ICR 9.1

Volume 9 • Issue 1

www.icrjournal.com

Overview of Technical and Cost Considerations in Complex Percutaneous Coronary Intervention J. Raider Estrada, Jonathan D. Paul, Atman P. Shah and Sandeep Nathan

Surgical Approaches to Aortic Valve Replacement and Repair – Insights and Challenges Basel Ramlawi, Mahesh Ramchandani and Michael J Reardon

Transcatheter Aortic Valve Replacement in Moderate-risk Aortic Stenosis Patients Lars G Svensson

The Role of Self-expanding Stents in Patients with Atypical Coronary Anatomy Robert-Jan van Geuns, Katherin Awad, Alexander IJsselmuiden and Karel Koch

Radcliffe Cardiology

Resolute Integrity™ ZOTAROLIMUS-ELUTING CORONARY STENT SYSTEM

Timing of DAPT Interruption and ST Through 1 Year Interruption duration >1 day Subsequent ST ARC Def/Prob (%)

p = 0.013 p = 0.004

p ≤ 0.001

3.61 0.84

0.11

Never Interrupted1

Interrupted 0–1 mo

Interrupted 1–12 mo

Patients

3827

166

903

Events

32

6

1

Median days to interruption

NA

3

249

Medtronic regards physicians as the ultimate DAPT decision-makers and supports current guidelines on this complex subject4

In the RESOLUTE Pooled DAPT analysis2: Over 20% of patients interrupted DAPT at some point during the first year after implant There was no increased risk for stent thrombosis with interruption of DAPT after one month with Resolute™ DES This significant statement of finding has led to unique CE Mark labeling3

Trademarks may be registered and are the property of their respective owners. For distribution only in markets where the Resolute Integrity™ coronary stent has been approved. Not for distribution in the USA, Japan or France. © 2014 Medtronic, Inc. All rights reserved. Printed in EU. UC201306452ML-04 1/14

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Including patients with no DAPT interruption except for ST while on DAPT through 12 months.

Post-hoc RESOLUTE DAPT analysis included RESOLUTE All Comers, RESOLUTE International, RESOLUTE US and RESOLUTE Japan. RESOLUTE FIM was not utilized due to a lack of DAPT information required in the study protocol. This analysis was not powered for stent thrombosis.

3 DAPT language in updated CE Mark IFU: “One year data from the RESOLUTE Clinical Program indicates low stent thrombosis rates for those that interrupted or discontinued DAPT any time after one month. While physicians should adhere to current ESC or ACC/AHA/SCAI Guidelines for PCI, patients who interrupt or discontinue DAPT medication one month or more after stent implantation are considered at low risk and showed no increased risk for stent thrombosis.”

4 Minimum 6 months of DAPT by ESC guidelines and minimum 12 months of DAPT by ACC/AHA/SCAI guidelines.

1 2

Simplify the challenge at medtronicstents.com

01/03/2014 01:13

Volume 9 • Issue 1 • Spring 2014

www.icrjournal.com

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

Editorial Board Fernando Alfonso

Giuseppe De Luca

Axel Linke

Instituto Cardiovascular, Hospital

Division of Cardiology “Federico II” University, Naples

Heart Center, Leipzig

Universitario Clínico “San Carlos”, Ciudad Universitaria, Madrid

Eric Eeckhout

David Antoniucci

Centre Hospitalier Universitaire Vaudois

Division of Cardiology,

Raimund Erbel

Careggi Hospital

West-German Heart Centre, University Duisburg-Essen

Olivier F Bertrand

Roxana Mehran Columbia University Medical Center

Gary S Mintz Cardiovascular Research Foundation

Jeffrey W Moses

Ted Feldman

Columbia University Medical Center

Cardiac Catheterization Laboratory Evanston Hospital

Marko Noc

University Hospital, Bern

Juan F Granada

Antonio Colombo

Columbia University Medical Center

Center for Intensive Internal Medicine, University Medical Center, Ljubljana

San Raffaele Hospital, Milan

A Pieter Kappetein

Alberto Cremonesi

Thoraxcenter, Erasmus University Medical Center, Rotterdam

Laval University, Quebec City

Lutz Buellesfeld

Department of Vascular and Endovascular

Demosthenes Katritsis

Jeffrey J Popma Harvard Medical School

Marc van Sambeek

Euroclinic, Athens

Department of Anesthesiology, Erasmus University Medical Center, Rotterdam

Department of Cardiology, University Hospital

Ajay J Kirtane

Gregg W Stone

Charles Nicolle, Rouen

Columbia University Medical Center

Columbia University Medical Center

Bernard De Bruyne

Martin B Leon

Renu Virmani

Cardiovascular Center, Aalst

Columbia University Medical Center

CVPath Institute, Inc.

Surgery, University of Siena

Alain Cribier

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

Circulation Contact David Ramsey david.ramsey@radcliffecardiology.com Commercial Contact Liam O’Neill liam.oneill@radcliffecardiology.com •

Cover image

3d render Heart atrium - back view © Maya2008 | shutterstock.com

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology.

Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice.

Radcliffe Cardiology, 7/8 Woodlands Farm, Cookham Dean, Berks, SL6 9PN. © 2014 All rights reserved

© RADCLIFFE CARDIOLOGY 2014

1

Established: June 2006 Frequency: Tri-annual

Current issue: Spring 2014

Aims and Scope • Interventional Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in interventional cardiology practice.

• Interventional Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field.

• Interventional Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • Interventional Cardiology Review is a tri-annual journal comprising review articles, editorials, and case reports.

• The structure and degree of coverage assigned to each category of the journal is determined by the Editor-in-Chief, with the support of the Editorial Board.

• Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion.

• Each edition of Interventional Cardiology Review is replicated in full online at www.icrjournal.com

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

• Invited contributors who are recognised authorities from their respective fields.

• Peer review – conducted by experts appointed for their experience and knowledge of a specific topic.

• An experienced team of Editors and Technical Editors.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion.

• The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind.

• Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

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

Submissions and Instructions to Authors • • • •

Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board.

Following acceptance of an invitation, the author(s) and Managing Editor formalise the working title and scope of the article.

Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details.

The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.icrjournal.com

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

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in Interventional Cardiology Review unless otherwise stated.

Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

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

Radcliffe Cardiology

Lifelong Learning for Cardiovascular Professionals

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Radcliffe Cardiology

© RADCLIFFE CARDIOLOGY 2014

01/03/2014 00:39

Spotlight: Innovation and the Heart

Discover the Scientific Programme www.escardio.org/ESC2014programme

• Clinical case submission • Hot Lines, Clinical Trial Updates

Mid Jan - 1 March

• Early Registration deadline • Late Registration deadline

31 May

& Registries submission

Mid March - 1 May

31 July

5 days of scientific Sessions 150 CV Topics 30 000 healthcare professionals from 140 countries 10 000 abstracts submitted 500 expert sessions 200 exhibiting companies & all year long on ESC Congress 365

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01/03/2014 01:08

Content

Foreword 06 Simon Kennon

Coronary

07 European Society of Cardiology ST-segment Elevation Myocardial

Infarction Guidelines in Perspective – Focused on Primary Percutaneous Coronary Intervention

Petr Kala

11 The Role of Self-expanding Stents in Patients with Atypical Coronary Anatomy

Robert-Jan van Geuns, Katherin Awad, Alexander IJsselmuiden and Karel Koch

Complex Bifurcation

17 Overview of Technical and Cost Considerations in Complex Percutaneous Coronary Intervention

J Raider Estrada, Jonathan D Paul, Atman P Shah and Sandeep Nathan

Bioresorbable Stents

23

The Bioresorbable Stent in Perspective—How Much of an Advance is It?

Structural

Viktor Kočka and Petr Widimský

26 Trans-catheter Aortic Valve Implantation Guidelines – Does the Latest Evidence Change our Views?

Hannah ZR McConkey and Bernard Prendergast

32

Surgical Approaches to Aortic Valve Replacement and Repair—Insights and Challenges

Basel Ramlawi, Mahesh Ramchandani and Michael J Reardon

37 Adoption of Transcatheter Aortic Valve Implantation in Western Europe

Darren Mylotte, Ruben LJ Osnabrugge, Giuseppe Martucci, Ruediger Lange,

Arie Pieter Kappetein and Nicolo Piazza

41 Transcatheter Aortic Valve Replacement in Moderate-risk Aortic Stenosis Patients L ars

G Svensson

44 Percutaneous Paravalvular Leak Closure A mar

Krishnaswamy, E Murat Tuzcu and Samir R Kapadia

49 Transcatheter Mitral Valve Devices – Functional Mechanical Designs C had

Kliger

Resistant Hypertension

54

Renal Sympathetic Denervation – A Review of Applications in Current Practice

4

ICR_contents_9.1NEW.indd 4

V ikas Kapil, Ajay K Jain and Melvin D Lobo INTERVENTIONAL CARDIOLOGY REVIEW

01/03/2014 00:30

Our Claim to FAME

The Results Are in

FAME 2 Trial

Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease

86% relative risk reduction for urgent revascularization in the FFR-guided PCI arm.

1

Only PressureWire™ from St. Jude Medical was used in FAME and FAME 2 trials.2

FAME2study.com

1. De Bruyne B, Pijls N, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease.

N Engl J Med. 2012;367(11):991-1001.

2. St. Jude Medical. Data on File.

Product referenced is approved for CE Mark.

Rx Only Please review the Instructions for Use prior to using these devices for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use. PressureWire is designed, developed and manufactured by St. Jude Medical Systems AB. PressureWire, ST. JUDE MEDICAL, the nine-squares symbol and MORE CONTROL. LESS RISK. are registered and unregistered trademarks and service marks of St. Jude Medical, Inc. and its related companies. Š2012 St. Jude Medical, Inc. All rights reserved.

IPN 2641-12

Untitled-2 5

01/03/2014 01:08

Foreword

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

I

am delighted to take on the editorship of Interventional Cardiology Review. I hope that it will be viewed as a publication that is of real value to the coronary and structural interventional cardiology community.

Interventional Cardiology Review will continue to publish articles that contain concise summaries of research data, providing clinical and practical information, written by experienced interventional cardiologists. In addition, there will be a shift in the emphasis of the journal. Firstly, despite an expanding array of different technologies for every intervention, direct comparisons between them are few and far between. I will be asking authors to provide objective data and opinions on the important differences between technologies. Secondly, health economics is increasingly important in deciding which interventions should be undertaken and I will be asking authors to provide relevant health economic data where possible.

