbia University Medical Center

Antoine Lafont Professor of Medicine, University of Paris

Martin B Leon Professor of Medicine, Columbia University Medical Center

Cardiovascular Center, Aalst

Axel Linke

Giuseppe De Luca

Roxana Mehran

Division of Cardiology “Federico II” University, Naples

Eric Eeckhout Associate Professor, Centre Hospitalier Universitaire Vaudois

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

Heart Center, Leipzig Associate Professor of Medicine, Columbia University Medical Center

Gary S Mintz Chief Medical Officer, Cardiovascular Research Foundation

Associate Professor of Medicine, Harvard Medical School

Carlos E Ruiz Director, Structural Heart Disease Department, Lenox Hill Heart and Vascular Institute, New York

Marc van Sambeek Associate Professor, Department of Anesthesiology, Erasmus University Medical Center, Rotterdam

Albert Schömig Professor of Medicine, Deutsches Herzzentrum and I Medizinische Klinik, Munich

Gregg W Stone Professor of Medicine, Columbia University Medical Center

Martyn Thomas Clinical Director for Cardiothoracics, St Thomas’ Hospital, London

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Interventional Cardiology Review wishes to thank the organisations below for their assistance. This does not constitute any official endorsement.

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Published by Radcliffe. Radcliffe is the trading name of Electric Word Plc. All information obtained by Radcliffe and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe 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. 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, 33–41 Dallington Street, London, EC1V 0BB, UK. © 2013 All rights reserved

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Established: June 2006 Frequency: Bi-annual

Current issue: Spring 2013

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

Structure and Format • Interventional Cardiology Review is a bi-annual journal comprising review articles, editorials, and case reports. • The structure and degree of coverage assigned to each category of the journal is determined by the Editor, 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, 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 and Editorial Board to determine their suitability for inclusion. • The Editor, following consultation with the Editorial Board, identifies appropriate reviewers, who are selected on the basis of their specialist knowledge in the relevant area. • Following review, papers 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 reserves the right to accept or reject any proposed amendments.

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Editor with guidance from the Editorial Board. Following acceptance of an invitation, the author(s) and Editor formalise the working title and scope of the article. Subsequently, the 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 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 (minimum order 1,000). Please contact Jonathan McKenna at jonathan.mckenna@radcliffepublishing.com

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

Copyright and Permission Radcliffe 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 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’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review. n

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Contents • Volume 8 • Issue 1 • Spring 2013

Foreword 06

Raimund Erbel

Coronary

→ Acute Coronary Syndrome

Acute Coronary Syndrome in Pre- and Post-partum Women – A Review

Gianfranco Aprigliano, Altin Palloshi, Nuccia Morici, Roberto Ferraresi, Michele Bianchi and Angelo Anzuini

→ Percutaneous Coronary Intervention

14 Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Unprotected Left Main Disease – A Review

Edward McNulty

→ Bifurcation Stenting

19 Dedicated Bifurcation Drug-eluting Stent BiOSS® – A Novel Device for Coronary Bifurcation Treatment

Robert J Gil, Dobrin Vassilev and Jacek Bil

→ Bioresorbable Scaffolds

Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review

Nienke S van Ditzhuijzen, Jurgen MR Ligthart, Nico Bruining, Evelyn Regar and Heleen MM van Beusekom

→ Contrast Delivery Systems

36 Understanding and Minimising Occupational Radiation in the Catheterisation Laboratory with PISAX and the ACIST CVi® Contrast Delivery System

Based on an interview with Olivier Bar, Interventional Cardiologist, Saint Gatien Clinic, Tours, France

→ Chronic Total Occlusion

Coronary Chronic Total Occlusion Recanalisation – Current Techniques and Approaches

On behalf of the North American Total Occlusion (NATO) Operators

Vijay S Ramanath and Craig A Thompson

46 Double Chronic Total Occlusion Recanalisation with Antegrade and Retrograde Techniques and the Use of a Novel Drug-eluting Stent with Biodegradable Polymer

Nikolaos V Konstantinidis and Georgios Sianos

Endovascular Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve W illem IM Willaert and Isabelle Van Herzeele

On behalf of the European Virtual reality Endovascular RESearch Team (EVEREST)

57 Endovascular Abdominal Aortic Aneurysm Repair – Patient Selection and Long-term Outcome Expectations – Current Challenges in 2013 R egula S von Allmen, Florian Dick, Thomas R Wyss and Roger M

ICR_contents_8.1NEW.indd 4

Greenhalgh

INTERVENTIONAL CARDIOLOGY REVIEW

18/04/2013 11:33

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Foreword

Raimund Erbel is Director of the Department of Cardiology, West German Heart Center, Essen, in the Division of Internal Medicine at the University Essen, Germany. Prior to his current position, Professor Erbel served as a consultant at the Medical Clinic, Johannes Gutenberg University Mainz, from 1982 to 1993. He studied at the University of Cologne and specialised in cardiology at the University of Düsseldorf. Published widely in leading journals, Professor Erbel is a member of numerous professional bodies, including a Fellow of the American Heart Association, American College of Cardiology, the European Society of Cardiology, and the American Society of Echocardiography. The recipient of several notable awards, Professor Erbel’s major research fields include coronary arteriosclerosis, aortic dissection, microtechniques in cardiology and percutaneous treatment of valvular heart disease.

owadays ‘interventional cardiology’ is not only looking to coronary arteries, but also to structural heart disease, valvular heart disease as well as cardiovascular diseases.

Since the introduction of percutaneous transluminal coronary angioplasty (PTCA), diagnostic tools for percutaneous coronary interventions (PCIs) now not only include coronary angiography but also intravascular ultrasound, optical coherence tomography and, recently, infrared spectroscopy. These different diagnostic imaging techniques are discussed in a review by van Beusekom et al. concerning bioresorbable coronary stents, called scaffolds. The acute coronary syndrome in pre- and post-partum women can be regarded as a big challenge for cardiologists but also gynaecologists and is covered by Aprigliano et al. in an interesting and stimulating review. The re-opening of occluded coronary vessels can be performed, but it can be regarded as the most intensive and most experience-requiring technology in interventional cardiology as demonstrated by Ramanath and Thompson. Elsewhere, McNulty reviews the current value of coronary artery bypass grafting versus PCI for unprotected left main disease; a typical heart term topic. As a young doctor, I already proposed carotid artery stenting in 1979 in a forum with neurologists and cardiologists at the University Aachen, Germany. People were laughing but became serious when such a question was discussed in the early beginnings of PTCA. However, 35 years later carotid artery stenting is an established cardiovascular interventional strategy, as presented by Willaert and Van Herzeele. The alternative to surgery is also endovascular treatment for abdominal aortic aneurysm (AAA). Patient selection and long-term outcome is discussed by Greenhalgh et al. I am convinced that interventional cardiologists will find this volume interesting, with reviews and new details for their daily work not only related to coronary but also to cardiovascular interventions. I hope everyone enjoys this volume of Interventional Cardiology Review. n

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18/04/2013 11:32

Simply Less Exposure. Managing radiation exposure is a concern in every cath lab1. Today’s complex procedures can require more images and the transradial approach can increase your proximity to the radiation source2. The ACIST|CVi® Contrast Delivery System allows you to maintain precise control of contrast injection3,4 while taking a step back from the radiation source, reducing your exposure whatever your approach5. Make the ACIST CVi system part of your radiation safety program. To learn more visit www.acist.com

1. International Commission on Radiological Protection (ICRP) Publication 85. Ann ICRP. 2000;30(2) 2. Mercuri M, Mehta S, Xie C, et al. JACC Cardiovasc Interv. 2011;4(3):347–352 3. Anne G, Gruberg L, Huber A, et al. J Invasive Cardiol. 2004;16(7):360–362 4. Call J, Sacrinty M, Applegate R, et al. J Invasive Cardiol. 2006;18(10):469–474 5. Brosh D, Assali A, Vaknin-Assa H, et al. Int J Cardiovasc Intervent. 2005;7(4):183–187 Bracco Group © 2013 ACIST Medical Systems, Inc. All rights reserved.

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16/04/2013 12:48

Coronary Acute Coronary Syndrome

Acute Coronary Syndrome in Pre- and Post-partum Women – A Review Gianfranco Aprigliano1, Altin Palloshi1, Nuccia Morici2, Roberto Ferraresi1, Michele Bianchi1 and Angelo Anzuini3 1. Interventional Cardiovascular Unit, Cardiology Department, Istituto Clinico Città Studi, Milan, Italy; 2. Cardiologia 1, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milan, Italy; 3. Cardiology Department, Istituto Clinico Mater Domini. Castellanza, Italy

Abstract Acute coronary syndrome (ACS) during pregnancy and the post-partum period are weighed by a high mortality rate for the mother and foetus. They should be considered as multifactorial diseases with a special role for sexual hormones. In this setting, ACS is mostly related to an early atherosclerotic disease, even if other conditions are responsible. Indeed, an important part is due to spontaneous coronary artery dissection, more common during delivery and the post-partum period. In the remaining situation, an isolated intracoronary thrombus or a normal angiographic pattern can be found at angiography. Pathophysiology is still uncertain with different hypothetical mechanisms. Prompt diagnosis of ACS and aetiology are essential for an optimal therapeutic strategy. Difficulties in treatment management is a matter for debate, especially in pre-partum women. In the last two decades improvements of diagnostic tools, coronary angiography and subsequent percutaneous treatment have changed the natural history of this rare condition.

Keywords Spontaneous coronary dissection, acute coronary syndrome, percutaneous coronary intervention, pregnancy, post-partum, acute myocardial infarction, sudden cardiac death, coronary thrombosis Disclosure: The authors have no conflicts of interest to declare. Received: 1 November 2012 Accepted: 13 January 2013 Citation: Interventional Cardiology Review, 2013;8(1):8–13 Correspondence: Gianfranco Aprigliano, via Mazzini, 9 A Cassina De’Pecchi, MI 20060, Milan, Italy. E: gianfrancoaprigliano@hotmail.com

Cardiovascular diseases represent the leading cause of mortality in pregnancy.1,2 They are classified as direct (acute onset disease) or indirect (worsening of pre-existing cardiac disease). This overview is focused on acute coronary syndrome (ACS) in pregnancy and the post-partum period. ACS in this setting is a rare condition, but in the last two decades its incidence has grown.3 This phenomenon may be partially due to a higher diagnostic accuracy secondary to the advent of troponin monitoring and increasing availability of catheter laboratories. On the other hand, pregnancy is a condition that may worsen the presence of atherosclerotic disease (AD) or impair coronary blood flow, yielding spasm, thrombus formation or spontaneous dissection. Finally, the increased pregnancies in women over 35 years who already have cardiac risk factors is a growing phenomenon.4 Generally ACS occurs during the third trimester of gestation and extends until the second month post-partum. Although peak incidence have been reported between the last month of gestation and the first two weeks post-partum.5 Clinical presentation vary from unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI) to ST elevation myocardial infarction (STEMI), which may be complicated by cardiogenic shock and death. The diagnosis is often difficult either because of its abrupt onset in non-suspected cohort or because of the fact that gestational status may mimic a variety of symptoms.

Epidemiology ACS during pregnancy is considered rare, representing only a small part of the adverse events. Its incidence ranges from 3 to 10 per 100,000 deliveries6 with high rates of maternal and foetal mortality.7 A recent US

Aprigliano_edited.indd 8

population-based study revealed that about two-thirds of ACS occurred during pregnancy whereas one-third occurred during the post-partum period.3 This study showed that between the years of 2000 and 2002 only 45 % of women with ACS underwent coronary angiography and 37 % received percutaneous or surgical treatment. Deepening for racial differences; black woman had the highest risk for ACS (11.4 cases every 100,000 deliveries) followed by white woman (7.6/100,000) and then hispanic woman (4.2/100,000).3 Furthermore, age was shown to be a strong risk factor for ACS since its incidence increased 5–8 times in women aged >35 years bereft of racial differences.3,8 Figure 1 extensively shows the distribution of ACS incidence in relation to age while Figure 2 evidences ACS according to racial differences. Previous studies reported thrombophilia (odds ratio (OR) 25.0), hypertension (OR 21.0), age >35 (OR 16.0), smoking (OR 8.4) and eclampsia (OR 15.0) as the strongest predictors for ACS.8,9 In the last two decades the incidence of ACS related to pregnancy increased due to a higher mean maternal age and growing presence of risk factors such as obesity, smoking and diabetes.8 Mortality is still high but differs greatly among studies, ranging from 5.1 % reported by James et al.3 to 37.0 and 38.0 % reported by Koul et al.10 and Hankins et al.,7 respectively. Interestingly, a 2008 report by Roth and Elkayam showed a 11 % mortality rate versus a 22 % rate reported by the same authors 12 years earlier.9 These results were interpreted as a significant improvement in the diagnosis and treatment of pregnancy-related ACS. A recent study by Shamloo et al. supported the same hypothesis in patients with spontaneous coronary artery dissection (SCAD) causing ACS in which aggressive treatment with stent implantation or coronary artery bypass was related to a lower mortality.11

18/04/2013 12:04

Acute Coronary Syndrome in Pre- and Post-partum Women – A Review Figure 1: Overall Acute Coronary Syndrome Incidence Related to Pregnancy

Figure 2: Racial Differences in Acute Coronary Syndrome Related to Pregnancy

45 40

35 20

30 25

20 10

5 0

10 5 20

Age< 35

Age n°/100,000 deliveries

Brief Overview on Cardiovascular Physiology During Pregnancy

Black

Frequency

Basically the following are identified:

Peripheral vascular resistance

volume changes; sympathetic activation; pro-coagulative state; and changes in connective tissue.

Firstly, a mother’s body needs to accommodate and allow sufficient nutrients to the foetus. For this reason there is an increased erythropoiesis and plasma volume. Total body liquids, including plasma, increase by almost 7–8 litres. These changes result in about 50 % cardiac output increase.13 Secondly, during delivery heart work increases by 70–80 % due to either sympathetic stimulation secondary to pain and anxiety or volume overload caused by 300–500 millilitres of blood rejected after each uterine contraction. At the same time vascular peripheral resistance reduces and heart rate increases.2 On the other hand, there is an increased level of clotting cascade factors resulting in a higher generation of thrombin14 while anticoagulant factors such as protein S and C reduce their activity. Moreover there is a decreased production of tissue plasminogen activator.15 Finally placenta contributes to produce more plasminogen activator inhibitor reducing fibrinolytic capacity.16,17 These physiological changes in haemostatic cascade are helpful in view of the natural need to reduce haemorrhagic phenomenon during the last trimester, delivery and post-partum period. The last step is designed to accommodate and facilitate foetus growth and delivery. The musculoskeletal system of the pelvis enhances its laxity by the influence of sexual hormones. They stimulate the release of relaxin and elastin hormones, which determine a remodelling of collagen fibres through the activation of the collagenolytic system. The latest similarly effects the fibrous tissue of the vascular system as well. This mechanism has been advocated as one of the most plausible hypothesis to explain SCAD.

INTERVENTIONAL CARDIOLOGY REVIEW

Aprigliano_edited.indd 9

White

Hispanic

Figure 3: Cardiovascular Changes During Pregnancy

Pregnancy is a new physiological state. A previously published review extensively focused on this topic.12 Figure 3 summarises the most important cardiovascular maternal changes during pregnancy.

• • • •

Age> 35

Stroke volume Blood volume

Myocardial oxygen consumption

Vascular changes

Level of thrombin Activity of anticoagulant factors (Protein C and S) Fibrinolytic activity

Levels of elastin and relaxin Collagenolytic activity

Hypercoagulability state

Aetiology ACS may be due to different causes. Figure 4 shows the aetiology of ACS based on coronary angiography findings. These data were derived from all previous studies available on PubMed.5,6,9 Most of them are due to consequences of premature AD worsened by pregnancy and heart overload. The second cause is SCAD causing partial or total vessel occlusion, which is usually more difficult to diagnose early. The third aetiology includes ACS with angiographic normal coronary arteries (NCA) in absence of AD or SCAD. Presence of isolated thrombus was revealed in 8 % of cases. Finally, rare conditions such as thromboembolism originating from prosthetic mechanical heart valve, valvular disease, atrial fibrillation or paradoxical embolism, all enclosed under other aetiology, may account for a very low percentage of ACS.

Atherosclerotic Disease AD is the most frequent aetiology of ACS in the general population. Likewise it is shown to be prevalent even in pregnancy ACS in about 40 % of cases.9 Clinical presentation, risk factors, diagnosis and treatment are comparable to conventional ACS, widely described in the literature.

Spontaneous Coronary Artery Dissection Epidemiology SCAD is the second cause of ACS during pregnancy. It represents a challenge due to extremely heterogeneous clinical presentations and

18/04/2013 12:04

Coronary Acute Coronary Syndrome Figure 4: Aetiology of Acute Coronary Syndrome Related to Pregnancy 50

0 Atherosclerosis

SCAD

Normal

Thrombus

Others

SCAD = spontaneous coronary artery dissection.

Figure 5: Manifestation of Spontaneous Coronary Artery Dissection in the Peri-partum Period 60 50 40 30 20 10 0 9th month of 1st week 2nd week pregnancy after delivery

2nd month

6th month

the difficulties to perform early diagnosis in patients usually with low cardiovascular risk factors. Initially reports consisted in only autopsy findings. The first case of sudden death in a young woman was described in 1931.18 Although mortality is still high the percutaneous intervention era has consistently reduced it from 48 % in the earliest reports19,20 to less than 20 % in the most recent reports.21–24 Interestingly, SCAD was not associated to hypertension but to elevated shear stress conditions such as physical effort,25–27 emotions and drug consumption 28,29 (i.e. cocaine and methamphetamine). In other conditions it was associated to connective disorders,30 vasculitis31 or autoimmune diseases.32,33 Pathogenesis The complete pathogenesis of SCAD is not yet fully understood. There is no clear correlation with the traditional cardiovascular risk factors. Nevertheless older pregnants (>35 years) and multiparous women seem to be at increased risk.34 Estro-progestinic hormones contribute to a prothrombotic status and laxity of collagen fibres of media arterial layer. This status under conditions of high shear stress, such as delivery, may facilitate SCAD. Autopsy findings of SCAD showed a dissection intersecting the deeper media layer toward the adventitia.35 Moreover in almost 50 % of the cases an eosinophilic inflammatory infiltrate in the site of dissection was detected.36,37 This evidence suggests a role for collagenolytic enzymes released during eosinophil degranulation into the media layers altering the reticular fibres.38–40 On the other hand, a reduced production of collagen seems to characterise the pregnancy.41 Nevertheless these authors do not exclude that these findings might also be a consequence of dissection.

Aprigliano_edited.indd 10

SCAD might be occupied by liquid or organised blood due to vasa vasorum rupture causing haematoma. Thus a dissection and a false lumen are created. At this point the evolution is unpredictable and highly variable.21 Dissection might extend distal or proximal, linear or circumferential. If the haematoma grows without breaking the intima, it will compress the lumen. Otherwise the haematoma might open into the true lumen. In all cases the consequences can cause highly variable aspects ranging from the simple reduction of blood flow to the complete occlusion of the vessel.42 The occlusion may be facilitated since in the absence of AD coronary arteries they do not have the same wall stiffness thus more likely a dissection can evolve and cause a protruding flow limiting haematoma. Summarising previous reviews related to the hypothesis generating mechanism of SCAD, the authors support a role for all the above mentioned factors working together in generating SCAD. Clinical Presentation ACS caused by SCAD is indistinguishable from others. Sometimes even angiography does not clearly show the dissection, especially when it causes a total occlusion of the vessel. In this case intravascular ultrasound (IVUS), if carefully employed, can evidence mechanism of occlusion. In the largest meta-analysis to date, out of 440 patients with unselected SCAD about 80 % occurred in women – among them 80 were observed during pregnancy. In the later subgroup SCAD occurred mainly in the post-partum period (83.8 %) with 50.0 % and 70.0 % of them during the first and second post-partum week, respectively.11 Only 13 patients (16.2 %) developed SCAD before delivery. Figure 5 graphically reports the distribution of SCAD over the peri-partum period. At angiography, the left anterior descending coronary artery (LAD) was the most frequently involved vessel in about 40 % of cases, while in more than 20 % of patients presented multivessel SCAD.11 Few interesting cases reported simultaneous involvement of other arterial districts (i.e. coronary and vertebral arteries).43 This high incidence of contemporary multivessel dissections supports the systemic mechanism of disease.

Normal Coronary Arteries About 13 % of ACS in this setting presented NCA at angiography.9 These findings may be partially explained by the presence of occlusive transient coronary spasm due to increased renin release and angiotensin production during uterine hypoperfusion in the supine position44 or secondary to vasoconstrictive agents used during pregnancies such as ergonovine.45 Furthermore thrombus creation and solution with distal embolisation/fragmentation cannot be ruled out in some cases considered as NCA.

Isolated Thrombus Isolated thrombus without evidence of AD, SCAD or spasm was reported in about 8 % of cases.10 Aetiological explanation seems to be basically grounded on the role of the hypercoagulable state (HS). As mentioned above, a pivotal feature of pregnancy is an acquired HS dominant during the third trimester and the post-partum period. This condition might worsen a pre-existing inherited thrombophilia such as antithrombin III, protein C, protein S deficiency and factor V Leiden mutation, or an acquired one such as antibody anti-phospholipids syndrome or hyperhomocysteinemia.46,47 Nevertheless, pregnancy-related HS is temporary and generally recovers after puerperium. On this evidence it is reasonable to attribute a role for HS in pregnancy ACS even in the presence of AD or SCAD. This acquired state is considered an independent risk factor for ACS.3,5

INTERVENTIONAL CARDIOLOGY REVIEW

18/04/2013 12:04

Acute Coronary Syndrome in Pre- and Post-partum Women – A Review Table 1: Different Risk Classes for the Most Common Cardiological Drugs During Pregnancy Drugs

Lactation

In Pregnancy Effects

Unfractioned

No contraindication

Risk category B

heparin and LMWH

Studies in animals have not

Tirofiban

demonstrated foetal risk. No

Not recommended

Eptifibatide

controlled studies in women or

Clopidogrel

Not recommended

animals demostrate adverse

Nitrates

No data available

effects in the second and third

trimester. Data not confirmed

in the first trimester.

Aspirin

Low doses are not

Risk category C

contraindicated

Studies in animals have revealed

Beta-blocker

Accumulation in

foetus adverse effects. No

breast milk, careful

available studies in women.

monitoring

These drugs should be given

Calcium channel

Not recommended

only if the potential benefit

blocker

outweighs potential foetus risk.

Abiciximab

Not recommended

ACE inhibitors

Compatible with

Risk category C but its use is

nursing mothers

contraindicated in first trimesters.

Statins

No data available

Risk category X

Studies in animals and humans

confirmed foetal abnormalities

and so its use is contraindicated

ACE = angiotensin converting enzyme; LMWH = low molecular weight heparin.

Diagnosis Diagnosis is often challenging as attention is mainly focused on pregnant women and children and not on young individuals with a low cardiovascular risk. Generally, presentation is abrupt without warning signs. Symptoms suggestive of ACS should always be investigated even if found in young healthy patients. An immediate emergency room evaluation should be performed when necessary. Attention should be oriented to exclude cardiac aetiology given the still high mortality. Electrocardiogram (ECG) is adequate to diagnose STEMI. In this case urgent coronary angiography, as in general ACS guidelines, is mandatory. In the setting of SCAD particular attention should be paid to non-diagnostic or atypical ECG during chest pain, since SCAD is very insidious and fluctuating from phases with no flow limiting dissection to variable degrees of obstruction to complete occlusion. This mechanism of disease could explain the variable features of ECG over time. Laboratory findings such as seriated troponin, creatine kinase (CK), creatine kinase muscle and brain subunits (CK-MB), fibrin degradation product (FDP) and brain natriuretic peptide (BNP) measurements are helpful to make a differential diagnosis or confirm ACS. Echocardiogram may give further information revealing regional wall motion abnormalities or ventricular dysfunction. If high-risk non-ST elevation ACS is confirmed, coronary angiography is mandatory to establish pattern of disease (SCAD, thrombosis, AD or spasm), its localisation and extension. Otherwise in case of low risk UA a watchful and waiting strategy is reasonable, maintaining a low indication threshold for coronary angiography. There is a different procedural risk in pregnant or post-partum patients with regard to radiologic exposure of the foetus,48 haemorrhagic risk and abortion hazard. Radial access and screen for uterus are strongly suggested in pregnants in order to reduce foetus x-ray exposure. In the last decade the increasing use of coronary angiography has allowed us to better understand and diagnose ACS. Furthermore the adequate

INTERVENTIONAL CARDIOLOGY REVIEW

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use of IVUS examination helped to better characterise the pattern of disease. However, based on the pathophysiology of SCAD, we suggest a careful implementation of IVUS prior to stent implantation in this subgroup of patients since no safety data exist and further spasm or dissection might occur.

Treatment Current guidelines do not report any clear indication on the treatment of ACS in pregnancy.49–52 On the other hand, a few reports suggest a management according to general ACS guidelines.53,54 As a matter of fact no general consensus has yet been established. Based on the above mentioned pathology and clinical features we strongly believe that treatment in this setting should be well-tailored on a patient-to-patient basis. In dealing with ACS we have to keep in consideration two major modalities: the interventional/surgical aspect and the pharmacological aspect. Both may have restrictions in different periods of pregnancy. To facilitate management we believe that patients should be classified in pre- and post-partum groups. In the post-partum ACS group treatment according to the general ACS guidelines49–52 is recommended since only the mother’s health is at risk and the only jeopardised function with regard to the newborn is lactation. Fortunately, the latter can be implemented by an artificial one. Thus, the physician is relatively facilitated either in terms of treatment intensity (i.e. use of double antiplatelet therapy or glycoprotein IIB/IIIA inhibitors) or in the choice of the type and number of stents required, such as drug eluting stents (DES), and finally surgery. On the contrary, the pre-partum ACS group is hampered by the presence of the foetus. These patients are at risk for spontaneous abortion, bleeding and teratogenic effects.9,55 Management should keep several factors in consideration. Regarding pharmacological treatment, there is limited information about most of drugs when used in pregnancy. Drugs have been divided in classes of risk ranging from A (potential foetal damage is remote) to D (administer only in life-threatening situation in absence of any other choice) and X (risk clearly outweighs the benefit).9 Table 1 summarises the safety and risk profiles for the most common cardiological therapy.56 Aspirin has been classified to an intermediate-risk (Class C) and its use is safe in the second and third trimester whereas in the first trimester there is incidence of birth defects in animal studies.55 Clopidogrel appears safer for the foetus, but regional anaesthesia and surgical intervention are contraindicated for high bleeding risk.57 Few data exist about glycoproteinIIB/IIIA inhibitor treatment in pregnancy, even if tirofiban and eptifibatide (Class B) are considered safer than abiciximab (Class C). Unfractioned heparin and low molecular weight heparin (LMWH) are safe and widely used in pregnancy (Class B).58 Actually, thrombolysis in pregnant is a relative contraindication for the high foetal and maternal haemorrhagic risk.59 Several cases in literature report ischaemic stroke,60 massive pulmonary embolism61–63 or prosthetic heart valve thrombosis64,65 treatment in pregnants, but no definitive data exist in this setting. X-ray exposure during percutaneous treatment may have teratogenic repercussion on the foetus. However, it has been shown that by adopting the above mentioned precaution even time-consuming procedures result in a low exposure,55 with an overall 1.47 relative risk of developing malignant disease.48

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Coronary Acute Coronary Syndrome Considering the different kind of pathogenetic mechanism of ACS in pregnants it is important to consider early how the amount of myocardium is at risk and rule out the aetiology. Furthermore it is necessary to tailor the optimal treatment. As a first-line strategy medical treatment and high intensive care units are reasonable. In case of pregnant patients a close interaction between cardiologist and gynaecologist is necessary to avoid a possible pharmacological adverse event both in mother and foetus.

Percutaneous Revascularisation Angiographic pattern plays a key role in percutaneous versus surgical option. A careful evaluation of the aetiology, localisation and extension of the disease allows us to choose the best treatment strategy. Spasm and SCAD should be immediately ruled out. While AD management is already established in the literature, no clear SCAD percutaneous treatment is yet to be standardised. Some authors suggest to pre-dilate an occluding dissection while others prefer a direct stenting.21,66,67 In case of a proximal non-occlusive coronary artery SCAD we suggest direct stenting in order to seal the dissection and limit further proximal or distal propagation secondary to pre-dilatation. On the contrary, distal and non-flow limiting coronary artery SCAD should be carefully evaluated and a conservative watching and waiting strategy considered. On the other hand AD and SCAD may often be associated with coronary spasm and overlapped thrombus. Thus in case of completely occluded vessel it might be difficult to reveal the underling mechanism. In these situations we suggest to initially restore blood flow by means of conventional angioplasty by using an undersized balloon as the first choice. Mechanical aspiration devices and IVUS usage are left at the operator’s discretion while the intra-aortic balloon pump or left ventricular assist devices are recommended in cardiogenic shock. A careful evaluation of the number and length of the stents required is strongly suggested to avoid a ‘full metal jacket’ implantation. Always keep in mind that during the acute phase diffuse coronary artery spasm may occur and we consider frequent use of vasodilators as appropriate to limit stent implantation to the culprit lesion. Anecdotally control angiography distant from the index procedure in these patients has surprisingly shown better angiographic aspects of the non-culprit segments. This is important and should be kept in mind during the acute phase in

1. Lewis G, The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: reviewing maternal deaths to make motherhood safer 2003-2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH , 2007:1–47. 2. Burt CC, Durbridge J, Management of cardiac disease in pregnancy, Contin Educ Anaesth Crit Care Pain, 2009;9(2):44–7. 3. James AH, Jamison MG, Biswas MS, et al., Acute myocardial infarction in pregnancy: a United States population-based study, Circulation , 2006;113(12):1564–71. 4. Ventura S, Mosher W, Curtin S, et al., Trends in pregnancy rates for the United States, 1976-97: an update, Natl Vital Stat Rep , 2001;49:1–9. 5. Roth A, Elkayam U, Acute myocardial infarction associated with pregnancy, Ann Intern Med, 1996;125:751–62. 6. Badui E, Enciso R, Acute myocardial infarction during pregnancy and puerperium: a review, Angiology, 1996;47:739–56. 7. Hankins GD, Wendel GD Jr, Leveno KJ, Stoneham J, Myocardial infarction during pregnancy: a review, Obstet Gynecol, 1985;65:139–46. 8. Ladner HE, Danielsen B, Gilbert WM, Acute myocardial infarction in pregnancy and the puerperium: a population-based study, Obstet Gynecol , 2005;105(3):480–4. 9. Roth A, Elkayam U, Acute myocardial infarction associated with pregnancy, J Am Coll Cardiol, 2008;52(3):171–80. 10. Koul AK, Hollander G, Moskovits N, et al., Coronary artery dissection during pregnancy and the postpartum period: two case reports and review of literature, Catheter Cardiovasc Interv, 2001;52:88–94. 11. Shamloo BK, Chintala RS, Nasur A, et al., Spontaneous coronary artery dissection: aggressive vs. conservative therapy, J Invasive Cardiol, 2010;22(5):222–8.

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order to identify the culprit lesion and avoid unnecessary treatment. A ‘keep it simple’ strategy is recommended when facing complex lesions, such as bifurcations trying to limit stent number by applying the concept of ‘provisional stenting technique’. No data exist on benefits and safety profile in DES implantation versus bare-metal stents. While in the post-partum period the choice of the stent type follows general consensus for percutaneous coronary interventions, in the pre-partum period it is very controversial. Finally, the young age and long-life expectancy of this cohort of patients should be considered for an optimal interventional treatment strategy.