In this issue, there are articles on TAVI in moderate risk patients, the treatment of paravalvular leaks and a review of transcatheter mitral valve devices as well as discussions relating to TAVI guidelines and geographical differences in TAVI uptake. The coronary section comprises reviews of absorbable and self-expanding stents as well as a discussion of ESC STEMI guidelines.

I hope you will find this issue an informative and enjoyable read. n

6

Foreword_ICR 9.1.indd 6

© RADCLIFFE CARDIOLOGY 2014

02/03/2014 18:40

Coronary

European Society of Cardiology ST-segment Elevation Myocardial Infarction Guidelines in Perspective – Focused on Primary Percutaneous Coronary Intervention Petr Kala Internal and Cardiology Department, Masaryk University and University Hospital Brno, Brno, Czech Republic

Abstract Patients suffering acute myocardial infarction with ST-segment elevation myocardial infarction (STEMI) require full attention of the whole STEMI network to save their lives and to improve the quality of life after a heart attack. Implementation of the most recent European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) STEMI Guidelines into the practice is the holy grail of the healthcare systems and all stakeholders. In relation to this, the Stent for Life Initiative can serve as one of very successful and effective models in Europe and beyond. Although the evidence-based approach may be applied to majority of patients, the tailored and updated therapy needs to be modified in concordance with the patients´ risk profile, experience and availability of medical resources. Some ‘hot topics’, issues, differences between the ESC and ACC/AHA Guidelines, latest information and perspectives are discussed in this short review; focused on primary percutaneous coronary intervention (PCI) as the most effective reperfusion therapy.

Keywords Acute myocardial infarction, ST-segment elevation myocardial infarction, primary percutaneous coronary intervention, clinical guidelines, thromboaspiration, radial access, ongoing ischaemia Disclosure: The author received fees for educational lectures from Boston-Scientific, and is a scientific advisory board member at Elli-Lilly and Saint-Jude Medical.

Received: 16 December 2013 Accepted: 07 February 2014 Citation: Interventional Cardiology Review, 2013;9(1):7–10 Correspondence: Petr Kala, Internal and Cardiology Department, Masaryk University and University Hospital Brno, Jihlavska 20, 625 00 Brno, Czech Republic.

E: kalapetr7@gmail.com

Patients suffering acute myocardial infarction with ST-segment elevation (STEMI) require full attention of the whole STEMI network to save their lives and to improve the quality of life after a heart attack.

Close cooperation among all stakeholders on a national and regional level has to be established. The emergency medical service (EMS) and direct transportation to the 24 hours a day, seven days a week (24/7) catheterisation laboratory play a crucial role together with the patient-oriented public education campaigns. The most recent Clinical Practice Guidelines of the European Society of Cardiology on patients with acute myocardial infarction with ST-segment elevation (ESC STEMI Guidelines) were published in 2012 and covered the complexity of organisational and medical aspects from the emergent diagnosis and treatment until outpatient care.1 The reason for establishing the Stent for Life Initiative and its ACT NOW. SAVE A LIFE public campaign as a joint initiative of the European Association of percutaneous coronary intervention (EAPCI) and European Percutaneous Cardiovascular Revascularization Course (EuroPCR) was the lack of implementation of the Guidelines into the practice across Europe. The incredible achievements in 16 participating countries and organisations can be followed online at www.stentforlife.com and are well documented in the recent publication of Kristensen et al.2 Atypical electrocardiogram (ECG) presentations that deserve prompt management in patients with signs and symptoms of ongoing myocardial ischaemia include:

© RADCLIFFE CARDIOLOGY 2014

Kala_version2_edited.indd 7

• l eft bundle branch block (LBBB); • ventricular paced rhythm; • patients without diagnostic ST-segment elevation but with persistent ischaemic symptoms; • isolated posterior myocardial infarction; and • ST-segment elevation in augmented vector right lead (aVR).1 The patients with ongoing ischaemic symptoms, even in the absence of ST-segment elevations, should be managed in the same way as the STEMI patients. This recommendation, based more on experience than evidence, may shorten the delay to diagnosis and optimal treatment, and at the same time may decrease the risk of bleeding after the potent antithrombotic medication. A bit provocative is the suggestion of new and simplified classification of acute coronary syndrome with/ without ongoing myocardial ischaemia (ACS w/wo OMI) instead of the currently used STEMI and non-STEMI. Such an approach may better reflect current treatment practice in some catheterisation laboratories (cath labs) and regions with the aim of facilitating the decisions made at the time of the first medical contact (FMC). The target of such simplification is the earliest selection of patients at high clinical risk that should be transported directly to the cath lab or 24/7 primary percutaneous coronary intervention (PCI) centre bypassing any other facility. Widimsky et al.3 defined the ACS w OMI as ongoing (or recurrent) clinical signs of acute myocardial ischaemia (i.e. persistent chest pain and/or dyspnoea at rest) plus at least one of the following:

7

02/03/2014 18:42

Coronary Figure 1: Timelines in the European Society of Cardiology and American College of Cardiology/American Heart Association ST-segment Elevation Myocardial Infarction Guidelines

STEMI

Primary PCI centre

Emergency Medical Service Non-primary PCI centre

ESC <60 min ACC/AHA ≤90min

PCI within 120 min?

Coronary Angiography

Yes

No

Transport to the primary PCI centre Coronary angiography between 3-24 hrs

Revascularization PCI / CABG

Medication

ESC, ACC/AHA ≤ 30min

Fibrinolysis

ACC = American College of Cardiology; AHA = American Heart Association; CABG = coronary artery bypass grafting; ESC = European Society of Cardiology; PCI = percutaneous coronary intervention; STEMI = ST-segment myocardial infarction.

1. ST-segment elevations in ≥2 consecutive ECG leads (≥2 mm for leads V2–V3, ≥0.5 mm for leads V7–V9 and ≥1 mm for other leads); 2. new onset bundle branch block (right or left); 3. persistent ST-segment depressions in ≥2 consecutive ECG leads (≥2 mm for chest leads and ≥1 mm for extremity leads); 4. cardiogenic shock or ‘pre-shock’ type of haemodynamic instability (low-to-normal blood pressure as well as tachycardia and cool extremities) due to suspected ischaemia; 5. malignant arrhythmias including resuscitated cardiac arrest with return of spontaneous circulation; 6. clinical signs of acute heart failure (Killip II–IV); and 7. new onset of a wall motion abnormality on cardiac imaging.

It is important to keep in mind that isolated findings as listed above (e.g. malignant arrhythmias without any clinical or ECG sign of acute ischaemia) do not fulfil this definition. The high clinical suspicion for acute myocardial infarction is important. Direct transport to the cath lab (bypassing any other location, e.g. intensive care unit or emergency room) is always required in groups 1–4. Patients from groups 5–7 should also be transported to a non-stop (24/7) primary PCI facility (either directly to the cath lab or they may be primarily admitted to the intensive cardiac care unit with the cath lab immediately available).

Healthcare systems with multiple organisational issues may especially benefit from such practical recommendations.

Time Intervals From Onset of Symptom Until Effective Treatment The principle aim of the medical systems in patients with STEMI is to prevent their death and to improve the quality of life after a heart attack. Besides the effective treatment of ventricular tachycardia and fibrillation in the pre-hospital phase, shortening of the total ischaemic time as much as possible is crucial. ‘Patient delay’ and ‘system delay’, where the patient delay means the delay between

8

Kala_version2_edited.indd 8

symptom onset and FMC followed by the system delay until reperfusion therapy.

There is one important question with potential clinical consequences: who represents the FMC? Based on the ESC Guidelines, FMC is defined as the point at which the patient is either initially assessed by a paramedic or physician or other medical personnel in the pre-hospital setting, or the patient arrives at the hospital emergency department and therefore often in the outpatient setting.1 According to the time intervals mentioned in the ESC Guidelines, the preferred/ accepted system delay from FMC to the most effective reperfusion strategy (primary PCI, i.e. wire passage) should not exceed 90/120 minutes (min) in most patients and ≤60/90 min in high-risk patients with large anterior STEMI and early presenters within two hours. In case of fibrinolysis, the recommended system delay (FMC to needle) is ≤30 min. The diagnosis of STEMI should be verified within 10 min of FMC, which in fact means that the FMC personnel has to have the 12-lead ECG available. In future, the time of the medical system activation (i.e. the time of the first phone call) should be involved in the time intervals monitoring. The definition of the FMC might be modified to the first phone or personal contact of the patient with any representative of the medical system.

Current recommendation for reperfusion and the difference between the ESC and ACC/AHA4 STEMI Guidelines is described in Figure 1.

Primary Percutaneous Coronary Intervention – Procedural Aspects and Issues Radial Over Femoral Access In Experienced Operators (Class IIa, Level of Evidence B) The role of radial access has been investigated for 20 years5 but in STEMI patients this topic has been especially highlighted. The Radial Versus Femoral Access for Coronary Intervention (RIVAL) STEMI subanalysis6,7 (1,958 patients) and Radial Versus Femoral Investigation in ST Elevation Acute Coronary Syndrome (RIFLE-STEACS)8 trial (1,001 patients) demonstrated a significant mortality benefit in a large cohort of STEMI patients treated with primary PCI via transradial approach (TRA) (44 % reduction in all-cause death in RIVAL STEMI and 60 % in cardiac death in RIFLE-STEACS). These findings were supported by two large meta-analyses published recently

by De Luca et al.9 and Karrowni et al.10 In the contrary, no survival benefit was found in the ST Elevation Myocardial Infarction Treated by RADIAL or Femoral Approach in a Multicenter Randomized Clinical Trial (STEMIRADIAL) in 707 patients.11 Although the direct association between the radial access and mortality may still be doubtful, the significantly lower risk of vascular and bleeding complications should promote the TRA as the preferred access site for most operators.12 Proper training and enough experience are necessary to achieve the optimal results that should receive the strongest level of evidence A in the upcoming guidelines.

Routine Manual Thrombus Aspiration (Class IIa, Level of Evidence B) Recently, the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction study (TAPAS) was the only randomised trial showing the clinical benefit of routine thrombus aspiration versus conventional primary PCI. The mortality at oneyear, as the secondary and not pre-specified clinical endpoint, was found less frequently in the manual thrombus aspiration group (3.6 versus 6.7 %, p=0.018).13,14 The concerns about the single-centre experience and the technique of conventional PCI (balloon predilation

INTERVENTIONAL CARDIOLOGY REVIEW

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ESC STEMI Guidelines in Perspective – Focused on Primary Percutaneous Coronary Intervention

before stenting) seem to be even more relevant after the first largescale international multicentre randomised Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial published

by Fröbert et al.15 This trial reflects the real-world practice using a unique enrolment of patients from the national comprehensive Swedish Coronary Angiography and Angioplasty Registry (SCAAR registry) and endpoints evaluation through national registries without losing a single patient to follow-up. The clot aspiration in comparison with the balloon treatment in 7,244 STEMI patients did not show any statistical difference in mortality as the primary endpoint at 30 days (3.0 versus 2.8 %; p=0.63). This finding was consistent across all pre-specified subgroups and no difference was observed in the rate of secondary endpoints obtained from the Swedish Websystem for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry and the national discharge registry (30-day rates of hospitalisation for recurrent myocardial infarction, stent thrombosis, target vessel revascularisation, target lesion revascularisation, and the composite of all-cause mortality or recurrent myocardial infarction). Currently, the routine manual thrombus aspiration seems to be not supported by the evidence and should be used only selectively. The data from the ongoing Trial of Routine Aspiration Thrombectomy With Percutaneous Coronary Intervention (PCI) Versus PCI Alone in Patients With ST-Segment Elevation Myocardial Infarction (STEMI) Undergoing Primary PCI (TOTAL) with more than 10,000 patients (ClinicalTrials.gov: NCT01149044) will probably have a definite impact on the indication of routine thrombus aspiration during STEMI.16

Periprocedural Pharmacotherapy Based on the STEMI Guidelines, the dual antiplatelet therapy (Aspirin and an adenosine diphosphate [ADP] receptor blocker) is recommended together with parenteral anticoagulant as early as possible before angiography1 (i.e. immediately after the diagnosis of STEMI is confirmed).

The novel agents, prasugrel or ticagrelor, should be preferred over clopidogrel17,18,19 in combination with bivalirudin,20 enoxaparin21 or unfractionated heparin.22 The use of glycoprotein IIb/IIIa inhibitors is indicated only as bailout in high-risk clinical situations, like the presence of large thrombus burden and no-flow phenomenon after PCI. The potential advantage of intracoronary administration of abciximab has been studied but the results have to be confirmed.23 Combination of the administration of potent drugs requires an individualised approach with respect to a patient´s risk profile (prothrombotic versus bleeding), complexity of coronary pathology, selected interventional strategy and a good clinical judgement.24 Recommendation of the ESC and ACC/AHA are shown in Tables 1 and 2.

Revascularisation Strategy for ST-segment Elevation Myocardial Infarction with Multivessel Disease Culprit-only PCI has been recommended in STEMI patients except for patients in cardiogenic shock and continuous ischaemia despite

1.

Steg PG, James SK, Atar D, et al., ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation, Eur Heart J, 2012;33:2569–619.

2. Kristensen SD, Laut KG, Fajadet J, et al., Reperfusion therapy for ST elevation acute myocardial infarction 2010/2011: current status in 37 ESC countries, Eur Heart J, 2014 [Epub ahead of print].

3. Widimsky P, Rokyta R, Stasek J, et al., Acute coronary syndromes with ongoing myocardial ischemia (ACS with OMI) versus acute coronary syndromes without ongoing ischemia (ACS without OMI), Cor et Vasa, 2013;55(3):e225–7.

4. O´Gara PT, Kushner FG, Ascheim DD, et al., 2013 ACCF/ AHA guideline for the management of ST-elevation

INTERVENTIONAL CARDIOLOGY REVIEW

Kala_version2_edited.indd 9

5.

6.

7.

Table 1: European Society of Cardiology Guidelines on Oral P2Y12 Antiplatelet Therapy in ST-segment Elevation Myocardial Infarction Clopidogrel IC* Clopidogrel, 300 mg loading

NA

Clopidogrel, 600 mg loading

IC/B

Prasugrel

IB

Ticagrelor

IB

*When prasugrel or ticagrelor are either not available or contraindicated. NA = not available.

Table 2: American College of Cardiology/American Heart Association Guidelines on Oral P2Y12 Antiplatelet Therapy in ST-segment Elevation Myocardial Infarction/Percutaneous Coronary Intervention Clopidogrel (600 mg loading)

IC for primary PCI

Prasugrel (60 mg loading)

IB for primary PCI

Ticagrelor (180 mg loading)

IB for primary PCI

Clopidogrel (with thrombolytics)

IC for non-primary PCI

Clopidogrel (without thrombolytics)

IB for non-primary PCI

Prasugrel (without thrombolytics)

IB for non-primary PCI

PCI = percutaneous coronary intervention.

successful infarct-related artery treatment.1 Recently, Wald et al. enrolled 465 patients with STEMI, multivessel disease and primary PCI of the infarct-related artery in the Randomized Trial of Preventive Angioplasty in Myocardial Infarction (PRAMI).25 The patients were randomly assigned to either preventive or no preventive PCI of the non-culprit vessels with at least 50 % stenoses. The study was stopped preliminary because of a highly significant decrease of the composite of death from cardiac causes, non-fatal myocardial infarction, or refractory angina in the preventive PCI group of patients (hazard ratio [HR] 0.35; p<0.001). Hazard ratios for the three components of the primary outcome were 0.34; 0.32 and 0.35, respectively. We are dealing with an exciting finding that needs further investigation.

One of the unanswered questions in STEMI patients is the additional value of the functional revascularisation concept based on the fractional flow reserve measurement (ongoing Comparison Between Fractional Flow Reserve Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With multivessel disease [COMPARE-ACUTE] trial, ClinicalTrials.gov: NCT01399736).

Conclusion Although the evidence-based approach described in the Guidelines may be applied to the majority of STEMI patients, the tailored and updated therapy needs to be modified in concordance with the patients´ risk profile, our experience and availability of medical resources. The establishment of the STEMI network and cooperation among all stakeholders can serve as the background for further improvements and new trials focused on clinical outcomes. n

myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2013;61:e78–140.

Kiemeneij F, Laarman GJ, Percutaneous transradial artery approach for coronary stent implantation, Cathet Cardiovasc Diagn, 1993;30:173–8.

Jolly SS, Yusuf S, Cairns J, et al., Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial, Lancet , 2011;377(9775):1409–20.

Mehta SR, Jolly SS, Cairns J, et al., Effects of radial versus femoral artery access in patients with acute coronary

syndromes with or without ST-segment elevation, J Am Coll Cardiol, 2012;60:2490–9.

8. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al., Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study, J Am Coll Cardiol, 2012;60:2481–9.

9. De Luca G, Schaffer A, Wirianta J, Suryapranata H, Comprehensive meta-analysis of radial vs femoral approach in primary angioplasty for STEMI, Int J Cardiol, 2013;168(3):2070–81.

10. Karrowni W, Vyas A, Giacomino B, et al., Radial versus Femoral Access for Primary percutaneous Interventions in

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11.

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ST-segment elevation myocardial infarction patients: a metaanalysis of randomized controlled trials, JACC Cardiovasc Interv, 2013;6:814–23.

Bernat I, Horak D, Stasek J, et al., ST Elevation Myocardial Infarction Treated by RADIAL or Femoral Approach in a Multicenter Randomized Clinical Trial : The STEMI-RADIAL Trial, J Am Coll Cardiol, 2013;S0735–1097(13)06023-3 [Epub ahead of print].

Joyal D, Bertrand OF, Rinfret S, et al., Meta-analysis of ten trials on the effectiveness of the radial versus the femoral approach in primary percutaneous coronary intervention, Am J Cardiol, 2012;109:813–8.

Svilaas T, Vlaar PJ, van der Horst IC, et al., Thrombus aspiration during primary percutaneous coronary intervention, N Engl J Med, 2008;358:557–67.

Vlaar PJ, Svilaas T, van der Horst IC, et al., Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study, Lancet, 2008;371:1915–20.

Fröbert O, Lagerqvist B, Olivecrona GK, et al., Thrombus

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16.

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Aspiration during ST-segment elevation myocardial infarction, N Engl J Med, 2013;369:1587–97.

Jolly SS, Cairns J, Yusuf S, et al., Design and rationale of the TOTAL trial: A randomized trial of routine aspiration ThrOmbecTomy with percutaneous coronary intervention (PCI) versus PCI ALone in patients with ST-elevation myocardial infarction undergoing primary PCI, Am Heart J, 2014;0:1–7.e1.

Montalescot G, Benefits for specific subpopulations in TRITON-TIMI 38, Eur Heart J Suppl, 2009;11:G18–24.

Steg PG, James S, Harrington RA, et al., Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis, Circulation, 2010;122:2131–41.

Alexopoulos D, Galati A, Xanthopoulou I, et al., Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study, J Am Coll Cardiol, 2012;60:193–9.

20. S tone GW, Witzenbichler B, Guagliumi G, et al., Bivalirudin during primary PCI in acute myocardial infarction, N Engl J Med, 2008;358:2218–30.

21. Antman EM, Morrow DA, McCabe CH, et al., Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction, N Engl J Med, 2006;354:1477–88.

22. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators, N Engl J Med, 1993;329:673–82.

23. Stone GW, Maehara A, Witzenbichler B, et al., Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial, JAMA, 2012;307:1817–26.

24. Kala P, Miklik R, Pharmaco-mechanic antithrombotic strategies to reperfusion of the infarct-related artery in patients with ST-elevation acute myocardial infarctions, J Cardiovasc Transl Res , 2013;6(3):378–87.

25. Wald DS, Morris JK, Wald NJ, et al., Randomized Trial of reventive Angioplasty in Myocardial Infarction, N Engl J Med, 2013;369(12):1115–23.

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The Role of Self-expanding Stents in Patients with Atypical Coronary Anatomy R obert- Ja n v a n Geuns, 1 Ka t h e r i n Aw a d , 2 A l e x a n d e r I J s s e l m u i d e n , 3 a n d K a r e l Ko c h 4 1. Erasmus Medical Centre, Rotterdam, The Netherlands; 2. Medical Affairs, STENTYS SA, Paris, France; 3. Albert Schweitzer Ziekenhuis, Dordrecht, The Netherlands; 4. Academisch Medisch Centrum, Amsterdam, The Netherlands

Abstract Despite advances with new generation stents, there remains some atypical coronary anatomy where optimal stenting continues to be a challenge; such as stent sizing in large, ectatic or aneurysmal vessels; tapered vessels; and in vasoconstricted arteries such as in ST-segment elevation myocardial infarction or chronic total occlusions. Balloon-expandable stents are tubular and cannot easily accommodate vessel diameter variations; thrombotic vessels increase the risk of distal embolisation and no-reflow; positive remodelling and vasodilation often result in subsequent malapposition; and patients with bifurcation lesions have a higher risk of adverse events. The STENTYS BMS and DES(P) stents have a self-expanding design, which enables a better anatomical fit to the vessel, even with diameter variations (up to 6.0 millimetres [mm]), and can adapt to changes in vessel size over time. The stents deploy atraumatically from distal to proximal, which could reduce distal embolisation and contain disconnectable bridges, which can be opened up at a side branch.