Surgical revascularisation Data regarding surgical revascularisation are almost lacking. Only a few cases reported the feasibility of surgery – mostly in the pre-partum patients.68 Similarly to the pharmacological and percutaneous strategies, surgery has different implications in pre- and post-partum women. In post-partum women indications for surgical revascularisation are based on general ACS guidelines and pattern of disease at angiography.49–52 In pre-partum women, cardiac surgery is hampered by high procedural risk. Foetal mortality ranges from 16 to 33 %.69 For this reason a conjunct decision with the gynaecologist should be obtained and contemporary caesarean delivery considered as appropriate during the last trimester.70,71

Conclusions ACS in pre- and post-partum women is a rare but dreadful situation. Unless developments in diagnostic and therapeutic tools are made, mortality will remain high. It should be considered a multifactorial disease with a special role for sexual hormones. Prompt diagnosis of ACS and aetiology together with the risk stratification is mandatory. On this ground, tailored non-invasive/invasive or surgical therapy should be shared together with the gynaecologist, particularly in pre-partum women. Knowledge of drug effects in pregnancy and mastering revascularisation techniques and materials are pivotal to succeed in managing these complicated cases. Further progress in drugs and devices may be helpful in the near future to better address and treat these patients – i.e. new antiplatelet drugs72 or the advent of bioresorbable stents.73 n

12. Ward C, Bushnell CD, James AH, The cardiovascular complications of pregnancy, Prog Cardiovasc Dis, 2007;50(2):126–35. 13. Desai DK, Moodley J, Naidoo DP, Echocardiographic assessment of cardiovascular hemodynamics in normal pregnancy, Obstet Gynecol, 2004;104:20–9. 14. Koh CL, Viegas OA, Yuen R, et al., Plasminogen activators and inhibitors in normal late pregnancy,postpartum and in the postnatal period, Int J Gynaecol Obstet, 1992;38:9–18. 15. Gore M, Eldon S, Trofatter KF, et al., Pregnancy-induced hanges in the fibrinolytic balance: evidence for defective release of tissueplasminogen activator and increased levels of the fastacting tissueplasminogen activator inhibitor, Am J Obstet Gynecol, 1987;156:674–80. 16. Jordaan DJ, Schoon MG, Badenhorst PN, Thrombophilia screening in pregnancy, Obstet Gynecol Surv, 2005;60:394–404. 17. FlahertyMP, LeesarMA, Dawn B, Acute Myocardial Infarction in a 19-Year-Old Female Owing to Hypercoagulable State of Pregnancy and the Puerperium, J Invasive Cardiol, 2008;20(9):E262–4. 18. Pretty HC, Dissecting aneurysm of coronary artery in a woman aged 42: Rupture, B Med J, 1931;1:667. 19. Koller PT, Cliffe CM, Ridley DJ, Immunosuppressive therapy for peripartum-type spontaneous coronary artery dissection: case report and review, Clin Cardiol, 1998;21(1):40–6. 20. Thompson EA, Ferraris S, Gress T, Ferraris V, Gender differences and predictors of mortality in spontaneous coronary artery dissection: a review of reported cases, J Invasive Cardiol, 2005;17(1):59–61. 21. Motreff P, Souteyrand G, Dauphin C, et al., Management of spontaneous coronary artery dissection: review of the literature and discussion based on a series of 12 young women with

acute coronary syndrome, Cardiology, 2010;115(1):10–8. 22. Vanzetto G, Berger-Coz E, Barone-Rochette G, et al., Prevalence, therapeutic management and medium-term prognosis of spontaneous coronary artery dissection: results from a database of 11,605 patients, Eur J Cardiothorac Surg, 2009;35(2):250–4. 23. Mortensen KH, Thuesen L, Kristensen IB, et al., Spontaneous coronary artery dissection: a Western Denmark Heart Registry study, Catheter Cardiovasc Interv , 2009;74(5):710–7. 24. Appleby CE, Barolet A, Ing D, et al., Contemporary management of pregnancy-related coronary artery dissection: A singlecentre experience and literature review, Exp Clin Cardiol, 2009;14(1):e8–16. 25. Sherrid MV, Mieres J, Mogtader A, et al., Onset during exercise of spontaneous coronary artery dissection and sudden death. Occurrence in a trained athlete: case report and review of prior cases, Chest, 1995;108:284–7. 26. Ellis CJ, Haywood GA, Monro JL, Spontaneous coronary artery dissection in a young woman resulting from an intense gymnasium “work-out”, Int J Cardiol, 1994;47:193–4. 27. Choi JW, Davidson CJ, Spontaneous multivessel coronary artery dissection in a long-distance runner successfully treated with oral antiplatelet therapy, J Invasive Cardiol, 2002;14:675–8. 28. Jaffe BD, Broderick TM, Leier CV, Cocaine-induced coronaryartery dissection, N Engl J Med, 1994;330:510–1. 29. Ijsselmuiden A, Verheye S, Cocaine-induced coronary artery dissection, JACC Cardiovasc Interv, 2009;2:1031. 30. Ades LC, Waltham RD, Chiodo AA, Bateman JF, Myocardial infarction resulting from coronary artery dissection in an adolescent with Ehlers-Danlos syndrome type IV due to a type III collagen mutation, Br Heart J, 1995;74:112–6. 31. Hunsaker JC 3rd, O’Connor WN, Lie JT, Spontaneous coronary

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Acute Coronary Syndrome in Pre- and Post-partum Women – A Review

arterial dissection and isolated eosinophilic coronary arteritis: Sudden cardiac death in a patient with a limited variant of Churg-Strauss syndrome, Mayo Clin Proc, 1992;67:761–6. 32. Chu KH, Menapace FJ, Blankenship JC, et al., Polyarteritis nodosa presenting as acute myocardial infarction with coronary dissection, Cathet Cardiovasc Diagn, 1998;44:320–4. 33. Aldoboni AH, Hamza EA, Majdi K, et al., Spontaneous dissection of coronary artery treated by primary stenting as the first presentation of systemic lupus erythematosus, J Invasive Cardiol, 2002;14:694–6. 34. Barret JM, Pregnancy related rupture of arterial aneurysms, Obstet Gynecol Surv, 1982;37:557–66. 35. Watson AJ, Dissecting aneurysm of arteries other than the aorta, J Pathol, 1956;72: 439–49. 36. Dowling GP, Buja ML, Spontaneous coronary artery dissection occurs with and without periadventitial inflammation, Arch Pathol Lab Med, 1987;111:470–2. 37. Borczuk AC, van Hoeven KH, Factor SM, Review and hypothesis: the eosinophil and peripartum heart disease (myocarditis and coronary artery dissection)-coincidence or pathogenetic significance?, Cardiovasc Res, 1997;33(3):527–32. 38. Rabinowitz M, Virmani R, Mcalliister HA Jr, Spontaneous coronary artery dissection and eosinophilic inflammation: a cause effect relationship, Am J Med, 1982;72:923–8. 39. Palomino SJ, Dissecting intramural hematoma of the left coronary artery in the puerperium: a case report and survey of literature, Am J Clin Pathol, 1968;51:119–25. 40. Asuncion CM, Hyun J, Dissecting intramural hematoma of the coronary artery in pregnancy and the puerperium, Obstet Gynecol, 1972;40:202–10. 41. Bonnet J, Aumailley M, Thomas D, et al., Spontaneous coronary artery dissection: case report and evidence of defect in collagen metabolism, Eur Heart J, 1986;7:904–9. 42. Foord AG, Lewis RD, Primary dissecting aneurysms of peripheral and pulmonary arteries: dissecting hemorrhage of media, Arch Pathol, 1959;68:553–77. 43. Sharma AM, Herrera B, Aronow HD, Simultaneous spontaneous coronary and vertebral artery dissection in a postpartum woman, J Invasive Cardiol, 2010;22(12):E229–32. 44. Gant NF, Daley GL, Chand S, et al., A study of angiotensin II pressor response throughout primigravid pregnancy, J Clin Invest, 1973;52:2682–9. 45. Hayashi Y, Ibe T, Kawato H, et al., Postpartum acute myocardial infarction induced by ergonovine administration, Intern Med, 2003;42:983–6. 46. Dentali F, Crowther M, Acquired Thrombophilia during Pregnancy, Obstet Gynecol Clin N Am, 2006;33:375–88. 47. Arampatzis S, Stefanidis I, Lakiopoulos V, et al., Postpartal recurrentnon-STelevationmyocardial infarction in essential thrombocythaemia: case report and review of the literature, Thromb J, 2010;8:12.

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48. Bithell JF, Stewart AM, Pre-natal radiation and childhood malignancy: a review of British data from the Oxford survey, Br J Cancer, 1975;31:271–87. 49. Hamm CW, Bassand JP, Agewall S, et al., ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC), Eur Heart J, 2011;32(23):2999–3054. 50. Wright RS, Anderson JL, Adams CD, et al., 2011 ACCF/ AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons, J Am Coll Cardiol, 2011;57(19):e215–367. 51. Kushner FG, Hand M, Smith SC Jr, et al., 2009 focused update of the ACC/AHA guidelines for the management of patients with ST‑Elevation myocardial infarction (updating the 2004 guideline and 2007 focusedupdate) and the ACC/ AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2009;54: 2205–41. 52. Van de Werf F, Bax J, Betriu A, et al., Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology, Eur Heart J, 2008;29(23):2909–45. 53. Adlam D, Cuculi F, Lim C, Banning A, Management of spontaneous coronary artery dissection in the primary percutaneous coronary intervention era, J Invasive Cardiol, 2010;22(11):549–53. 54. Poh CL, Lee CH, Acute myocardial infarction in pregnant women, Ann Acad Med Singapore, 2010;39:247–53. 55. El-Deeb M, El-Menyar A, Gehani A, Sulaiman K, Acute coronary syndrome in pregnant women, Expert Rev Cardiovasc Ther, 2011;9(4):505–15. 56. Briggs GG, Freeman RK, Yaffe SJ, Drugs in Pregnancy and Lactation, 7th edition, Philadelphia, PA: Lippincott Williams & Wilkins, 2005. 57. Martin M, Romero E, Moris C, [Acute myocardial infarction during pregnancy. Treatment with clopidogrel], Med. Clin (Barc) , 2003;121:278–9. 58. Sanson BJ, Lensing AW, Prins MH, et al., Safety of low-molecular weight heparin inpregnancy: a systematic review, Thromb Haemost , 1999;81:668–72.

59. Ludwig H, Genz HJ, Thrombolytic treatment during pregnancy, Thromb Haemost , 1981;46:438. 60. Murugappan A, Coplin WM, Al-Sadat AN, et al., Thrombolytic therapy of acute ischemic stroke during pregnancy, Neurology, 2006;66:768–70. 61. Hall RJ, Young C, Sutton GC, Cambell S, Treatment of acute massive pulmonary embolism by streptokinase during labour and delivery, Br Med J, 1972;4:647–9. 62. Fagher B, Ahlgren M, Astedt B, Acute massive pulmonary embolism treated with streptokinase during labor and the early puerperium, Acta Obstet Gynecol Scand , 1990;69:659–61. 63. Leonhardt G, Gaul C, Nietsch HH, et al., Thrombolytic therapy in pregnancy, J Thromb Thrombolysis , 2006;21:271–6. 64. Tissot H, Vergnes C, Rougier P, et al., [Fibrinolytic treatment with urokinase and streptokinase for recurrent thrombosis in two valve prostheses for the aortic and mitral valves during pregnancy], J Gynecol Obstet Biol Reprod, 1991;20:1093–6. 65. Witchitz S, Veyrat C, Moisson P, et al., Fibrinolytic treatment of thrombus on prosthetic heart valves, Br Heart J, 1980;44:545–54. 66. Paraskevaidis S, Theofilogiannakos EK, Chatzizisis YS, et al., Spontaneous dissection of right coronary artery manifested with acute myocardial infarction, Open Cardiovasc Med J, 2010;4:178–80. 67. Maeder M, Ammann P, Angehrn W, Rickli H, Idiopathic spontaneouscoronary artery dissection: incidence, diagnosis and treatment, Int J Cardiol, 2005;101:363–9. 68. Silberman S, Fink D, Berko RS, et al., Coronary artery bypass surgery during pregnancy, Eur J Cardiothorac Surg, 1996;10(10):925–6. 69. Patel A, Asopa S, Tang AT, et al., Cardiac surgery during pregnancy, Tex Heart Inst J, 2008;35(3):307–12. 70. Ferrari E, Tozzi P, von Segesser LK, Spontaneous coronary arterydissection in a young woman: from emergency coronary artery bypassgrafting to heart transplantation, Eur J Cardiothorac Surg, 2005;28:349–51. 71. Martins RP, Leurent G, Corbineau H, et al., Coronary angiography of pregnancy-associated coronary artery dissection: a high-risk procedure, Cardiovasc Revasc Med, 2010;11(3):182–5. 72. Tello-Montoliu A, Seecheran NA, Angiolillo DJ, Successful pregnancy and delivery on prasugrel treatment: considerations for the use of dual antiplatelet therapy during pregnancy in clinical practice, J Thromb Thrombolysis , 2012; Nov 10 [Epub ahead of print]. 73. 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;58(15):1578–88.

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Coronary Percutaneous Coronary Intervention

Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Unprotected Left Main Disease – A Review Edward McNulty Kaiser San Francisco Medical Center, and Assistant Clinical Professor, University of California San Francisco School of Medicine, San Francisco, California, US

Abstract There have been over a dozen studies in the drug-eluting stent era comparing the effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery for the treatment of unprotected left main disease. These studies have been both randomised and observational in nature. While both methodologies provide important insights, careful consideration of their respective strengths and limitations is imperative in generalising their findings.

Keywords Left main coronary artery disease, percutaneous coronary intervention, coronary artery bypass surgery Disclosure: The author receives research funding from the National Institutes of Health and from the Kaiser Foundation Research Institute; no relations with industry. Received: 21 October 2012 Accepted: 18 January 2013 Citation: Interventional Cardiology Review, 2013;8(1):14–8 Correspondence: Edward McNulty, Kaiser Permanente Medical Center, 2200 O’Farrell Street, San Francisco, CA 94115, US. E: edward.j.mcnulty@kp.org

The debate over the optimal mode of revascularisation for unprotected left main (ULM) coronary artery disease intensified with the advent of drug-eluting stents (DES). Professional society guidelines addressing ULM disease have been revised at an increasing frequency, 1,2 the significance of randomised comparisons has been variously interpreted, and observational comparisons have become a veritable cottage industry. Making matters even more complicated, the debate is often depicted in simplified, polarised terms in the lay press and at national meetings. Not surprisingly, patients and clinicians alike are often left confused. The intention of this review is to place the ‘debate’ in context and highlight a few of the crucial issues in generalising the evidence base for those who manage ULM disease in clinical practice.

The Evolution of the ‘Gold Standard’ Coronary artery bypass graft (CABG) surgery had been unchallenged as the standard of care for patients with ULM disease for decades. Before addressing the evidence for percutaneous coronary intervention (PCI) as an alternative, it is important to briefly consider the quality of that supporting CABG as an alternative to medical therapy for ULM disease. Only two of the seminal randomised trials comparing CABG with medical therapy included patients with left main disease.3,4 A pooled analysis of these patients revealed a significant survival advantage for CABG with a relatively large treatment effect (odds ratio [OR] 0.32, 95 % confidence interval [CI] 0.15–0.70 p=0.004).5 Observational data gave support to this finding,6 and the paradigm of CABG to prolong longevity for left main disease remained essentially unchallenged for three decades. There are important caveats concerning these early randomised trials that warrant emphasis. First, only 150 patients in total were randomised, quite a small number by contemporary standards. Second, they represent a pooled subgroup analysis and should be viewed with the attendant limitations of such analyses.7 Third, and

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perhaps most importantly, both surgery and medical therapy have evolved tremendously over the ensuing decades. CABG now routinely includes the use of mammary conduits, and surgical mortality has improved considerably – in the registry component of the Coronary Artery Surgery Study (CASS) it was over 4 % for patients with left main disease, a rate that most would consider unacceptable today. Conversely, ‘medical therapy’ at the time of these trials consisted of digitalis, beta-blockers and nitrates. Not even aspirin was routinely administered. Suffice it to say, the evidence base for the longevity benefits of CABG over medical therapy for treating left main coronary disease is neither large nor current.

Observational Trials of Coronary Artery Bypass Graft for Unprotected Left Main Disease Although randomised clinical trials (RCTs) are considered the most robust assessment of efficacy, they have important limitations. Patients in RCTs tend to be younger, more often male and have fewer co-morbid conditions.8 Generalising results from these trials must therefore be done with caution. For example, the vast majority of patients in the aforementioned Veterans Affairs and European studies were under 60 years of age and most had stable symptoms. It is therefore tempting to use observational data from ‘real-world’ practice to supplement that from RCTs. However, accounting for bias in observational studies is challenging. As mentioned above, observational data have been used to support the value of CABG in prolonging life for patients with left main coronary artery (LMCA) disease. However, most observational trials include patients who have varying degrees of suitability for CABG. Poor surgical candidates are less likely to undergo surgery, and are also more likely to suffer adverse outcomes by virtue of the conditions that confer poor candidacy for surgery. The presence of a such a selection bias in observational comparisons of CABG and medical therapy was raised over three decades ago.9 Accounting for this bias remains even more imperative today if we are to leverage large and increasingly

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Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Unprotected Left Main Disease Figure 1: Severe Distal Left Main Coronary Disease in a Patient with Advanced Chronic Obstructive Lung Disease Prior to Percutaneous Coronary Intervention (A) and Following Percutaneous Coronary Intervention (B) with a Single Drug-eluting Stent

sophisticated observational registries and administrative data sets to make valid conclusions.

Challenging the Gold Standard – Drug-eluting Stents for Unprotected Left Main Disease Initially, PCI for ULM disease was reserved for patients ineligible for CABG. With the emergence of DES, PCI has been more commonly used in patients who previously would have been treated with CABG.10 There have been over 4,000 patients included in observational comparisons of PCI with CABG for ULM disease.11–21 The duration of follow-up in these studies has ranged from one to five years. Meta-analyses including many of these trials have also been performed.22,23 A common finding of these studies has been comparable mortality following PCI or CABG, with patients undergoing PCI more likely to have repeat revascularisation procedures. However, these observational studies typically include patients with varying degrees of surgical eligibility, making treatment selection bias a potential limitation. This bias can confound these studies if the conditions responsible for poor surgical candidacy are independently associated with worse outcomes. To account for such potential ‘confounding by indication’, various statistical methods are commonly employed, including standard multivariable regression or Cox proportional hazards analyses, methods utilising inverse probability weighting (propensity scoring and matching) and instrumental variables. However, robust as these methods may seem, with the possible exception of instrumental variables (the least frequently used), they are ultimately dependent upon measured variables.24 If the conditions responsible for poor surgical candidacy are not measured, then confounding by indication compromises the validity of these observational comparisons. Most cardiovascular studies measure typical cardiovascular risk factors. However, the reasons PCI is selected instead of CABG for treating patients with ULM disease are often a consequence of clinical conditions not captured by typical cardiovascular data sets; despite a proliferation of observational comparative effectiveness studies, the reasons for surgical ineligibility have been poorly characterised. Using mixed methods, we found that the majority of patients undergoing ULM PCI as alternative to CABG at our institution had reasons for surgical

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Table 1: Reasons for Ineligibility for Coronary Artery Bypass Graft in Patients Undergoing Unprotected Left Main Percutaneous Coronary Intervention as an Alternative to Coronary Artery Bypass Graft Grouped According to Whether Captured by Typical Cardiovascular Data Registries Typically Captured Conditions

Conditions Not Typically Captured

Advanced age

Poor targets/inadequate conduits

Severe lung disease

Frailty

Severe systolic dysfunction

Aortic calcification

Renal insufficiency

Malignancy

Peripheral vascular disease

Immunosuppressed

Cerebrovascular disease

Haematological abnormality

Obesity

Liver disease

Pulmonary hypertension

Neuropsychiatric

Large nonviable myocardium

Gastrointestinal bleeding

Immobile Chest/abdominal wall abnormality Infection Adapted from McNulty, et al., 2011.25

ineligibility that were not typically measured by a standard cardiovascular data registry (see Table 1).25 If unmeasured, these conditions could still confound observational comparisons despite adjusting with the most commonly employed techniques to account for bias, including propensity scoring or matching. While unmeasured clinical conditions generally bias outcomes against PCI, patients with more complex anatomy are more likely to undergo CABG; since severity of disease is also associated with outcome, this could also lead to a selection bias. While observational comparisons can provide insight into real-world practice, their limitations need to be carefully considered.

Coronary Artery Bypass Graft Versus Percutaneous Coronary Interventions for Unprotected Left Main Disease – Randomised Trials There have been three small randomised trials in the DES era comparing CABG with PCI for ULM disease and one large subgroup of a larger RCT. The first was the Study of Unprotected Left Main Stenting Versus Bypass

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Coronary Percutaneous Coronary Intervention Surgery (LE MANS) trial. One hundred and five patients with ULM disease were randomised to CABG or PCI, with 35 % of the patients in the PCI arm receiving DES. This study showed similar rates of one-year cardiac death, myocardial infarction (MI), stroke or repeat intervention.26 In a study of 201 patients, Boudriot et al. found that PCI with sirolimus-eluting stents (SES) was inferior to CABG for the combined endpoint of cardiac death, MI or repeat revascularisation.27 Most recently in the Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trial of 600 patients with ULM disease, PCI with SES was non-inferior to CABG for the combined endpoint of death, MI and repeat revascularisation.28 However, the non-inferiority margin chosen was wide and the observed event rate in the CABG arm lower than expected. This led to a somewhat liberal interpretation of ‘non-inferior’ whereby a doubling of event rates in the PCI arm would still be considered non-inferior. Finally, in the subgroup of 705 patients with ULM disease in the TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries (SYNTAX) trial, patients undergoing PCI with paclitaxel-eluting stents had similar combined three-year rates of death, MI, stroke or repeat revascularisation to those undergoing CABG. PCI was associated with a significant reduction in stroke (1.2 versus 4.0 %, p=0.02) but an increase in repeat revascularisations (20.0 versus 11.7 %, p=0.004) with no difference in all-cause death (7.3 versus 8.4 %, p=0.64).29 Although a ‘pre-specified subgroup’

a significant but not clinically meaningful improvement in angina frequency and no difference in overall quality of life.32 For the left main subgroup, there was no difference in angina frequency at one-year. Whether short-term quality of life benefits are important is a subjective question that will vary depending on individual patient and family circumstances. For someone self-employed in a difficult economic position, the prospect of a short recovery might outweigh the potential for repeat procedures, whereas for someone with sufficient social supports, CABG offers the time-tested opportunity to reduce future trips to the hospital at the expense of a few difficult months. Of course, short-term quality of life gains must be carefully weighed against long-term survival benefits in subpopulations where CABG is the superior therapy.

of the SYNTAX trial, since the parent trial did not meet the goal of non-inferiority, these findings should be viewed as hypothesis generating. Recently, Capodanno et al. performed a meta-analysis incorporating the results of these three trials and the SYNTAX ULM subgroup.30 At one-year there was equivalence in terms of death with fewer strokes and more repeat revascularisation procedures in patients undergoing PCI. Although there have been an order of magnitude, more patients randomised between DES versus CABG for the treatment of ULM disease than for CABG versus medical therapy, the duration of follow-up has been limited; the possibility of a late difference in mortality or MI cannot be excluded.

revascularisation) were higher in patients with intermediate and high SYNTAX scores (indicating more complex anatomy).29 In the subgroup of patients with ULM disease, MACCE was similar for patients with low (0–22) or intermediate (23–32) SYNTAX scores, but far worse for those with high scores treated with PCI. Approximately one-third of patients screened for the SYNTAX trial were excluded for having anatomy that precluded PCI. If one also considers these patients, then the majority of those with ULM disease had SYNTAX scores >33. An anatomic consideration that deserves special attention is involvement of the distal left main bifurcation (see Figure 1). Observational data has demonstrated worse outcomes for patients undergoing PCI for distal ULM disease,34,35 and patients with higher SYNTAX scores are more likely to have distal bifurcation involvement.

While the clinical endpoints discussed above are often combined to obtain adequate power for clinical trials, the concept of ‘major adverse cardiac and cerebrovascular events’ (MACCE) is not always easy to convey to patients. Even among clinicians, there have been debates as to whether excess repeat revascularisation procedures are ‘offset’ by fewer strokes, and as to whether a MI should be weighed as heavily as a death.31 Although it is tempting to address potential adverse outcomes individually for each mode of revascularisation, the limited nature of the data, especially in terms of the duration of follow-up, makes such post hoc ‘parsing’ challenging, and translating this information to facilitate true shared decision-making is problematic.

Endpoints – Major Adverse Cardiac and Cerebrovascular Events or Quality of Life? Many have argued that even broad composite endpoints such as death, MI, stroke or repeat revascularisation are inadequate to compare true morbidity, and that additional outcomes taking into account post-procedure recovery ought to be measured for a more accurate comparison of CABG and PCI. Fortunately, well-validated instruments measuring health status have been applied in this regard, most recently in the SYNTAX trial. Early after revascularisation, overall quality of life was much worse with CABG than for PCI (on the order of having symptomatic heart failure or lung disease). However, by one-year this difference had disappeared with CABG being associated with

McNulty_edited.indd 16

Selective Use of Percutaneous Coronary Intervention – Anatomic Stratification? Up to this point we have treated ULM disease uniformly in comparing treatments. Obviously there are clinical and anatomic differences in patients with ULM disease, and these will have a bearing on outcomes following PCI or CABG. Professional society guidelines now advocate using indices of the anatomic complexity disease such as the SYNTAX Score33 to aide in the triage of patients with ULM disease to PCI or CABG.1,2 This is supported by evidence from the SYNTAX trial, where three-year rates of MACCE (death, stroke, MI and repeat

While it is tempting to conclude that patients with less complex anatomy, especially without distal bifurcation involvement, fare equally well after PCI or CABG, it is important to remember that this conclusion is based on inferences from analysing a subgroup (lower SYNTAX scores) of a large subgroup (those with left main disease) within a trial in which non-inferiority was not demonstrated for the parent study population. In that light it is interesting that professional societies should endorse such an approach when these results have been described as ‘hypothesis generating’ by the study authors. At the present time, given worse outcomes associated with PCI for distal left main disease, for patients who are reasonable surgical candidates with severe disease extending into both the adjacent circumflex and left anterior descending arteries, current evidence favours CABG as the optimal mode of revascularisation.

Selective Use of Percutaneous Coronary Intervention for Unprotected Left Main Disease – Stratification by Surgical Risk? PCI has long been an option for ULM disease in patients with ‘prohibitive surgical risk’. However, prohibitive surgical risk has been poorly characterised. While risk scores developed for cardiothoracic surgery have been shown to predict outcomes following PCI for unprotected

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Coronary Artery Bypass Grafting Versus Percutaneous Coronary Intervention for Unprotected Left Main Disease

left main coronary artery (ULMCA),36 these risk scores measure typical cardiovascular risk factors; as discussed earlier, the conditions rendering patients ineligible for CABG are often not typical risk factors. Risk scores can never replace clinical judgment, and patients with similar scores can vary markedly in terms of surgical candidacy. It is also likely that in some patients even PCI as an alternative to medical therapy is not likely to offer meaningful benefit and may in fact cause harm; the utility PCI, especially in the ‘frail phenotype’, should be the focus of further investigation.

Medical Therapy for Unprotected Left Main Disease? Often overlooked in the heated rhetoric regarding the optimal mode of revascularisation for ULM disease is the basic issue of what constitutes significant left main disease in the first place, and whether in fact medical therapy alone might be sufficient treatment for some patients. Although a diameter stenosis of >50 % is typically considered ‘significant’, there is substantial interobserver variation in the angiographic assessment of left main disease and poor correlation of visual assessment with haemodynamically significant disease.37,38 Largely forgotten is the finding that the mortality advantage of CABG over medical therapy among patients with ULM disease in the CASS Registry was confined to patients with reduced systolic function and diameter stenoses >70 %.6,39 With the evolution of medical therapy, recent investigations have assessed the role of medical therapy alone for ‘intermediate’ or ambiguous LMCA. Both intravascular ultrasound40 and fractional flow reserve (FFR) guided38 approaches have shown equivalent outcomes if PCI is deferred in patients with minimum lumen area >6 mm2 or FFR >0.80. The role of medical therapy alone, especially in minimally symptomatic patients with normal systolic function or for more moderate incidentally discovered disease, should not be discounted.

mode of revascularisation, and for patients with ‘surgical disease’ the recommendation regarding the mode of revascularisation most often comes from the catheterisation laboratory cardiologist.42 Soliciting a ‘surgical opinion’ is a laudable goal, but which surgical opinion? A colleague in a multispecialty practice? One less inclined to operate? If there are revenue implications, should the patient be informed? Conversely, for patients at high risk of complications with CABG in whom ad hoc ULM PCI is feasible, should the patient be taken off the table and subjected to the risks and inconveniences of a separate procedure simply to satisfy a ‘formality’? Finally, as any clinician who has encountered this situation can attest, some patients are likely to be overwhelmed with the information and true ‘shared decision-making’ will be difficult if not impossible. Research into decision aides for both patients and clinicians and other models is desperately needed to clarify the most effective strategy for facilitating informed and transparent decisions.

Future Directions Finally, this debate will likely forever be over a ‘moving target’. As we digest evidence from trials and incorporate them into practice guidelines, devices, techniques and medical therapies evolve in the interim such that the older data become potentially obsolete and less relevant to contemporary practice. For example, while the SYNTAX trial is a useful source of data, some have suggested the results would have been more favourable for PCI with ‘second-generation’ DES.43 Second-generation DES are being compared with CABG in the ongoing Evaluation of XIENCE PRIME™ Everolimus Eluting Coronary Stent System (EECSS) or XIENCE V® EECSS Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) and Nordic-Baltic-British Left Main Revascularization Study (NOBLE) trials, both large, well-powered trials.

Conclusions Putting it Together – The Present Now that professional society guidelines have endorsed PCI as an option for the treatment of ULM disease in a subset of patients eligible for CABG, how are we to best incorporate this into present clinical practice? Guidelines also advocate a ‘heart team’ approach in which patients receive counselling on the merits and risks of PCI and CABG from a team of individuals consisting of at least one cardiologist and one cardiothoracic surgeon.41 While this certainly sounds like good medicine, implementation in practice is likely to be challenging. Cardiologists typically dictate decisions regarding the

1. Wijns W, Kolh P, Danchin N, et al., Guidelines on myocardial revascularization, Eur Heart J, 2010;31:2501–55. 2. 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, J Am Coll Cardiol, 2011;58:2550–83. 3. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group, N Engl J Med, 1984;311:1333–9. 4. Varnauskas E, Twelve-year follow-up of survival in the randomized European Coronary Surgery Study, N Engl J Med, 1988;319:332–7. 5. Yusuf S, Zucker D, Peduzzi P, et al., Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration, Lancet, 1994;344:563–70. 6. Chaitman BR, Fisher LD, Bourassa MG, et al., Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS), Am J Cardiol, 1981;48:765–77.

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Medical, percutaneous and surgical therapy for ULM disease has improved dramatically over the past three decades. Along with these improvements, decisions regarding the optimal mode of revascularisation have become more complicated with both PCI and medical therapy being viable options in a subset of patients. Identifying the subset appropriate for alternatives to CABG and translating the risks and benefits of these alternatives to individual patients in a transparent fashion is no simple matter. While clinical and anatomic scores may be helpful in this regard, they are no replacement for clinical judgment and the ‘art’ of medicine. n

7. Pocock SJ, Assmann SE, Enos LE, Kasten LE, Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems, Stat Med, 2002;21:2917–30. 8. Van Spall HG, Toren A, Kiss A, Fowler RA, Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review, JAMA, 2007;297:1233–40. 9. Jones EL, King SB 3rd, Craver JM, et al., The spectrum of left main coronary artery disease: variables affecting patient selection, management, and death, J Thorac Cardiovasc Surg, 1980;79:109–16. 10. Huang HW, Brent BN, Shaw RE, Trends in percutaneous versus surgical revascularization of unprotected left main coronary stenosis in the drug-eluting stent era: a report from the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR, Catheter Cardiovasc Interv, 2006;68:867–72. 11. Palmerini T, Marzocchi A, Marrozzini C, et al., Comparison between coronary angioplasty and coronary artery bypass surgery for the treatment of unprotected left main coronary artery stenosis (the Bologna Registry), Am J Cardio l, 2006;98:54–9. 12. Sanmartin M, Baz JA, Claro R, et al., Comparison of drugeluting stents versus surgery for unprotected left main coronary artery disease, Am J Cardiol, 2007;100:970–3. 13. Brener SJ, Galla JM, Bryant R 3rd, et al., Comparison of

percutaneous versus surgical revascularization of severe unprotected left main coronary stenosis in matched patients, Am J Cardiol, 2008;101:169–72. 14. Wu C, Hannan EL, Walford G, Faxon DP, Utilization and outcomes of unprotected left main coronary artery stenting and coronary artery bypass graft surgery, Ann Thorac Surg, 2008;86:1153–9. 15. Mäkikallio TH, Niemelä M, Kervinen K, et al., Coronary angioplasty in drug eluting stent era for the treatment of unprotected left main stenosis compared to coronary artery bypass grafting, Ann Med, 2008;40:437–43. 16. White AJ, Kedia G, Mirocha JM, et al., Comparison of coronary artery bypass surgery and percutaneous drug-eluting stent implantation for treatment of left main coronary artery stenosis, JACC Cardiovasc Interv, 2008;1:236–45. 17. Rodés-Cabau J, Deblois J, Bertrand OF, et al., Nonrandomized comparison of coronary artery bypass surgery and percutaneous coronary intervention for the treatment of unprotected left main coronary artery disease in octogenarians, Circulation, 2008;118:2374–81. 18. Park DW, Seung KB, Kim YH, et al., Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical

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Coronary Percutaneous Coronary Intervention Revascularization) registry, J Am Coll Cardiol , 2010;56:117–24. 19. Kang SH, Park KH, Choi DJ, et al., Coronary artery bypass grafting versus drug-eluting stent implantation for left main coronary artery disease (from a two-center registry), Am J Cardiol, 2010;105:343–51. 20. Chieffo A, Magni V, Latib A, et al., 5-year outcomes following percutaneous coronary intervention with drug-eluting stent implantation versus coronary artery bypass graft for unprotected left main coronary artery lesions the Milan experience, JACC Cardiovasc Interv, 2010;3:595–601. 21. Capodanno D, Caggegi A, Capranzano P, et al., Validating the EXCEL hypothesis: a propensity score matched 3-year comparison of percutaneous coronary intervention versus coronary artery bypass graft in left main patients with SYNTAX score ≤32, Catheter Cardiovasc Interv, 2011;77:936–43. 22. Lee MS, Yang T, Dhoot J, Liao H, Meta-analysis of clinical studies comparing coronary artery bypass grafting with percutaneous coronary intervention and drug-eluting stents in patients with unprotected left main coronary artery narrowings, Am J Cardiol, 2010;105:1070–5. 23. Naik H, White AJ, Chakravarty T, et al., A meta-analysis of 3,773 patients treated with percutaneous coronary intervention or surgery for unprotected left main coronary artery stenosis, JACC Cardiovasc Interv, 2009;2:739–47. 24. Yeh RW, Mauri L, Choosing methods to minimize confounding in observational studies: do the ends justify the means?, Circ Cardiovasc Qual Outcomes, 2011;4:581–3. 25. McNulty EJ, Ng W, Spertus JA, et al., Surgical candidacy and selection biases in nonemergent left main stenting: implications for observational studies, JACC Cardiovasc Interv, 2011;4:1020–7. 26. Buszman PE, Kiesz SR, Bochenek A, et al., Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization, J Am Coll Cardiol, 2008;51:538–45.