Self-apposing technology could therefore provide a potential solution to current challenges with balloon-expandable stent technology.

Keywords Self-expanding, self-apposing, malapposition, left main, chronic total occlusion, saphenous vein graft, aneurysm, tapered vessel, atypical anatomy, STENTYS Disclosure: Robert-Jan van Geuns, Alexander IJsselmuiden and Karel Koch have received consultancy and speaker fees from STENTYS. Katherin Awad is an employee of STENTYS. Received: 7 December 2013 Accepted: 27 January 2014 Citation: Interventional Cardiology Review, 2014;9(1):11â&#x20AC;&#x201C;6 Correspondence: Robert-Jan van Geuns, Interventional Cardiologist, Erasmus Medical Centre, Thoraxcentrum, Department Cardiology, Postbus 2040, 3000 CA Rotterdam, The Netherlands. E: r.vangeuns@erasmusmc.nl

Significant advances have been made with new generation stents to further improve the results of percutaneous coronary intervention (PCI) and outcomes for patients. Drug-eluting stents introduced in the early 2000s, thinner strut stent platforms, and bioabsorbable polymers and stents are among these developments. 1 Despite these advances, there remain some areas where optimal stenting continues to be a challenge, in some cases affecting patient outcome. Stent sizing is often a challenge in large, ectatic or aneurysmal vessels; tapered vessels; and in vasoconstricted arteries such as in ST-segment elevation myocardial infarction (STEMI) or chronic total occlusions (CTOs). The rate of major adverse cardiac events (MACE) and particularly stent thrombosis after primary PCI in patients with STEMI continues to be higher than in PCI for stable patients. 2 Restenosis and MACE rates after PCI of saphenous vein grafts (SVGs) or bifurcations are also higher than in simple stenting of a native artery. 3,4,5 The incidence of no-reflow and reduced microvascular perfusion in vessels with a large thrombus burden is also greater, one cause of which is distal embolisation. 6 Atypical coronary arteries and presentations such as these continue to pose a challenge today in PCI with current balloon-expandable stents. This article examines whether self-expandable stents could address some of these issues and provide an alternative solution in the treatment of atypical coronary anatomy.

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Challenges with Current Balloon-expandable Stents Vessel lumen sizes are often variable, whereas balloon-expandable stents are tubular by nature. Thus, conventional stents are not able to adapt effectively to atypical coronary anatomy; such as in ectatic or aneurysmal vessels, or in tapered vessels.5,7,8 Currently, the proximal optimisation technique (POT) is used in tapered vessels to try to overcome this restriction. It involves sizing the stent to the distal vessel and then overinflating the proximal segment of the stent with an oversized balloon in a two-step process. This technique is particularly common in the treatment of bifurcation lesions, especially of the left main coronary artery (LMCA).8 The challenge remains when diameter variations are large or varying, due to the subsequent deformation of the stent structure or the inability of the stent to achieve apposition.9 Figure 1 shows the result of a balloon-expandable stent deployed in a tapered, aneurysmal tube, after the POT was applied.

Vessels with a large thrombus burden, such as a SVG or in patients with STEMI, carry the risk of distal embolisation when stenting with a balloon-expandable stent due to balloon-deployment from the centre of the stent towards the outside, high-pressures which squeeze out the thrombus, and large cell sizes through which thrombus may prolapse.6,10 In addition, thrombotic vessels often pose a challenge for the operator to accurately identify the appropriate stent size.10

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Coronary Figure 1: A Balloon-expandable Stent Compared with a Self-apposing Stent Deployed In Tapered, Aneurysmal Tubes

malapposition rate of 28 % for balloon-expandable stents at three days post-primary PCI for STEMI.10 Treatment of bifurcation lesions with balloon-expandable stents continues to have a higher risk of restenosis and stent thrombosis than stenting a simple vessel. Questions still remain regarding these tapered vessels; such as stent sizing, covering the ostium of the side branch, malapposition in the main branch when treating the side branch, as well as stent strut deformation and its effect on the integrity of the stent structure and on drug delivery.4,5,7

The STENTYS Self-Apposing ® Stent

Balloon-expandable Stent

STENTYS Self-apposing® Stent

Left: Deployment of a balloon-expandable stent in a tapered, aneurysmal tube, which varies from 5.0 to 3.5 mm, and has an aneurysm of 6.5 mm diameter in the middle, using the proximal optimisation technique (POT) to address variations in vessel diameter. Right: The STENTYS Self-Apposing® stent showing good apposition in the same aneurysmal, tapered tube. No ballooning was performed.

Figure 2: The Deployment of a STENTYS Self-Apposing ® Stent and the Available Commercialised Sizes

The STENTYS stent is deployed from distal to proximal by retracting an outer sheath.

Size

Length in Vessel (mm)

17

Small

22

27

17

Medium

22

27

17

Large

22

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Recommended Vessel Diameter

Maximum Vessel Diameter

~2.5 to 3.0 mm

4.0 mm

~3.0 to 3.5 mm

5.0 mm

~3.5 to 4.5 mm

6.0 mm

Recommended vessel diameter is the indicated vessel diameter for the stent size to ensure sufficient radial force and minimal foreshortening. Stents can grow up to the maximum vessel diameter in case of ectatic or tapered vessels.

Similarly, in a CTO situation, there is a transient impairment of vasomotor function post-recanalisation and thus there is limited vessel response to intracoronary nitrates making stent size selection more challenging.11 Using high deployment pressures during stent deployment risks perforation, media injury or necrotic core prolapse. However, positive remodelling post-procedure is common after STEMI and CTO primarily due to vasodilation, but also thrombus dissolution after STEMI.10,12,13 In fact, 70 % of CTOs treated have shown luminal gain in the first eight months.12 Stent oversizing and using higher pressures with balloon-expandable stents is a common technique to minimise subsequent malapposition. Despite the use of this technique, the Randomized Comparison Between the STENTYS Self-Expanding Coronary Stent and a Balloon-expandable Stent in Acute Myocardial Infarction study (APPOSITION II) showed a stent

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The STENTYS BMS and DES(P) stents are self-expanding stents made out of nitinol, a nickel-titanium alloy. They have a memory shape such that the stent self-deploys gently and atraumatically without the need for a deployment balloon. Due to its super-elastic properties and short stent struts, the stent platform is also self-apposing and conforms to the shape of the vessel in which is it is deployed, allowing for a more anatomical fit (see Figure 1).10,13 The stent is deployed by retracting a sheath, which releases the stent gradually from distal to proximal in a flower-like shape (see Figure 2). The stent expands until it reaches the vessel wall, and exerts a continuous, gentle outward force onto the wall of the vessel, such that any positive remodelling over time would be accommodated by the stent through subsequent expansion.10,13 The available sizes for the STENTYS BMS and DES(P) can be seen in Figure 2. Each size is flexible enough to cover a range of indicated vessel diameters, and can even grow beyond this size in case of positive remodelling or extreme tapering.

In addition to its self-apposing design, the STENTYS stent contains small, disconnectable bridges all along the stent, which can be disconnected to provide an opening to the side branch. A percutaneous transluminal coronary angioplasty (PTCA) balloon is inflated at low pressures within the distal cell to disconnect several bridges around the side branch to create access. The stent then self-expands into the side branch, thus providing a flap to cover ostial side branch disease.

The instructions for use (IFU) for the STENTYS BMS and DES(P) lists the stent indications as: improving coronary luminal diameter in native coronary arteries and coronary bypass grafts in the treatment of acute coronary syndrome (ACS); de novo lesions in vessels involving a side branch (bifurcation); and de novo lesions in vessels with diameter variations (e.g. tapered, ectatic).

How the STENTYS Self-Apposing ® Stent Could Address These Issues In ectatic, tapered or aneurysmal vessels, the STENTYS stent, due to its self-apposing design, is able to appose itself all along the vessel even in cases of large diameter variations, thus avoiding malapposition.

As a result, POT and complex ballooning such as the use of kissing balloons are not required (see Figure 1).

The STENTYS stent can expand beyond the range indicated in case of tapered or ectatic vessels (see Figure 2). In particular, the large STENTYS stent is indicated for vessels from 3.5 to 4.5 millimetres (mm), but can be used in vessels up to 6.0 mm without additional treatment, if necessary.

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Self-expanding Stents in Atypical Coronary Anatomy

Gentle deployment of the STENTYS stent from distal to proximal (see Figure 2) may capture loose thrombus and reduce the likelihood of thrombus dislodging and travelling distally during stent deployment.

In addition, high pressure ballooning is not required during stent deployment,10 although low pressure post-dilation is advised to ensure sufficient stent expansion. Small cells (see Figure 3) also provide a cover for thrombus to reduce the degree of thrombus prolapse. The STENTYS stent could thus be a good solution in vessels with a large thrombus burden such as SVGs or in a STEMI patient, where distal embolisation and no-reflow occur more frequently than in stable cases.

In a STEMI patient, or in a CTO lesion, the vessel is often constricted and does not represent its true size, thus making sizing during the procedure difficult. In addition, the vessel size has been shown to increase days after the procedure once the vessel relaxes, vasospasm dissipates and thrombus dissolves.13 The STENTYS stent is self-expanding and one size covers a range of vessel diameters, which makes sizing during the procedure easier. The stent can also continue to expand post-procedure if the vessel undergoes positive remodelling, thus ensuring good apposition even over time.10 The disconnection feature of the STENTYS stent, which unlocks bridges at a side branch, can be used in the treatment of bifurcation lesions to create a wide enough opening to facilitate the deployment of additional stents or the use of devices, if deemed necessary by the operator. Due to the self-expanding nature of the STENTYS stent, malapposition in the main branch is not an issue, even when side branch access is granted.14 In addition, the stent apposes well to tapered main branch vessels, which are commonly found in the bifurcation anatomy. Drug delivery is maintained over the length of the stent, even at the side branch, as no strut deformation takes place.