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27. Boudriot E, Thiele H, Walther T, et al., Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis, J Am Coll Cardiol, 2011;57:538–45. 28. Park SJ, Kim YH, Park DW, et al., Randomized trial of stents versus bypass surgery for left main coronary artery disease, N Engl J Med, 2011;364:1718–27. 29. Kappetein AP, Feldman TE, Mack MJ, et al., Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial, Eur Heart J, 2011;32:2125–34. 30. Capodanno D, Stone GW, Morice MC, et al., Percutaneous coronary intervention versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of randomized clinical data, J Am Coll Cardiol, 2011;58:1426–32. 31. Kaul S, Diamond GA, Trial and error. How to avoid commonly encountered limitations of published clinical trials, J Am Coll Cardiol, 2010;55:415–27. 32. Cohen DJ, Van Hout B, Serruys PW, et al., Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery, N Engl J Med, 2011;364:1016–26. 33. Sianos G, Morel MA, Kappetein AP, et al., The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease, EuroIntervention, 2005;1:219–27. 34. Palmerini T, Sangiorgi D, Marzocchi A, et al., Ostial and midshaft lesions vs. bifurcation lesions in 1111 patients with unprotected left main coronary artery stenosis treated with drug-eluting stents: results of the survey from the Italian Society of Invasive Cardiology, Eur Heart J, 2009;30:2087–94. 35. Chen SL, Ye F, Zhang JJ, et al., Distal left main coronary bifurcation lesions predict worse outcome in patients undergoing percutaneous implantation of drug-eluting stents: results from the Drug-Eluting Stent for the Treatment of Left Main Disease (DISTAL) Study, Cardiology, 2009;113:264–73.

36. Garg S, Stone GW, Kappetein AP, et al., Clinical and angiographic risk assessment in patients with left main stem lesions, JACC Cardiovasc Interv, 2010;3:891–901. 37. Lindstaedt M, Spiecker M, Perings C, et al., How good are experienced interventional cardiologists at predicting the functional significance of intermediate or equivocal l eft main coronary artery stenoses?, Int J Cardiol, 2007;120:254–61. 38. Hamilos M, Muller O, Cuisset T, et al., Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis, Circulation, 2009;120:1505–12. 39. Caracciolo EA, Davis KB, Sopko G, et al., Comparison of surgical and medical group survival in patients with left main coronary artery disease. Long-term CASS experience, Circulation, 1995;91:2325–34. 40. de la Torre Hernandez JM, Hernández Hernandez F, Alfonso F, et al., Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study, J Am Coll Cardiol, 2011;58:351–8. 41. Holmes DR Jr, Mohr F, Hamm CW, Mack MJ, Venn diagrams in cardiovascular disease: the Heart Team concept, Ann Thorac Surg, 2013;95:389–91. 42. Hannan EL, Racz MJ, Gold J, et al., Adherence of catheterization laboratory cardiologists to American College of Cardiology/American Heart Association guidelines for percutaneous coronary interventions and coronary artery bypass graft surgery: what happens in actual practice?, Circulation, 2010;121:267–75. 43. Claessen BE, Stone GW, Smits PC, et al., Would SYNTAX have been a positive trial if XIENCE V had been used instead of TAXUS?: A meta-analysis of a first-generation vs. a second-generation drug-eluting stent system, Neth Heart J, 2010;18:451–3.

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Coronary Bifurcation Stenting

Dedicated Bifurcation Drug-eluting Stent BiOSS ® – A Novel Device for Coronary Bifurcation Treatment R obert J G i l , 1 ,2 D o b r i n Va s s i l e v 3 a n d Ja c e k B i l 1 1. Invasive Cardiology Department, Central Clinical Hospital of the Ministry of Interior, Warsaw, Poland; 2. Institute of Experimental and Clinical Medicine, Polish Academy of Science, Warsaw, Poland; 3. National Heart Hospital, Sofia, Bulgaria

Abstract The Bifurcation Optimisation Stent System (BiOSS®) (Balton®, Poland) is a coronary, dedicated bifurcation, balloon-expandable stent made of 316 litre stainless steel tube with strut thickness of 120 micrometre (µm). It is covered with a mixture of a biodegradable polymer and an antiproliferative substance – paclitaxel (BiOSS Expert version) or sirolimus (BiOSS Lim version). The stent consists of two parts (the proximal with a larger diameter in relation to the distal one) connected with two connection struts (average 1.2 mm in length) at the step-up middle zone. The stent is crimped on a bottle-shaped semi-complaint balloon (Bottle®, Balton, Poland). Our intravascular ultrasound (IVUS) study revealed that the construction of the BiOSS stent assures an easy access to the side branch and is comparable to the classic stent lumen enlargement with less injury to the area adjacent to the most sensitive part of the bifurcation. A total number of 65 lesions in 63 consecutive patients were enrolled in the First-In-Man (FIM) registry for BiOSS Expert, where we achieved a 100 % device success rate. The long-term clinical results were satisfactory and closely related to the high-risk profile of the treated population. Our data demonstrated that simple and fast bifurcation treatment with a single dedicated bifurcation paclitaxel-eluting stent (BiOSS Expert) is feasible and highly successful. Based on the data collected in animal experiments and preliminary data in humans with BiOSS Lim, releasing sirolimus from the surface of the biodegradable coating, one may presume that this version will provide even better clinical results compared with the paclitaxel one.

Keywords Dedicated bifurcation stent, paclitaxel, sirolimus, drug-eluting stent Disclosure: Robert J Gil is a medical consultant for Balton. The remaining authors have no conflicts of interest to declare. Received: 11 March 2013 Accepted: 5 April 2013 Citation: Interventional Cardiology Review, 2013;8(1):19–22 Correspondence: Robert J Gil, Invasive Cardiology Department, Central Clinical Hospital of the Internal Affairs and Administration Ministry, 137 Woloska Street, 02-507 Warsaw, Poland. E: robert.gil@cskmswia.pl Support: The publication of this article was supported by Balton.

The treatment of coronary bifurcation lesions (BL) is still challenging for interventional cardiologists, due to the relatively high-risk of the side branch (SB) closure and the increased long-term restenosis.1 The idea of a dedicated bifurcation stent (DBS) was proposed as a solution for problems associated with the BL treatment by means of a classical stent.1 Three groups of stents are available at the moment: a proximal main vessel (MV) stent (Axxess™, Devax, US), MV stenting across the SB with different designs making possible permanent access to the SB, and finally, purely SB dedicated stents (Tryton™, Sideguard™ and Biguard™). Neither of these stents match proximal–distal MV size difference nor take into account vessel angulations. The Bifurcation Optimisation Stent System (BiOSS®) (Balton®, Poland) is completely different from the above systems.

the same technology as the Luc-Chopin2 stent developed by Balton. The polymer layers release paclitaxel in a time-controlled process of their slow biodegradation (lasting eight weeks), inhibiting a neointima formation process.2 The stent consists of two parts, proximal and distal, connected with two connection struts (depending on size 0.9–1.5 mm, average 1.2 mm long) at the step-up middle zone (see Figure 1A). The proximal part of the stent has a larger diameter in relation to the distal part. The diameter ratio of proximal to distal parts varies between 1.15 and 1.3, ensuring physiological compatibility and optimal flow conditions. There are three lengths (15, 18 and 23 mm) of BiOSS stents available on the market. The proximal part is always a bit shorter than the distal one (average 1 mm). The nominal foreshortening of the stent is less than 0.5 %. The stent strut/vessel area ratio varies between 15 and 18 %.

Device Description BiOSS Expert (Balton, Poland) is a coronary bifurcation balloon-expandable stent made of 316 litre stainless steel with strut thickness of 120 micrometre (µm) and covered with a mixture of a biodegradable polymer and paclitaxel – an antiproliferative drug. The coating process of the stent by a biodegradable polymer and paclitaxel uses

Gil_Balton.indd 19

The stent is crimped on a bottle-shaped balloon (Bottle®, Balton, Poland). Bottle balloons are available in a wide range of sizes and lengths allowing the left main stem treatment as well (see Table 1). The balloon nominal pressure is 10 atmospheres (atm), whereas the rated burst pressure is 18 atm. The balloon is semi-complaint with an

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Coronary Bifurcation Stenting Figure 1: (A) BiOSS® Stent, (B) Bottle® Balloon, (C) BiOSS® Stent Crimped on Bottle® Balloon, (D) BiOSS® Stent on Inflated Bottle® Balloon

Note the different sizes and lengths of the two parts and the intermediate zone.

Table 1: BiOSS® Stent Lengths and Sizes

Figure 2: BiOSS® Stent Implantation Procedure

Nominal Stent Diameter (mm)

Catalogue Number Distance Proximity

Nominal Stent Length (mm)

ZSTB2.50x3.25x1514L

2.50

3.25

ZSTB2.75x3.50x1514L

2.75

3.50

ZSTB3.00x3.50x1514L

3.00

3.50

ZSTB3.00x3.75x1514L

3.00

3.75

ZSTB3.50x4.25x1514L

3.50

4.25

ZSTB3.75x4.50x1514L

3.75

4.50

ZSTB2.50x3.25x1814L

2.50

3.25

ZSTB2.75x3.50x1814L

2.75

3.50

ZSTB3.00x3.50x1814L

3.00

3.50

ZSTB3.00x3.75x1814L

3.00

3.75

ZSTB3.50x4.25x1814L

3.50

4.25

ZSTB3.75x4.50x1814L

3.75

4.50

ZSTB2.50x3.25x2314L

2.50

3.25

ZSTB2.75x3.50x2314L

2.75

3.50

ZSTB3.00x3.50x2314L

3.00

3.50

ZSTB3.00x3.75x2314L

3.00

3.75

ZSTB3.50x4.25x2314L

3.50

4.25

ZSTB3.75x4.50x2314L

3.75

4.50

Nominal Stent Diameter (mm)

Bifurcation

BiOSS stent

a mid-marker positioned at the beginning of a distal part

implanted BiOSS stent with a wide access to the side branch

increase in a diameter size of 0.25 mm at 14 atm, both proximally and distally (see Figure 1B). The delivery system for the BiOSS stent is a rapid exchange system compatible with 0.014-inch guidewires and with 5 French (1.63 mm internal diameter) guiding catheters. The BiOSS stent is introduced over a single guidewire, which (opposite to many other dedicated systems guided on two guidewires) eliminates the risk of wire wrap (twisting) or other complications with double guidewire driven systems (see Figures 1C and D).

Catalogue Number Distance Proximity

Nominal Stent Length (mm)

ZSTB2.50x3.25x1514S

2.50

3.25

ZSTB2.75x3.50x1514S

2.75

3.50

ZSTB3.00x3.50x1514S

3.00

3.50

ZSTB3.00x3.75x1514S

3.00

3.75

ZSTB3.50x4.25x1514S

3.50

4.25

BiOSS – the Mechanism of Action

ZSTB3.75x4.50x1514S

3.75

4.50

ZSTB2.50x3.25x1814S

2.50

3.25

ZSTB2.75x3.50x1814S

2.75

3.50

ZSTB3.00x3.50x1814S

3.00

3.50

ZSTB3.00x3.75x1814S

3.00

3.75

ZSTB3.50x4.25x1814S

3.50

4.25

ZSTB3.75x4.50x1814S

3.75

4.50

ZSTB2.50x3.25x2314S

2.50

3.25

ZSTB2.75x3.50x2314S

2.75

3.50

ZSTB3.00x3.50x2314S

3.00

3.50

ZSTB3.00x3.75x2314S

3.00

3.75

ZSTB3.50x4.25x2314S

3.50

4.25

ZSTB3.75x4.50x2314S

3.75

4.50

The delivery balloon for the BiOSS stent has three markers (proximal, middle and distal), which assures the exact stent placement at the point of the bifurcation. The proximal end of a mid-marker is again positioned exactly at the beginning of a narrower distal part for the correct implantation. The 1.2 mm intermittent zone ensures ‘self-positioning’ of a stent after balloon deflation as well as wide opening to the SB. After BiOSS stent implantation (during which the main vessel segment is straightened), the proximal and distal main vessel segments return to their initial position/angulation, opening the side of the stent to the branch. The wider proximal part of the stent ensures lateral stretching of the SB lateral wall counterbalancing the carina displacement from the distal part of a stent (see Figure 2). Moreover, this stent

Gil_Balton.indd 20

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Dedicated Bifurcation Drug-eluting Stent BiOSS® – A Novel Device for Coronary Bifurcation Treatment Figure 3: Angiographic Images from BiOSS® Stent Implantation in the Bifurcation Left Anterior Descending/First Diagonal Branch – (A) Before Stent Implantation, (B) Stent Implantation with Clearly Visible Three Markers and (C) the Final View

Figure 4: Optical Coherence Tomography Analysis – (A) Proximal Stent Struts, (B) Carina with Stent Struts and a Wide Access to the Side Branch and (C) Distal Stent Struts

provokes much less carina displacement because it mimics the exact bifurcation construction with the proximal – distal main vessel diameter mismatch. These changes result in the proximal and distal parts adequate configuration, matching vessel exact sizes. The specific configuration of the stent system ensures a ‘kissing-like’ effect. Figure 3 depicts angiographic results of BiOSS Expert stent implantation, whereas Figure 4 presents intravascular ultrasound (IVUS) and optical coherence tomography (OCT) analysis, respectively.

optimisation technique (POT), which is strongly recommended by the European Bifurcation Club.1 In addition, smaller variability in vessel and lumen areas at the level of the distal limb after BiOSS stent implantation was found. This was clearly connected with carina and plaque shift after stent implantation. These findings confirm that BiOSS stent construction limits carina and plaque shift towards SB, which are two major factors responsible for the SB compromise.5

Clinical Applicability From the beginning, BiOSS stent construction has questioned whether a 1.2 mm long intermediate zone of a stent was the weakest part, predisposing to restenosis and intrastent thrombosis. Recently published results from a three-month study3 and the known results of a 12-month study4 of BiOSS Expert Registry deny those assumptions. In addition, our IVUS study showed that BiOSS stent provides a comparable increase of the lumen in most stenosed parent vessels (MV and MV) to a classical stent. Simultaneously, BiOSS stent construction (of course in case of proper implantation) provides better access to the SB in comparison with the classic drug-eluting stents (DES). It was proven by the significantly bigger window length found in the BiOSS group – a parameter, which represents the access to the SB.5 The analysis of the plaque, lumen and vessel areas show that BiOSS stent construction assures the realisation of the proximal

INTERVENTIONAL CARDIOLOGY REVIEW

Gil_Balton.indd 21

BiOSS Expert stent should be classified as DBS treating MV and ensuring the SB access. Our experience showed that this device is very user-friendly. The vast majority of implantations were possible using radial access (>90 %) and 6 French compatible equipment (including also left main [LM] cases). Moreover, such a stent ensured ideal immediate efficacy (100 % device success rate). It is worthwhile stressing how easy rewiring of the SB is after BiOSS Expert stent implantation. This device’s success rate is clearly superior to all other reported procedural success rates of dedicated coronary bifurcation stents (100 % for BiOSS Expert versus 75–95 % for other types of devices). This high success rate is a result of the obvious lack of problems frequently occurring with other dedicated devices, like guidewires criss-crossing, improper device orientation and big device profile.4

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Coronary Bifurcation Stenting Figure 5: Six-month Clinical Results of BiOSS® Lim First-In-Man Registry 3 Months n=60

Figure 6: Preliminary Late Lumen Loss Observed in BiOSS® Lim First-In-Man Registry Based on 12-month Angiographic Follow-up

30 days n=60

Death

0 0 0

0.5

4 (6.7 %)*

0.4

Stroke

0 0 0

TLR

0 0 1

0.2

TVR

0 0 1

PCI in another vessel

0.1

5 (8.33 %)

* periprocedural asymptomatic increase in Tnl concentration. MI = myocardial infarction; PCI = percutaneous coronary intervention; ST = stent thrombosis; TLR = target lesion revascularisation; TVR = target vessel revascularisation.

Moreover, in our studies an additional stent in SB was necessary in only 10 % of patients (majority of them had a procedure on the left main stem [LMS]), which confirms that the BiOSS stent fits well to the provisional T-stenting (PTS) strategy. A good angiographic result was achieved with a low rate of final kissing balloon technique (only in 13 % of cases), which is sometimes very demanding, especially for inexperienced operators. It suggests that a bottle-like shape of a stent delivery balloon and the balloon used for post-dilatation (Bottle) is associated with a kissing-like result.4 The analysis of 12-months worth of angiograms revealed a rather small (p<0.01) reduction of minimum lumen diameter (MLD) for the MV and the main branch (MB) (12.1 % and 14.0 %, respectively) and a significant increase of MLD for the SB (19 %). In association with such a process, the percentage diameter stenosis (DS) increased both in the MV and MB, while it decreased in the SB. The late lumen loss was significantly different for the MV and MB (0.46 mm and 0.39 mm, respectively) and very small (<0.1 mm) for the SB. It is not easy to explain this phenomenon; however, it seems rational to believe that optimised flow conditions due to the BiOSS design with less effect of shear stress are responsible.4 It is very likely that the ongoing randomised trial, which aims to compare BiOSS Expert stent and classical DES (POLish Bifurcation Optimal treatment Strategy [POLBOS study]) will show real clinical usefulness of this novel device.

1. Hildick-Smith D, Lassen JF, Albiero R, et al., Consensus from the 5th European Bifurcation Club meeting, EuroIntervention , 2010;6(1):34–8. 2. Buszman P, Trznadel S, Milewski K, et al., Novel paclitaxel-eluting, biodegradable polymer coated stent in the treatment of de novo coronary lesions: a prospective multicenter registry, Catheter Cardiovasc Interv, 2008;71(1):51–7. 3. Gil RJ, Vassiliev D, Michalek A, et al., First-in-man study of

Gil_Balton.indd 22

0.6

LLL

6 Months n=50

0.3

0 MV MB SB

LM group

non-LM group

0.39 0.24 0.15

0.24 0.19 0.06

LLL = late lumen loss; LM = left main; MB = main branch; MV = main vessel; SB = side branch.

BiOSS Lim – Sirolimus Version Recently, Balton has started a First-In-Man (FIM) study with a sirolimus version of the BiOSS stent (BiOSS Lim). Very promising results for a study performed in normal nonatherosclerotic porcine coronary arteries (both inflammation and injury scores were very low, and relatively small neointimal proliferation) showed that the BiOSS platform with sirolimus is more potent than paclitaxel and would ensure excellent clinical results. Recently, data collected from the BiOSS Lim FIM study prolonged this belief (see Figure 5). We proved that the late lumen loss after BiOSS Lim implantation is smaller when compared with the paclitaxel-eluting version BiOSS Expert (see Figure 6).

Conclusions Our experience with the BiOSS stent led us to believe that this device is easy to use and compatible with modern low size equipment, shortening the procedural and fluoroscopy time and decreasing the contrast volume.4,6 The elimination of carina displacement (as a main mechanism of SB compromise) by BiOSS stent keeps the side branches patent and does not require further treatment. In diseased vessels, with atherosclerotic plaque presence, these could be translated into a smaller number of peri-procedural myocardial infarctions and less late stent thromboses. n

paclitaxel-eluting stent BiOSS (Bifurcation Optimisation Stent System) dedicated for coronary bifurcation stenoses: three months results, Kardiol Pol , 2012;70(1):45–52. 4. Gil RJ, Vassiliev D, Michalek A, et al., Dedicated paclitaxeleluting bifurcation stent BiOSS® (Bifurcation Optimisation Stent System): 12-month results from a prospective registry of consecutive all-comers population, EuroIntervention, 2012;8(3):316–24. 5. Gil RJ, Michalek A, Bil J, et al., Comparative analysis of

lumen enlargement mechanisms achieved with bifurcation dedicated stent BiOSS® and classical coronary stent implantations by means of provisional side branch stenting strategy – the intravascular ultrasound study, 2012 (under review in In J Cardiovasc Imaging). 6. Vassilev D, Gil R, Milewski K, Bifurcation Optimisation Stent System (BiOSS Lim) with sirolimus elution: results from porcine coronary artery model, EuroIntervention , 2011;7(5):614–20.

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Coronary Bioresorbable Scaffolds

Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review Nienk e S v a n Dit zhuijzen , 1 ,2 J u r g e n M R L i g t h a r t , 1 N i c o B r u i n i n g , 1 E v e l y n R e g a r 1 a n d Heleen MM van Beusekom1 1. Department of Cardiology, Division of Experimental Cardiology; 2. Cardiovascular Research School COEUR, Erasmus University Medical Centre, Rotterdam, The Netherlands

Abstract Various fully bioresorbable stents (BRS) have been recently developed, allowing for temporary scaffolding of the vessel wall. The potentially unique advantage of BRS to temporary scaffold the vessel could reduce the risk of adverse clinical outcomes caused by acute vessel geometry changes, late malapposition, jailed side branches or inflexibility of permanent stents. The design of BRS is, however, not similar for all stents, resulting in differences in degradation and behaviour. To assess the performance of BRS, the effect of degradation and behaviour on the vessel wall should be accurately evaluated. Intracoronary imaging techniques such as intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS) allow for detailed longitudinal evaluation of the stent and the vessel wall and might therefore aid in improving design and behaviour of BRS.

Keywords Intracoronary imaging, bioresorbable stent, intravascular ultrasound, optical coherence tomography, near-infrared spectroscopy Disclosure: The authors have no conflicts of interest to declare. Received: 20 March 2013 Accepted: 25 March 2013 Citation: Interventional Cardiology Review, 2013;8(1):23–35 Correspondence: Heleen MM van Beusekom, Department of Cardiology, Division of Experimental Cardiology, Ee2355a Erasmus University Medical Centre, Dr. Molewaterplein 50-60, 3015 GE Rotterdam, The Netherlands. E: h.vanbeusekom@erasmusmc.nl

The indications for percutaneous coronary intervention (PCI) have expanded steadily during the past years. After the days of the revascularisation of obstructive coronary artery disease (CAD) by balloon angioplasty,1 the introduction of coronary stents has essentially contributed to PCI being one of the most frequently performed invasive therapeutic procedures worldwide. Bare metal stents (BMS) provided a solution to acute vessel occlusion by sealing dissection flaps and at the same time reducing the risk of restenosis through prevention of acute recoil and inward remodelling.2 The development of drug-eluting stents (DES) solved the problem of in-stent restenosis by reducing neointimal hyperplasia3,4 and recently, bioresorbable stents (BRS) have been developed. These BRS allow for temporary scaffolding of the vessel. Since they are gradually resorbed, they might allow the return of vasomotion, late luminal enlargement and late expansive remodelling. In contrast, conventional metallic stents cage the coronary artery by implanting a permanent foreign body that can lead to non-conformability of the stented vessel.5,6 Acute changes in the geometry of coronary arteries following implantation of these stents have been related to adverse clinical outcomes.7 Furthermore, acute or late strut malapposition as well as the jailing of side branches caused by the metallic cage might be associated with adverse clinical outcomes.8 Malapposition could contribute to thrombosis and a side branch jailed by the metallic cage can jeopardise access to the side branch and potentially promote restenosis. The unique potential advantages of BRS to allow for temporary scaffolding could reduce the risk of adverse clinical outcomes caused by acute vessel geometry changes, late malapposition, jailed side branches or inflexibility of the permanent stent, because of the disappearance of the stent over

van Beusekom.indd 23

time.9,10 These unique potential benefits of BRS over conventional metallic stents eventually led to the development of several types of BRS. To evaluate this development and the behaviour of BRS over time, the use of catheter-based intracoronary imaging techniques is gaining momentum. The aim of this review article is to describe the results of using clinically available invasive imaging techniques for the evaluation of BRS and put their contribution into perspective.

Challenges For the Evaluation of Bioresorbable Stents Polymers tend to have substantial different material characteristics compared with metallic stents and thus pose a variety of challenges for application as scaffolds in coronary arteries. Table 1 shows a detailed description of the BRS of which published data is currently available. The majority of BRS have a balloon-expandable design that requires careful sizing to ensure the stent does not crack upon deployment due to over-expansion. Self-expanding scaffold designs11 as well as a scaffold with a slide and lock design12 have also been developed. Most of the BRS are composed of translucent material, and therefore different approaches are used to allow for visualisation under X-ray – stents are equipped with radio-opaque markers on either both ends of the stent or on both ends of the balloon, or a proprietary iodinated material is added to the polymer, allowing visualisation of the complete stent. As a result of the non-radio-opaque design of most of these devices, angiography has limited sensitivity to diagnose stent under-expansion or evaluate stent degradation. Limitations of coronary angiography as a luminogram technique, the limited spatial resolution and the inability to visualise non-radio-opaque

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van Beusekom.indd 24

Balloon-expandable

No Paclitaxel

Magnesium alloy

6-crown

Balloon-expandable

Sirolimus

Radio-opaque

markers on balloon

2 radio-opaque

markers on balloon

2 radio-opaque

markers on balloon

2 radio-opaque

gold markers

X-ray Visibility 2 radio-opaque

Everolimus

poly-D, L-lactide Poly-L-lactide coated

BVS 1.1

Poly-L-lactide coated

Tyrosine derived

REVA Gen I

Balloon-expandable

Everolimus

Balloon-expandable

Everolimus

Balloon-expandable

Everolimus

Balloon-expandable

Everolimus

Balloon-expandable

Everolimus

Iodinated

acid linker

Non-radio-opaque

Sirolimus

acid and sebacic

Balloon-expandable

Therapeutic Inc.)

Sheet

mixed with salicylic

10 swine

(Bioabsorbable

Preclinical – porcine II

Polylactide anhydride

Non-radio-opaque

BTI Gen I

Sirolimus

acid linker

Balloon-expandable

Sheet

acid and sebacic

Polylactide anhydride

Therapeutic Inc.)

17 swine

Sirolimus

mixed with salicylic

Preclinical – porcine I

Balloon-expandable

poly-carbonate

Slide and spiral lock

(Bioabsorbable

BTI Gen I

expected to start 2012

350 patients

approval’

Randomised trial;

Iodinated

Tyrosine derived

Sirolimus

‘CE Mark

Balloon-expandable

REVA: ReZolve II

Slide and spiral lock

poly-carbonate

Prospective, open-label 50 patients

ReZolve I

RESTORE

Tyrosine derived

Paclitaxel

REVA Gen II:

Balloon-expandable

platinum markers

2 radio-opaque

platinum markers

2 radio-opaque

platinum markers

2 radio-opaque

platinum markers

2 radio-opaque

platinum markers

2 radio-opaque

poly-carbonate

Slide and lock

hoops

In-phase, zig-zag

hoops

In-phase, zig-zag

hoops

In-phase, zig-zag

hoops

In-phase, zig-zag

hoops

Circumferential

platinum markers

2 radio-opaque

(REVA Medical)

Prospective, open-label 27 patients

poly-D, L-lactide

RESORB

with amorphous

6,000 patients

ABSORB III and IV

poly-D, L-lactide

randomised control trial

with amorphous

Poly-L-lactide coated

501 patients

Prospective,

poly-D, L-lactide

ABSORB II

with amorphous

1,000 patients

poly-D, L-lactide

ABSORB EXTEND Registry

with amorphous

(Abbott Vascular)

ABSORB Cohort B Prospective, open-label 101 patients

with amorphous

(Abbott Vascular)

ABSORB Cohort A Prospective, open-label 30 patients

Poly-L-lactide coated

Balloon-expandable

BVS 1.0

Circumferential

poly-D, L-lactide

Poly-L-lactide

18 swine coated with amorphous hoops

Preclinical – porcine

(Abbott Vascular)

BVS 1.0

(Biotronik) tantalum markers

DREAMS 4.0

Expected

Balloon-expandable

DREAMS-II

6-crown

open-label

Magnesium alloy

alloy

4-crown

(Biotronik)

46 patients

Prospective,

DREAMS-I

BIOSOLVE-I

non-randomised

63 patients

PROGRESS-AMS Prospective,

Metal magnesium

Balloon-expandable

AMS (Biotronik)

4-crown

alloy

Metal magnesium

Drug Release No

expandable

Stent Strut Pattern Implantation Zig-zag helical Heated and balloon

monofilament

Stent Backbone Poly-L-lactic acid

Preclinical – porcine

Subjects (n) 50 patients

safety report

Study Design Feasibility and

AMS (Biotronik)

Study First-in-man

(Kyoto Medical)

Bioresorbable Stent Igaki-Tamai

Table 1: Summary of Bioresorbable Stents that are Currently Under Development

Diameter: 3.0

Length: 13

Diameter: 3.0

Length: 13

Diameter: 3.0

Length: 18

Diameter: 3.0

Length: 18

Diameter: 3.0

Length: 16

Diameters: 2.5, 3.0, 3.5

Lengths: 12, 18, 28

Diameters: 2.5, 3.0, 3.5

Length: 18

Diameters: 2.5, 3.0, 3.5

Lengths: 12, 18, 28

Diameter: 3.0

Lengths: 12, 18

Diameter: 3.0

Lengths: 12, 18

Diameter: 3.0

Lengths: 12, 18

Diameters: 3.25, 3.5

Length: 16

Diameters: 3.0, 3.5

Lengths: 10, 15

Diameter: 2.5–3.5

Length: 10

Diameters: 3.0, 3.5, 4.0

Size (mm) Length: 12

Coronary Bioresorbable Scaffolds

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van Beusekom.indd 25

INTERVENTIONAL CARDIOLOGY REVIEW

ARTDIVA

open-label

Prospective,

Preclinical – porcine

18 male swine

5 sites

patient number;

Unknown

Myolimus

Balloon-expandable

Novolimus

Poly-L-lactic acid

Poly-lactic acid

Balloon-expandable

Sirolimus

zig-zag hoops

In-phase,

Balloon-expandable

luminal with

Radio-opaque distal and proximal markers

L-lactide polymer

Preclinical

8 mini-swine

Iron

3.0, 3.5

Diameters: 2.5, 2.75,

ABSORB = Bioabsorbable everolimus-eluting coronary stent system; ABSORB EXTEND = Clinical Investigation: A continuation in the clinical evaluation of the ABSORB Bioresorbable Vascular Scaffold (BVS) System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions; AMS = Absorbable magnesium stent; ART = Arterial Remodeling Transient; ARTDIVA = Arterial Remodeling Transient DIsmantling Vascular Angioplasty; BIOSOLVE = Prospective, multicentre, first-in-man trial of the drug-eluting absorbable metal scaffold (DREAMS); BTI = Bioabsorbable Therapeutics Inc; BVS = bioresorbable vascular scaffold; CE = European Conformity; DESolve = DESolve™; DREAMS = Drug-Eluting Absorbable Metal Scaffold; MeRes = Merilimus Eluting Resorbable Coronary Scaffolding; NA = not applicable; ON ABS = Orbus Neich Absorbable stent; PROGRESS-AMS = Clinical Performance Angiographic Results of Coronary Stenting with Absorbable Metal Stents; RESORB trial = REVA Endovascular Study Of a bioResorBable coronary Stent; RESTORE = ReZolve® Sirolimus-Eluting Bioresorbable Coronary Scaffold; REVA = Reva Medical.

Shenzhen, China)

(Lifetech Scientific,

iron stent

Biodegradable

Lengths: 13, 16, 19,

Diameter: 3.0–7.0

Length: 20–100

Diameter: 3.0

Lengths: 15, 18

Diameters: 2.75–4.0

Length: 12–28

Diameters: 3.0, 3.5

Diameters: 3.0, 3.25, 3.5

Lengths: 14, 18

Diameters: 3.0, 3.25, 3.5

Length: 14

Diameter: 3.0

Length: 13

Diameter: 3.0

Size (mm) Length: 13

formulation (radiopaque) 24, 29, 32, 37

Science, India)

coated with a Poly-D,

Special coating

FIM planned in 2013

Sirolimus

(Meril Life

Balloon-expandable

Poly-L-lactide

Preclinical;

MeRes

Balloon-expandable

based material

Poly-L-lactide

(Amaranth Medical Inc.)

Preclinical – porcine

double ring

Ab-luminal sirolimus and +CD34 anti-bodies

and poly-L-lactide

Helically linked

Amaranth

of swine

lactone, poly-D-lactide

Poly-L-lactide-co-ε-capro

radio-opaque markers

Distal and proximal

Non-radio-opaque

and proximal marker

Radio-opaque distal

and proximal marker

Radio-opaque distal

Unknown number

Preclinical – porcine

(Orbus Neich)

ON ABS

Biotechnology Co.)

Huaan

(Shandong

Xinsorb

Technologies)

Remodelling

(Arterial

ART18AZ

Technologies)

Remodelling

49 swine

Preclinical – porcine

(Arterial

ART18AZ

Poly-L-lactic acid

open-label

120 patients

Prospective,

DESolve Nx

Balloon-expandable

zig-zag hoops

In-phase,

Poly-L-lactic acid

open-label

(Elixir Medical)

16 patients

acid linker

Prospective,

DESolve

DESolve I

Non-radio-opaque

acid and sebacic

Sirolimus

Therapeutic Inc.)

Balloon-expandable

mixed with salicylic

Polylactide anhydride

(Bioabsorbable

Planned

acid linker

X-ray Visibility Non-radio-opaque

BTI Gen II

Drug Release Sirolimus

Stent Strut Pattern Implantation Sheet Balloon-expandable

acid and sebacic

Stent Backbone Polylactide anhydride mixed with salicylic

Subjects (n) 11 patients

Therapeutic Inc.)

Study Study Design Whisper

(Bioabsorbable

Bioresorbable Stent BTI Gen I

Table 1: Summary of Bioresorbable Stents that are Currently Under Development (Cont.)

Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review

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Coronary Bioresorbable Scaffolds structures could be overcome using high-resolution catheter-based intravascular imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT).13,14 Furthermore, to evaluate the chemical composition of the tissue behind or on top of the stent, near-infrared spectroscopy (NIRS) could be used. These high-resolution diagnostic modalities allow for detailed evaluation of the vessel over time. Before BRS-implantation, intracoronary imaging can help determine the appropriate stent size in terms of diameter and length because of the ability to visualise the extent of coronary plaque and side branches. Vascular injury caused by the implantation procedure can be accurately evaluated and furthermore, the expansion, apposition, mechanical integrity and resorption process of the stent as well as the position with regard to side branches can be visualised. Moreover, of the translucent BRS, the underlying plaque can be evaluated.

Intracoronary Imaging of Bioresorbable Stents Using Clinically Available Techniques Greyscale Intravascular Ultrasound IVUS is an intravascular imaging technique that provides realtime high-resolution images of the vessel wall and treatment devices. Depending on the distance from the catheter, the axial resolution is approximately 80–150 micrometers, the lateral resolution 200–300 micrometers. Based on the echogenicity and the thickness of the material, different features of the vessel wall, treatment devices and the coverage of these devices can be evaluated.15 IVUS can adequately identify the lumen and vessel contours, allowing for the evaluation of plaque burden and vessel remodelling. Calcified components can be detected by IVUS with high accuracy; however, the ultrasound is backscattered by calcium causing acoustic shadowing, and therefore it is impossible to evaluate the extent of the calcium or evaluate underlying structures. The polymeric struts of BRS have an echogenic intensity similar to calcified components without acoustic shadowing, allowing for visualisation of the struts. They are depicted as hyper-refractive boxes with an echogenic blooming effect, causing a double-strut appearance on IVUS (see Figure 1). This allows for the assessment of the short- and long-term outcome of BRS and the treatment failures, such as strut malapposition, restenosis or stent thrombosis. However, the resolution of IVUS limits the assessment of the dimensions of thrombi and therefore makes guidance of their removal difficult. Furthermore, greyscale IVUS has a limited ability to make a distinction between morphological components of plaque, e.g. between lipid-rich and fibro-lipid plaque, and to quantify the degradation of BRS struts due to visual assessment. To assess morphological components of plaque and degradation of the BRS, IVUS-based imaging techniques such as IVUS-virtual histology (IVUS-VH), which classifies plaque into four components, and IVUS-echogenicity, which calculates the relative fraction of hypoechogenic versus hyperechogenic tissue volumes, could be used. Furthermore, for the treatment of thrombosis, OCT with its higher resolution, could be a very attractive imaging modality.

Intravascular Ultrasound Virtual Histology IVUS-VH is the first available IVUS backscattering image analysis system built on the 20 megahertz (MHz) phased array IVUS platform. Data acquisition is similar to standard IVUS but data analysis is performed on dedicated consoles. IVUS-VH is mainly used for tissue characterisation and classifies plaque into four components that are labelled with a specific colour – calcium appears white, fibrous tissue green, fibrolipidic tissue greenish-yellow and necrotic core red.16,17 The

van Beusekom.indd 26

ability to visualise the full circumference of the lumen and vessel wall is similar to conventional greyscale IVUS. However, conventional IVUS has limited ability to discriminate between plaque composition and to assess BRS strut degradation. IVUS-VH depicts most stent struts as dense calcium artefacts and thus allows for estimation of the stent degradation by comparing the amount of dense calcium directly after implantation with follow-up. Since the polymeric struts do not cause acoustic shadowing, the composition of the plaque behind the stent can be evaluated.18 However, interference with the strut artefact limits the determination of dense calcium and necrotic core in the plaque behind the stent.

Intravascular Ultrasound Echogenicity IVUS echogenicity analysis is a technique that calculates the relative fraction of hypoechogenic versus hyperechogenic tissue volumes. Tissue components are classified as either hypoechogenic or hyperechogenic using the mean grey value of the adventitia.19–21 Degradation of BRS can be determined by comparing the hyperechogenicity values directly after implantation with follow-up. Immediately after implantation the stented region typically shows increased hyperechogenicity compared with pre-implantation, suggesting the introduction of the stent. Over time, this hyperechogenicity diminishes, suggesting resorption of the BRS.22 Figure 1 shows cross-sections of a poly-l-lactic-acid (PLLA) and a metal BRS over time using IVUS and IVUS-echogenicity analysis. In case of dramatic changes in the plaque morphology, e.g. high neointimal burden or development of calcified plaque, the e chogenecity analysis could however be affected. OCT is not affected by the presence of calcium and because of its ability to longitudinally assess BRS, OCT could be a useful technique for BRS analysis.

Optical Coherence Tomography OCT is a high-resolution intracoronary imaging technique that uses a near-infrared light source (approximately 1,300 nanometres [nm] wavelength) to create the image. The axial resolution is about 10–15 micrometres, one order of magnitude higher than that of conventional IVUS, allowing for more detailed imaging. As a result of its high resolution, OCT can visualise the presence of atherosclerotic plaque, characterise the structure and extent of coronary plaque and quantify lumen dimensions as well as the extent of lumen narrowing in great detail.23,24 However, OCT has a limited penetration depth of 1–2 millimetres (mm), which is dependent on the penetration depth of the incident light beam into the vessel wall – the depth of penetration is greatest for fibrous tissue, least for red thrombi, and intermediate for calcified and lipid-rich tissue.25,26 Despite the limited penetration depth, the high resolution of OCT enables imaging of the length of atherosclerotic plaque and therefore potentially makes it possible to select the most appropriate stent length, landing zones and reference lumen dimensions that allow for optimal stent diameter selection. OCT also enables the visualisation of stent expansion, permitting safe and predictable post-dilatation in case of stent under-expansion. Furthermore, OCT is able to quantify the interaction of the stent with the vessel wall by its ability to determine stent apposition, the degree of malapposition, prolapse and intra-stent or edge dissections.27–29 Several studies have been performed to evaluate the reliability of OCT for the assessment of atherosclerotic plaque and stents, by assessing variability within and reproducibility of the data. An OCT reproducibility study of quantitative stent analysis showed that the relative difference for lumen area, stent area, tissue coverage area, tissue coverage thickness and strut coverage was around 1 % for the inter- and intra-observer reproducibility.23 For the lumen area on frame level, low

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Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review Figure 1: Greyscale Intravascular Ultrasound and Intravascular Ultrasound Echogenicity Analysis of a Polylactic Acid-based and Magnesium-based Bioresorbable Stent

Polylactic Acid-based Bioresorbable Stent BL 6M A B

Magnesium-based Bioresorbable Stent BL G

6M H

C C

12M I

A–F) Cross-sectional images of greyscale IVUS (A–C) and corresponding IVUS echogenicity (D–F) directly after implantation (BL), at six and 24 months (M) after implantation of a PLA-based bioresorbable stent. At baseline and six-month greyscale IVUS clearly shows the double-layered appearance of the bioresorbable stent (BRS) struts. The IVUS-echogenicity analysis indicates the BRS struts as green areas showing the presence of struts at BL and 6M with disappearance of the struts at 24M. G–L) Cross-sectional images of greyscale IVUS (G–I) and corresponding IVUS echogenicity (J–L) analysis directly after implantation (BL), at six and 12 months (M) following implantation of a magnesium-based bioresorbable stent. The greyscale and IVUS-echogenicity analysis of this BRS is similar to the PLA-based stent, showing the presence of struts at BL, 6M and 12M (double-layered on greyscale IVUS, green on IVUS-echogenicity). BL = baseline; BRS = bioresorbable stent; IVUS = intravascular ultrasound; M = months; PLA = polylactic acid.

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Coronary Bioresorbable Scaffolds intra- and inter-observer variability have been reported.30 Furthermore, a recently published study that evaluated pullbacks of stented coronary segments in time showed a very low per-frame and per-stent inter-study variability for mean lumen and stent area, suggesting that OCT is a reliable imaging tool for the assessment of repeated OCT examinations in longitudinal studies.31 Longitudinal evaluation of BRS is important for the quantification of strut degradation and the effect of the underlying plaque on the performance of BRS.32,33 The unique ability of OCT to reconstruct three-dimensional (3D) images allows for accurate evaluation of the interaction between the stent and the vessel wall, e.g. stent location, expansion and stent strut apposition.34 Jailed side branches have always been a source of concern because of the possible occurrence of thrombosis, alteration of shear stress, embolisation or endothelial coverage. Moreover, using 3D OCT, a classification based on the number of compartments delineated by the struts and the geometric configuration in front of the ostium has been developed.10 OCT potentially allows for selecting the most appropriate stent length, landing zones and reference lumen dimensions that allow for optimal stent diameter selection. Another light-based intracoronary imaging technique – NIRS – might, however, provide a better possibility to select the appropriate stent length and landing zones by its ability to assess the presence and location of lipid-core plaques with high accuracy.35,36

Near-infrared Spectroscopy This technique uses near-infrared light of wavelengths from 800 to 2,500 nm to identify specifically the presence of lipid core plaques (LCP).35,36 The primary presentation of the data is the chemogram, a plot of NIRS values obtained during a rotational pullback within the coronary artery, that assigns the probability of the presence of LCP (yellow=high, red=low). The lipid core burden index (LCBI) score summarises the fraction of LCP in the imaged section of the coronary vessel on a scale of 0–1,000. Since NIR spectroscopy alone only provides chemical information, a combined LipiScan™ IVUS system (TVC Imaging system™; InfraReDx, Inc) has been developed to provide structural information as well. This new imaging catheter combines the advantages of NIRS and IVUS, and enables the determination of the structure of a plaque simultaneously with its chemical composition.37–40 A series of cases that highlight the potential clinical applications of the TVC Imaging system has been reported recently, showing that it may enhance detection of culprit and non-culprit lesions having architectural and compositional features of vulnerable plaque.41 Moreover, TVC imaging potentially helps in deciding on the correct stent length and to identify lesions at greater risk of distal embolisation during PCI.42 In studies evaluating BRS, the TVC system is mainly used for the evaluation of the change in LCBI from pre- to post-implantation and for the evaluation of the lipid content within the coverage of the stent at follow-up.43

Intracoronary Evaluation of Currently Available Bioresorbable Stent – Lessons Learned Bioresorbable technologies for stents were already investigated in the mid-1980s with the pioneering work at Duke University. Back then the first polylactic acid (PLA)-based bioabsorbable stent was a braided, self-expanding stent. Five years later the first balloon-expandable PLA stent was developed at Duke University.44 Until now, few different fully BRS have been tested in humans and animals. Table 1 shows the currently available BRS and their design. The design of BRS is important regarding the efficacy and safety, e.g.

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mechanical integrity and extent of re-endothelialisation, of the device. To accurately investigate the safety and efficacy of these BRS in vivo, longitudinal evaluation of their behaviour is mandatory and selection of the follow-up time-points should be performed carefully, taking the resorption and degradation pattern known from preclinincal studies in consideration. Table 2 shows studies evaluating BRS at specific time-points using different imaging techniques.

Igaki-Tamai® Stent (Kyoto Medical Planning Co Ltd, Kyoto, Japan) The Igaki-Tamai BRS represents the first fully biodegradabable PLA-based coronary stent tested in humans in the late 1990s. This stent is self-expanding, requires storage and expansion at pre-specified temperatures and needs a larger guide catheter (8 French [Fr]). In the first report that described the Igaki-Tamai® stent, angiography and IVUS were used to evaluate the safety and efficacy of the stent up to six months. Acceptable restenosis and target lesion revascularisation (TLR) rates (both 6.7 %) and no deaths, myocardial infarction (MI) or coronary artery bypass grafts (CABG) were demonstrated. However, against expectation, the stent did not fully degrade six months after implantation and therefore clinical and imaging follow-up investigations were extended.11 Currently, imaging and clinical data of the first-in-man (FIM) Igaki-tamai is available up to 10 years demonstrating long-term safety, with similar major adverse cardiac event (MACE) rates to those of BMS (MACE free survival at 10-year 50 %) without stent recoil and vessel remodelling.19

Absorbable Magnesium Stent (Biotronik, Berlin, Germany) The absorbable magnesium stent (AMS) is a magnesium-based balloon-expandable stent. A study in swine showed that this stent has a faster degradation time than PLA-based BRS, with a complete absorption of the stent within two months.45 The first evaluation of this BRS in humans was therefore performed in a prospective, non-randomised, multicentre clinical trial (PROGRESS-AMS) using angiography and IVUS (40 MHz; Boston Scientific, Natick, US or 20 MHz; Eagle Eye, Volcano, Rancho Cordova, US) at baseline and at four-month follow-up. Furthermore, clinical follow-up was performed at four, six and 12 months.46 The imaging results showed good scaffolding of the vessel, but a high event rate and in-stent late loss due to vessel recoil (55 %) and neointima formation (45 %).47 Therefore, a new device was developed including a prolonged scaffolding time and the anti-proliferative drug paclitaxel (Drug-Eluting Absorbable Metal Scaffold [DREAMS]; AMS 3.0). This paclitaxel-eluting AMS 3.0 was first evaluated in animal studies 48 and lead to a prospective, multicentre, FIM trial – the BIOSOLVE-1 (prospective, multicentre, first-in-man trial of the drug-eluting absorbable metal scaffold [DREAMS]) study. Angiographic follow-up was chosen at six and 12 months because of findings from animal trials that showed that the conversion of the magnesium to magnesium hydroxide is completed after six months and absorption to amorphous calcium apatite at 12 months. To capture all the potential late events and complications, clinical follow-up was planned up to 36 months.49 At six months, vascular restoration was achieved with the return of vasomotion50 and no substantial expansive or constrictive remodelling was observed.51 Furthermore, the absorption of the BRS was observed by IVUS-VH suggesting absorption by a reduction in dense calcium, by IVUS echogenicity suggesting absorption by a reduction in hyperechogenic tissue components, and by OCT confirming that the visibility of the stent began to fade.50 The recently published one-year results showed feasibility and safety of the AMS with 100 % procedural and device success, a TLR rate of 7 % and no

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Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review

QCA

4 YR 4.5 YR 5 YR 10 YR

3.5 YR

1.5 YR

3 YR

15 M

2 YR

9 M

1 YR

7 M

6 M

Table 2: The Various Follow-up Time-points Used in Clinical and Preclinical Studies Evaluating Bioresorbable Stents 4 M 4.5 M

BLpost 1 day 5 days 7 days 10 days 14 days 1 M

3 M

BLpre

(n=1)

2 M

Study QCA

Histo

IVUS

QCA

Igaki-Tamai FIM

QCA

IVUS echo

IVUS IVUS

QCA QCA

IVUS echo

IVUS IVUS IVUS echo IVUS IVUS IVUS IVUS QCA

IVUS echo

Absorbable magnesium stent – porcine study IVUS

IVUS

PROGRESS-AMS QCA QCA QCA

QCA

(40 or 20 MHz)

QCA

Histo

(40 or 20 MHz) (40 or 20 MHz)

Histo Histo

AMS 3.0 – porcine studies

Vasomotion

BIOSOLVE-1 QCA QCA QCA QCA QCA

IVUS IVUS IVUS IVUS IVUS echo

IVUS echo

IVUS-VH IVUS-VH IVUS-VH IVUS-VH

OCT OCT OCT

Vasomotion

IVUS-VH IVUS-VH IVUS-VH IVUS-VH IVUS-VH

IVUS IVUS IVUS IVUS IVUS

ABSORB cohort A QCA QCA QCA QCA QCA

OCT OCT OCT OCT OCT

IVUS echo IVUS echo

IVUS-VH IVUS-VH IVUS-VH IVUS-VH

IVUS IVUS IVUS IVUS

ABSORB Cohort B-G1 QCA QCA QCA QCA

IVUS echo IVUS echo

IVUS IVUS

ABSORB Cohort B-G2 QCA QCA

IVUS echo

IVUS-VH

IVUS

QCA

OCT

IVUS echo

IVUS-VH

IVUS

QCA

OCT OCT OCT OCT

IVUS-VH IVUS-VH

OCT

OCT OCT

IVUS

QCA

ABSORB EXTEND QCA QCA

QCA

IVUS-VH

IVUS

QCA QCA

IVUS-VH

IVUS IVUS

OCT

ABSORB II

IVUS-VH IVUS-VH

NIRS

IVUS-VH

OCT OCT

NIRS NIRS

OCT

QCA

ABSORB III and IV

IVUS

imaging cohort

QCA

OCT QCA

QCA

IVUS IVUS

OCT QCA

IVUS

QCA

IVUS

REVA – porcine study

IVUS IVUS

QCA

IVUS

QCA

IVUS

QCA QCA QCA

RESORB FIM

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van Beusekom.indd 29

INTERVENTIONAL CARDIOLOGY REVIEW

van Beusekom.indd 30 3 M

4 M 4.5 M

6 M

7 M

9 M

QCA

OCT OCT

IVUS IVUS

QCA OCT

IVUS

QCA

IVUS

QCA

IVUS IVUS IVUS

QCA

15 M

1.5 YR

2 YR

3.5 YR

4 YR 4.5 YR 5 YR 10 YR

IVUS

3 YR

OCT

IVUS

QCA

IVUS

QCA

OCT

IVUS

QCA

IVUS

1 YR

OCT

QCA

OCT OCT

IVUS IVUS

QCA

OCT OCT OCT OCT OCT

IVUS IVUS IVUS IVUS IVUS

QCA

OCT

QCA

OCT

QCA

OCT

QCA

Amaranth – preclinical

QCA

OCT

ABSORB = A Bioabsorbable everolimus-eluting coronary stent system; ABSORB EXTEND = Clinical Investigation: A continuation in the clinical evaluation of the ABSORB Bioresorbable Vascular Scaffold (BVS) System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions; AMS = absorbable magnesium stent; ART = Arterial Remodeling Technologies; ARTDIVA = Arterial Remodeling Transient DIsmantling Vascular Angioplasty; BIOSOLVE-1 = prospective, multicentre, first-in-man trial of the drug-eluting absorbable metal scaffold (DREAMS); BLpost = Baseline post-BRS-implantation; BLpre = Baseline pre-BRS-implantation; BTI = Bioabsorbable Therapeutics Inc; DESolve = DESolve™; FIM = first-in-man; IVUS = Intravascular ultrasound; IVUS-VH = intravascular ultrasound virtual histology; M = month; MeRes = Merilimus Eluting Resorbable Coronary Scaffolding; MHz = megahertz; NIRS = near-infrared spectroscopy; OCT = optical coherence tomography; ON-ABS BRS = Orbus Neich Absorbable stent; PROGRESS-AMS = Clinical Performance Angiographic Results of Coronary Stenting with Absorbable Metal Stents; QCA = quantitative coronary angiography; RESORB trial = REVA Endovascular Study Of a bioResorBable coronary Stent; RESTORE = ReZolve® Sirolimus-Eluting Bioresorbable Coronary Scaffold; REVA = Reva Medical; YR = year.

QCA

OCT OCT OCT

QCA

OCT

QCA

OCT OCT

QCA

OCT

QCA

Biodegradable iron stent

MeRes – engineering tests NA

QCA

ON-ABS BRS – preclinical QCA

QCA

OCT

QCA

Xinsorb – porcine study

QCA

QCA QCA

OCT OCT

QCA

ARTDIVA

OCT

ART18AZ – porcine

OCT OCT OCT OCT

IVUS IVUS IVUS IVUS

DESolve Nx QCA QCA QCA QCA QCA

OCT OCT

IVUS IVUS

OCT

QCA

OCT

DESolve – FIM

QCA

DESolve – preclinical

OCT OCT OCT

IVUS IVUS IVUS

BTI – FIM QCA QCA QCA QCA

QCA

IVUS

QCA

BTI – porcine study II

OCT OCT

QCA

IVUS

BTI – porcine study I

QCA

QCA QCA

OCT

RESTORE

IVUS

QCA

2 M

ReZolve – preclinical

BLpost 1 day 5 days 7 days 10 days 14 days 1 M

IVUS IVUS

BLpre

Study

Table 2: The Various Follow-up Time-points Used in Clinical and Preclinical Studies Evaluating Bioresorbable Stents (cont.)

Coronary Bioresorbable Scaffolds

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Invasive Imaging of Bioresorbable Coronary Scaffolds â&#x20AC;&#x201C; A Review Figure 2: Example of the ABSORB BVS 1.0 at Baseline Before and After Implantation and at Six Months, Two and Five Years After Implantation Dist

Mid

Prox C

A B C

BL pre

BL post

A B C

6M FUP

A B C

2YR FUP

A B C

5YR FUP The angiogram BLpre depicts the stented segment before implantation of the BVS 1.0. The orange lines (Aâ&#x20AC;&#x201C;C) indicate the distal, mid and proximal portion of the stent, depicted in the IVUS and OCT cross-sections. The red circles in the IVUS and OCT cross-sections indicate the proximal and distal marker of the BVS. BL = baseline; BVS = bioresorbable vascular scaffold; Dist = distal; FUP = follow-up; IVUS = intravascular ultrasound; M = months; OCT = optical coherence tomography; pre = pre BVS implantation; post = post BVS-implantation; Prox = proximal; YR = year.

cardiac death or scaffold thrombosis. 9 The second-generation AMS 4.0 underwent additional design changes and elutes sirolimus. Preclinical swine data show lower inflammation and injury scores, and a higher endothelialisation score on histopathology at 28 and 56 days. BIOSOLVE-II planning is underway and will commence later in 2013.52

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Abbott Vascular Bioresorbable Stent (Bioresorbable Vascular Scaffold; Abbott Vascular, Santa Clara, Ca, US) This BRS is a PLLA-based stent that elutes the antiproliferative drug everolimus and has the vastest imaging experience. The in vivo polymer degradation profile of the stent was established in a porcine

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Coronary Bioresorbable Scaffolds coronary artery model and showed a mass loss of 30 % at 12 months with further reduction to 60 % mass loss by 18 months.53 The FIM evaluation of the Abbott vascular BRS (bioresorbable vascular scaffold [BVS] 1.0; Abbott Vascular, Santa Clara, Ca, US) was performed in the ABSORB (A Bioabsorbable everolimus-eluting coronary stent system) Cohort A study with imaging planned at six months and clinical follow-up at 12 months.20 Greyscale IVUS and OCT showed scaffold shrinkage between baseline and six months and therefore design changes were made. Invasive imaging evaluation was extended up to two years and clinical follow-up up to five years to capture potential late events.33,53 Between six months and two years, angiography showed a similar in-stent late lumen loss (LLL) and IVUS and OCT showed an increased minimum lumen area (MLA) and mean lumen area. After evaluation of the imaging results at two years, an extra invasive imaging evaluation was planned at five years and demonstrated an increased MLA and reference vessel diameter inside the scaffold. No MACE occurred and no scaffold thrombosis was seen, indicating late luminal enlargement and safety of the scaffold up to five years.54â&#x20AC;&#x201C;56 Figure 2 shows an example of the BVS 1.0 before and after implantation, at six months, two and five years. The new generation Abbott vascular BRS (BVS 1.1) is studied in the ABSORB Cohort B trial, consisting of two arms: cohort B1, including 45 patients that underwent invasive (quantitative coronary angiography [QCA], IVUS, IVUS-VH, IVUS echogenicity and OCT) follow-up assessment at six and 24 months and cohort B2, including 56 patients that underwent the same invasive imaging assessment at 12 and 36 months. These two arms were chosen because, despite the prolonged scaffolding time at six-month follow-up of the BVS 1.1, it remained uncertain whether this favourable result at six months would persist in humans or whether a delayed inflammatory response accompanied by late recoil and neointimal hyperplasia would occur mid-term at 12 months. In the cohort B1 group angiography and IVUS showed a slight decrease in lumen area up to two years.21,57 OCT showed a similar lumen area decrease from baseline to six months, with no further changes at two years and an increased scaffold area up to two years. The IVUS-VH results showed a non-significant reduction in dense calcium up to six months.57 In the cohort B2 group, LLL at one-year was the same as found at two years in the cohort B1 group.21,58 The return of vasomotion, assessed by challenging the scaffolded segments with incremental doses of acetylcholine and nitrates, was observed at 12 months and even more pronounced at 24 months, suggesting a link between scaffold degradation and restoration of vasomotion in the treated segments.58 IVUS echogenicity analysis showed that at the expected time of total degradation and bioresorption, two years after implantation, the acoustic signals exhibited only a little evidence of polymer residues in both revisions of the BVS.20,21 In the currently ongoing ABSORB EXTEND (Clinical Investigation: A continuation in the clinical evaluation of the ABSORB Bioresorbable Vascular Scaffold (BVS) System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions) trial, a non-randomised, single-arm, continued access trial, patients are treated with a 3.0 or 2.5 x 18 mm, or 3.0 x 28 mm BVS 1.1 to continue assessment of the safety and performance of this scaffold. A consistency in outcomes between ABSORB EXTEND and ABSORB Cohort B is seen.59 In the ABSORB II trial, a prospective, randomised control trial that aims to compare the safety and efficacy of the BVS 1.1 versus Xience PRIME, patients with stable angina and single or two vessel disease will be included and randomised on a 2:1 basis to BVS 1.1 and

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Xience PRIME stent implantation. IVUS-VH and NIRS will be used in addition to angiography and IVUS, pre- and post-procedure and at two-year follow-up to assess vessel geometrical and compositional changes over time as well as signs of scaffold resorption.43,60 Recently presented is the ABSORB III and IV pivotal clinical trial programme, a clinical programme consisting of two integrated randomised trials designed to achieve approval of ABSORB in the US and to demonstrate the superiority of ABSORB compared with DES. In the ABSORB III trial patients will be randomised on a 2:1 basis to ABSORB or Xience, in the ABSORB IV trial patients will be randomised 1:1 to ABSORB or Xience and a subgroup of these patients will be randomised to angiography, IVUS, OCT and vasomotion analysis.61

REVA (REVA Medical Inc, San Diego, US) The first generation REVA BRS is a non-drug-eluting scaffold composed of tyrosine-derived polycarbonate, with a unique radio-opaque slide and lock mechanism to allow for visualisation on X-ray. The first REVA BRS were tested in Yucatan mini-swine immediately after implantation, at five days, three and six months and one, 1.5, two and 4.5 years after implantation using in vivo QCA, IVUS and OCT.62 The first-time evaluation of the REVA BRS in humans was performed in the RESORB (REVA Endovascular Study Of a bioResorBable coronary Stent) trial directly after implantation, at four, 12 and 36 months and showed a minimum lumen diameter increase post-procedure and the absence of late recoil was suggested because of an unchanged external elastic lamina at follow-up. However, there was a higher TLR rate than anticipated between four and six months, and therefore design changes were made.63 The second generation sirolimus-eluting REVA BRS was first tested preclinically in swine using QCA, IVUS and OCT directly after placement, at one, three, six and 12 months. 62 Thereafter, the ReZolveÂŽ Sirolimus-Eluting Bioresorbable Coronary Scaffold (RESTORE) clinical trial was initiated.64 At six-month follow-up two MACE were reported, one TLR for focal in-stents restenosis, and one TLR directly related to protocol deviation at implant. Twelve months data will be presented at EuroPCR in May 2013. Furthermore, the RESTORE II trial has commenced investigating the sheathless ReZolve2 scaffold system, which will provide necessary data for the European Conformity (CE) marking.65

Bioabsorbable Therapeutic Inc (Menlo Park, CA, US) The Bioabsorbable Therapeutic Inc (BTI) BRS is synthetised entirely from salicylic acid bioabsorbable polymer derivates and contains a top coat for sirolimus drug-elution. The first evaluation of the BTI was performed in domestic swine using QCA and IVUS post-implantation, at one and two weeks, and at one, three and six months after implantation. QCA showed good mechanical performance during placement and at follow-up a preserved apposition with maintained radial strength was observed using IVUS and OCT.66 Another evaluation of the BTI BRS in swine using QCA, IVUS and OCT directly after implantation, at one, three, six, nine, 12, 15 and 18 months demonstrated gradual degradation of the device. After 15 months most of the struts were not identified by OCT, probably because of replacement by neointimal tissue.67 The FIM study performed in 11 patients using QCA, IVUS and OCT post-implantation at six and 12 months showed acceptable safety and the absence of recoil. Insufficient neointimal suppression was however found, which was thought to be due to insufficient drug dosing on the surface area and a too fast drug release. New improvements are made with the second generation BTI that has improved manufacturing with a higher drug dose with slower release and an optimised stent pattern.67

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Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review DESolve (Elixir Medical, Sunnyvale, US) The DESolve BRS is a PLA-based BRS with radial strength for over three months in which bioresorption occurs between one and two years as shown by OCT data from swine. In the FIM study, angiography, IVUS and OCT were performed post-implantation and at six-month follow-up, and showed no late scaffold recoil and low neointimal hyperplasia.68 The next evaluation of the DESolve BRS will be performed in the DESolve™ Nx study in which patients will be followed-up for five years. In a subset of patients QCA, IVUS and OCT will be performed at six, 12 and 24 months to provide more detailed information on the BRS and its degradation in time.68–70

ART18AZ (Arterial Remodeling Technologies, Noisy le Roi, France) The ART18Z is a drug-free, flexible, bioresorbable polymer scaffold of which the polymer chains have no specific orientation resulting in more freedom to follow deformations and a supported overexpansion of 25 % without cracking or malapposition. Dismantling starts at three months with recovery of arterial function, and the resorption is expected within 18–24 months. The first evaluation of the Arterial Remodeling Technologies (ART) BRS was performed in porcine coronary arteries using QCA pre- and post-implantation at three, six and nine months and OCT at three, six and nine months. QCA and OCT analysis showed low acute recoil and low LLL at three and six months with a lumen area enlargement at nine months. 71 The FIM evaluation, the Arterial Remodeling Transient Dismantling Vascular Angioplasty (ARTDIVA) trial, is a prospective, multicentre, open-labelled, single-group interventional investigation that aims to evaluate the safety of the ART BRS in the treatment of patients with single de novo native coronary artery lesions up to 12 months. The first impressions are excellent procedural performances and good apposition. To date, nine ART BRS have been implanted in patients and no MACE have been reported.72–74

Xinsorb (Shandong Huaan Biotechnology Co Ltd, China) The Xinsorb BRS is a fully resorbable, balloon-expandable, PLLA stent coated with a thin layer containing sirolimus. The first evaluation was performed in a study comparing Excel™ DES (JW Medical System, Weihai, China) to Xinsorb DES. QCA analysis before, immediately after, and at one and three months after implantation suggests a successful prevention of elastic recoil and suppression of neointimal formation with a mildly delayed (1–3 months) re-endothelialisation of the stented vessel. Longer term follow-up is, however, required to validate the long-term efficacy of this Xinsorb BRS and before a FIM trial will be conducted, further preclinical examination will be performed.75

ON-ABS BRS (OrbusNeich, Fort Lauderdale, FL, US) The OrbusNeich Absorbable (ON-ABS) BRS is composed of three distinct bioabsorbable polymer systems – Poly-D-lactide, PLLA and L-lactide-co-ε-caprolactone. This BRS is currently under preclinical evaluation using QCA and OCT before, directly after and at one, two, three and six months following implantation in swine.76 Preliminary OCT data immediately after implantation demonstrate a well apposed scaffold, no tissue prolapse, no broken struts and less than 2 % acute recoil.77 The FIM evaluation of this device is scheduled to start beginning 2014.78

Amaranth (Amaranth Medical Inc, Mountain View, CA, US) The Amaranth BRS is a non-drug-eluting PLLA-based scaffold and is studied preclinically using QCA and OCT immediately after and at one,

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van Beusekom.indd 33

three and seven months after implantation. QCA showed minimal scaffold recoil, sustained structural integrity and a comparable radial strength up to seven months when compared with BMS. Neointimal thickness increased within 28 days and stabilised until 90 days. However, between 90 days and seven months the neointimal thickness seemed to decrease, suggesting late luminal enlargement. The FIM investigation started in 2013. Later in 2013 a drug-eluting version of this BRS will be tested in a porcine model.79

MeRes (Meril Life Science, India) The MeRes (Merilimus Eluting Resorbable Coronary Scaffolding) BRS is another PLLA-based BRS, eluting sirolimus and coated with a special coating formulation that ensures the visibility of the stent under X-ray. The currently available results are from engineering tests that demonstrate a desirable performance. Preclinical tests in porcine coronary arteries are currently starting to understand the biological behaviour of the stent and the FIM clinical trials are expected to start in 2013.80

Lifetech Iron Bioresorbable Stents (Lifetech Scientific, Shenzhen, China) This BRS is a biodegradable iron stent. A feasibility study of biodegradable nitriding iron stents was performed in coronary arteries of mini-swine in order to develop this stent. Eight iron stents were compared with eight vision stents (Abbott Vascular, CA, US) at four weeks after implantation using OCT. OCT data showed good biocompatibility with a similar neointimal proliferation in both stents. No thrombosis, inflammation and necrosis was observed in both groups and OCT showed 99 % neointimal coverage of the iron stents. Corrosion of the iron stents was observed without any signs of iron-related organ toxicity.81 However, not mentioned above, there are other BRS that are currently under development. These are the Sahajanand (Sahajanand medical technologies Pvt Ltd, India), Avatar (S3V; Vascular technologies Pvt LTd, India) and Zorion (Zorion Medical, IN, US). Detailed descriptions of these BRS are not yet publicly available.