STENTYS Cases in Atypical Coronary Anatomy Left Main Bifurcation A male patient of 73 years with three hours of chest pain presented at the catheterisation laboratory with STEMI. Diagnostic angiography showed Thrombolysis In Myocardial Infarction (TIMI) I flow in the anterolateral (AL) region with a suspected ostial lesion in the left anterior descending (LAD) artery. Upon examination with intravascular ultrasound (IVUS), it was found that the left main (LM) measured 6.8 mm and the proximal LAD measured 5.6 mm. At the level of the stenosis, there was a mean lumen area (MLA) of 3.2 square millimetres (mm²) (see Figure 4a). The AL branch was treated with two XIENCE PRIME stents (Abbott Vascular, Santa Clara, CA, US) of sizes 2.25 x 18.00 mm and 2.25 x 12.00 mm in an overlapping manner. The LM/LAD arteries were pre-dilated with a TREK 3.0/12.0 mm semi-compliant balloon (Abbott Vascular). Due to the varying vessel diameters along the lesion, the very large diameters of the LM and LAD, and to prevent undersizing and malapposition especially in the LM, a self-apposing STENTYS stent (STENTYS SA, Paris, France) was selected to stent the lesion. A STENTYS DES(P) 3.5–4.5/27.0 mm can grow to over 6.0 mm in tapered vessels, and can also be disconnected at a side branch in bifurcation cases thus avoiding strut deformation. The stent was positioned (see Figure 4b) and deployed, and subsequent post-dilation was performed with a 5.0 mm balloon within the stent. A balloon was tracked through the most distal cell into the left circumflex (Cx) artery where it was inflated between the struts, resulting in a disconnection of the stent bridges and an opening of the stent towards the circumflex. The final result was astonishing (see Figure 4c) and the post-procedure result was maintained out to three months.

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Figure 3: Comparison of Cell Size Between a Balloon-expandable Stent and a STENTYS Self-Apposing® Stent

Left: MULTI-LINK VISION stent (Abbott Vascular, Santa Clara, US), which shows a cell size >3.5 mm². Right: STENTYS Self-Apposing® stent (STENTYS SA, Paris, France), which shows a cell size measuring ~1 mm².

Aneurysmal vessel A 76-year-old male with a history of PCI of the LAD in 1990 (anteroseptal infarction), and a 2012 echocardiogram showing akinesia of the apex, and anterior and lateral walls, presented with a non-STEMI (NSTEMI). He was known to have had transient ischaemic attacks (TIAs) and hypertension. The baseline angiogram showed a large aneurysmal right coronary artery (RCA) with long, significant stenoses (see Figure 4d). It is technically challenging to appose balloon-expandable stents to ectatic, aneurysmal, large vessels such as this one, and thus treatment with a STENTYS stent was chosen.

Pre-dilation was performed using a TREK balloon (Abbott Vascular) of size 3.0/10.0 mm at 10 atmospheres (atm). A STENTYS 3.5–4.5/27.0 mm was subsequently positioned (see Figure 4e) and deployed over the lesion, followed by post-dilation with a 4.5/20.0 mm balloon at 10 atm. The final angiogram showed an optimal result (see Figure 4f).

At six months, the patient had no events and was angina-free.

Saphenous Vein Graft A 53-year-old male patient had a history of an inferior-posterior infarct in 1993 and coronary artery bypass grafting (CABG) in 1994. In 2010, his left internal mammary artery (LIMA) to the LAD was found to be patent, but a SVG was occluded at the distal anastomosis. In 2011, he was a participant in stem cell therapy. The patient presented with severe anginal complaints with Canadian Cardiovascular Society (CCS) grade 3/4, despite extensive anti-anginal medication. A coronary angiogram revealed a 100 % occluded RCA and left coronary artery (LCA), a patent LIMA to the LAD with collaterals to the RCA, and a significant ostial lesion in the distally occluded SVG (see Figure 5a). The challenge of this case was the ostial location of the lesion and the risk of distal embolisation. The lumen diameter was quite large, increasing the risk of possible undersizing. A self-apposing stent was considered due to its deployment from distal to proximal, which could limit the risk of distal embolisation, and its ability to provide better apposition of this large, irregular venous contour, even after resolution of thrombus/ debris following PCI. A 6-French guiding catheter with good support was selected (Multipurpose (MP) 2.0). After pre-dilation, a STENTYS DES(P) 3.5–4.5/22.0 mm was positioned at the ostium of the SVG (see Figure 5b) and deployed. Post-dilation of the ostium was performed

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Coronary Figure 4: Baseline and Final Angiograms Showing Tapered Vessels or Extreme Diameter Variations That Have Been Treated Successfully with a STENTYS Self-Apposing ® Stent D

A MLA 3.2 mm2

6.8 mm

5.5 mm LCX

LM

LAD

B

E

C

F

A) Left Main: baseline angiogram with IVUS measurements; B) Left Main: STENTYS placement; C) Left Main: final result; D) Aneurysm: pre-procedure; E) Aneurysm: STENTYS placement; F) Aneurysm: final result. IVUS = intravascular ultrasound; LAD = left anterior descending; LCX = left circumflex; LM = left main; MLA = mean lumen area.

with a 3.0/12.0 mm Maverick balloon (Boston Scientific, Natick, MA, US) at 16 atm. The entire stent was then post-dilated with a 4.5/8.0 mm Quantum Apex non-compliant balloon (Boston Scientific) at 12–16 atm.

The final angiogram showed a good result (see Figure 5c).

Chronic Total Occlusion A male patient of 74 years had a history of PCI of a diagonal in 2002, a coronary angiogram revealing a CTO of the RCA and a 90 % stenosis

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of the Cx in 2011, and PCI of the Cx in 2012. He presented with severe anginal complaints, with CCS grade 3/4 despite extensive anti-anginal medication. Angiography was performed via the radial artery and a CTO of the mid-RCA was confirmed (see Figure 6a). No significant stenoses were found in the LCA, and there were small collaterals to the posterior descending artery (PDA). An Amplatz Left 2.0 (AL2) guiding catheter (Cordis Corporation, a Johnson & Johnson company, Miami Lakes, FL, US) was chosen for good backup with a Pilot 50/150

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Figure 5: Baseline and Final Angiograms Showing a Saphenous Vein Graft That Has Been Treated Successfully with a STENTYS Self-Apposing ® Stent A

B

C

A) SVG: pre-procedure; B) SVG: STENTYS positioning; C) SVG: final result. SVG = Saphenous vein graft.

Figure 6: Baseline and Final Angiograms Showing a Chronic Total Occlusion That Has Been Treated Successfully with a STENTYS Self-Apposing ® Stent A

B

C

E

F

A

B

A

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D

C

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D

B

D

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A) CTO: pre-procedure; B) CTO: after wiring; C) CTO: final result; D) CTO: OCT post-procedure; E) CTO: OCT at seven days. CTO = chronic total occlusion; OCT = optical coherence tomography.

wire (Abbott Vascular), and the occlusion was crossed (see Figure 6b).

Pre-dilation was performed with incremental balloon diameters starting at 1.25 mm, then 2.00 mm and then 2.50 mm to restore flow. Due to concern about the actual vessel size post-recanalisation and the risk of long-term malapposition, stent thrombosis and repeat PCI or restenosis,

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the STENTYS technology was selected. STENTYS DES(P) stents of sizes 3.0–3.5/27.0 mm and 3.0–3.5/22.0 mm were placed proximally and distally, respectively, in an overlapping manner. Both stents were post-dilated with a Quantum Apex (Boston Scientific) non-compliant balloon of size 3.5/15.0 mm at 14 atm. Optical coherence tomography

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Coronary (OCT) confirmed good stent apposition to the vessel wall (see Figure 6d), and the final angiogram showed an optimal result (see Figure 6c).

At seven days post-procedure, the patient underwent another coronary angiogram, which showed a sustained optimal result. OCT at seven days (see Figure 6e) revealed an increase in minimum lumen area of 11 % since post-procedure. One year later, the patient was performing heavy physical exercise on his horse farm without anginal complaints.

Clinical Implications Self-expanding stents have been used in non-coronary interventions for many years due to their unique characteristics allowing them to adapt to varying anatomy. Previous versions using mesh designs have been limited due to uncontrolled expansion and the absence of local drug delivery, which is essential in smaller vessels. With the introduction of this easy-to-deliver, well-controlled, self-expanding stent, the interventional cardiologist has a new and unique tool in their toolbox. The above-described clinical examples are clear demonstrations of the potential of this technology. Currently, the device has indications in selected cases with extreme calibre difference along the segment to be treated, or an expected significant change in diameter in the future. Implantation success in experienced hands is quite high; however, due to its large profile, very complex calcified lesions may not always be successfully crossed whereas the latest generation of flexible, thin-strut, balloon-expandable stents could be successful in these lesions.

Some smaller clinical studies and registries have been completed as a starting point for the collection of the evidence necessary for full acceptance of this technology. The STENTYS clinical programme consists of the APPOSITION series of trials in STEMI patients, the OPEN trials for bifurcation lesions, an ADEPT trial for SVGs, and a new all-comer Sizing registry of 3,000 patients looking at cases where a STENTYS stent has been implanted where sizing has been a concern (e.g. aneurysm ectatic vessel, bifurcation/left main, CTO, SVG, tapered vessel, thrombus-containing lesion, NSTEMI, STEMI, unstable angina). The SIZING registry was initiated in June 2012 and enrolment is still ongoing; no results have yet been publicly presented or published. The randomized Comparison Between the STENTYS Self-Apposing Bare Metal and Paclitaxel-Eluting Coronary Stents for the Treatment of Saphenous Vein Grafts (ADEPT) trial in 57 patients completed enrolment in early 2014. Results on the primary endpoint of in-stent late lumen loss at six months are expected late 2014.

1. Muramatsu T, Onuma Y, Zhang YJ, et al., Progress in treatment by percutaneous coronary intervention: the stent of the future, Rev Esp Cardiol , 2013;66(6):483–96.

2. Holmes DR Jr, Kereiakes DJ, Garg S, et al., Stent thrombosis, J Am Coll Cardiol, 2010;56:1357–65.

3. Nair S, Fath-Ordoubadi F, Clarke B, et al., Late outcomes of drug eluting and bare metal stents in saphenous vein graft percutaneous coronary intervention, EuroIntervention , 2011;6(8):985–91.

4. Louvard Y, Lefèvre T, Morice MC, Percutaneous coronary intervention for bifurcation coronary disease, Heart, 2004;90(6):713–22.

5. Stankovic G, Darremont O, Ferenc M, et al., Percutaneous coronary intervention for bifurcation lesions: 2008 consensus document from the fourth meeting of the European Bifurcation Club, EuroIntervention, 2009;5:39–49.