Future Perspective on the Use of Intracoronary Imaging in the Bioresorbable Stent Era The use of various imaging modalities is important to evaluate the different aspects of the degradation and behaviour of the stents. Co-registration of the different imaging modalities could, however, be challenging. A sub-study of the ABSORB cohort B1 compared QCA, IVUS and OCT findings and showed that OCT was most accurate in assessing stent length compared with nominal length (95 % confidence interval [CI] of the difference: -0.19; 0.37 and -0.15; 0.47 mm2). QCA consistently underestimated the length and IVUS showed low accuracy with several outliers and random variability. Within the three imaging modalities, poor agreement for MLA estimation was seen and no linear relation between any of the methods was demonstrated.82 Three-dimensional QCA allows for integration with IVUS or OCT and could therefore be used for accurate co-registration.83 Both IVUS and OCT correlate well with 3D QCA in assessing lumen size.84

Preclinical Study Considerations Not all aspects regarding BRS can be addressed or answered in clinical studies. Therefore, well-established human-like models expressing coronary or peripheral arterial disease in which BRS can be implanted in the vascular bed they are intended for, are necessary. An easily accessible model is the farm bred swine fed a high-cholesterol but calorie-restricted diet. These swine show coronary artery disease (CAD)

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Coronary Bioresorbable Scaffolds and a similar coronary anatomy to humans. They allow to study the development of atherosclerosis using intracoronary imaging, and to assess the longitudinal vascular response to bare metal and drug-eluting BRS in the presence of disease, which may exacerbate the vascular response. Moreover, the ability to obtain corresponding histological sections allows for the validation of BRS-behaviour, e.g. degradation and drug release, in the presence of coronary atherosclerosis.85 Furthermore, functional vascular assessment (vasomotion) can be performed both in vivo and in vitro and can be compared with corresponding histology. Histological assessment of BRS is, however, challenging. Since BRS disappear or become flexible upon degradation, the utmost care needs to be taken in the preparation for histology to prevent post-mortem

1. Grüntzig AR, Senning A, Siegenthaler WE, Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty, N Engl J Med, 1979;301(2):61–8. 2. Serruys PW, de Jaegere P, Kiemeneij F, et al., A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group, N Engl J Med, 1994;331(8):489–95. 3. Sousa JE, Costa MA, Abizaid A, et al., Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study, Circulation , 2001;103(2):192–5. 4. Sousa JE, Costa MA, Abizaid AC, et al., Sustained suppression of neointimal proliferation by sirolimus-eluting stents: oneyear angiographic and intravascular ultrasound follow-up, Circulation , 2001;104(17):2007–11. 5. Serruys PW, Garcia-Garcia HM, Onuma Y, From metallic cages to transient bioresorbable scaffolds: change in paradigm of coronary revascularization in the upcoming decade?, Eur Heart J, 2012;33(1):16–25b. 6. Colombo A, Karvouni E, Biodegradable stents : “fulfilling the mission and stepping away”, Circulation , 2000;102(4):371–3. 7. Gyongyosi M, Yang P, Hassan A, et al., Intravascular ultrasound predictors of major adverse cardiac events in patients with unstable angina, Clin Cardiol , 2000;23(7):507–15. 8. Forrest JK, Lansky AJ, Meller SM, et al., Evaluation of XIENCE V Everolimus-Eluting and Taxus Express2 Paclitaxel-Eluting Coronary Stents in Patients With Jailed Side Branches From the SPIRIT IV Trial at 2 Years, Am J Cardiol, 2013 [Epub ahead of print]. 9. 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;381:836–44. 10. Okamura T, Onuma Y, García-García HM, et al., 3-Dimensional optical coherence tomography assessment of jailed side branches by bioresorbable vascular scaffolds: a proposal for classification, JACC Cardiovasc Interv, 2010;3(8):836–44. 11. Tamai H, Igaki K, Kyo E, et al., Initial and 6-Month Results of Biodegradable Poly-l-Lactic Acid Coronary Stents in Humans, Circulation , 2000;102(4):399–404. 12. Pollman MJ, Engineering a bioresorbable stent: REVA programme update, EuroIntervention , 2009;5 Suppl F:F54–7. 13. Scanlon PJ, Faxon DP, Audet AM, et al., ACC/AHA guidelines for coronary angiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions, Circulation , 1999;99(17):2345–57. 14. Sones FM Jr, Shirey EK, Cine coronary arteriography, Mod Concepts Cardiovasc Dis , 1962;31:735–8. 15. Mintz GS, Nissen SE, Anderson WD, et al., American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents, J Am Coll Cardiol , 2001;37(5):1478–92. 16. Nair A, Kuban BD, Tuzcu EM, et al., Coronary plaque classification with intravascular ultrasound radiofrequency data analysis, Circulation , 2002;106(17):2200–6. 17. 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;46(11):2038–42. 18. Brugaletta S, Garcia-Garcia HM, Garg S, et al., Temporal changes of coronary artery plaque located behind the struts of the everolimus eluting bioresorbable vascular scaffold, Int J Cardiovasc Imaging , 2011;27(6):859–66. 19. 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 ,

van Beusekom.indd 34

contraction and processing artefacts. The resulting changes in length and diameter of the segment of interest affect measurements and cross-correlation to imaging and could subsequently affect interpretation of the data. Depending on the chosen processing method, post-mortem changes cannot always be prevented but should be monitored and clearly described when reporting the data.

Conclusion For the longitudinal evaluation of BRS, multiple intracoronary catheter-based imaging modalities are typically used. The main benefit of these intravascular imaging techniques is the ability to study the longitudinal changes in appearance and behaviour of BRS, which will aid in improving design and behaviour of these devices. n

2012;125(19):2343–53. 20. 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;373(9667):897–910. 21. Serruys P OY, on behalf of the ABSORB A and B investigators, editor. ABSORB Cohort B: 6M, 12M, 18M and 24M Follow-up. PCR BVS Focus group meeting; 8-9 March 2012; Rotterdam, The Netherlands. 22. Bruining N, de Winter S, Roelandt JR, et al., Monitoring in vivo absorption of a drug-eluting bioabsorbable stent with intravascular ultrasound-derived parameters a feasibility study, JACC Cardiovasc Interv, 2010;3(4):449–56. 23. Gonzalo N, Serruys PW, Piazza N, Regar E, Optical coherence tomography (OCT) in secondary revascularisation: stent and graft assessment, EuroIntervention , 2009;5 Suppl D:D93–100. 24. Okamura T, Garg S, Gutiérrez-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;5(8):932–8. 25. Yabushita H, Bouma BE, Houser SL, et al., Characterization of human atherosclerosis by optical coherence tomography, Circulation , 2002;106(13):1640–5. 26. Kubo T, Xu C, Wang Z, et al., Plaque and thrombus evaluation by optical coherence tomography, Int J Cardiovasc Imaging, 2011;27(2):289–98. 27. Ozaki Y, Okumura M, Ismail TF, et al., The fate of incomplete stent apposition with drug-eluting stents: an optical coherence tomography-based natural history study, Eur Heart J, 2010;31(12):1470–6. 28. Prati F, Regar E, Mintz GS, et al., Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis, Eur Heart J, 2010;31(4):401–15. 29. Prati F, Guagliumi G, Mintz GS, et al., Expert review document part 2: methodology, terminology and clinical applications of optical coherence tomography for the assessment of interventional procedures, Eur Heart J, 2012;33(20):2513–20. 30. Okamura T, Onuma Y, Garcia-Garcia HM, et al., First-in-man evaluation of intravascular optical frequency domain imaging (OFDI) of Terumo: a comparison with intravascular ultrasound and quantitative coronary angiography, EuroIntervention , 2011;6(9):1037–45. 31. Jamil Z, Tearney G, Bruining N, et al., Interstudy reproducibility of the second generation, Fourier domain optical coherence tomography in patients with coronary artery disease and comparison with intravascular ultrasound: a study applying automated contour detection, Int J Cardiovasc Imaging, 2013;29(1):39–51. 32. Onuma Y, Garg S, Okamura T, et al., Ten-year follow-up of the IGAKI-TAMAI stent. A posthumous tribute to the scientific work of Dr. Hideo Tamai, EuroIntervention , 2009;5 Suppl F:F109–11. 33. Tanimoto S, Bruining N, van Domburg RT, et al., Late stent recoil of the bioabsorbable everolimus-eluting coronary stent and its relationship with plaque morphology, J Am Coll Cardiol, 2008;52(20):1616–20. 34. Karanasos A, Tu S, van der Linden M, et al., Online 3-dimensional rendering of optical coherence tomography images for the assessment of bifurcation intervention, Can J Cardiol, 2012;28(6):759.e1–3. 35. Gardner CM, Tan H, Hull EL, et al., Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system, JACC Cardiovasc Imaging , 2008;1(5):638–48. 36. Waxman S, Dixon SR, L’Allier P, et al., In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study, JACC Cardiovasc Imaging, 2009;2(7):858–68. 37. Regar E, Invasive imaging technologies: can we reconcile light and sound?, J Cardiovasc Med (Hagerstown), 2011;12(8):562–70.

38. Garg S, Serruys PW, van der Ent M, et al., First use in patients of a combined near infra-red spectroscopy and intra-vascular ultrasound catheter to identify composition and structure of coronary plaque, EuroIntervention , 2010;5(6):755–6. 39. Schultz CJ, Serruys PW, van der Ent M, et al., First-in-man clinical use of combined near-infrared spectroscopy and intravascular ultrasound: a potential key to predict distal embolization and no-reflow?, J Am Coll Cardiol , 2010;56(4):314. 40. Wentzel JJ, van der Giessen AG, Garg S, et al., In vivo 3D distribution of lipid-core plaque in human coronary artery as assessed by fusion of near infrared spectroscopyintravascular ultrasound and multislice computed tomography scan, Circ Cardiovasc Imaging , 2010;3(6):e6–7. 41. Madder RD, Steinberg DH, Anderson RD, Multimodality direct coronary imaging with combined near-infrared spectroscopy and intravascular ultrasound: Initial US experience, Catheter Cardiovasc Interv, 2013;81(3):551–7. 42. Goldstein JA, Maini B, Dixon SR, et al., Detection of lipidcore plaques by intracoronary near-infrared spectroscopy identifies high risk of periprocedural myocardial infarction, Circ Cardiovasc Interv , 2011;4(5):429–37. 43. 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;164(5):654–63. 44. Stack RS, Califf RM, Phillips HR, et al., Interventional cardiac catheterization at Duke Medical Center, Am J Cardiol, 1988;62(10 Pt 2):3F–24F. 45. Heublein B, Rohde R, Kaese V, et al., Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology?, Heart , 2003;89(6):651–6. 46. 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;369(9576):1869–75. 47. Waksman R, Erbel R, Di Mario C, et al., Early- and long-term intravascular ultrasound and angiographic findings after bioabsorbable magnesium stent implantation in human coronary arteries, JACC Cardiovasc Interv, 2009;2(4):312–20. 48. Waksman R, Lessons learned from preclinical studies of magnesium scaffolds (Biotronik’s DREAMS program), Presented at: PCR focus group on bioresorbable vascular scaffolds, Rotterdam, The Netherlands, 8-9 March 2012. 49. Haude M, Erbel R, Verheye S, et al., Twelve-month safety and performance results of the paclitaxel-eluting bioabsorbable magnesium scaffold in the prospective, multicenter first-inman trial - BIOSOLVE-I, Presented at: European Society of Cardiology Congress, Munich, Germany, 25-29 August 2012. 50. Haude M, Erbel R, Erne P, et al., Two-year clinical data of cohort 1 and multi-modality imaging results up to 1 year follow-up of the BIOSOLVE-I study with the paclitaxel-eluting bioabsorbable magnesium scaffold (DREAMS), Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-25 October 2012. 51. Koolen J, Erbel R, Verheye S, et al., Intravascular ultrasound results with the drug eluting absorbable metal scaffold in the BIOSOLVE-I study up to twelve months follow-up, Presented at: European Society of Cardiology Congress, Munich, Germany, 27 August 2012. 52. Haude M, Biotronik: from PROGRESS to DREAMS, Presented at: PCR Focusgroup, Rotterdam, The Netherlands, 7-8 March 2013. 53. Ormiston JA, Serruys PW, Regar E, et al., A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial, Lancet , 2008;371(9616):899–907. 54. Karanasos A, Simsek C, Serruys P, et al., Five-year optical coherence tomography follow-up of an everolimus-eluting bioresorbable vascular scaffold: changing the paradigm of coronary stenting?, Circulation , 2012;126(7):e89–91. 55. Onuma Y, Nieman K, Webster M, et al., Five-year clinical

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Invasive Imaging of Bioresorbable Coronary Scaffolds – A Review outcomes and non-invasive angiographic imaging results with functional assessment after bioresorbable everolimus-eluting scaffold implantation in patients with de novo coronary artery disease, Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 56. García-García HM, Schultz C, Duckers E, et al., Five-year follow-up of the ABSORB bioresorbable everolimus-eluting vascular scaffold system: multimodality imaging assessment, EuroIntervention, 2013;8(10):1126–7. 57. Serruys PW, Onuma Y, Ormiston JA, et al., Evaluation of the second generation of a bioresorbable everolimus drugeluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes, Circulation , 2010;122(22):2301–12. 58. 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;58(15):1578–88. 59. Van Geuns RJ, Preliminary data from ABSORB EXTEND: a report of the 6-month clinical outcomes from the first 269 patients registered, Presented at: EuroPCR, Paris, France, 15-18 May 2012. 60. Diletti R, Why do we use IVUS-VH 45MHz and Lipiscan in the ABSORB II trial?, Presented at: PCR BVS Focus group meeting, Rotterdam, The Netherlands, 8-9 March 2012. 61. Stone GW, ABSORB III and IV: pivotal clinical trial program, Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 62. Kaluza G, The REVA Tyrosine-Derived Polycarbonate Bioresorbable Scaffold: Long-term Outcomes Using Multimodality Imaging, Presented at: Transcatheter Cardiovascular Therapeutics, San Francisco, CA, US 7-11 November 2011. 63. Grube E, Bioabsorbable stents: the Boston Scientific & REVA technology, Presented at: EuroPCR, Barcelona, Spain, 19-22 May 2009.

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64. Abizaid A, REVA: Clinical update and case presentation, Presented at: PCR BVS Focus group meeting, Rotterdam, The Netherlands, 6-9 March 2012. 65. Abizaid A, ReZolve Clinical Program Update, Presented at: PCR Focusgroup, Rotterdam, The Netherlands, 7-8 March 2013. 66. Jabara R, Pendyala L, Geva S, et al., Novel fully bioabsorbable salicylate-based sirolimus-eluting stent, EuroIntervention , 2009;5 Suppl F:F58–64. 67. Jabara C, Matsumoto, Bio-mechanical properties and ABC of bioresorption of adipic acid, Presented at: PCR BVS Focus group meeting, Rotterdam, The Netherlands, 8-9 March 2012. 68. Verheye S, DESolve First In Man Study: Preliminary results, Presented at: PCR BVS Focus group meeting, Rotterdam, The Netherlands, 8-9 March 2012. 69. Verheye S, Elixir Technology, Presented at: EuroPCR, Paris, France, 15-18 May 2012. 70. Verheye S, Multicenter First-in-Man evaluation of the myolimus-eluting bioresorbable coronary scaffold: 6 month imaging and 12-month clinical results, TCT 2012, Miami & Verheye S, First-in-man results with a myolimus-eluting bioresorbable PLLA-based vascular scaffold (Elixir DESolve), Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 71. Lafont, ART bioresorbable scaffold dedicated for vascular scaffolding, Presented at: EuroPCR, Paris, France, 15-18 May 2012. 72. Lafont A, Sizing does not matter: ART concept, Presented at: EuroPCR, Paris, France, 15-18 May 2012. 73. ART. ART news, 2012; Available at: www.art-stent.com/news (accessed 26 March 2013). 74. Fajadet J, Bioresorbable vascular scaffolds: latest designs and clinical study evidence, The ART stent: design and early first-in-man experiences, Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 75. Shen L, Wang Q, Wu Y, et al., Short-term effects of fully bioabsorbable PLLA coronary stents in a porcine model,

Polymer Bulletin , 2012;68:1171–81. 76. Cottone RJ, Structural lessons learned: blended PLLA scaffold partitioned coating with abluminal sirolimus drug elution matrix and luminal +CD34 antibody for EPC capture, Presented at: PCR BVS Focus group meeting, Rotterdam, The Netherlands, 8-9 March 2012. 77. Cottone RJ, Blended PLLA scaffold partitioned coating with abluminal sirolimus drug elution matrix and luminal +CD34 antibody for EPC capture, Presented at: EuroPCR, Paris, France, 15-18 May 2012. 78. Cottone RJ, Blended PLLA scaffold with partitioned coating of abluminal sirolimus drug elution matrix and luminal antihCD34 antibody for EPC capture, Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 79. Iqbal J, Amaranth Bioresorbable Scaffold - pre-clinical data, Presented at: PCR Focusgroup, Rotterdam, The Netherlands, 7-8 March 2013. 80. Naber CK, Leapfrogging to bioresorbable scaffolds: update on MeRes, Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 24 October 2012. 81. Wu C, A preliminary study of biodegradable n stent in mini-swine coronary artery, Presented at: Transcatheter Cardiovascular Therapeutics, Miami, US, 22-26 October 2012. 82. Gutiérrez-Chico JL, Serruys PW, Girasis C, et al., Quantitative multi-modality imaging analysis of a fully bioresorbable stent: a head-to-head comparison between QCA, IVUS and OCT, Int J Cardiovasc Imaging , 2012;28(3):467–78. 83. Tu S, Holm NR, Koning G, et al., Fusion of 3D QCA and IVUS/ OCT, Int J Cardiovasc Imaging , 2011;27(2):197–207. 84. 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(6):1315–27. 85. van Ditzhuijzen NS, van den Heuvel M, Sorop O, et al., Invasive coronary imaging in animal models of atherosclerosis, Neth Heart J, 2011;19(10):442–6.

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Coronary Contrast Delivery Systems

Understanding and Minimising Occupational Radiation in the Catheterisation Laboratory with PISAX and the ACIST CVi® Contrast Delivery System Based on an interview with Olivier Bar, Interventional Cardiologist, Saint Gatien Clinic, Tours, France

Abstract This paper provides an overview of radiation exposure and its associated risks in the cardiac catheterisation laboratory (cath lab), as well as strategies to minimise radiation exposure for operators, cath lab staff and patients. The benefits of using a mobile 2 mm lead equivalent radiation shield (PISAX) and adoption of an automated contrast injection system (the ACIST CVi® Contrast Delivery System) are discussed, and the potential advantages of their combination are reviewed.

Keywords ACIST CVi®, PISAX, catheterisation, occupational radiation, contrast delivery system, radiation protection, combination approaches Disclosure: The interviewee has no conflicts of interest to declare. Received: 19 March 2013 Accepted: 10 April 2013 Citation: Interventional Cardiology Review, 2013;8(1):36–40 Correspondence: Olivier Bar, E: o.bar@ciic.fr

Support: The publication of this article was funded by ACIST Medical Systems, Inc.

An Introduction to Radiation X-rays, so-called because their nature was at the time unknown, were discovered by the German physicist Wilhelm Roentgen in 1895, one year before the discovery of ‘natural’ radioactivity by Henri Becquerel.1 X-rays found application in radiography a few years after their discovery, although the first side effect attributed to radiation injury (depilation) had been described prior to this – in March 1896. X-ray imaging subsequently developed into an important medical technique. It was estimated that more than two billion X-ray examinations were performed in the US in 2008 2 and that medical uses represent the largest source of radiation exposure to the US population.3 However, although X-ray imaging has great medical benefits, it poses an important risk for patients and healthcare staff, which is reviewed in this article. The International Commission on Radiological Protection (ICRP) recommends the use of the ‘effective dose (ED)’ measure to evaluate the effects of partial exposure and equate the associated risks to those of whole-body exposure. • R adiation dose = (radiation energy absorbed by patient) / (mass of tissue irradiated). • Unit: 1 gray (Gy) = 1 joule per kilogram (J/kg). • ED = absorbed dose corrected for radiation type (e.g. X-ray) and tissue type weighting factors. • Unit: 1 sievert (Sv) = 1 Gy to the whole body.

Biological Effects of Radiation The effects of ionising radiation on health are classified broadly as either deterministic or stochastic. Exposure to high levels of radiation causes tissue damage as a consequence of the killing or gross malfunction

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of cells. These ‘deterministic’ effects only occur above a given dose threshold and exhibit steeply increasing severity with increasing dose above this threshold. Examples of deterministic effects of radiation are skin injury and the formation of cataracts.5 Conversely, stochastic effects of radiation can occur at any dose level (rather than above a threshold), exhibiting an increasing probability of the effect proportionate to the exposure level. Typical stochastic effects are the mutation of cells following DNA damage or the development of a malignancy.6,7 No proof exists of stochastic effects at doses less than 100 millisievert (mSv); however, the ICRP recommends a linear, no-threshold regression model to evaluate risk in this dose range.8 The ICRP quantifies the relationship between ED and the probability of developing lethal cancer as approximately 5 % per 1 Sv of exposure.7 Thus for a population receiving a 0.2 Sv dose, this translates to 1 % of individuals who may in the long term develop lethal cancer as a consequence of exposure. For a typical cardiac examination administering a lower dose, an ED of 10 mSv, the risk of cancer has been estimated at 1 in 2,000.7 The ICRP recommends an annual limit of 20 mSv/year for occupational exposure and 1 mSv/year for the public.7

Radiation in the Catheterisation Laboratory The cath lab is an environment in which the working staff (cardiologists, radiographers, technicians, nurses and trainees) risk radiation exposure on almost a daily basis, and achieving adequate protection for staff during procedures remains problematic. Staff exposure to radiation in the cardiac cath lab is generally considered to be higher than in other therapeutic laboratories that use X-ray equipment (radiology, urology, operating rooms) because the staff work in close proximity to the patient. In addition, factors including the configuration of the X-ray equipment, the distance to the X-ray source, the number of cases

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Understanding and Minimising Occupational Radiation in the Cath Lab with PISAX and the ACIST CVi® System Table 1: Typical Effective Doses for Radiographic Procedures and their Corresponding Risks Examination

Typical Effective Dose (mSv)

Risk of Fatal Cancer

Posteroanterior chest X-ray

0.02

1.0 per 1,000,000

Anteroposterior pelvic X-ray

0.70

3.5 per 100,000

Chest CT

8.00

4.0 per 10,000

Abdominal CT

10.00

5.0 per 10,000

Figure 1: The PISAX Shield

CT = computed tomography; mSv = millisievert. Adapted from ICRP Publication 87, 2000.3

Table 2: Adult Effective Dose Values and Ranges for Interventional Procedures Examination

Typical Effective Dose (mSv)

Range Reported in the Literature (mSv)

Coronary angiography (diagnostic) 7

2.0–15.8

Coronary percutaneous

6.9–57.0

4.1–9.0

Aortography

4.0–48.0

Pelvic vein embolisation

44.0–78.0

transluminal angioplasty; stent placement Thoracic angiography of pulmonary artery or aorta

mSv = millisievert. Adapted from Mettler, et al., 2008.4

performed per day, and the often long period of screening required for a procedure can all contribute to this relatively high level of exposure. The radiation dose measures for staff members in the cath lab who wear dosimeter badges both inside and outside their lead aprons are generally among the highest in the hospital. There are two different sequences of radiation exposure in the cath lab – fluoroscopy and acquisition (cine). Fluoroscopy is used for catheter, balloon and stent placement, and involves 50–90 % of the total X-ray operation time. However, fluoroscopy only accounts for approximately 20 % of the total radiation exposure to staff and patients. Acquisition is used to acquire diagnostic images and to generate a permanent high-quality record of the procedure. Although representing only 5–30 % of the total X-ray tube operation time, approximately 80 % of the total radiation exposure to staff and patients occurs during cine. Significant reductions in exposure can be realised by being aware of when cine is or will be used and applying radiation safety measures accordingly. For example, it is generally not necessary to be as close to the patient during acquisition runs because modern catheters are safer and remote-assisted injectors are now available.

Minimising Radiation Exposure in the Catheterisation Laboratory The level of radiation exposure in the cath lab can be reduced considerably through the adoption of preventive practices, by employing appropriate physical shielding, by reducing exposure time, and by increasing the distance between staff and the radiation source. It remains vital that all staff understand the importance of self-monitoring and recognise the risks of radiation. In France, regulations introduced in 2004 mandate two days of training for all doctors and technicians involved in situations where patients are exposed to radiation.

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The PISAX shield significantly reduces radiation dose to the operator, with a minimal impact on procedural time. Specifications: 2 mm lead equivalence; 200 × 80 cm; and 1,000-fold exposure reduction.

Distance The intensity of radiation exposure at a given point relates to the distance from the emitting X-ray source through the inverse square law. This means that doubling the distance between the source of scattered radiation (the patient body) and the operator will reduce the exposure by a factor of four. In addition, operator exposure varies according to the beam projection used – left oblique projections are much more unfavourable (in a typical situation where the operator is on the right side of the patient) and craniocaudal angulations increase radiation exposure even more. An angle of 60 ° results in an operator exposure dose threefold higher than an angle of 30 °.9 The second operator or assistant is generally less exposed to radiation than the first operator, but is certainly more at risk than other staff in the room. Compliance with an optimal distance focus intensifier (DFI) value, generally 100 cm, is key to allowing an energy reduction delivered by the X-ray tube of a factor of three.9

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Coronary Contrast Delivery Systems Figure 2: The ACIST CVi® Contrast Delivery System

The ACIST CVi Contrast Delivery System, which reduces the fluoroscopy time, allows the operator to stand at a greater distance during imaging, facilitating use of the 2 mm lead equivalent PISAX protection shield, while maintaining precise control over the flow and volume of contrast media.

Figure 3: A Reduction in Radiation Dose Over the Lead Apron of 96 % with the PISAX Shield

Radiation dose (mSv)

25 20

23.35

96 % reduction with PISAX

Shielding Radioprotective shielding can significantly reduce the level of exposure, if used and maintained appropriately. Protective equipment includes lead aprons, thyroid collars and leaded glasses. A thyroid shield is mandatory to protect the neck. It is recommended that cath lab staff should wear a protective apron of at least 0.5 mm lead equivalence (providing a reduction factor of approximately 100-fold).10 Protective leaded eyewear is recommended because the lens appears to be highly sensitive to exposure.

10 5

0.96 0

PISAX shield-

PISAX shield+

mSv = millisievert.

Lead glasses (0.75 mm lead equivalent) should be worn to counter specific risks such as cataract. These measures, however, do not protect against radiation exposure to the head, arms and legs. Therefore, many cath labs use overhanging lead screens to prevent radiation exposure to the brain. These should be a minimum of 0.5 mm lead equivalence. Suspended lead shields around the cath lab table help to minimise radiation exposure to the legs.

There are several techniques available that allow for increasing the distance between the radiation source and the operator, including the use of the ACIST CVi Contrast Delivery System, which is discussed later in this article.

Mobile lead shields provide a further opportunity to reduce radiation exposure for the operator. A newly developed mobile shield (PISAX) is available (see Figure 1).

Collimation and Edge Filter

Time

Collimation and edge filter are types of housing placed at the exit of the X-ray tube. Collimation allows a reduction of both patient and staff exposure by narrowing the imaging field of interest. Edge filter allows a partial reduction of the primary beam corresponding to low attenuation parts of the patient’s body, such as the lung. These two options improve image quality and result in a decrease in the energy delivered to the patient.

The length of time during which an individual is exposed to radiation is a significant determinant of risk. On average, the procedure time for a diagnostic coronary angiogram is approximately 30 minutes, and an interventional procedure or electrophysiology/pacing study would take 90–120 minutes. However, the time required for fluoroscopy and cine screening varies greatly depending on the nature of the procedure and the experience of the operator. Every effort should

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Understanding and Minimising Occupational Radiation in the Cath Lab with PISAX and the ACIST CVi® System

be made by the operating cardiologist in the cath lab to minimise fluoroscopy and cine screening time.

flow of contrast during the angiography runs. The adoption of this technique allows for a reduction in contrast and radiation dose.15

An effective way to reduce the exposure time is adoption of the ACIST CVi Contrast Delivery System. In a study by Brosh et al., a reduction of the fluoroscopy time of 25 % was reported with use of the ACIST CVi system, compared with a manual injection technique.11 Additionally, the three-dimensional (3D) rotational angiography technique can help to reduce fluoroscopy time. In 3D rotational angiography all projections of each coronary artery system are visualised in one cine angiogram during a longer, continuous injection of contrast. One study reported a reduction in radiation dose of 35 % with this technique.12

Combination Approaches

About the ACIST CVi System

A study was conducted to compare the annual dosimetry results measured outside the lead apron of two interventional cardiologists working with the ACIST CVi system with or without the PISAX radiation shield. Both cardiologists performed more than 500 procedures per year and individual dosimetry results were weighted by their relative activity.

The ACIST CVi system (see Figure 2) was developed to facilitate contrast injection in all angiography procedures. The ACIST CVi system uses the sterile AngioTouch® pneumatic hand controller, allowing the operator to control the flow and volume of contrast media directly from the sterile field. The system allows for precise control of injection volume and timing, leading to a significant reduction in the amount of contrast delivered.11,13,14 The ACIST CVi Contrast Delivery System was adopted by Clinique St Gatien, France, in 2000. The ACIST CVi Contrast Delivery System allows the operator to stand at a greater distance during imaging, facilitating use of the 2 mm lead equivalent PISAX protection shield while maintaining precise control over the flow and volume of contrast media.

Using ACIST CVi to Improve Radiation Protection During image acquisition runs, the use of the ACIST CVi injector allows the operator to stand further away from the patient than would be possible with a conventional injection system, thus significantly improving radiation protection. Dr Bar’s group has studied the effect of using the ACIST CVi system on radiation exposure, comparing the radiation exposure of the left hand when using a hand manifold technique and the ACIST CVi contrast delivery technique. In this study, a reduction in radiation dose of 3.4-fold was seen in diagnostic angiography procedures and a 1.7-fold reduction occurred during percutaneous coronary intervention (PCI) procedures (publication in press). Additionally, the ACIST CVi system facilitates the adoption of 3D rotational angiography, allowing for a safer distance and a consistent

Use of the PISAX radiation shield with the ACIST CVi system is a modern and efficient way of working that can lead to a significant reduction in whole-body radiation exposure. In order to take full advantage of the benefits of the PISAX radiation protection shield, it is required that the operator stand behind the shield during the cine runs, while simultaneously delivering contrast. The ACIST CVi system provides the physician with the option to stand safely behind the shield when contrast is delivered and the angiogram is recorded.

These results show a dramatic reduction of dose to unprotected body parts of staff (arm, head and legs) when the specific mobile 2 mm lead shield PISAX is used together with the ACIST CVi system (see Figure 3).

Conclusions Interventionists are encouraged to remain vigilant regarding the particularly high level of radiation in the cath lab setting. Preventative measures should be implemented to limit staff exposure, including minimising fluoroscopy and cine time, increasing the distance from the radiation source during imaging, and employing appropriate physical shielding. The ACIST CVi system can help to reduce radiation dose both to staff and to patients by reducing procedure times, and enables the interventionist to increase their distance from the radiation source (the body of the patient) during image acquisition while maintaining precise control of contrast injection. A profound reduction in radiation exposure of 96 % was observed when the ACIST CVi system was used in conjunction with the 2 mm lead equivalent PISAX radiation protection shield, which allows the operators to shield themselves during angiography while controlling contrast delivery. This modern combination of devices contributes to making the cath lab safer both for staff and for patients. n

Dr Olivier Bar received his Medical Degree from the University of Nantes, France, in 1990. Since 1995, Dr Bar has been a full-time interventional cardiologist at the Saint Gatien Clinic in Tours, France, where he has conducted over 5,000 PCI procedures and established the CoreValve® transcatheter aortic valve implantation (TAVI) programme. For many years, Dr Bar has been particularly interested in radiation protection for both patients and interventionists. He is responsible for the Inter-University course on radiation protection in interventional cardiology, and in 2005 was involved in setting up a national training course for interventional cardiologists on both patient and operator radiation protection. Over the past five years, nearly 600 interventional cardiologists in France have participated in this training course. In 2006, Dr Bar published the first French national survey of patient radiation exposure in interventional cardiology.16 Recently, in 2012, he contributed to original articles on brain tumours among interventional cardiologists17 and the factors affecting patients’ maximum skin dose during interventional procedures.18

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Coronary Contrast Delivery Systems 1.

Berk RN, Eugene W. Caldwell Lecture. The American Journal of Roentgenology: past, present, and future, AJR Am J Roentgenol, 1995;164(6):1323–8. 2. Reuters Press Release, Auchard E, Google says working to solve health record dilemma, 2007. Available at: www.reuters.com/article/2007/10/18/us-googlehealth-idUSN1739661420071018 (accessed 21 March 2013). 3. ICRP (International Commission on Radiological Protection). Managing Patient Dose in Computed Tomography. ICRP Publication 87, Ann ICRP , 2000;30(4). 4. Mettler FA Jr, Huda W, Yoshizumi TT, Mahesh M, Effective doses in radiology and diagnostic nuclear medicine: a catalog, Radiology , 2008;248(1):254–63. 5. Cooper JR, Radiation protection principles, J Radiol Prot , 2012;32(1):N81–7. 6. Jacob S, Michel M, Spaulding C, et al., Occupational cataracts and lens opacities in interventional cardiology (O’CLOC study): are X-Rays involved?, BMC Public Health, 2010;10:537. 7. The 2007 recommendations of the International Commission on Radiological Protection. ICRP Publication 103, Ann ICRP , 2007;37(2–4):1–332. 8. International Commission on Radiological Protection, Lowdose extrapolation of radiation-related cancer risk. ICRP Publication 99, Ann ICRP, 2005;35(4).

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Hirshfeld JW Jr, Balter S, Brinker JA, et al., ACCF/AHA/ HRS/SCAI clinical competence statement on physician knowledge to optimize patient safety and image quality in fluoroscopically guided invasive cardiovascular procedures. A report of the American College of Cardiology Foundation/ American Heart Association/American College of Physicians Task Force on Clinical Competence and Training, J Am Coll Cardiol , 2004;44(11):2259–82. 10. Betsou S, Efstathopoulos EP, Katritsis D, et al., Patient radiation doses during cardiac catheterization procedures, Br J Radiol, 1998;71(846):634–9. 11. Vañó E, Rosenstein M, Liniecki J, et al., Education and training in radiological protection for diagnostic and interventional procedures. ICRP Publication 113, Ann ICRP , 2009;39(5):7–68. 12. Brosh D, Assali A, Vaknin-Assa H, et al., The ACIST power injection system reduces the amount of contrast media delivered to the patient, as well as fluoroscopy time, during diagnostic and interventional cardiac procedures, Int J Cardiovasc Intervent, 2005;7(4):183–7. 13. Klein AJ, Garcia JA, Hudson PA, et al., Safety and efficacy of dual-axis rotational coronary angiography vs. standard coronary angiography, Catheter Cardiovasc Interv , 2011;77(6):820–7. 14. Anne G, Gruberg L, Huber A, et al., Traditional versus

automated injection contrast system in diagnostic and percutaneous coronary interventional procedures: comparison of the contrast volume delivered, J Invasive Cardiol, 2004;16(7):360–2. 15. Call J, Sacrinty M, Applegate R, et al., Automated contrast injection in contemporary practice during cardiac catheterization and PCI: effects on contrast-induced nephropathy, J Invasive Cardiol, 2006;18(10):469–74. 16 Bar O, Maccia C, Pagès P, Blanchard D, A multicentre survey of patient exposure to ionising radiation during interventional cardiology procedures in France, EuroIntervention, 2008;3(5):593–9. 17. Roguin A, Goldstein J, Bar O, Brain tumours among interventional cardiologists: a cause for alarm? Report of four new cases from two cities and a review of the literature, EuroIntervention , 2012;7(9):1081–6. 18. Journy N, Sinno-Tellier S, Maccia C, et al., Main clinical, therapeutic and technical factors related to patient’s maximum skin dose in interventional cardiology procedures, Br J Radiol, 2012;85(1012):433–42. 19. Gómez-Menchero AE, Díaz JF, Sánchez-González C, et al., Comparison of dual-axis rotational coronary angiography (XPERSWING) versus conventional technique in routine practice, Rev Esp Cardiol (Engl Ed), 2012;65(5):434–9.

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Coronary Chronic Total Occlusion

Coronary Chronic Total Occlusion Recanalisation – Current Techniques and Approaches Vija y S R a m a n a t h a n d Cra i g A Th o m p s o n On beha lf of the N o r t h A m e r i c a n To t a l O c c l u s i o n ( N ATO ) O p e ra t o r s Division of Cardiovascular Medicine, Yale University School of Medicine, Connecticut, US

Abstract Coronary chronic total occlusions (CTOs) are among the most challenging coronary artery lesions to treat percutaneously. In the last decade, great strides have been made to develop techniques to improve success rates. While success rates among high-volume operators are >90 %, non-CTO operators still continue to struggle with this lesion subset. Thus, efforts have been made to develop algorithms to help operators achieve successful recanalisation consistently and improve patient outcomes. The North American Total Occlusion (NATO) algorithm emphasises dual coronary injection using two guide catheters, which allows for switching from an antegrade to retrograde approach or vice versa should the initial strategy fail – the so-called ‘hybrid’ approach. Special attention is paid to four angiographic characteristics: 1) location of the proximal cap, 2) lesion length, 3) presence and suitability of collateral vessels for retrograde crossing and 4) location and quality of target vessel distal cap. The ultimate goal of this algorithm is to provide a strategy to achieve successful CTO revascularisation while using the least amount of fluoroscopy, contrast and equipment possible.

Keywords Percutaneous coronary intervention, coronary chronic total occlusion Disclosure: The authors have no conflicts of interest to declare. Received: 8 July 2012 Accepted: 12 January 2013 Citation: Interventional Cardiology Review, 2013;8(1):41–5 Correspondence: Craig A Thompson, Associate Professor of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, US. E: craig.thompson@yale.edu

Coronary chronic total occlusions (CTOs) remain one of the most challenging percutaneous challenges in interventional cardiology, with technical success rates of only ~50–70 %.1,2 This lesion subset often poses the greatest risk and often requires techniques and equipment not typically utilised for more acute coronary lesions. However, successful percutaneous CTO revascularisation is associated with improved long-term survival, decreased rates of angina, improved left ventricular systolic function, and less need for coronary artery bypass surgery, as compared with unsuccessful attempts.3–5 Thus, over the last decade, much effort has been put forth to develop techniques to tackle these complex lesions and to provide operators with strategies to optimise their success rates to >90 %. Multiple reports have been published on techniques that can be used to optimise successful CTO percutaneous coronary intervention (PCI). However, only a few reports provide operators with a clear-cut algorithm, which can be used to guide the operator towards a successful CTO-PCI on a consistent basis, and even fewer include a discussion on the histopathology of CTO lesions, an important component in understanding the rationale for certain PCI strategies, which otherwise may seem counter-intuitive. In this review, we discuss the basic histopathology of CTOs followed by approaches and techniques in an algorithmic format, for consistent successful CTO recanalisation as developed by the North American Total Occlusion (NATO) group.

after a coronary occlusion forms, the original thrombus becomes more organised with collagen-dense fibrous tissues at the proximal and distal caps.6 As the occlusion ages, the plaque becomes less lipid-laden, more calcified, and tends to lose its previously existent microchannels, thus making it more difficult to cross antegrade (see Figure 1).6,7 Moreover, further histological analysis has shown that the lesion is not homogenous in its rigidity. Rather, the distal fibrous cap is less rigid compared with the proximal cap.7 This is an important factor when one considers an antegrade versus retrograde approach. The proximal fibrous cap, which is the entry point of the CTO for an antegrade approach, thus is the site where a higher risk for wire migration into the subintimal space is observed, as compared with the distal cap, which serves as the entry site of the CTO when a retrograde approach is employed.

Histopathology of Chronic Total Occlusions

In order to accurately assess the lesion, we strongly advocate the use of a dual guide catheter strategy with shorter catheters (i.e. ~90 cm long) in the retrograde vessel and often the antegrade vessel. Should

The histopathology process of CTOs is not yet fully understood. One widely accepted theory as suggested by autopsy studies is that

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Pre-intervention Angiographic Set-up and Analysis Undoubtedly, procedural success is highly dependent on a thorough angiographic evaluation of the target CTO lesion before the optimal PCI strategy can be determined. Such an evaluation includes assessment of the presence and location of collateral vessels and length of the CTO lesion to ultimately decide on the initial PCI strategy.

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Coronary Chronic Total Occlusion Figure 1: Cross-sectional Views from Histopathological Specimens A

A: 1.5 year chronic total occlusion (CTO) with organised thrombus and a microchannel identified within the original lumen, with a mild degree of calcification; B: five-year CTO with heavy calcium and no identifiable microchannels. Images courtesy of Sumitsuji, et al.

Figure 2: Photo of the Entire Corsair™ Microcatheter with Zoomed-in Image of the Catheter Tip

localise the entry point of the CTO lesion angiographically and/or with intravascular ultrasound (IVUS). The second is lesion length. Lesions are categorised dichotomously to those <20 mm or those ≥20 mm in length. Lesion length is best determined with dual vessel injections as mentioned above. Lesions ≥20 mm are more likely to have higher failure rates and often require increased fluoroscopy time and hence increased procedure time. This complex subset of CTOs often requires early adoption of an antegrade dissection with re-entry or a primary retrograde approach. The next angiographic characteristic that needs consideration is the size of vessel lumen at the distal cap and the presence of significant side branches at the distal cap. Finally, one must evaluate the size and suitability of collateral vessels for retrograde crossing. This is visualised arising from the healthier donor vessel, which joins the CTO vessel beyond the distal cap. Ideally, the donor vessel should have minimal tortuosity, should provide more than one collateral branch to the CTO vessel, all of which increase the operator’s ability to safely pass wires and microcatheters while avoiding donor vessel damage and intraprocedural ischaemia.

The Tools of the Trade Before diving deep into a discussion on the techniques of CTO-PCI, it is important to first lay out the devices typically used in CTO interventions, especially those most frequently utilised according to the techniques of the NATO operators.

Guidewires Image courtesy of Tsuchikane, et al., 2010.8

the operator need to switch from one technique to the other during the intervention, this would allow easy transition between antegrade and retrograde techniques. Other recommended equipment includes long (35–45 cm) sheaths and large bore guides (7 or 8 French [Fr]) for optimal support and delivery of equipment (e.g. microcatheters, balloons, stents), particularly when transfemoral arterial access is used. In situations where the operator prefers transradial access, a 6 Fr system can be successfully used depending on the operator’s experience and level of comfort. Next, simultaneous dual injection should be performed, particularly in any case where contralateral collateral circulation exists. Dual injection is best performed on low magnification such that table panning is not needed, and is performed wherein the donor vessel is injected first followed by injection of the occluded vessel to reduce radiation exposure. This technique allows for accurate assessment of lesion length, size and location of the distal target vessel, presence of a significant bifurcation at the distal cap, and for determining the optimal PCI strategy. Furthermore, dual injection helps to reveal the presence of tortuous collateral vessels, including bridging collaterals, and can provide clarity regarding location of the angioplasty wire (true lumen versus subintimal space) during CTO crossing attempts. Evaluating the presence of bridging collaterals is needed regardless of whether an antegrade or retrograde approach is undertaken, since avoiding such vessels during crossing attempts will reduce the likelihood of vessel perforation.

Determining the Initial Percutaneous Coronary Intervention Strategy According to the NATO algorithm, the initial CTO-PCI strategy is based on four angiographic characteristics. The first of these is the proximal cap location and morphology. It is imperative to be able to

Thompson.indd 42

Recognising that there are a number of guidewires that are commonly utilised for CTO-PCI, the NATO operators recommend the following four wire designs: • h ydrophilic or polymer-jacketed 0.014” wires with a tapered tip, such as the Fielder XT™ (Asahi Intecc, Nagoya, Japan) and Runthrough taper™ (Terumo Corporation, Tokyo, Japan); • non-tapered, polymer-jacketed hydrophilic 0.014” wires for retrograde approaches, such as the Fielder FC™ (Asahi Intecc, Nagoya, Japan) and Pilot 50™ (Abbot Vascular); • high-gram polymer-jacketed such as the Pilot 200™ (Abbott Vascular) for complex, long and/or tortuous lesions; and • high-gram tapered non-jacketed tip such as the Confianza Pro 12™ (Asahi Intecc) used for lesion penetration and true lumen re-entry. Caution is needed in using such wires particularly if there is ambiguity regarding the target vessel pathway and/or target coronary segment. Most high-volume CTO operators recommend a 30 degree primary bend on the wire ~1 mm from the wire tip. On occasion, a secondary bend may be needed in order to help navigate through the vessel.

Microcatheters These devices are typically employed for retrograde advancement across the donor and collateral vessels.8 The Corsair™ (Asahi Intecc, Aichi, Japan) is a 2.7 Fr over-the-wire (OTW) catheter with a distal lubricious outer coating (see Figure 2). Its shaft consists of eight thin wires wound together with two larger wires, forming a spiral structure. This design allows a bidirectional rotation to be transmitted to the distal shaft to cross even tortuous collateral channels during retrograde advancing, though it can also be used during antegrade approaches.

Over-the-wire Microcatheters and Balloons Examples of OTW microcatheters include the Finecross™ (Terumo Corporation) and Quick-Cross™ (Spectranetics Corporation, Colorado

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Coronary Chronic Total Occlusion Recanalisation – Current Techniques and Approaches

Figure 3: (A) Diagram of the CrossBoss ™ Catheter and (B) The Stingray ™ Catheter and The Stingray ™ Guidewire A

Figure 4: Schematic Diagram of Stingray™ Re-entry Balloon Shown in (A) Superior View, (B) Longitudinal View and (C) Oblique View with Re-entry Wire Advanced at Distal Cap of Chronic Total Occlusion

Tracks via fast spin technique Highly torqueable coiled-wire shaft Spin should reduce push required

A traumatic 3F rounded distal tip

0.014” guidewire compatible (OTW)

2.4F distal shaft diameter 6F guide catheter compatible

B Compatibility: 0.014” guidewire 6F guide catheter

Self-orienting balloon has flat shape

StingrayTM Guidewire Probe

0.019” diameter (0.48 mm) lesion entry profile

Offset exit ports for StingrayTM Guidewire

Arrows point to the radio-opaque markers to determine relation of device to target site of re-entry. Images courtesy of Whitlow, et al., 2012.10

Figure 5: (A) Angiographic Still-frame Showing Successful Antegrade Crossing of Chronic Total Occlusion Using the CrossBoss™ (Black Arrow), Followed by (A) True Lumen Re-entry (White Arrow) Using the Stingray™ Device (Black Arrow) A

OTW = over-the-wire. Images courtesy of BridgePoint Medical.

Springs, CO, US). Such devices are useful for wire exchanges. The Tornus™ (Asahi Intecc, Nagoya, Japan) is a uniquely designed OTW microcatheter with a braided wire mesh used for lesion crossing in particularly resistant CTOs. Finally, OTW balloons are helpful in providing wire support.

Lesion Crossing and Re-entry Devices These include the Crossboss™ catheter (Bridgeport Medical, Plymouth, MN), a metal OTW microcatheter with a blunt tip that pierces through the lesion preventing extraluminal entry, without the need for a leading wire, but requires a ‘rapid-spinning’ motion technique (see Figure 3).6 As with many of the aforementioned devices, there is an associated learning curve for the operator with this microcatheter. In instances where the device leaves the true lumen, re-entry is then accomplished using the Stingray™ balloon and Stingray™ guidewire (BridgePoint Medical). This uniquely designed balloon is a 1 mm flat balloon containing three ports all connected to a single guidewire lumen (see Figure 4).6 The most distal port is used to position the balloon. The remaining two ports are oriented 180 degrees from each other such that when the balloon is inflated, one port is aimed at the lumen while the other to the adventitial layer of the vessel. Under fluoroscopic guidance, the 0.014” Stingray guidewire with its distal tapered end is used to then re-enter the true lumen.

General Considerations and Initial Plan of Attack Regardless of whether an antegrade or retrograde approach is initially chosen, the NATO operators recommend strategic planning using a ‘hybrid’ approach, which allows the operator to switch between the two approaches should the initial approach fail. The purpose of

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the hybrid approach is to maximise procedural efficiency by achieving vessel recanalisation while minimising radiation and contrast dye exposure. This does require the operator to change strategies early on if the current approach is proving to be fruitless. Decidingon the initial direction (antegrade versus retrograde) is based on the patient’s coronary anatomy from angiographic visualisation using dual injection (discussed earlier). The NATO operators recommend considering the following characteristics when evaluating coronary anatomy: • • • • •

ability to identify and safely engage the proximal cap; lesion length; presence of significant branches and collaterals; size and location of the distal cap; and ability to use collateral vessels for a retrograde approach.

These five factors help determine the initial strategy in addition to a ‘plan B’ should the initial approach fail. In general, lesions <20 mm can be successfully treated with an antegrade approach using a wire escalation strategy (discussed below). Longer and/or more complex lesions but with identification of proximal and distal caps tend to be best treated with a primary dissection re-entry technique. When an operator is faced with a more complex lesion with uncertainty as to the proximal and/or distal cap, such lesions are more likely to be successfully treated with an initial retrograde approach.

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Coronary Chronic Total Occlusion Figure 6: North American Total Occlusion Algorithm for Chronic Total Occlusion Percutaneous Coronary Intervention

1. Dual injection

1 - Ambiguous proximal cap 2. 2 - Poor distal target 3 - Appropriate “interventional” collaterals

no Antegrade

yes

3. Lesion length <20 mm

yes

6. Retrograde

no 5. Antegrade dissection and re-entry

4. Antegrade wiring

Controlled (Stingray)

Retrograde true lumen puncture

Retrograde dissection and re-entry

Wire based (LaST)

7. Switch Strategy LaST = Limited Antegrade Subintimal Tracking.

In general, given the complexity of this lesion subset, when performing CTO-PCI, one must be mindful of fluoroscopy time during the procedure. Exposure of >10 Gray markedly increases the risk of radiation-induced skin injury. Thus, once this threshold is reached, unless the lesion has been successfully crossed and there is only a minimal amount of additional procedural time remaining, the procedure should be aborted. Certain techniques can be employed to limit radiation exposure to the patient, operator and catheterisation laboratory staff. These include the use of viewing on the lowest magnification, fluoroscopy storing rather than cine acquisition, coning and use of shutters, and decreasing frame rates. Another important consideration is the amount of radiocontrast dye already used.

Chronic Total Occlusions Percutaneous Coronary Intervention According to the North American Total Occlusion Algorithm Now that the general concepts of CTO-PCI have been laid out along with a description of the typical devices, the remainder of this discussion will focus on the specific technical aspects of the hybrid strategy of CTO-PCI as developed by the NATO operators – wire escalation and dissection and re-entry techniques for both antegrade and retrograde approaches.

Wire Escalation The technique of wire escalation is typically employed as an initial strategy for ‘less complex’ CTOs <20 mm in length with good visualisation of both the proximal and distal caps. The initial choice of wire is a low-gram, polymer-jacketed wire (e.g. Fielder XT). Due to the typical morphology of a CTO (concave-shaped proximal cap with convex distal cap), a tapered wire is recommended from the antegrade direction while a non-tapered wire is recommended with a retrograde approach. The lesion is then probed with emphasis on keeping the wire tip free. Should the wire buckle, an OTW support catheter can be advanced to provide column strength for the tip,

Thompson.indd 44

followed by further lesion probing. Should the operator continue to experience wire buckling or the wire simply remains ineffective despite multiple attempts, which should occur for no more than a few minutes, wire exchange should occur. Choice of subsequent wire is dictated on lesion characteristics; for longer and/or tortuous lesions, a high-gram, non-tapered, polymer-jacketed wire is recommended (e.g. Pilot 200). This wire design helps prevent exit from the true lumen and is optimal for vessel tracking. In contrast, a high-gram tapered wire (e.g. Confianza Pro 12) can be used for shorter lesions whose course is well understood. Once wire substitution has occurred, it is again recommended that lesion probing be performed with the new wire for a few minutes, just as was done with the initial wire. If the lesion still remains unable to be crossed, conversion to a dissection/re-entry technique should be performed or at least considered.

Intimal Dissection/Re-entry Technique – Antegrade Approach Antegrade dissection is defined as when the guidewire or microcatheter enter the subintimal space (area within vessel wall) from the antegrade direction. This is deliberately performed using either a guidewire in the so-called ‘knuckle-wire’ technique or the blunt-tipped CrossBoss catheter (BridgePoint Medical). The knuckle-wire technique involves a loop formation of the wire (typically, polymer-jacketed), which is advanced through the lesion. This technique has proven to be a safe method to traverse the lesion because of its decreased likelihood of piercing through the adventitial layer of the vessel wall. Moreover, a knuckled wire is unlikely to enter side branches or small collateral channels and cause perforation. Still, caution is needed to control the size of the knuckle such that it is not larger than the expected target vessel size. Alternatively, the CrossBoss catheter offers a second and highly effective method to cross the CTO segment when a wire escalation strategy is unsuccessful.9 This device, with its 3 Fr blunted distal tip, creates a small channel in between the intima and adventitia while avoiding the formation of a false lumen haematoma. In doing

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Coronary Chronic Total Occlusion Recanalisation – Current Techniques and Approaches

so, it creates the optimal environment for the Stingray system to allow reaccess of the true lumen, as the accidental creation of a false lumen haematoma would hinder contact of the vessel wall with the Stingray balloon. The Stingray balloon is inflated to low pressures (3–4 atmospheres [atm]) followed by insertion of a dedicated re-entry wire such as the Stingray guidewire or a Confianza Pro 12 guidewire.10 Multiple angiographic views from orthogonal angles may be needed to determine the orientation of the exit ports of the Stingray balloon (i.e. right versus left, above versus below) to the target site of re-entry (see Figures 4 and 5). Following this, re-entry of the guidewire into the true lumen is performed and confirmed fluoroscopically by either ipsilateral injection of the collateral vessels or via contralateral injection. In instances where there is difficulty or inability to advance the Stingray wire into the distal true lumen, a plastic-jacketed wire can be substituted in and then positioned in the distal vessel true lumen. Another technique for true lumen re-entry, aside from the Stingray device, is the wire-based Limited Antegrade Subintimal Tracking (LaST) and redirection method. This technique is used as a bailout strategy when antegrade wiring and the Stingray both fail or are deemed inappropriate. It involves positioning a microcatheter near the site of re-entry followed by insertion of a stiff polymer-jacketed wire or a stiff tapered wire into the distal true lumen.

Intimal Dissection/Re-entry Technique – Retrograde Approach The most common dissection/re-entry technique to connect the proximal and distal true lumens via a retrograde approach is reverse

Controlled Antegrade and Retrograde Tracking (reverse CART). In reverse CART, the guidewire and microcatheter (e.g. Corsair, Asahi Intecc) are advanced from the donor vessel, across the collateral vessel and into the CTO segment. An antegrade guidewire is placed in the CTO segment (either alone or along with a crossing catheter or balloon) adjacent to the retrograde microcatheter and then inflated. Once a channel has been created between the proximal and distal CTO caps, the retrograde wire is then advanced into the proximal CTO vessel followed by wire externalisation. A 300 cm or longer wire is required for wire externalisation via the antegrade guide catheter. At this point, PCI can then be performed from the antegrade approach during a reverse CART technique.

The North American Total Occlusion Algorithm and Summary Ultimately, the goal of any CTO-PCI is to provide a safe and successful recanalisation of the diseased vessel without compromising important side branches. The NATO algorithm (see Figure 6) was designed as a strategy to aid operators achieve maximal success in CTO-PCI, and has been validated in a small prospectively studied cohort.11 This report was written to serve as a general guide for CTO-PCI among operators who are familiar with the equipment discussed above. For those who wish to adopt and implement these techniques in their practice, but have little or no familiarity with the techniques of CTO-PCI and the various technologies discussed above, the NATO operators encourage attending combined didactic and hands-on training programmes supplemented by attendance at local/national CTO conferences to become proficient in CTO-PCI techniques. n

Appendix: The North American Total Occlusion (NATO) operators include: Emmanouil S Brilakis (VA North Texas Healthcare System and UT Southwestern Medical Center, Dallas, TX, US), J Aaron Grantham (Mid-America Heart Institute, Kansas City, MO, US), Stephane Rinfret (Quebec Heart and Lung Institute, Laval University, Quebec City, Canada), R Michael Wyman (Torrance Memorial Medical Center, Torrance, CA, US), M Nicholas Burke (Minneapolis Heart Institute, Mineapolis, MN, US), Dimitris Karmpaliotis, Nicholas Lembo, David E Kandzari (Piedmont Heart Institute, Atlanta, GA, US), Ashish Pershad (Banner Good Samaritan Medical Center, Phoenix, AZ, US), Christopher E Buller (University of Toronto, Toronto, Canada), Tony DeMartini (Prairie Cardiovascular, Springfield, IL, US), William L Lombardi (PeaceHealth Cardiology, Bellingham, WA, US) and Craig A Thompson (Yale University School of Medicine, New Haven, CT, US).

1. Grantham JA, Marso SP, Spertus J, et al., Chronic total occlusion angioplasty in the United States, JACC Cardiovasc Interv , 2009;2:479–86. 2. 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. 3. Sirnes PA, Myreng Y, Mølstad 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. 4. Dzavik V, Carere RG, Mancini GB, et al., Predictors of improvement in left ventricular function after percutaneous revascularization of occluded coronary arteries: a report from the Total Occlusion Study of Canada (TOSCA), Am Heart J,

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2001;142:301–8. 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. 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. 7. Godino C, Carlino M, Al-Lamee R, Colombo A, Coronary chronic total occlusion, Minerva Cardioangiol , 2010;58:41–60. 8. 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. 9. Werner GS, The BridgePoint devices to facilitate recanalization of chronic total coronary occlusions through controlled subintimal reentry, Expert Rev Med Devices, 2011;8:23–9. 10. Whitlow PL, Lombardi WL, Araya M, et al., Initial experience with a dedicated coronary re-entry device for revascularization of chronic total occlusions, Catheter Cardiovasc Interv, 2012;80:807–13. 11. 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.

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Coronary Chronic Total Occlusion

Double Chronic Total Occlusion Recanalisation with Antegrade and Retrograde Techniques and the Use of a Novel Drug-eluting Stent with Biodegradable Polymer Nik ola o s V Ko n s t a n t i n i d i s a n d G e o r g i o s S i a n o s 1st Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece

Abstract Percutaneous recanalisation of coronary chronic total occlusions (CTOs) has proved an efficient and safe treatment option with steadily ascending success rates, especially since the advent and constant refinement of the retrograde approach. Uptake remains low, even though experienced operators have in the last five years reached an unprecedented maturity level, producing success rates in the range of 90 %, clearly comparable to non-occlusive coronary artery disease treatment. Antegrade and retrograde techniques are currently considered complementary components of a CTO procedure, rather than discrete treatment strategies. We report on the case of a successful CTO recanalisation procedure on a young patient with two chronically occluded coronary arteries and a large ischaemic burden. Both CTOs were addressed in the same session employing a range of dedicated CTO recanalisation techniques, without compromising on safety issues related to contrast dye consumption and radiation exposure. A novel drug-eluting stent (DES) with biodegradable polymer was used to treat the lesions.

Keywords Chronic total occlusion, percutaneous coronary intervention, CTO recanalisation, drug-eluting stents, CORACTO stent, biodegradable polymer Disclosure: The authors have no conflicts of interest to declare. Received: 20 March 2013 Accepted: 27 March 2013 Citation: Interventional Cardiology Review, 2013;8(1):46–9 Correspondence: Georgios Sianos, Department of Cardiology, AHEPA University Hospital, Stilponos Kiriakidi 1, 54636, Thessaloniki, Greece. E: gsianos@auth.gr

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

Coronary chronic total occlusions (CTOs) are identified in up to one-third of all patients referred for diagnostic coronary angiography,1 with an incidence increasing with age.2 CTOs still represent the most technically challenging lesion subset that interventional cardiologists face. The benefits of successful CTO recanalisation are related to improved survival,3,4 most notably in patients with a large ischaemic burden (>10 %),5 improvement in anginal status6 and left ventricular function,7 decreased need for coronary artery bypass grafting (CABG) surgery, and increased exercise tolerance.8,9 Yet, no more than 10 % of all CTOs have been treated with percutaneous techniques over a long period of time.10 In 2005 the retrograde approach for CTO percutaneous coronary intervention (PCI) was introduced11 and revolutionised the field of CTO recanalisation. Antegrade techniques further evolved hand in hand with retrograde techniques. Increasing operator experience, along with the development of CTO-dedicated wires and microcatheters, led to a progressive rise in the success rates of CTO PCI to more than 90 % in expert hands.12,13 Over time retrograde techniques reached a maturity level and were standardised. This led to the recent concept of considering antegrade and retrograde techniques as two complementary and inseparable components of a CTO procedure, alternatively applied and combined when necessary. At present, CTO strategy depends on two important parameters – anatomy and operator experience – both with antegrade and retrograde techniques. For operators experienced in all CTO techniques, anatomy dictates the strategy.

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We present the case of a patient with a large ischaemic burden and two chronically occluded coronary arteries that were successfully addressed in the same session, practising the whole spectrum of CTO revascularisation techniques.

Case Study Presentation A 56-year old male with hypertension, hyperlipidaemia and mild impairment of renal function presented with Class III angina (Canadian Cardiovascular Society Classification). He had no history of myocardial infarction. He underwent myocardial scintigraphy that was positive for provocable ischaemia and revealed a high percentage of myocardium at risk (>25 %). Following that, he underwent a diagnostic coronary angiography (see Figure 1) that revealed an occluded left anterior descending (LAD) artery at its proximal and mid-segment after the take-off of a big first septal branch. The left circumflex (LCx) coronary artery had mild wall irregularities at its mid-segment. The right coronary artery (RCA) was proximally occluded and was well collateralised from the first diagonal branch (D1) with collateral channels grade 2 (CC2).14 The ejection fraction (EF) was 65 % and there were no segmental wall motion abnormalities. Due to the high percentage of myocardium at risk and the presence of two CTOs, CABG was proposed to the patient as the best therapeutic option. The patient refused surgery and, in view of his young age, was then considered for percutaneous recanalisation of his occluded coronary arteries.

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Double CTO Recanalisation with the Use of a Novel DES with Biodegradable Polymer Figure 1: Diagnostic Coronary Angiography A

A: right coronary artery (RCA) totally occluded proximally; B: left anterior descending (LAD) coronary artery totally occluded at its proximal and mid-segment; C: bilateral contrast injection depicting the retrograde filling of the RCA via CC2 septal collaterals from the LAD.

Figure 2: Left Anterior Descending Coronary Artery Recanalisation A

I A: a Fielder FC wire supported by a Finecross microcatheter subintimally crosses the occlusion, failing to reach distal true lumen; B: parallel wire technique, with a Pilot 150 successfully crossing the occlusion; C: prediltation with an Invader CTO 1.25x20 mm balloon; D: subsequent predilatation with an Invader 2.5x15 mm balloon; E/F: implantation of a CORACTO 3.0x17 mm stent distally and a CORACTO 3.0x28 mm stent proximally covering the occlusion; G: from the middle of the occlusion a sizeable first diagonal branch (D1) was revealed with a 99 % ostial stenosis; H: following dilatation of D1 ostium with an Invader 2.0x15mm balloon, kissing balloon postdilatation (with an Invader NC 3.5x20 mm in the LAD and an Invader 2.0x15 mm in the D1) was performed; I) final angiographic result without residual stenosis and TIMI 3 flow both in LAD and D1. CTO = chronic total occlusion; D1 = first diagonal branch; LAD = left anterior descending artery.

Figure 3: Right Coronary Artery Recanalisation A

A: a Fielder FC wire without support of a microcatheter crosses the CC2 septal collaterals and reaches the distal RCA (septal surfing technique); B: a Corsair microcatheter advanced through the collateral channel to the distal cap; C: anchoring technique with the inflation of an Invader 2.0x12 mm balloon in a proximal conus branch; D: The retrograde Fielder FC wire advanced in the subintimal space, failing to reach the proximal true lumen. A Pilot 150 wire advanced antegradely in the occlusion fails to cross to the distal true lumen. E: After antegrade dilatation and creation of antegrade subintimal space with an Invader 3.0x15 mm balloon a Pilot 150 wire was easily advanced retrogradely to the antegrade guiding catheter (reverse CART technique); F: the Corsair microcatheter advanced to the antegrade guiding catheter through the occlusion, enabling a RG3 wire externalisation; G: using the RG3 wire the lesion was predilated consecutively with an Invader CTO 1.25x20 mm and an Invader 2.5x15 mm balloon; H/I: stent implantation was performed with a CORACTO 3.0x32 mm stent distally and a CORACTO 3.0x32 mm stent proximally. A third stent (CORACTO 2.75X17 mm) was necessary for the treatment of a dissection distal to the first stent (insert); J: postdilatation with an Invader NC 3.5x20 mm balloon; K: bilateral contrast injection depicting the restoration of TIMI 3 flow both in RCA and LAD. CTO = chronic total occlusion; LAD = left anterior descending artery; RCA = right coronary artery; CART = controlled antegrade retrograde subintimal tracking.

Treatment After bifemoral arterial access, a 6 French (Fr) Extra backup 4 catheter (Launcher®, Medtronic, Minneapolis, MN, US) was placed at the left main (LM) coronary artery and a 6 Fr Judkins Right (JR) 4 catheter (Launcher, Medtronic, Minneapolis, MN, US) was placed at the ostium of the RCA. Bilateral contrast injection was performed to visualise the distality of the occluded vessels and assess the details of the occlusions.

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The LAD was treated first. The lesion was initially approached with a Fielder FC guidewire (Asahi Intecc, Aichi, Japan) supported by a Finecross™ microcatheter (Terumo Interventional Systems, Somerset, New Jersey, US). The Fielder FC wire was advanced at the subintimal space and was unable to be connected with the distal true lumen (see Figure 2A). Next, we proceeded with the parallel wire technique with the use of a Pilot 150 guidewire (Abbott Vascular, Santa Clara,

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Coronary Chronic Total Occlusion Figure 4: Six-Month Follow-up Control Angiography Revealing No Signs of In-stent Restenosis in the Left Anterior Descending Artery (panels A and B) and No Signs of In-stent Restenosis in the Right Coronary Artery (panels C and D) A

CA, US). This wire punctured the proximal cap at a different position and was easily advanced to the distal true lumen (see Figure 2B). Subsequently, the Finecross was advanced through the occlusion and the Pilot 150 was exchanged to a Runthrough™ guidewire (Terumo Interventional Systems, Somerset, New Jersey, US). The occlusion was initially predilated with an Invader™ CTO 1.25x20 mm balloon (Alvimedica Medical Technologies, Turkey) (see Figure 2C). Further predilatation was performed with an Invader 2.5x15 mm balloon (see Figure 2D). The occlusion was then stented with implantation of a CORACTO™ 3.0x17 mm (Alvimedica Medical Technologies, Turkey)

and failed to reach the proximal true lumen. The occlusion was then approached antegradely. A Pilot 150 wire was advanced in the occlusion but could not cross to the distal true lumen (see Figure 3D). Applying the principle of the reverse Controlled Antegrade Retrograde subintimal Tracking (CART) technique, we dilated the occlusion antegradely with an Invader 3.0x15 mm balloon. After antegrade dilatation and the creation of antegrade subintimal space, a Pilot 150 wire was easily advanced retrogradely to the antegrade GC (reverse CART technique) (see Figure 3E). The Corsair was also advanced to the antegrade GC through the occlusion (see Figure 3F) and a RG3

distally and a CORACTO 3.0x28 mm proximally, without covering the ostium of the first septal branch (see Figures 2E/F). After stent implantation Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow was established at the LAD. From the middle of the occlusion a sizeable D1 was revealed with a 99 % stenosis at its ostium and TIMI 1 flow (see Figure 2G). The D1 was wired with a Fielder FC wire and its ostium was dilated with an Invader 2.0x15 mm balloon. Following kissing balloon postdilatation (with an Invader NC 3.5x20 mm in the LAD and an Invader 2.0x15 mm in the D1) (see Figure 2H), an optimal angiographic result was obtained in both branches with TIMI 3 flow (see Figure 2I). For the LAD recanalisation, total procedural time was 46 minutes, contrast consumption was 75 cubic centimetres (cc) and radiation dose was 1.3 Gray (Gy).

wire (Asahi Intecc, Aichi, Japan) was then externalised from the right femoral artery. Using this wire, the lesion was predilated consecutively with an Invader CTO 1.25x20 mm and an Invader 2.5x15 mm balloon (see Figure 3G). Following the predilatation, stent implantation was performed with a CORACTO 3.0x32 mm stent distally and a CORACTO 3.0x32 mm stent proximally. A third stent (CORACTO 2.75X17 mm) was necessary for the treatment of a dissection distal to the first stent (see Figure 3H/I). After postdilatation with an Invader NC 3.5x20 mm balloon (see Figure 3J) an optimal angiographic result was obtained (see Figure 3K). Total procedural time was 115 minutes, the contrast media used was 360 cc and the radiation dose reached 2.8 Gy.