6. Onuma Y, Thuesen L, van Geuns RJ, et al., Randomized study

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In terms of results, the STENTYS stent showed in the Assessment of the Safety and Performance of the STENTYS Self-expanding Coronary Stent System in Acute Myocardial Infarction (APPOSITION I) study that the culprit vessel increases by 19 % three days after a STEMI procedure, and the stent follows this increase (18 % increase). 13 Patients with a STENTYS stent implanted had 0 % stent malapposition after three days, compared with 28 % malapposition for the balloon-expandable control stent in the Randomized Comparison Between the STENTYS Self-Expanding Coronary Stent and a Balloon-expandable Stent in Acute Myocardial Infarction (APPOSITION II) randomised, controlled trial.10 At one-year after STEMI in the large, 1,000-patient, Post-market Registry to Assess the Stentys Self-expanding Coronary Stent in Acute Myocardial Infarction in Real Life registry (APPOSITION III), STENTYS patients had a cardiac death rate of only 2 %. This study also demonstrated the need for low-pressure post-dilation for additional plaque modification to ensure sufficient stent expansion. The Randomized Comparison Between the STENTYS Self-apposing Sirolimus-eluting Coronary Stent and a Balloon-expandable Stent in Acute MyocardIal Infarction (APPOSITION IV) trial randomising the pre-market STENTYS Sirolimus-eluting stent to the Medtronic Resolute in STEMI patients showed a significantly greater number of fully covered stents at four months in the STENTYS arm. The feasibility of disconnecting a STENTYS stent at a bifurcation has been demonstrated in the STENTYS Coronary Bifurcation Stent System for the Per­c utaneous Treatment of de novo Lesions in Native Bifurcated Coronary Arteries (OPEN I) trial with a subsequent six-month MACE rate for the STENTYS DES (P) of 3.7 %. 14 The Assessment of the Long-term Safety and Efficacy of the STENTYS Paclitaxel-eluting Self-expanding Stent in Coronary Bifurcation Lesions (OPEN II) bifurcation registry of 217 patients treated with the STENTYS DES (P) showed a six-month MACE of 10.1 %, and no difference in survival between patients receiving kissing balloon inflations or not at the end of the procedure.

Conclusion In challenging anatomy such as tapered vessels, bifurcations, left main, SVGs, CTOs, and aneurysmal or ectatic vessels, the STENTYS Self-Apposing stent could provide an alternative solution over balloon-expandable stents to achieving simplified stent sizing with improved apposition, both during the procedure and in the days following in case of positive remodelling. n

to assess the effect of thrombus aspiration on flow area in patients with ST-elevation myocardial infarction: an optical frequency domain imaging study -- TROFI trial, Eur Heart J, 2013;34(14):1050–60.

7. Hildick-Smith D, Lassen JF, Albiero R, et al., Consensus from the 5th European Bifurcation Club meeting, EuroIntervention, 2010;6:34–8.

8. La Manna A, Geraci S, Tamburino C, A self-expandable coronary stent system to treat complex coronary stenosis complicated by poststenotic aneurysm: an optical coherence tomographic evidence-based case report, J Invasive Cardiol , 2011;23(12):E277–80.

9. Foin N, Sen S, Allegria E, et al., Maximal expansion capacity with current DES platforms: a critical factor for stent selection in the treatment of left main bifurcations?, EuroIntervention, 2013;8:1315–25.

10. van Geuns RJ, Tamburino C, Fajadet J, et al., Self-expanding

versus balloon-expandable stents in acute myocardial infarction: results from the APPOSITION II study, JACC Cardiovasc Interv, 2012;5(12):1209–19.

11. Galassi AR, Tomasello SD, Crea F, et al., Transient impairment of vasomotion function after successful chronic total occlusion recanalization, J Am Coll Cardiol , 2012;59(8):711–8.

12. Ogita M, Ako J, Sakakura K, et al., Distal reference segment luminal gain following percutaneous coronary intervention for chronic total occlusion, Int Heart J , 2011;52(5):270–3.

13. Amoroso G, van Geuns RJ, Spaulding C, et al., Assessment of the safety and performance of the STENTYS self-expanding coronary stent in acute myocardial infarction: results from the APPOSITION I study, EuroIntervention, 2011;7:428–36.

14. Verheye S, Ramcharitar S, Grube E, et al., Six-month clinical and angiographic results of the STENTYS® self-apposing stent in bifurcation lesions, EuroIntervention, 2011;7:580–7.

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Complex Bifurcation

Overview of Technical and Cost Considerations in Complex Percutaneous Coronary Intervention J R a ider Estra da , Jo n a t h a n D Pa u l , A t m a n P S h a h a n d S a n d e e p N a t h a n University of Chicago Medicine, Section of Cardiology, Chicago, Illinois, US

Abstract Complex percutaneous coronary intervention (PCI), encompassing an ever-expanding range of challenging lesion sets and patient populations, accounts for a significant proportion of PCI procedures being performed currently. Specific lesion types associated with lower rates of procedural success and higher rates of recurrence or major adverse cardiac events (MACE) include multivessel disease, unprotected left main coronary artery disease, fibrocalcific or undilatable lesions, chronic total occlusions, degenerated saphenous vein graft lesions, thrombotic lesions, and bifurcation disease. Validated tools and technical strategies currently exist to address most procedural scenarios encountered and should be familiar to the complex PCI operator. Anticipated clinical outcomes, projected resource utilization, and cost considerations should all factor into the decisions of when, how, and in whom to intervene.

Keywords Percutaneous coronary intervention, complex coronary artery disease, bifurcation lesion, multivessel disease, drug-eluting stents, cost-effectiveness Disclosure: J Raider Estrada, MD, and Jonathan D Paul, MD, have no conflicts of interest to declare. Atman P Shah, MD, is a Consultant/on the speakers bureau for Medtronic, Abbott, and Maquet. Sandeep Nathan, MD, MSc, is a Consultant/on the speakers bureau for Medtronic, Boston Scientific, and Maquet.

Received: 10 February 2014 Accepted: 23 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):17–22 Correspondence: Sandeep Nathan, MD, MSc, Associate Professor of Medicine, University of Chicago Medicine, 5841 South Maryland Ave, MC 5076, Chicago, IL 60637.

E: snathan@medicine.bsd.uchicago.edu

While the breadth of procedural offerings in interventional cardiology (IC) has exponentially expanded over the past four decades to include cardiac structural, peripheral arterial, and venous interventions, percutaneous coronary intervention (PCI) remains at the core of the field, accounting for the greatest percentage of therapeutic catheter-based procedures performed by IC practitioners in the US. Beginning with the historic series of coronary angioplasties performed by Dr Andreas Grüentzig in 1977, PCI has steadily advanced in its range of application and technical sophistication.1,2 Shortly after the landmark procedures were performed and reported at the Annual Scientific Sessions of the American Heart Association in 1977, a percutaneous transluminal coronary angioplasty (PTCA) registry was established at the National Heart, Lung and Blood Institute (NHLBI) in order to track the expansion, progress, and outcomes of this thenfledgling procedure.3,4 Dorros and colleagues reported on clinical outcomes and complications in the first 1,500 patients undergoing PTCA in the US (September 1977 to April 1981).5 The rate of PTCA success was 63 % at that time and the rate of major peri-procedural complications (myocardial infarction, emergency surgery, or in-hospital death) was 9.2 % with standalone mortality of 1.1 % (0.85 % in patients with single vessel disease; 1.9 % in those with multivessel disease).5 Even in the very earliest PTCA experience, lesion complexity and presenting acuity predictably affected clinical outcomes, a theme that has carried through to contemporary PCI.

Evolution of Complex Percutaneous Coronary Intervention A recent publication from the NHLBI-sponsored PTCA and Dynamic registries sheds light on temporal trends in PCI spanning the several

© RADCLIFFE CARDIOLOGY 2014

Nathan_AMc(NEW).indd 17

decades and multiple technological eras that have passed since the origins of the procedure. Specifically, the report documented the ingress of the field into clinical and procedural scenarios that fall under the rubric of complex PCI.6 Over the 20-year period studied, latter PCI cohorts were characterized by greater proportions of lesions bearing thrombus or calcium and patients with more medical comorbidities compared with the original PTCA cohort. Within the five consecutive Dynamic Registry waves studied (1997–2006), a period notable for the adoption of atherectomy, thrombectomy, cutting/scoring balloon angioplasty, and routine use of bare metal stents (BMS) and, later, drugeluting stents (DES), the proportion of American College of Cardiology/ American Heart Association (ACC/AHA) Type C lesions intervened upon grew. Although initial technical success rates were reportedly high, lesions bearing markers of complexity, such as bifurcation disease, ostial location, calcification, and total occlusion, accounted for a significant proportion (9–36 %) of patients requiring repeat PCI within 30 days of their index intervention. Other investigators have independently confirmed in concurrent datasets that complex PCI (lesions evidencing thrombus, calcification, bifurcation or ostial location, chronic occlusion), was also associated with increased in-hospital and 1-year mortality rates compared with PCI of simpler lesions.7 Two large studies have now demonstrated that public reporting of PCI outcomes ostensibly influences the behavior and case selection choices of IC operators, suggesting that operators may be veering away from complex cases they believe will result in poorer outcomes.8,9 These data lend insight into the nuanced and, at times, conflicting considerations that factor into case selection and strategy for complex PCI. Fortunately, however,

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Complex Bifurcation Table 1: Factors Affecting Lesion Scoring in the SYNTAX Score Lesion Characteristic

Impact On Lesion Score

Diameter Reduction Total occlusion

x5

Significant lesion (diametric stenosis 50–99 %)

x2

Total Occlusion • Age >3 months or unknown

+1

• Blunt stump

+1

• Bridging

+1

• First segment visible beyond

+1 per

total occlusion

non-visualized segment

• SB

Yes, SB <1.5 mm

+1

Yes, SB both < and ≥1.5 mm

+1

Trifurcations • 1 diseased segment

+3

• 2 diseased segments

+4

• 3 diseased segments

+5

• 4 diseased segments

+6

Bifurcations • Type A, B, C

+1

• Type D, E, F, G

+2

• Angulation <70°

+1

Aorto-ostial stenosis

+1

Severe tortuosity

+2

Length >20 mm

+1

Heavy calcification

+2

Thrombus

+1

‘Diffuse disease’/small vessels

+1 per segment number

A significant lesion is defined as >50 % diametric luminal reduction by visual assessment in vessels larger than 1.5 mm. A multiplicative factor of 2 (designated above by ‘x’) is assigned to stenoses of 50–99 % severity and a multiplicative factor of 5 to total (100 %) occlusions.

Other relevant lesion characteristics are assigned additive values, as denoted above by ‘+’.

The total SYNTAX score reflects the cumulative lesion scores. SB = Side branch.

Figure 1: Duke/ICPS (SYNTAX) and Medina Bifurcation Classification Systems

The SYNTAX bifurcation classification combines elements of both the Duke and Institut Cardiovasculaire Paris Sud (ICPS) systems, assigning letter designations A–G to the various patterns of obstructive plaque shown above. In the Medina classification of coronary bifurcation lesions, a binary value is assigned depending on the presence (1) or absence (0) of stenosis in each of three lesion segments: prebranch parent vessel, postbranch parent vessel, and side branch ostium, yielding a 3-digit sequence separated by commas.

such considerations have not impeded the advancement of PCI techniques and technologies that have continued to flourish, fueled

18

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by scientific innovation and the clinical need for minimally invasive solutions to the growing burden of advanced coronary heart disease.

Highlighted below are selected procedural and cost considerations in complex PCI subsets with particular focus on bifurcation disease, representing a commonly encountered, technically challenging, and well-studied complex lesion subset.

Landscape of Contemporary Percutaneous Coronary Intervention and Challenges Associated with Specific Lesion Sets What began as simple balloon dilation of single, de novo coronary lesions has evolved into myriad variations on the theme of complex coronary intervention, the majority involving the implantation of one or more DES and a significant proportion utilizing adjunctive devices for PCI guidance and optimization. Indeed, 60 % or more of the DES used in the US are implanted in an ‘off-label’ capacity (in terms of US Food and Drug Administration [FDA] labeling), often in the context of the complex coronary lesions described below or for patients with significant medical comorbidities. 10–12 It bears mention that while complex PCI subsets abound in clinical practice, a uniformly adopted definition for complex coronary artery disease (CAD) is lacking in the cardiovascular literature. Lesion scoring schema such as the prospectively validated SYNergy between PCI with TAXUS™ and Cardiac Surgery (SYNTAX) score provide valuable guidance for the decision to intervene and the strategy of percutaneous intervention.13 In the SYNTAX score (www.syntaxscore.com), which incorporates aspects of many pre-existing scoring systems, additive or multiplicative numerical values are assigned via a computerized algorithm to each obstructive lesion noted, based on dominance, number of lesions, segments involved per lesion, and six additional groups of queries relating to lesion characteristics (see Table 1).13 The total SYNTAX score represents the sum of the individual lesions scores and has prognostic value independent of medical comorbidity and other patient-specific metrics. In the SYNTAX trial, which randomly assigned 1,800 patients with multivessel or left main coronary artery (LMCA) disease to coronary artery bypass graft (CABG) surgery versus PCI with DES, higher scores portended poorer outcomes with multivessel PCI.13–15 Challenges in contemporary catheter-based therapy for CAD generally stem from one or more of the following factors: the extent, severity, distribution, and characteristics of the coronary lesions, number of vessels diseased, LMCA involvement, presentation acuity and procedural urgency, burden of ischemia, hemodynamics/ventricular function, and medical comorbidities. Specific lesion sets that are associated with lower rates of procedural success and higher rates of recurrence or major adverse cardiac events (MACE) include multivessel disease, unprotected LMCA disease, fibrocalcific or undilatable lesions, chronic total occlusions, degenerated saphenous vein graft lesions, thrombotic lesions, hemodynamically unstable patients, and bifurcation/trifurcation disease. Broad technical considerations relevant to each of these lesion subtypes are summarized in Table 2, with bifurcation disease also addressed below in greater detail. In a published Dynamic Registry PCI experience that predated the advent of DES, the majority (55.1 %) of attempted lesions fulfilled at least one of the aforementioned criteria for complexity with over a quarter of lesions demonstrating two or more complex characteristics.7 Similarly, following the introduction of DES in the US in 2003, investigators from the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) Registry found that the majority (60.2 %) of intervened lesions fulfilled

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Table 2: Technical Considerations Relevant to Various Complex Lesion Subtypes

Multivessel disease

Major Concerns Objective assessment of lesion severity,

selection of lesions, complete revascularization, FFR, DES with adjunctive lesion

FFR- or ischemia-guided PCI, staging of

renal function, cost concerns

multivessel PCI when appropriate

Unprotected left main

Objective assessment of lesion severity/extent, DES, intravascular imaging, mechanical

Selection of ostial and mid-shaft lesions

coronary artery disease

stent sizing and apposition,

versus distal bifurcation/trifurcation,

bifurcation/ trifurcation disease

bifurcation techniques when necessary

Fibrocalcific disease

Inability to dilate lesions, pass devices

Rotational atherectomy, orbital,

Lesion debulking/plaque modification

Inability to fully expand stents

atherectomy cutting/scoring

with atherectomy, cutting/scoring

balloon angioplasty

balloon use

Chronic total occlusions Inability to traverse occluded segment or

Specialty wires, large-bore guide

Wire escalation/microcatheter support,

catheters, guide catheter extensions,

subintimal tracking and re-entry,

subintimal dissection re-entry tools,

reverse CART

microcatheters, DES

Degenerated saphenous Distal atheroembolization, ‘no reflow,’ high

Distal embolic protection devices,

Use of embolic protection filters and

vein graft disease

intracoronary vasodilators, DES

pre-treatment of graft with vasodilators,

advance therapeutic devices

restenosis, aggressive disease progression

Tools Non-invasive assessment of ischemia, preparation tools, intravascular imaging circulatory support (when necessary)

Technical Approach SYNTAX score to guide case selection,

covering length of entire diseased vessel

with DES

Thrombotic lesions

Thromboembolization, ‘no reflow,’ sidebranch Aspiration thrombectomy catheters,

GPI use and thrombectomy prior to stent

compromise, stent malapposition, and

implantation, intravascular imaging to

thrombosis

confirm DES sizing/apposition

Hemodynamically

Hypotension/hypoperfusion, ventricular

IABP, mechanical circulatory support

Early use of mechanical circulatory

unstable patients

arrhythmias, circulatory collapse

devices (TandemHeart®1, Impella®2,

support devices in patients with

ECMO/ECLS)

hemodynamic compromise

Bifurcation lesions

Complete lesion/ostial coverage, side

Dedicated bifurcation stent

Mandatory vs. provisional side branch

branch compromise, restenosis/thrombosis, (outside of US), DES,

stenting techniques, 1 vs. 2 vs. 3 DES

DES usage

techniques, lesion debulking

rheolytic thrombectomy, platelet GPI

intravascular imaging

CART=controlled antegrade and retrograde subintimal tracking; DES=drug-eluting stent; ECMO/ECLS= extracorporeal membrane oxygenation/life support; FFR=fractional flow reserve; GPI=glycoprotein inhibitor; IABP=intraaortic balloon pump; PCI=percutaneous coronary intervention. 1. CardiacAssist, Pittsburgh, Philadelphia; 2. Abiomed, Danvers, Massachusetts.

either ACC/AHA B2 or C lesion criteria.16 Thus, a large proportion of contemporary PCI procedures invoke some measure of technical complexity. While it is beyond the scope of this article to discuss each of the aforementioned complex lesion subtypes in detail, suffice it to say that tools and validated strategies currently exist for each scenario listed. It is incumbent upon the operator aspiring to tackle complex disease in the catheterization laboratory, to gain intimate familiarity with these data and technical strategies.

Bifurcation Disease—Classification and Percutaneous Therapeutic Options Within the spectrum of complex coronary lesions approachable by PCI, bifurcation disease merits special consideration as it is encountered frequently, accounting for 15-25 % of PCIs in some series, and has been associated with higher-than-average technical complexity and lower success rates.7,17,18 Optimal percutaneous treatment of bifurcation disease is guided by an extensive body of bench and clinical investigation with available data bearing out the potential consequences of inappropriate treatment, such as restenosis and/ or thrombosis of one or both vessels involved. Multiple bifurcation classification systems have been developed with the common goal of clarifying optimal interventional strategy and predicting complication risk.17–20 All schemas quantify the extent and location of plaque burden with some also incorporating the angle between parent and daughter vessel. The SYNTAX bifurcation classification, modified from the wellknown Duke and Institut Cardiovasculaire Paris Sud (ICPS) criteria, along with the Medina classification, representing a contemporary, simplified system, are shown in Figure 1.13,20,21 Side branch angulation is missing from both of these classification systems, although it is now well-recognized as an additional metric with important prognostic

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value.21 Whichever the system applied, ‘true’ bifurcation disease is characterized by obstructive disease in the parent vessel, pre- and post-side branch, as well as obstructive disease within the ostium of the side branch.

Even more numerous than bifurcation classification systems are the technical approaches described to date, varying widely in terms of the number of stents mandatorily used, completeness of coverage of the side branch ostium, and procedural complexity. A consensus classification of families of bifurcation techniques was proposed by the European Bifurcation Club (EBC) some years ago.21,22 This system, referred to as the MADS classification, is an acronym with each letter corresponding to a different choice for first vessel/segment addressed and approach to initial stent deployment. ‘M’ stands for Main proximal vessel first, ‘A’ for main Across side branch first, ‘D’ for Distal first, and ‘S’ for Side branch first. Various bifurcation techniques, including those double-stent techniques detailed in Figure 2 along with several others, are categorized under each lettered group and further broken out by the use of one, two, or three stents. Two-stent techniques that do not insure complete side branch coverage include the variations on the T-stent technique (see Figure 2) including classical and reverse T-stenting. More advanced techniques that allow for complete side branch coverage include variations on crush stenting, culotte stenting, and classical or modified simultaneous kissing stent (SKS) techniques.17,20,22 The results of numerous published clinical trials and registries of bifurcation technique have been evaluated in the context of several meta-analyses.23–31 These systematic reviews have found with great consistency that in the current era of DES, a simple, single-stent

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Complex Bifurcation Figure 2: Commonly Used Double-stent Bifurcation Techniques

A. T-stenting; B. Reverse T-stenting; C. Crush; D. Culotte; E. Simultaneous kissing stents.

Diagrammatic representations of bifurcation stenting techniques grouped by incomplete/ absent side branch ostial coverage (A, B) versus complete ostial coverage (C, D, E). Note in Figure 2B, the side branch stent is placed in a provisional fashion and therefore requires dilatation of a cell of the parent vessel stent to allow passage (arrow).