Due to the fact that the LAD recanalisation was uncomplicated with low consumption of contrast media and low radiation exposure, the occlusion of the RCA was also addressed at the same session.

Control angiographic follow-up at six months (see Figure 4) revealed an excellent angiographic result without signs of in-stent restenosis both in the LAD and the RCA coronary arteries, while the patient remained completely asymptomatic.

Discussion The intention was to perform a short and focused antegrade attempt for the RCA recanalisation and, in case of failure, to proceed with the retrograde techniques. However, while retrieving the Fielder FC wire from D1 we explored the accessibility of the collateral channels from the first septal branch. The Fielder FC wire without support of a microcatheter, using the septal surfing technique, easily crossed the CC2 septal collateral and was advanced to the distal RCA, reaching the distal cap of the occlusion (see Figure 3A). A Corsair microcatheter (Asahi Intecc, Aichi, Japan) was also advanced through the collateral channel to the distal cap (see Figure 3B). Due to the proximal location of the occlusion, the RCA guiding catheter (GC) was stabilised at the ostium of the RCA using anchoring technique in a proximal conus branch with the inflation of an Invader 2.0x12 mm balloon (see Figure 3C). Following that, an attempt to recanalise the RCA was done retrogradely with a Fielder FC wire. The wire was advanced in the subintimal space

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For years PCI remained the least favourable therapeutic option for coronary CTOs over optimal medical treatment and CABG, never exceeding 10 % and even decreasing in popularity over time.10 The reason was threefold: the low success rates of conventional antegrade techniques, unchanged over time, until recently, and averaging 70–80 %4 in experienced hands, the lack of prospective randomised trials demonstrating superiority of CTO PCI on hard clinical endpoints, and the suboptimal results of balloon angioplasty and stent performance in this hard anatomical setting.15 The first generation of drug-eluting stents (DES) definitely improved clinical and angiographic endpoints, but there were still concerns about long-term outcomes related to increased stent thrombosis rates, compared with bare metal stents (BMS), and mechanical issues such as stent fractures.16,17 A recent study evaluating DES long-term safety and efficiency in CTO lesions revealed that DES were superior to BMS in reducing major adverse cardiac events (MACEs), target lesion revascularisation (TLR) and target vessel failure (TVF)

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Double CTO Recanalisation with the Use of a Novel DES with Biodegradable Polymer

at five-years.18 Next generation stents with biodegradable polymer, recently introduced in clinical practice, proved non-inferior to current generation DES with regard to clinical and angiographic endpoints.19 Notably, in a randomised CTO clinical study, a novel stent with biodegradable polymer – the CORACTO stent – proved superior to a BMS of similar design.20 Late lumen loss (LLL) was 0.77 ± 0.63 mm at six months. No death, myocardial infarction or stent thrombosis occurred at six-month follow-up and 24-month overall TVR rate was 10.8 % with no reported stent fracture,20 results outweighing the performance of DES in historical cohorts.17

Recent trends in practice support the implementation of the retrograde approach during the same procedure, but after a short (approximately 15 minutes of radiation time and 50–75 ml of contrast media), focused antegrade failure.13 Moreover, the concept of CTO PCI as a unique entity with complementary antegrade and retrograde components has gradually matured over the years. At present, more experienced operators interchangeably employ both antegrade and retrograde techniques in a non-dogmatic manner, switching from one approach to another, always based on clinical and anatomical criteria, with great efficacy and safety.

The CORACTO stent was developed in 2002 and it is a stainless steel stent with a strut thickness of 80 micrometres (μm) and a biodegradable polymer coating of 4 μm allowing controlled release of 1.7 μm/mm2 of Rapamycin. The coating is a poly(lactic-co-glycolic acid)-based copolymer, which is biocompatible and bioabsorbable, degrading into lactic acid and glycolic acid. After the degradation and complete drug release in 10–12 weeks there is a BMS remaining in the coronaries.

CTO PCI is related to certain procedural and in-hospital complications, well described in literature,13,21 but traditionally is considered a low risk procedure. There are no randomised trials comparing CTO versus non-CTO PCI, but indirect comparisons demonstrate a comparable low incidence of procedural events with MACE rates not exceeding 4–5 %.4 Retrograde techniques, due to their inherent complexity, are associated with certain complications not observed during antegrade CTO recanalisation, that tend to be minor and easily treatable in the majority of the cases. These complications may involve the occluded artery (retrograde perforation/dissection), the collaterals (rupture/haematoma of the septal or epicardial collaterals, perforation to the right ventricle [RV]/left ventricle [LV], septal wire trapping, epicardial flow disruption with ischaemia) and the donor artery (dissection/thrombosis potentially life-threatening, spasm leading to ischaemia).12,13

Technical and procedural success rates for CTO PCI have steadily risen over the last five years, as a result of increased operator experience, the development of novel CTO dedicated wires and microcatheters, the refinement of antegrade techniques, and the introduction of the retrograde approach.21 Success rates with modern antegrade techniques are currently in the range of 80 %. Retrograde techniques in expert hands added another 15 % of procedural success in CTO PCI, alongside shifting the field from lesion-related to collateral circulation-related predictive factors of failure, such as visible collateral connections, <90 degree collateral body tortuosity, and <90 degree angle between the distal collateral anastomosis with the CTO vessel.12,13 In the initial stages of their development, the retrograde techniques were mainly used as a second-line therapy after failure of the antegrade approach in repeat procedures. Current evidence suggests that they should be reserved for second attempts after antegrade failure, or as strategies of choice by experienced operators in very complex CTOs, where the expected antegrade success rate is <50 %.13

1. Kahn JK, Hartzler GO, Retrograde coronary angioplasty of isolated arterial segments through saphenous vein bypass grafts, Cathet Cardiovasc Diagn, 1990;20:88–93. 2. 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. 3. 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. 4. 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. 5. 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. 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.

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Conclusion In this report we describe a case of double CTO percutaneous recanalisation in a symptomatic young patient. Both antegrade and retrograde techniques were interchangeably employed, without prejudice or strict predetermined order, to facilitate successful CTO recanalisation. Thanks to increasing operator experience and development of more sophisticated techniques, CTO PCI is currently achieving high procedural success rates and serves as an alternative and efficient approach for complex CTO treatment. For safety and efficacy reasons, experience in the field of CTO PCI (>300 CTOs and >50 retrograde procedures per year) should be considered a prerequisite for such recanalisation attempts. In case safety criteria for CTO PCI cannot be met, optimal medical treatment or CABG should be preferred. n

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. 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. 10. 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. 11. 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. 12. 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. 13. 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. 14. 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. 15. Sianos G, CTO PCI at the crossroads, EuroIntervention , 2010;6:303–7. 16. Colmenarez HJ, Escaned J, Fernández 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. 17. 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 toChronic Occlusions With Sirolimus-Eluting Stents/Total Occlusion Study of Coronary Arteries-4) trial, JACC Cardiovasc Interv, 2009;2:97–106. 18. De Felice F, Fiorilli R, Parma A, et al., Five-Year Outcomes in Patients With Chronic Total Coronary Occlusion Treated With Drug-Eluting vs Bare-Metal Stents: A Case-Control Study, Can J Cardiol , 2012 [Epub ahead of print]. 19. Masahiro N, One-Year Outcome of a Trial Comparing Second Generation Drug-eluting Stents Using Either Biodegradable Polymer or Durable Polymer. The NOBORI Biolimus-Eluting versus XIENCE/PROMUS Everolimus-eluting Stent Trial (next), American College of Cardiology Scientific Session, 2013. Available at: http://my.americanheart.org/idc/ groups/ahamah-public/@wcm/@sop/@scon/documents/ downloadable/ucm_450001.pdf (accessed 26 March 2013). 20. Reifart N, Hauptmann KE, Rabe A, et al., Short and long term comparison (24 months) of an alternative sirolimus-coated stent with bioabsorbable polymer and a bare metal stent of similar design in chronic coronary occlusions: The CORACTO trial, EuroIntervention , 2010;6:356–60. 21. 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.

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Endovascular

Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve W illem I M Wi l l a e r t 1 a n d I s a b e l l e Va n H e r z e e l e 2 ,3 On beha lf of t he Europea n V i r t u a l r e a l i t y E n d o v a s c u l a r RE S e a r c h Te a m ( E V E R E S T) 1. Consultant Vascular Surgeon, Department of Thoracic and Vascular Surgery, AZ Maria Middelares Hospital, Ghent, Belgium; 2. Consultant Vascular Surgeon, Department of Thoracic and Vascular Surgery, Ghent University Hospital, Ghent, Belgium; 3. Honorary Senior Lecturer, Department of Biosurgery and Surgical Technology, Imperial College London, London, UK

Abstract Carotid artery stenting (CAS) remains an appealing intervention to reduce the stroke risk because of its minimal invasive nature. Nevertheless, landmark randomised controlled trials have not been able to resolve the controversies surrounding this complex procedure as the peri-operative stroke risk in a non-selected patient population still seems to be higher after CAS in comparison to carotid endarterectomy. What is more, these trials have highlighted that patient outcome after CAS is influenced by patient- and operator-dependant factors. The CAS procedure exhibits a definitive learning curve resulting in higher complication rates if the procedure is performed by inexperienced interventionists or in low-volume centres. This article will outline strategies to improve the performance of physicians carrying out the CAS procedure by means of proficiency-based training, credentialing, virtual reality rehearsal and optimal patient selection.

Keywords Carotid artery stenting, learning curve, training, virtual reality simulation, procedure rehearsal Disclosure: The authors received a research grant from Simbionix, Cleveland, US. Received: 2 February 2013 Accepted: 12 April 2013 Citation: Interventional Cardiology Review, 2013;8(1):50–6 Correspondence: Isabelle Van Herzeele, Department of Thoracic and Vascular Surgery, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. E: Isabelle.vanherzeele@ugent.be

In the western world stroke is the third most common cause of death with a reported incidence of >200/100,000 persons annually. 1 More than 10 % of these ischaemic strokes are attributable to atherosclerosis of the internal carotid artery. 1 Large landmark trials have confirmed the effectiveness of carotid endarterectomy (CEA) for reducing the stroke risk by r emoving the embolic atherosclerotic plaque. In the 1990s, as endovascular techniques became more widespread, carotid artery stenting (CAS) was introduced as a minimally invasive alternative therapy. Initial observational and case studies of CAS suggested that the procedure was feasible, safe and effective in treating carotid stenotic disease with high technical success rates. In 2004, the US Food and Drug Administration (FDA) approved the first endovascular device system for CAS in the US in patients at high risk for CEA. 2 In 2011, based on the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial results,3 comparing CAS with CEA for patients with symptomatic and asymptomatic carotid disease, the FDA expanded the indication to all patients with high-grade carotid artery stenosis. 4 Although the CREST trial showed that CAS was equivalent to CEA for the primary composite endpoint of peri-procedural death, stroke or myocardial infarction, the trial did not resolve all the controversies surrounding CAS.3 Similar to the results of European randomised controlled trials (RCTs) such as the Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE)5 and Endarterectomy Versus Angioplasty in patients with Severe Symptomatic carotid Stenosis (EVA-3S),6 CAS seemed to be associated with a higher

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peri-procedural stroke rate (offset by a lower rate of myocardial infarction in the CREST trial). To date, the heterogeneity of the major trials and their different inherent methodological problems make it difficult to present clear guidelines for either CAS or CEA. This fact is highlighted by the disparity in recommendations made by the different vascular, neurological, radiology and cardiology societies in their respective consensus documents across the continents. What the large CAS trials have also pointed out is the impact of patient-specific and physician-related factors on the outcome after CAS. This analysis has identified certain risk factors; these include patient age,7–10 gender,11 symptom status,7,8 timing and type11 of symptoms before CAS,8–10 patient co-morbidities,9,12,13 concurrent medications,7 and specific anatomic configurations of the arch and carotid vessels.14 Physician-related factors such as level of training and experience of the lead interventionist, as well as the overall hospital volume with the CAS procedure, should also be taken into consideration.15 This article will outline the effect of operator experience on procedural outcome and provide strategies, which may increase performance and patient safety after CAS. Therefore, the focus will be on factors including generic training, pre-procedural rehearsal and the process of optimising patient selection for CAS, but not on risk factor management and CAS-specific (technical) device developments.

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Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve

Learning curves are a well-recognised phenomenon for any new or technically challenging procedure. A clear learning curve for CAS was objectively documented by Lin et al. in 2005.16 In this report 200 patients were divided into four consecutive groups of 50 patients and peri-procedural complications were analysed. The authors observed a significant increase in technical success rate after 50 procedures and a concomitant reduction in total procedural time and contrast volume used. The 30-day stroke and death rate was 8 % after 50 interventions and 2 % after a 100 cases, but continued to decrease significantly after 150 procedures (0 %, p<0.05). It was speculated that the decrease in procedure time (from 60 to 40 minutes) lead to enhanced results by decreasing the embolic risk associated with reduced catheter manipulations and in situ thrombosis of indwelling catheters. Analysis of the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) study by Gray et al. confirmed that site volume also correlated strongly with the incidence of major complications (death and stroke).15 This inverse relationship was even clearer for individual physician volume. The conclusion that a patient should be operated in a high-output centre by a physician with a high caseload seems justified. Based on the CAPTURE registry data the minimum number of carotid artery stenting procedures to achieve a major complication rate below the American Heart Association (AHA) guidelines of 3 % (a threshold set for patients undergoing CEA) was 72 patients. This is considerably higher than what has previously been suggested by national and international societies,17–19 and also higher than the threshold used to enroll trial physicians into randomised trials like CREST.3 Nallamothu and colleagues focused their efforts on examining the relationship between operator experience and 30-day CAS mortality rates using national Medicare administrative data from 24,701 procedures performed by 2,339 physicians between 2005 and 2007.20 This provides an insight into the consequences of actual ‘real life’ practice patterns as opposed to the controlled environment of pre-credentialed RCTs. They found a 30-day mortality of nearly 2 % among Medicare beneficiaries. This is significantly higher than mortality rates for elderly patients documented in the major trials and registries (0.7–1.0 %).3 Suboptimal patient selection with inclusion of older patients may be partly responsible, but inexperienced CAS practitioners and low-volume centres also played a significant role. Moreover, the median annual operator volume in Medicare beneficiaries during the study period was only three per year (interquartile range, 1.4–6.5). These low-volume operators (<6 CAS procedures per year) were found to have an increased odds of death compared with patients treated by high-volume operators (>24 procedures per year). Furthermore, a clear learning curve was noted – inexperienced practitioners (cases 1–11) had twice the mortality rate compared with more experienced interventionists (>12 procedures). As a result of the evident learning curve and severe complications associated with CAS, several subspecialty societies have created various credentialing and consensus documents dealing with CAS competency requirements.17 The larger trials comparing CAS to CEA have also instituted credentialing processes to ensure that the physician investigators overcome the initial learning curve of CAS prior to participating in a trial.3,21 The rigorous credentialing process in CREST did indeed appear to lead to superior results compared with the previous European SPACE and EVA-3S data, where inclusion criteria for trial participants were less stringent and controlled.3 The results led on to The CREST Abbott Vascular (Santa Clara, CA) premarket approval supplement

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Figure 1: Evidence of In-trial Learning During CREST – Death or Major Stroke Rates in Carotid Artery Stenting Decrease for Symptomatic Patients with Time 50 % Symptomatic Patients Enrollment March 2006

4 Death or Major Stroke %

The Learning Curve for Carotid Artery Stenting

3.6 % 3

2.5 %

1 0.8 % 0

2000–2004 N=160

2005 N=111

2006 N=131

0.0 %

2007 N=120

2008 N=77

presentation on January 2011 at the US FDA Circulatory System Devices Advisory Panel where they presented the Rx Acculink™ carotid stent system for consideration of an expanded indication for use in a standard operative risk population.4 Once again in this presentation a clear relationship between the peri-procedural complication rate and temporal inclusion in CREST became evident, signifying obvious within-trial learning (i.e. increasing physician experience during the trial duration resulted in a risk reduction with time for patients undergoing CAS) (see Figure 1). Although the trials and registries mentioned above have highlighted that physician and centre experience influence outcome, societies still need to create definitive guidelines for physician credentialing, physician training programmes, and patient and device selection criteria in a bid to enhance the CAS outcomes. The trials looking at the learning curve indicate that the minimum caseload necessary to obtain experience in CAS seems higher than put forward in the initial consensus guidelines.

Strategies to Improve Procedural Performance and Patient Outcome Virtual Reality Simulation and Physician Training, Proctoring and Credentialing Although deeply rooted into medical education, the traditional training model devised by Halsted using the ‘see one, do one, teach one' approach has inherent drawbacks and exposes patients to risks associated with the aforementioned learning curve. It is unstructured, lacks objective feedback and may be ethically challenged as it puts patients at unnecessary risks, especially during complex high-risk procedures such as CAS. Nonetheless, this Halstedian approach is still the gold standard in most training institutions, where trainees progressively learn endovascular procedures on patients under experienced supervision. Proctoring is also a fine-tuned example of this type of a training process. There are several alternatives to learn CAS and to acquire the necessary skills to enhance procedural performance. These include industry-sponsored courses and carotid simulation training modules. Generic training using virtual reality (VR) simulation has several potential advantages over the classic approach aiming to provide skills acquisition. It allows the trainee to learn in an environment where he or she is central to the learning process, as opposed to the stressful patient-centred theatre environment. Skills acquisition can take place at the trainees own pace, taking

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Endovascular into account the variability in innate capabilities of each individual learner. Thus, this kind of training shifts the emphasis from caseload learning to proficiency-based learning. This learning process is more structured, allows trainees to effectively learn from mistakes and permits a gradual increase of procedural difficultly within the training process until predefined benchmark criteria are fulfilled. All this is achieved without harm to the patient. The training process does not limit itself to the interventionists, but team training is also possible in a simulated environment. Additionally, crisis scenarios that are not often encountered in real life can be practised until proficiency is reached both by the interventionist and by the team. It is important to stress that learning new procedures entails more than psychomotor skills acquisition alone. Any training curriculum has to incorporate a cognitive component as well, including elements regarding patient evaluation and selection, risk factor management, procedural technique, clinical decision-making and peri-operative patient management. At present the available courses are not standardised or based on predefined and validated benchmark criteria, partly because it is difficult to define these due to the heterogeneity of the physicians performing CAS (cardiologists, [neuro]radiologists, neurosurgeons and vascular surgeons). Professional organisations representing the major three endovascular specialties have already tried to list specific criteria to steer a credentialing process for individual operators performing CAS.17–19 These criteria include cognitive and technical aspects as well as minimum volume requirements. Once again there is variation across the different subspecialties regarding threshold requirements, but in general, volume requirements seem invariably low (often around 25 cases) especially in light of the recent learning curve data.4 One should also not overestimate the role of absolute volume, as quantity does not necessarily guarantee clinical or qualitative competence (i.e. experience does not always equate to expertise) – ‘slow’ learners may reach the same expertise as ‘quick’ learners, but will need a larger caseload to reach the necessary level of competence. The FDA has also encouraged educational initiatives, and in particular the incorporation of simulation technology into training packages, prior to granting privileges for physicians wishing to perform the CAS procedure on patients. 2 This interest in VR simulation has sparked efforts to scientifically validate this technology for training and assessment purposes. There is growing evidence that VR simulators have a role in physician training and credentialing by shortening and flattening the learning curve. Patel et al. showed that cardiologists performing five consecutive VR carotid arteriograms resulted in a significant improvement in total procedure time, contrast use, fluoroscopy time and number of errors with catheter manipulations. 22 Our own European Virtual reality Endovascular RESearch Team (EVEREST) has shown that a two-day CAS course, including supervised simulation training, leads to significantly improved performances with respect to procedure completion time, fluoroscopy use and delivery–retrieval time of the embolic protection device (EPD). Procedural errors observed post-course reduced significantly and expert raters regarded 60 % of the interventionists competent during a non-complex virtual CAS procedure after attending the two-day course compared with 0 % before the course.23 Chaer et al. reported their experience with VR simulation in training residents in non-complex endovascular procedures and for the first time observed transfer of the acquired benefits to the real operative environment leading to higher quality

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performances on patients (VR to operating room [OR] transfer).24 Endovascular simulator training does require close mentoring including expert feedback to ensure correct and prompt skills acquisition. The simulator training itself cannot be regarded as a standalone teaching tool.25,26 VR simulation seems to be particularly useful for inexperienced interventionists or more experienced practitioners wishing to learn new procedures. Current generation VR simulators probably lack the fidelity to refine the skills of experienced interventionists, potentially because of biomechanical limitations such as impaired haptic feedback. However, as mentioned by Satava, training on a simulator is not about the simulator itself, but about the structured and proficiency-based training curriculum of which the simulator is an integral part. 27 This curriculum includes cognitive components, errors identification and technical skills acquisition to predefined expert benchmark levels.27 Although currently expert-derived benchmark levels of performance of skill for CAS are not yet available, their identification will eventually allow us to define the levels of skill that are needed prior to treating real patients. Subsequently, simulators will be able to evaluate performances and may be used as a reliable and objective credentialing tool. Van Herzeele et al. have already shown that high-fidelity simulators are able to objectively differentiate level of CAS experience (i.e. construct validity) across four groups of experienced interventionists based on basic assessment parameters recorded by the VR simulator (procedure time, fluoroscopy time and number of recorded angiograms). 28 The simulator derived error scoring is currently not a valid mode of assessment and needs refinement, but expert-based rating scales have been validated to assess the quality of the executed procedure on the simulator in the interim.29 The European board of vascular surgery exam is an example where board certification is granted only after basic endovascular skills have been evaluated while working on the Simulator for Testing and Rating Endovascular SkillS (STRESS) machine. Assessment is carried out using previously validated, expert-derived rating scales for basic endovascular skills, as automated error scoring recorded by the simulators themselves is still unreliable.30 Once benchmark levels of skill are defined and the fidelity of the simulator error scoring is improved, patient safety may be enhanced by objective evaluation and credentialing prior to independent CAS practice. This process of creating proficiency-based simulator curricula for interventional procedures is the focus of continuing research in simulation science. The benefit of VR simulation training is not solely reserved for the inexperienced practitioners. Experienced CAS practitioners can use VR simulation as a tool to safely integrate new CAS technology that arises during the course of their career. An example is the application of new proximal EPDs that aim to protect the brain from peri-operative (micro) embolisation, especially during crossing of the lesion and angioplasty of the stenosis.31 These include the Mo.Ma® Ultra Device (Medtronic Invatec, Frauenfeld, Switzerland) and Gore® Flow Reversal System (W. L. Gore and Associates, Flagstaff, Arizona, US) that use either stasis or reversal of flow to minimise the embolic burden during the CAS intervention itself. Moreover, the MICHI™ neuroprotection system (Silk Road Medical Inc, Sunnyvale, Califona, US) not only uses flow reversal but also a cervical approach to avoid any manipulation in the arch and has been shown to reduce the embolic load significantly.32 In order to learn the procedural sequencing together with the endovascular skills required to use the Gore flow reversal system safely, an endovascular

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Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve

VR simulator module has been created and may thus minimise the negative consequences of the learning effect of these complex devices on patients.

Figure 2: Schematic Overview of the Steps of Patient-specific Rehearsal

1. CTA

Virtual Reality Simulation and Procedure Rehearsal Patient-specific VR rehearsal, also referred to as ‘procedure’ or ‘mission’ rehearsal, is a new technological advancement within simulation science, which allows patient-specific computerised tomography (CT) scans to be incorporated into the simulation software (see Figure 2), enabling rehearsal of actual patient cases. This patient-specific role complements the established role of simulators as a ‘generic’ training tool. The concept of pre-procedural rehearsal has already been implemented successfully in other high-stake industries such as the military and aviation.33,34 Likewise, VR simulators may also be used to detect potential difficulties, surgical errors, and analyse near miss incidents in the medical domain to prevent subsequent complications in patients. Due to its procedural complexity, this technology was initially created for the CAS procedure. Technically, patient-specific rehearsal seems a practical and effective tool to plan CAS cases pre-operatively, evaluate different approaches, identify potential hazards and optimise endovascular tool selection. Patient-specific VR rehearsal seems an ideal tool to complement a tailored approach to each individual CAS case. Case reports certainly indicate that this technology could be useful in the immediate pre-operative setting.35–38 Initially the process of incorporating individual patient data into simulators required technological support from the simulation company, which proved a time consuming and costly process.35 The introduction of the commercially available PROcedure Rehearsal Studio™ software (Simbionix USA Corp, Cleveland, Ohio, US) was a definite step forward, as it allows physicians to create these patient-specific simulations themselves in a cost-effective manner. These simulations were found to exhibit a high degree of realism although the quality of the patient-specific rehearsal is dependent on the quality of the source CT (or magnetic resonance imaging [MRI]) data.39 One of the most evident benefits of patient-specific VR rehearsal for CAS is the opportunity for physicians to evaluate how specific endovascular tools may interact with the anatomy of an actual patient during catheterisation of the common and internal carotid artery, placement of the EPD, stent and balloon. Research has shown that patient-specific rehearsal can indeed provide interventionists with a detailed evaluation of case complexity and influence both experienced and inexperienced interventionists, most notably for the optimal fluoroscopy C-arm position, choice of selective catheter, choice of sheath or guiding catheter and balloon dilatation strategy.40 The pre-operative knowledge of the optimal endovascular tools could result in using fewer endovascular tools with a decrease in hazardous manipulations in dangerous anatomic regions such as the aortic arch. Furthermore, it could also prove to be cost-effective as the use of unnecessary material is avoided. Subsequent research established that in a simulated environment, both from a quantitative and qualitative perspective, CAS procedures were performed to a higher standard if a pre-operative VR rehearsal had taken place. The operation was carried out more rapidly, the fluoroscopy pedal was pressed less frequently and for a shorter duration, and fewer errors were committed during the intervention.41 Error reduction was apparent by a decrease in excessive catheter

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2. 3D recon

3. VR simulation

4. CAS procedure

CAS = carotid artery stenting; CTA = computed tomography angiography; VR = virtual reality.

manipulation, a reduction in the suboptimal selection of vascular stents, and a decrease in suboptimal C-arm angles to delineate the different vessels during the procedure. Catheterisation of target carotid vessels was accomplished faster and the EPD was deployed for a shorter duration, reducing the risk for clot formation and stroke in high risk areas such as the internal carotid artery. In addition, it was established that full-length rehearsals are not always necessary and part-task rehearsals, focusing on the most crucial procedure steps, may be as effective while saving time.42 Patient-specific rehearsal may also be used as an ultimate form of pre-operative warm-up. Warm-up exerts its effect by increasing the physical and mental preparedness (cognitive arousal effect) and by increasing the individual’s perceived control of the situation (i.e. confidence).43 VR simulators seem to be an ideal tool for warm-up, using either patient-specific or generic preset simulated cases. Furthermore patient-specific rehearsal can also be viewed as an excellent training tool, applied predominately in the latter stages of the training process, where it may tailor and facilitate the transfer of skills acquired in the laboratory environment to treat real patients in the actual angiosuite in a safe manner (VR to OR transfer). Another area of interest is patient-selection. VR rehearsal may be able to provide information on procedure feasibility, specific hazards and risk stratification, and aid the physician in his or her decision-making process. This technology can be used in conjunction with existing expert-based anatomic scoring systems for CAS.44 These scoring systems intend to guide less experienced practitioners in patient selection by identifying patients at higher risk of peri-operative complications. Limitations of the current generation of PROcedure rehearsal software relate to the use of ‘static’ Digital Imaging and Communications in Medicine (DICOM) imagery as source data for the simulations and its influence on simulation fidelity. Although CT or MRI data provides information on the anatomy and specific configurations of the arch and carotid vessels, information such as the degree of calcification, vessel wall atheroma or vessel wall thickness are not incorporated into the simulation. Therefore, biomechanical properties including the reaction of vessels and stenoses to rigid guidewires, stents and balloons are not always replicated accurately. Future software updates will have to incorporate these biomechanical properties to improve the simulator fidelity and allow all facets of the real operation to be replicated.

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Endovascular Figure 3: Three Potential Rehearsal Environments – Laboratory, Simulated Operating Suite (Imperial College London) and the Angiosuite (So-called In Situ Simulation)

Figure 4: Anatomic Scoring System for Carotid Artery Stenting No arch disease

Normal target vessel

Angulated distal ICA

Normal target vessel

Angulated distal ICA

Normal target vessel

Angulated distal ICA

Normal target vessel

Angulated distal ICA

Normal target vessel

Angulated distal ICA

Standard lesion

(0.4)

3.3 (1.2)

3.5 (1.2)

4.3 (1.2)

3.7 (1.5)

4.5 (1.4)

4.3 (1.9)

5.1 (1.7)

5.3 (1.8)

6.1 (1.7)

5.0 (2.2)

5.9 (1.9)

Pinhole stenosis

2.9 (1.2)

3.8 (1.2)

3.9 (0.9)

4.8 (1.0)

4.1 (1.7)

5.0 (1.3)

4.7 (1.8)

5.6 (1.5)

5.8 (1.6)

6.6 (1.6)

5.5 (2.2)

6.4 (1.8)

Standard lesion

3.6 (1.4)

4.5 (1.2)

4.7 (1.6)

5.5 (1.1)

4.9 (1.4)

5.7 (1.0)

5.0 (1.9)

5.9 (1.3)

6.0 (1.4)

6.9 (1.3)

5.8 (1.8)

6.7 (1.6)

Pinhole stenosis

4.1 (1.5)

5.0 (1.3)

5.1 (1.6)

6.0 (0.7)

5.3 (1.4)

6.2 (1.2)

5.5 (1.5)

6.3 (1.4)

6.5 (1.4)

7.4 (0.9)

6.3 (1.6)

7.1 (1.6)

Standard lesion

4.6 (1.6)

5.5 (1.0)

5.7 (1.3)

6.5 (1.2)

5.9 (1.4)

6.7 (0.9)

6.0 (1.4)

6.8 (1.2)

7.0 (0.7)

7.8 (0.6)

6.8 (1.6)

7.6 (1.1)

Pinhole stenosis

5.1 (1.3)

6.0 (0.9)

6.1 (1.4)

7.0 (1.2)

6.3 (1.4)

7.2 (1.2)

6.4 (1.6)

7.3 (0.8)

7.5 (1.1)

8.3 (0.9)

7.2 (1.2)

8.1 (1.0)

Normal arch

Angulated distal ICA

Arch atheroma Diseased ECA CCA problem

Normal target vessel

Normal access

Bovine arch

ECA Diseased problem CCA

Type III arch

Normal access

Bovine arch

and Type III arch Standard lesion

5.5 (1.4)

6.3 (1.2)

6.5 (1.4)

7.3 (1.1)

6.7 (1.4)

7.6 (1.3)

6.4 (1.3)

7.2 (1.2)

7.4 (1.1)

8.2 (0.8)

7.2 (1.3)

8.0 (0.7)

Pinhole stenosis

6.0 (1.4)

6.8 (1.3

7.0 (1.3)

7.8 (0.8)

7.2 (1.5)

8.0 (0.8)

6.8 (1.7)

7.7 (1.1)

7.9 (0.7)

8.7 (0.6)

7.6 (1.2)

8.5 (0.8)

≤4.9

5.0–5.9

6.0–6.9

≥7.0

CCA = common carotid artery; ECA = external carotid artery; ICA = internal carotid artery.

If the fidelity of patient-specific VR rehearsal is further improved, this opens the door for additional applications. VR rehearsals can be used as a post-operative debriefing tool to re-enact unexpected events or complications that occurred during surgery, and to understand factors associated with positive and negative operative outcomes. Using this tool to both rehearse the procedure beforehand and refine operative technique afterwards can be considered an example of ‘deliberate practice’, as described by Ericsson in 2003.45 This kind of targeted practice of new or evolving skills (as opposed to repetitive practice of previously obtained skills) may prevent arrested development and ensure that experienced interventionists continue to learn during the course of their career, eventually resulting in expert performance. Patient-specific VR rehearsal can also be applied to educate patients and provide them with a detailed plan and prognosis of intended treatment. If increasing fidelity results in VR simulation mimicking every aspect of human interaction, these simulators could even serve as a tool for procedural prototyping – using them as ‘guinea pigs’ to

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develop and refine new surgical techniques and products within the domain of CAS and other complex endovascular procedures.

Team Training The initial case reports evaluating procedure rehearsal for CAS primarily focused on its role as a technical adjunct for the interventionist performing the procedure. Although this is crucial, patient-specific rehearsal has the potential to be much more than a technical tool alone, as it can also be used to train the entire interventional team and improve non-technical performances. Non-technical skills such as teamwork, communication and decision-making are vital in complex procedures.46 Numerous adverse events within the OR and emergency department are caused by human error and could be prevented by enhanced teamwork.46 Similarly, the endovascular suite is a complex multidisciplinary environment in which communication errors and equipment-related malfunctions have been shown to account for nearly half of all operative failures.47 Many of the CAS procedure rehearsals conducted at Imperial College London and Ghent University, Belgium are conducted as ‘whole’ team rehearsals and involve the interventionist, scrub and circulating nurse, and anaesthetist who are present in the subsequent real intervention. In this respect procedure rehearsal can be considered a powerful and comprehensive team training tool. These rehearsals are not solely focused on the technical elements of the procedure but also on training and evaluating non-technical skills. There is evidence that these non-technical and team interaction skills can be trained by complex, high-fidelity full team simulations48 and can have a positive effect on procedural outcome.48 Rehearsals to train the team can either be carried out in the laboratory environment, or in an authentic learning environment such as a simulated operating environment or real angiosuite (so-called in situ simulation) and so enhance contextualisation (see Figure 3). An example of such a high-fidelity simulation environment is the Simulated Operating Suite (SOS) at Imperial College London. The SOS is a replicated, fully functional, simulated operating theatre environment including all the necessary operative and recording equipment. Another example is ORCAMP (Orzone, Gothenburg, Sweden), a virtual angiosuite that allows integration of existing endovascular simulators and has been developed for training and assessment of the entire endovascular team. 49 A drawback of these simulation environments are the financial costs and their limited availability. To circumvent this, simulators can be placed in the actual operating theatre or angiosuite, which was done frequently at the EVEREST centres. However, this kind of in situ simulation does rely on the availability of unused theatre capacity.

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Carotid Artery Stenting – Strategies to Improve Procedural Performance and Reduce the Learning Curve Patient Selection Correct patient selection is paramount to ensure procedural and clinical success for CAS, since outcomes are influenced by the physician’s experience and patient-specific characteristics such as anatomy. Experts in the field now advocate a patient-tailored approach towards the CAS procedure.50 To meet this goal, in 2009 a scoring system was developed by CAS experts to evaluate the influence of anatomic factors on procedural difficulty44 (see Figure 4). The aim of this scoring system is to grade expected difficulty for CAS and guide inexperienced operators in proper case selection by identifying high-risk patients. The scoring system has been derived by expert opinion, using a Delphi consensus methodology. Anatomic characteristics of the arch and carotid arteries are graded from 1 (straightforward) to 9 (difficult). In the consensus document, 12 individual anatomic features were incorporated allowing for 96 combination anatomies. A scoring system for combination anatomy was produced, comprising broad agreement bands presented as traffic light colours – red for particularly difficult anatomy (score >7.0), amber for moderate difficulty (score 5.0–5.9) and green for lesser difficulty (score <4.9) The use of this scoring system may reduce peri-procedural stroke rates by the selection of patients appropriate to the operator’s level of expertise.

preparation and identifying high-risk patients more effectively, especially when inexperienced interventionists are involved.

Discussion Due to its minimally invasive nature, CAS remains an attractive procedure to reduce stoke risk in patients with atherosclerosis of the internal carotid artery. Nonetheless the initial enthusiasm has been tempered by evidence that peri-operatieve stroke risks may be higher with CAS than after CEA. This observation is partly attributable to inexperienced interventionists and their learning curve, inadequate training and suboptimal patient selection. Several strategies to improve performance and outcome after CAS exist. Apart from medical optimisation and CAS device refinement, patient selection, proficiency-based training and rigorous credentialing seem key factors associated with improved success after CAS. Incorporation of VR simulation into proficiency-based curricula for CAS seems paramount to increase physician experience with the procedure. Ongoing research in the field of simulation science indicates that this technology can enhance training and provide physicians with the necessary tools to increase their experience levels. Virtual reality ‘procedure rehearsal’ seems a promising adjunct in tailoring this training to specific patients.

Recently this scoring system has been validated using patient-specific

National and international societies of the different subspecialties

VR simulation.51 Novice interventionists performed three CAS cases of increasing difficulty, as defined by the scoring table (i.e. green, amber and red), requiring significantly more time to complete each case, with use of more fluoroscopy time, angiographies and contrast volume. More importantly, the quality of the procedure significantly deteriorated with increasing case complexity, falling below the arbitrary score of competent performance for the more difficult cases as measured by expert derived qualitative rating scales for CAS. These scoring systems, together with the use of VR simulation, may contribute to improved patient safety and outcome by enhancing pre-operative procedural

should now strive to create refined guidelines for CAS training, competency and credentialing. These will probably be more stringent than previously documented, as there is growing evidence of a steep and long learning curve associated with the procedure. In the near future, better trained CAS interventionists should be able to perform CAS to a higher standard and select patients more accurately, resulting in improved outcome and increased patient safety. CAS stroke rates may then become equivalent to CEA in specific patient groups, with the two strategies being complementary to each other in a patient-tailored approach to carotid stenosis and stroke treatment. n

1. Rosamond W, Flegal K, Friday G, et al., Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation , 2007;115:e69–71. 2. US Food and Drug Administration Center for Devices and Radiological Health Medical Devices Advisory Committee Circulatory System Devices Panel Meeting, 2004. Available at: www.fda.gov/ohrms/dockets/ac/04/transcripts/4033t1.htm (accessed 4 March 2013). 3. Brott TG, Hobson RW 2nd, Howard G, et al., Stenting versus endarterectomy for treatment of carotid-artery stenosis, N Engl J Med , 2010;363(1):11–23. 4. CREST sponsor presentation. Meeting materials non-FDA generated, 2011. Available at: www.fda.gov/ AdvisoryCommittees/ CommitteesMeetingMaterials/ MedicalDevices/MedicalDevicesAdvisoryCommittee/ CirculatorySystemDevicesPanel/ucm240575.htm (accessed 5 March 2013). 5. Eckstein HH, Ringleb P, Allenberg JR, et al., Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial, Lancet Neurol , 2008;7(10):893–902. 6. Mas JL, Trinquart L, Leys D, et al., Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial, Lancet Neurol , 2008;7(10):885–92. 7. Theiss W, Hermanek P, Mathias K, et al., Predictors of death and stroke after carotid angioplasty and stenting: a subgroup analysis of the Pro-CAS data, Stroke , 2008;39:2325–30. 8. Gray WA, Yadav JS, Verta P, et al., The CAPTURE registry: predictors of outcomes in carotid artery stenting with embolic protection for high surgical risk patients in the early post-approval setting, Catheter Cardiovasc Interv , 2007;70:1025–33. 9. Chiam PT, Roubin GS, Panagopoulos G, et al., One-year clinical outcomes, midterm survival, and predictors of mortality after carotid stenting in elderly patients, Circulation , 2009;119:2343–8.

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10. Topakian R, Strasak AM, Sonnberger M, et al., Timing of stenting of symptomatic carotid stenosis is predictive of 30-day outcome, Eur J Neurol , 2007;14:672–8. 11. Howard VJ, Lutsep HL, Mackey A, et al., Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), Lancet Neurol , 2011;10(6):530–7. 12. Vogel TR, Dombrovskiy VY, Haser PB, et al., Outcomes of carotid artery stenting and endarterectomy in the United States, J Vasc Surg, 2009;49:325–30. 13. Jackson BM, English SJ, Fairman RM, et al., Carotid artery stenting: identification of risk factors for poor outcomes, J Vasc Surg, 2008;48:74–9. 14. Sayeed S, Stanziale SF, Wholey MH, Makaroun MS, Angiographic lesion characteristics can predict adverse outcomes after carotid artery stenting, J Vasc Surg, 2008;47:81–7. 15. Gray WA, Rosenfield KA, Jaff MR, et al., Influence of site and operator characteristics on carotid artery stent outcomes: analysis of the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) clinical study, JACC Cardiovasc Interv, 2011;4(2):235–46. 16. Lin PH, Bush RL, Peden EK, et al., Carotid artery stenting with neuroprotection: assessing the learning curve and treatment outcome, Am J Surg , 2005;190(6):850–7. 17. American College of Cardiology Foundation; American Society of Interventional & Therapeutic Neuroradiology; Society for Cardiovascular Angiography and Interventions, et al., ACCF/SCAI/SVMB/SIR/ASITN 2007 clinical expert consensus document on carotid stenting: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (ACCF/SCAI/SVMB/SIR/ ASITN Clinical Expert Consensus Document Committee on Carotid Stenting), J Am Coll Cardiol, 2007;49(1):126–70. 18. Rosenfield K, Babb JD, Cates CU, et al., Clinical competence statement on carotid stenting: training and credentialing for carotid stenting--multispecialty consensus recommendations: a report of the SCAI/SVMB/ SVS Writing Committee to develop a clinical competence statement on carotid interventions, J Am Coll Cardiol, 2005;45(1):165–74.

19. Connors JJ 3rd, Sacks D, Furlan AJ, et al., Training, competency, and credentialing standards for diagnostic cervicocerebral angiography, carotid stenting, and cerebrovascular intervention: a joint statement from the American Academy of Neurology, the American Association of Neurological Surgeons, the American Society of Interventional and Therapeutic Neuroradiology, the American Society of Neuroradiology, the Congress of Neurological Surgeons, the AANS/CNS Cerebrovascular Section, and the Society of Interventional Radiology, J Vasc Interv Radiol, 2009;20(7 Suppl):S292–301. 20. Nallamothu BK, Gurm HS, Ting HH, et al., Operator experience and carotid stenting outcomes in Medicare beneficiaries, JAMA , 2011;306(12):1338–43. 21. Hopkins LN, Roubin GS, Chakhtoura EY, et al., The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase, J Stroke Cerebrovasc Dis, 2010;19(2):153–62. 22. Patel AD, Gallagher AG, Nicholson WJ, Cates CU, Learning curves and reliability measures for virtual reality simulation in the performance assessment of carotid angiography, J Am Coll Cardiol, 2006;47(9):1796–802. 23. Van Herzeele I, Aggarwal R, Neequaye S, et al., Experienced endovascular interventionalists objectively improve their skills by attending carotid artery stent training courses, Eur J Vasc Endovasc Surg, 2008;35(5):541–50. 24. Chaer RA, Derubertis BG, Lin SC, et al., Simulation improves resident performance in catheter-based intervention: results of a randomized, controlled study, Ann Surg, 2006;244(3):343–52. 25. Bagai A, O’Brien S, Al Lawati H, et al., Mentored simulation training improves procedural skills in cardiac catheterization: a randomized, controlled pilot study, Circ Cardiovasc Interv, 2012;5(5):672–9. 26. Boyle E, O’Keeffe DA, Naughton PA, et al., The importance of expert feedback during endovascular simulator training, J Vasc Surg , 2011;54(1):240–8. 27. Satava RM, Identification and reduction of surgical error using simulation, Minim Invasive Ther Allied Technol , 2005;14:257–61.

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Endovascular 28. Van Herzeele I, Aggarwal R, Choong A, Bet al., Virtual reality simulation objectively differentiates level of carotid stent experience in experienced interventionalists, J Vasc Surg, 2007;46(5):855–63. 29. Van Herzeele I, Aggarwal R, Malik I, et al., Validation of videobased skill assessment in carotid artery stenting, Eur J Vasc Endovasc Surg, 2009;38(1):1–9. 30. Berger P, Willems MC, Van Der Vliet JA, et al., Validation of the Simulator for Testing and Rating Endovascular SkillS (STRESS)machine in a setting of competence testing, J Cardiovasc Surg (Torino) , 2010;51(2):253–6. 31. Mousa AY, Campbell JE, Aburahma AF, Bates MC, Current update of cerebral embolic protection devices, J Vasc Surg, 2012;56(5):1429–37. 32. Pinter L, Ribo M, Loh C, et al., Safety and feasibility of a novel transcervical access neuroprotection system for carotid artery stenting in the PROOF Study, J Vasc Surg, 2011;54(5):1317–23. 33. Allerton D, Principles of Flight Simulation Volume 27, AIAA education series , Chichester, UK: John Wiley and Sons, 2009. 34. Krebs WK, McCarley JS, Bryant EV, Effects of mission rehearsal simulation on air-to-ground target acquisition, Hum Factors, 1999;41:553–8. 35. Cates CU, Patel AD, Nicholson WJ, Use of virtual reality simulation for mission rehearsal for carotid stenting, JAMA, 2007;297:265–6. 36. Roguin A, Beyar R, Real case virtual reality training prior to carotid artery stenting, Catheter Cardiovasc Interv,

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2010;75(2):279–82. 37. Hislop SJ, Hedrick JH, Singh MJ, et al., Simulation case rehearsals for carotid artery stenting, Eur J Vasc Endovasc Surg, 2009;38:750–4. 38. Willaert WI, Aggarwal R, Van Herzeele I, et al., Role of patientspecific virtual reality rehearsal in carotid artery stenting, Br J Surg, 2012;99(9):1304–13. 39. Willaert WI, Aggarwal R, Nestel DF, et al., Patient-specific simulation for endovascular procedures: qualitative evaluation of the development process, Int J Med Robot, 2010;6(2):202–10. 40. Willaert WI, Aggarwal R, Van Herzeele I, et al., Patient-specific endovascular simulation influences interventionalists performing carotid artery stenting procedures, Eur J Vasc Endovasc Surg , 2011;41(4):492–500. 41. Willaert WI, Aggarwal R, Daruwalla F, et al., Simulated procedure rehearsal is more effective than a preoperative generic warm-up for endovascular procedures, Ann Surg, 2012;255(6):1184–9. 42. Willaert W, Aggarwal R, Harvey K, et al., Efficient implementation of patient-specific simulated rehearsal for the carotid artery stenting procedure: part-task rehearsal, Eur J Vasc Endovasc Surg , 2011;42(2):158–66. 43. Stewart D, Macaluso A, De Vito G, The effect of an active warm-up on surface EMG and muscle performance in healthy humans, Eur J Appl Physiol, 2003;89:509–13. 44. Macdonald S, Lee R, Williams R, et al., Towards safer carotid artery stenting: a scoring system for anatomic suitability,

Stroke, 2009;40:1698–703. 45. Eriksson KA, Deliberate practice and the acquisition and maintenance of expert performance in medicine and related domains, Acad Med , 2004;79(10 Suppl):S70–81. 46. Risser, DT, Rice MM, Salisbury ML, et al., The potential for improved teamwork to reduce medical errors in the emergency department. The MedTeams Research Consortium, Ann Emerg Med, 1999;34:373–83. 47. Albayati MA, Gohel MS, Patel SR, et al., Identification of patient safety improvement targets in successful vascular and endovascular procedures: analysis of 251 hours of complex arterial surgery, Eur J Vasc Endovasc Surg, 2011;41:795–802. 48. Arora S, Sevdalis N, HOSPEX and concepts of simulation, J R Army Med Corps, 2008;154:202–5. 49. Lonn L, Edmond JJ, Marco J, et al., Virtual reality simulation training in a high-fidelity procedure suite: operator appraisal, J Vasc Interv Radiol, 2012;23(10):1361–6.e2. 50. Cremonesi A, Gieowarsingh S, Spagnolo B, et al., Safety, efficacy and long-term durability of endovascular therapy for carotid artery disease: the tailored-carotid artery stenting experience of a single high-volume centre (tailored-CASE Registry), EuroIntervention , 2009;5:589–98. 51. Willaert WI, Cheshire NJ, Aggarwal R, et al., Improving results for carotid artery stenting by validation of the anatomic scoring system for carotid artery stenting with patient-specific simulated rehearsal, J Vasc Surg, 2012;56(6):1763–70.

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Endovascular

Endovascular Abdominal Aortic Aneurysm Repair – Patient Selection and Long-term Outcome Expectations – Current Challenges in 2013 Regu l a S vo n Al l men , Flor ian D ic k , Thom as R Wy ss and Roge r M G r e e nhalgh Imperial College Vascular Surgery Research Group, Division of Surgery, Oncology, ReproductiveBiology and Anaesthetics, Charing Cross Hospital, London, UK

Abstract Endografts for repair of abdominal aortic aneurysm were first reported in the late 1980s and commercially available grafts were developed rapidly during the 1990s. This prompted a head-to-head comparison of the new, less invasive, endovascular technology with the existing gold standard of open repair. The first and largest randomised trial of open versus endovascular repair for large aneurysms started in the UK in 1999. Other trials comparing open and endovascular repair followed in the Netherlands, France and the US. Only the UK trial has reported long-term follow-up to 10 years. This has shown no statistically significant difference in long-term survival after open or endovascular repair. Aneurysm-related mortality curves converged at six years, which is described as endovascular aortic repair (EVAR) ‘catch up’ on open repair. It appears that this convergence is probably largely attributable to secondary sac rupture after endovascular repair, which is fatal in about two-thirds of cases. At this point, we have reached a crossroads and only longer-term follow-up data can provide the vital answer to the outcome of endovascular repair in the long run. This article gives a brief overview of the development and the current evidence of endovascular aortic repair and discusses the most important factors that are leading the way to the future of this technology.

Keywords Abdominal aortic aneurysm, endovascular procedures, outcomes, long-term care Disclosure: The authors have no conflicts of interest to declare. Received: 30 November 2012 Accepted: 15 January 2013 Citation: Interventional Cardiology Review, 2013;8(1):57–60 Correspondence: Roger M Greenhalgh, Emeritus Professor of Surgery, Imperial College at Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. E: r.greenhalgh@imperial.ac.uk

Endovascular aortic aneurysm repair (EVAR) was introduced by Volodos in the Ukraine. He attributed much of the concept to Charles Dotter of solid angioplasty fame. The Volodos publication received little attention in the Western world at the time towards the end of the Soviet Union era.1 It was at the 1990 Charing Cross Symposium in London that many in vascular disease management first heard about it. The speaker was the inventor/interventional radiologist, Julio Palmaz. His announcement came as a huge shock to the audience and surgeons looked extremely grim. He described the use of his Palmaz stent to trap and fix a Dacron tube at the neck of an aortic aneurysm, and reported the cases he had done with the surgeon, Juan Parodi, both from Argentina. The subsequent publication by Parodi, Palmaz and Barone reached a huge Western world audience. 2 It was then realised that the domain of abdominal aortic aneurysm would no longer be exclusively surgical. High-class catheter skills would be required in future either by learning these or working in harmony with those who have such skills. Unknown to the audience was the work and achievement of breakthrough by Volodos in the Ukraine.

The Endovascular Aortic Repair Trials 1 and 2 Endovascular aortic repair was introduced in London in 1993 and by 1996, the Endovascular aortic repair (EVAR) trials 1 and 2 were designed

Greenhalgh.indd 57

as separate randomised controlled trials for two different populations of patients.3 EVAR trial 1 was to test EVAR against open repair as reference standard in patients anatomically suitable for EVAR, which proved possible in 54 % of all patients at that time. EVAR trial 1 patients were physically fit enough for open repair from the anaesthesiological point of view and so it was a straight choice between the old method and the new.4 Trials with similar protocols followed in the Netherlands, France and the United States. These trials are the Dutch Randomised Aneurysm Management (DREAM),5 Anévrisme de l’aorte abdominal: Chirurgie versus Endoprothese (ACE)6 and American Outcome following Endovascular versus open Repair (OVER)7 trials, respectively. No substantial disagreements have been reported in these from EVAR trial 1, which was the first to post 10-year results in 2010.4 EVAR trial 2 is quite different and rather surprisingly has never been copied and remains unique. It is therefore the sole trial, which addresses the potential for EVAR in patients in whom the anaesthetic evaluation recommended against open repair at the time. Again, all of the patients who were included in the trial were anatomically suitable for EVAR. The options facing patient and clinician in this instance were either to offer EVAR (possibly under local anaesthesia) or to wait for any improvement in physical state to bring the patient into the range of open repair.8

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Endovascular Figure 1: Group A – Secondary Sac Ruptures Occurring within 30 Days of the Primary Operation EVAR procedure

Corrective procedure and 30d mortality Open repair

Open repair

3 days Technical problems, 5 days

Open repair, †

8 days

†

Limb extention awaited 8 days

Open repair, †

Figure 2: Group B – Secondary Sac Ruptures Occurring Beyond 30 Days of the Primary Operation, Without Identified Prior Complications. Secondary Sac Rupture Occurred in Three Cases ‘Out of the Blue’ EVAR procedure

Corrective procedure and 30d mortality †

32 days

†

1.3 years 2.9 years

†

3.1 years

EVAR modification

Missed follow up at 3 years 3.6 years

†

In EVAR trial 2, patients were randomised to either EVAR with medical care or medical care alone, and results were reported at 30 days, five years and 10 years. The striking finding is how many patients died in association with the poor underlying condition, which prevented open repair (OR) being considered in the first place. Obviously, the associated co-morbidities were the driver here. Against this background, EVAR did not alter the expected day of death. However, it has proved difficult to withhold EVAR in such patients once they are aware that they have a swollen aorta with a natural expectation of bursting. Many seek repair after being given the facts. There is some support for EVAR in the EVAR 2 situation in the per-protocol analysis but the randomised findings are clear overall, where EVAR showed a significantly lower rate of aneurysm-related mortality, but not for all-cause mortality. For the EVAR 1 trial, aneurysm-related mortality has proven to be a crucial method of evaluating outcome. Sadly again, only EVAR trial 1 uses aneurysm-related mortality whereas all 4 trials, EVAR 1, DREAM, ACE and OVER use all-cause mortality. Early benefit in favour of endovascular against open repair is lost in these trials. For EVAR 1, the absolute aneurysm-related mortality benefit of EVAR is 4 % in the early years but is lost at six years. From that point, the curves run together and stay conjoined in the latest follow-up report.

Long-term Outcome of Endovascular Versus Open Repair This topic is the rage at international meetings at this moment. This is simply because so much hangs on the late performance of EVAR and what will happen next. Loud voices from the podium preach reassurance in terms of EVAR. This is understandable, as patients prefer EVAR. It is estimated that in the US, approximately 75 % of patients receive EVAR ahead of OR, and also in many other countries,

Greenhalgh.indd 58

certainly in Europe, EVAR is well ahead in terms of procedures reported. Huge research and development has gone into devices, and excellent training is available to assure optimal results the world over. However, it is facts that we need and that we must have to safeguard our patients and do all in our power to maintain optimal long-term results from aortic aneurysm repair.

Factors to Determine the Ultimate Outcome of Endovascular Against Open Repair There are three factors, which can affect outcomes. Our inclination is towards meeting these problems head-on rather than assuming all is in order and that there is no problem in the long-term outcome of EVAR. It is likely that these factors will be the key to long-term success. The crucial results will come from long-term randomised controlled trials, which provide the highest level of evidence and will influence practice. Registries provide helpful collaborative data but there is always a problem in terms of whether the series is consecutive and if entry to it is properly defined at the outset. It is fairly useless to have large cohorts of registry data from sources never intended for EVAR follow-up or where such crucial information as pre-operative aortic diameter was never recorded. It is also unfounded to say that ‘real-life’ data are superior if by ‘real life’ is meant a registry of today recording results on smaller aneurysms and followed only for a few months. To compare such with randomised controlled trials is a misjudgement as the latter were consecutive, prospective and for a known indication and size of aneurysm. Thus, the answer has to come from trials long under way and the focus has to be on long-term outcomes of up to 15 years.

Reinterventions and Endoleaks During the follow-up of EVAR, computerised tomography (CT) has been the mainstay. In the EVAR trials, long-term follow-up is by annual CT scan. There is an understandable trend towards ultrasound after the 10-year EVAR trials results were published. This is driven mainly by cost considerations and patient convenience. Endoleaks have been detected during EVAR follow-up and these have required reintervention, especially when considered dangerous. A core-laboratory was set up using a validated three-dimensional workstation (Vitrea 2, Version 4.3.044.0, Vital Images Inc., Minnetonka, MN, US) to process all available decent-quality CT scans of the EVAR trials.9 An audit was performed and published on those EVAR devices, which were reported to have suffered secondary sac rupture. Of note, these ruptures were associated with a 67 % mortality.10 Three groups were described by the authors. In Group A there were five patients who suffered rupture before 30 days (see Figure 1). These ruptures would have been avoided if a CT scan had been performed before hospital discharge. Some who hear these results have alleged “any fool should know that”. It is regrettable that pioneers of these procedures who submitted their practice to a very early randomised controlled trial did not know this in 1999 when the trials began. Instead, when an EVAR procedure was nearing completion, a final flush angiogram would be performed and, if satisfactory, patients were discharged very soon and in some cases on the very same day. We are not referring to individual practice but this happened partly to show that it could be done. Whether it should be done was always another matter. But a CT scan would have detected in all probability a dangerous situation, which needed correction before discharge from hospital. This soon became accepted practice.

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Endovascular Abdominal Aortic Aneurysm Repair Figure 3: Group C – Secondary Sac Ruptures Occurring Beyond 30 Days. In All of These Cases Prior Complications Have Been Identified

1.6 years

Endoleak 1b

Sac growth

†

2.4 years

Endoleak 2

Sac growth

†

2.5 years

Endoleak 1a, migration

Sac growth

†

3 years

Migration

3 years

Endoleak of undefined origin

† EVAR modification, † Sac growth

3.3 years

†

3.4 years

Endoleak 2

Sac growth

EVAR modification, †

3.5 years

Endoleak 2

Sac growth

Open repair

3.6 years

Endoleak 1a

Sac growth

Open repair

3.7 years

Endoleak 1b

Sac growth

Open repair

4.5 years

Endoleak 1b and 2

Sac growth

†

4.7 years

Left limb kink, Endoleak 3

Sac growth

†

4.8 years

Endoleak 1b

Sac growth

4.9 years

Endoleak 2

Sac growth

4.9 years

Endoleak 1b

Sac growth

EVAR modification † EVAR modification

5.9 years

Sac growth

†

6.1 years

Sac growth

†

In Group B were five patients who suffered rupture after 30 days and without known endoleaks. Three of these were ‘out of the blue’ (see Figure 2). One was at 32 days and really like Group A. The fifth refused proper follow-up and suffered fatal rupture. Group C had 17 patients and these had sac rupture but with known underlying endoleaks (see Figure 3). A dangerous ‘cluster’ was described of types 1 and 3 endoleaks, migration, kinking and type 2 endoleak with sac expansion.10 Fifteen of the 17 had sac expansion and what has been referred to by Gilling-Smith as endotension, although that term is a concept rather than a measurement of pressure in the sac.11 It is visualised that an endoleak leads to expansion of the sac and rupture. Migration and kinking with poor endograft fit to the aorta is conceptually predisposed to dangerous endoleaks. These factors as a ‘cluster’ were fed into the statistical analysis of all EVAR patients in trials 1 and 2 and there was a statistically significant correlation (see Table 1)10. The ‘cluster’ denotes a dangerous finding in the late follow-up of EVAR.

Later Generation Endograft Devices Exciting new devices are appearing that are especially designed to improve late performance of EVAR. It is very encouraging that this is being addressed so widely. Huge resources are going into this. Key to advances is the attention paid to improved conformability to the aortic neck and to the iliac landing zones. The potential weaknesses

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Greenhalgh.indd 59

Corrective procedure and 30d mortality

Complication

EVAR procedure

Table 1: Cox Regression Analysis of Factors Associated with Graft Rupture After Endovascular Abdominal Aortic Repair Covariate

Adjusted Multivariate Hazard Ratio (95% CI)

p-value

Top neck diameter (cm)

2.07 (0.59–7.20)

0.253

Neck length (cm)

0.82 (0.28–2.38)

0.711

Maximum common iliac diameter (cm)

0.97 (0.30–3.17)

0.956

‘Cluster’ of complications: including

8.83 (3.76–20.76)

<0.0001

endoleak type 1, type 2 with sac growth, type 3 and migration or kinking CI = confidence interval. Hazard ratios represent change in hazard per unit increase in covariate. Neck length and maximum common diameter were log transformed because of skewness, thus hazard ratios represent change in hazard per 2.7 unit increase in covariate. The multivariate models factored in trial 1 or 2, baseline age, sex, abdominal aortic aneurysm diameter, log (length of primary endovascular aortic repair procedure), time of deployment, graft shape (straight and uni-iliac versus bi-iliac) and graft manufacturer (Cook/Zenith, Medtronic/Talent, Gore/Excluder, other).10

of the methodology are taken on board and newer devices orientate towards this. Kinking of endograft at the aortic neck may occur as a result of angulation of the neck and the same applies to the iliac landing zone. The more recently available devices conform to an aortic shape better and it is to be expected and hoped that this will translate into improved long-term results. In principle, the

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Endovascular newer devices should reduce endoleak in the late stages and so reduce secondary sac expansion and subsequent rupture, but this is speculative and unproved at this point. Migration of endograft has been addressed by certain manufacturers for years. Hooks and barbs are by no means applied by all manufacturers and neither is suprarenal fixation. All manufacturers are nevertheless completely mindful of the need to avoid endograft downward movement and with this the risk of type 1 endoleak. Easier deployment with more reliable placement and the ability to adjust position is another very helpful improvement. There is an inevitable move towards percutaneous deployment introduced to avoid groin wound problems. Various sealing methods improve these techniques but the drift towards lower profile of endografts needs to be monitored carefully to be sure that the thinner and flimsier materials are as durable. Otherwise late failure becomes an increased risk. All in all, the newer devices should improve EVAR late results and reduce secondary sac rupture but the most rigorous follow-up is required to track this.

Abuse of Instructions for Use Roy Greenberg’s group has drawn attention to this.12 It emerges that as endograft deployment has gathered ground and clinicians have become more confident, EVAR is preferred even outside the instructions for use. This is less a comment on deployment for aneurysm of less than 5.5 cm than a concern that EVAR is expected by some to cope with aortic anatomies, which lie beyond the reliable compass of EVAR. The UK Small Aneurysm Trial (UKSAT)13 and The Department of Veterans Affairs Aneurysm Detection and Management (ADAM)14 trials have made a global impact upon discouragement of unnecessary correction of abdominal aortic aneurysm of less than 5.5 cm yet still

1. Volodos NL, Shekhanin VE, Karpovich IP, et al., A self-fixing synthetic blood vessel endoprosthesis, Vestn Khir Im I I Grek , 1986;137(11):123–5. 2. Parodi JC, Palmaz JC, Barone HD, Transfemoral intraluminal graft implantation for abdominal aortic aneurysms, Ann Vasc Surg , 1991;5(6):491–9. 3. Brown LC, Epstein D, Manca A, et al., The UK Endovascular Aneurysm Repair (EVAR) trials: design, methodology and progress, Eur J Vasc Endovasc Surg, 2004;27(4):372–81. 4. Greenhalgh RM, Brown LC, Powell JT, et al., Endovascular versus open repair of abdominal aortic aneurysm, N Engl J Med , 2010;362(20):1863–71. 5. De Bruin JL, Baas AF, Buth J, et al., Long-term outcome of open or endovascular repair of abdominal aortic aneurysm, N Engl J Med, 2010;362(20):1881–9. 6. Becquemin JP, Pillet JC, Lescalie F, et al., A randomized

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a vast number of these procedures is performed.12 There remains no evidence to support such practice. Of increasing concern is that a somewhat ‘cavalier attitude’ to EVAR deployment is creeping in, which is driven by a type of machismo approach to demonstrate ability to fix any aorta with EVAR. Certainly the patients prefer it but would they prefer the method if it is explained to them that the proposed procedure is beyond the manufacturer’s instructions for use and that late failure could be an increased risk? Of course, the experienced operators should and must push the boundaries but each individual operator needs to be mindful of the risks of late EVAR failure.

Summary Three factors will determine the long-term success of EVAR or the resurrection of the open surgical method for younger and physically fit patients. First, there is the urgent need to correct the ‘cluster’ of dangerous endoleaks and this implies ongoing careful surveillance. If CT has given way to ultrasound, it is because that method is very reliable especially in measuring front to back maximal infrarenal aortic diameter. However, if either endoleak is suspected or an increase of 5 mm sac diameter occurs in a year, CT is required to reveal any potential underlying endoleak, migration or true sac diameter increase and the reason for it. A renewed effort to search for this ‘cluster’ is mandatory. This ought to affect late EVAR results by reducing late sac ruptures. Second, the availability of the excellent latest devices should help to reduce late complications. However, thirdly, an inclination to use EVAR beyond instructions for use by the less expert performers could put the long-term results of EVAR into question. Full training in EVAR deployment continues to be of the utmost importance, however, open surgical expertise and catheter skills are equally required. It has to be recognised that in some situations, an open repair is not a failure in clinical practice but the best way forward for a particular patient with unfavourable anatomy. n

controlled trial of endovascular aneurysm repair versus open surgery for abdominal aortic aneurysms in low- to moderaterisk patients, J Vasc Surg, 2011;53(5):1167–73. 7. Lederle FA, Freischlag JA, Kyriakides TC, et al., Outcomes following endovascular vs open repair of abdominal aortic aneurysm: a randomized trial, JAMA , 2009;302(14):1535–42. 8. Greenhalgh RM, Brown LC, Powell JT, Endovascular repair of aortic aneurysm in patients physically ineligible for open repair, N Engl J Med, 2010;362(20):1872–80. 9. Wyss TR, Dick F, England A, et al., Three-dimensional imaging core laboratory of the endovascular aneurysm repair trials: validation of methodology, Eur J Vasc Endovasc Surg, 2009;38(6):724–31. 10. Wyss TR, Brown LC, Powell JT, Greenhalgh RM, Rate and predictability of graft rupture after endovascular and open abdominal aortic aneurysm repair: data from the EVAR Trials,

Ann Surg , 2010;252(5):805–12. 11. Gilling-Smith G, Brennan J, Harris P, et al., Endotension after endovascular aneurysm repair: definition, classification, and strategies for surveillance and intervention, J Endovasc Surg, 1999;6(4):305–7. 12. Schanzer A, Greenberg RK, Hevelone N, et al., Predictors of Abdominal Aortic Aneurysm Sac Enlargement After Endovascular Repair, Circulation , 2011;123(24):2848–55. 13. Powell JT, Brown LC, Forbes JF, et al., Final 12-year followup of surgery versus surveillance in the UK Small Aneurysm Trial, Br J Surg, 2007;94(6):702–8. 14. Lederle FA, Johnson GR, Wilson SE, et al., The aneurysm detection and management study screening program: validation cohort and final results. Aneurysm Detection and Management Veterans Affairs Cooperative Study Investigators, Arch Intern Med, 2000;160(10):1425–30.

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