Figure 3: Rotational Atherectomy and Culotte Stenting of a Medina 1,0,1 Bifurcation

However, specific situations exist where one may wish to commit early to a complex bifurcation strategy. Intermediate to large side branches (>2.5 mm diameter), particularly those that are comparably sized as the parent vessel, side branches evidencing contiguous obstructive disease extending away from the ostium, side branch territories with demonstrable ischemia, or significant/flow-limiting dissection may merit consideration of a more complex bifurcation strategy with deliberate stenting of the side branch. Figure 3 depicts step-wise detail of a culotte stenting procedure in which calcified de novo and restenotic disease in the bifurcation of an LAD and large diagonal branch warranted a complex, multistent approach following debulking with rotational atherectomy. In planning percutaneous therapy for complex bifurcation disease, careful pre-procedure consideration of the coronary anatomy, aforementioned criteria, and various technical strategies, is therefore warranted.17,20–22

Cost-effectiveness Considerations in Routine and Complex Percutaneous Coronary Intervention

Calcified de novo and restenotic disease of the left anterior descending (LAD)/diagonal bifurcation is seen in Panel A with blue arrows at areas of disease confirmed to be obstructive by angiography and fractional flow reserve. Rotational atherectomy (B, red arrow) was first performed on both the LAD and the first diagonal branch followed by culotte stenting.

After predilatation, a drug-eluting stent is placed from LAD into the diagonal (C), jailing the continuation of the LAD. The LAD was re-wired through the first stent, which is then dilated and a second stent advanced into the mid-LAD through the fenestration in the first stent (D).

Care is taken upon deployment to ensure that the second stent is not completely occluding the diagonal ostium (E). Kissing balloon inflations are performed in the stented bifurcation (F) yielding an excellent angiographic result (G) and complete stent coverage of the entire diseased area (H) with minimal distortion of the native carina. Repeat angiography and optical coherence tomography with spectral domain longitudinal reconstruction (I) performed 3 years later reveals widely patent and well-healed bifurcation stents.

strategy using provisional side branch stenting, when feasible, is superior to complex (double stent) strategies with respect to rates of myocardial infarction and stent thrombosis.23–31 If a satisfactory angiographic result is obtained with parent vessel stenting ± side branch ballooning, forgoing side branch stenting is appropriate based on the available data and, moreover, will save on procedural time and cost, radiation exposure, and contrast usage.17,20–22 As fractional flow reserve (FFR) was demonstrated to be an important discriminatory tool for guiding the performance of single- or multivessel PCI in the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME-2) study, so too has the value of FFR been demonstrated in assessing the functional significance of jailed side branch stenoses.32 Ahn et al. studied 230 jailed side branch stenoses in bifurcation lesions where main vessel stenting was performed and found that only 17.8 % of jailed side branch lesions were associated with functional significance (FFR <0.80).33 Moreover, visual discrimination of ‘significant’ side branch stenoses by angiography alone was limited at best.

20

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When broadly considering the cost impact of treatment strategies in patients with CAD, multiple therapeutic comparisons are of clinical and fiscal relevance. The first set of considerations relates to medical management versus revascularization in the setting of stable CAD. The next relates to mode of revascularization, surgical versus percutaneous, with the additional matter of routine versus selective use of DES in the latter group. In the interest of brevity, we will focus on cost-effectiveness of various revascularization strategies as it relates to patients with complex disease. While it is beyond the scope of this article to explore economic modeling in detail, it bears mention that variability and complexity of cost modeling methodology, differences in individual costs within the US healthcare system and across countries, and local trends in the practice of IC have all contributed to the lack of uniformity in conclusions regarding the cost-effectiveness of various revascularization strategies.34 Since commercial approval in the US in 2003, use of DES has grown, peaking in late 2005 at nearly 90 % and since settling into its current usage rate in over two-thirds of PCI procedures.35 Numerous randomized and non-randomized comparisons of BMS versus DES in PCI have been conducted and have uniformly found a reduction in target vessel revascularization (TVR) without significant reduction in death or myocardial infarction.36,37 Available economic analyses have not, however, uniformly upheld the cost-effectiveness of DES use in contemporary PCI. As noted, given the lack of mortality benefit with DES, the economic case to be made in favor of DES usage rests primarily with the ratio of incremental cost of these devices over BMS to enhanced quality of life (QoL) for patients who enjoy greater freedom from repeat revascularization following DES implant.38 Groeneveld et al. conducted a systematic review of the published literature on costs and QoL metrics associated with DES versus BMS use, incorporating eight QOL and four cost publications.38 In this analysis, patients receiving DES had $1,600 to $3,200 higher initial costs with the 1-year total cost differential dropping to $200 to $1,200. Wide variability in the relative rates of restenosis between BMS and DES in the studies included drove the large observed range in cost per revascularization avoided ($1,800–$36,900). Although all included studies were in agreement that restenosis negatively affects QOL, routine use of DES to avoid restenosis was found unlikely to be cost-effective. In another systematic review of DES cost-effectiveness, Ligthart and colleagues similarly found wide variability in the reported cost-effectiveness

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of DES that the authors concluded was influenced by the quality of the studies analyzed, source of study funding, and the country in which the studies were conducted.34 Ryan et al. have suggested however that DES usage would be economically favorable if used selectively in patients at moderate to high risk of BMS restenosis with sensitivity analyses demonstrating an acceptable cost-effectiveness ratio of <$10,000 per repeat revascularization avoided if the expected BMS TVR rate in a given population exceeded 11 % and cost savings if the BMS TVR rate exceeded 19 %.39 As noted, use of FFR guidance in single or multivessel PCI with implantation of second-generation DES in the FAME-2 trial yielded substantial reductions in the ischemic composite endpoint over optimal medical therapy (4.3 % in the PCI group and 12.7 % in the medical therapy group, hazard ratio [HR] with PCI 0.32; 95 % confidence interval [CI] 0.19 to 0.53; p<0.001).32 An economic analysis of these data found that while initial costs of drug-eluting stent PCI performed in the setting of FFR <0.80 were significantly higher compared with FFR followed by optimal medical therapy ($9,927 versus $3,900; p<0.001), the observed $6,027 difference decreased over the study’s 1-year follow-up to $2,883 (p<0.001), offset by the cost of subsequent revascularization procedures in the medical therapy arm. The incremental cost-effectiveness ratio (ICER) of PCI guided by an abnormal FFR in FAME-2 was $36,000 per quality-adjusted life year (QALY), an economically favorable value as it is below the standard willingness to pay threshold of $50,000 per QALY.40 Taken together, these data indicate that cost-containment strategies in PCI should include objective assessment of functional significance to guide lesion selection and estimation of restenosis/revascularization risks to help guide the use of DES versus BMS along with strategies to minimize the number of stents implanted and experience-based choices regarding adjunctive device use.

Relevant to the economics of complex PCI, a few recent studies have re-examined the age-old controversy of CABG versus drug-eluting stent PCI in multivessel CAD. As mentioned above, the SYNTAX trial randomly assigned 1,800 patients with multivessel or unprotected LMCA disease to CABG surgery versus PCI with paclitaxel-eluting DES. Twelvemonth rates of major adverse cardiac or cerebrovascular events were significantly higher in the PCI group (17.8 % versus 12.4 % for CABG; p=0.002), primarily due to an increased rate of repeat revascularization (13.5 % versus 5.9 %; p<0.001) with no difference in all-cause mortality, thus failing to demonstrate non-inferiority between the two treatment arms.15 However, when outcomes were stratified by tertiles of SYNTAX score there was noted to be an interaction between the SYNTAX score and treatment allocation with comparable MACE rates between PCI and CABG in those subjects with low (0–22) or intermediate (23–32) scores.

A formal cost-effectiveness analysis conducted by Cohen et al. based on the SYNTAX data found that in the overall study population total costs for the index procedure and hospitalization were $5,693/patient higher in the CABG group, but follow-up costs $2,282/patient higher in the PCI group (driven primarily by the need for repeat TVR), thus economically favoring PCI at 1 year despite high resource utilization for PCI (average 4.5 DES per procedure; range 0–14 DES).41 Although PCI was deemed to be the economically dominant strategy in the primary analysis, disease complexity as quantified by tertiles of SYNTAX score once again served as an interaction term. The 1-year cost savings with PCI diminished from $6,154/patient among patients with low

1.

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, Circulation ,

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2.

3.

4.

SYNTAX scores to $3,889/patient in patients with intermediate SYNTAX scores to $466/patient in patients with high SYNTAX scores. A similar interaction was also found in terms of disease complexity and qualityadjusted life expectancy with CABG strongly favored in patients with the highest SYNTAX scores. In 1,900 patients with diabetes randomized to drug-eluting stent PCI versus CABG in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM), total 5-year costs were similarly $3,641 higher per CABG patient. However, when the trial data were projected over a lifetime survival horizon, CABG posted significant gains in quality-adjusted life expectancy relative to PCI.42 Careful assessment of up-front costs, anticipated intermediate- and long-term outcomes, and the need for repeat procedures and hospitalization must therefore accompany technical planning of revascularization in patients with complex multivessel CAD. Percutaneous chronic total occlusion (CTO) revascularization is another sector of contemporary interventional practice that has recently seen renewed interest and utilization driven by advances in technology as well as the development of hybrid percutaneous treatment algorithms.43 Limited data exist regarding cost-effectiveness of percutaneous revascularization of CTOs versus medical management and, at the time of writing, no formal cost-modeling versus CABG exists although the presence of one or more CTOs is often cited as the primary reason for CABG referral.44 Gada et al. used a decision-analytic model to evaluate the morbidity and costs associated with CTO PCI versus optimal medical therapy in patients with Canadian Cardiovascular Society class III–IV angina.45 Assuming a reference case mean age of 60 years and CTO PCI success rate of 67.9 % and 5 years of simulated follow-up, along with literature-defined assumptions regarding procedural probabilities, costs, and outcomes, CTO PCI was more costly than optimal medical therapy ($31,512 versus $27,805), but resulted in greater QALYs (2.38 versus 1.99), thus resulting in an economically favorable ICER of $9,505 per QALY. As experience grows with use of the hybrid CTO algorithm as well as with current strategies for tackling bifurcation lesions with conventional DES or with dedicated bifurcation stent systems available outside the US, additional cost modeling data addressing these complex PCI subsets will hopefully be forthcoming.46

Conclusions Technically complex PCI procedures, while increasingly performed, remain associated with lower rates of procedural success and higher rates of MACE compared with more straightforward catheter-based interventions. Multivessel and unprotected LMCA disease, fibrocalcific lesions, chronic total occlusions, and bifurcation disease comprise many of the lesion sets requiring additional resource allocation, procedural planning, and sophistication. Bifurcation lesions, in particular, have been the subject of intense systematic study and some degree of controversy.

Current consensus supports a simple, single-stent/provisional side branch strategy when possible. Cost considerations in PCI are perhaps most relevant to patients with extensive, multivessel disease in whom CABG may also be a viable therapeutic option. Objective assessment of disease complexity, estimation of technical feasibility, and consideration of medical comorbidities should all factor into the decision regarding optimal revascularization strategy. n

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Wilensky RL, Selzer F, Johnston J, et al., Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI Dynamic Registry), Am J Cardiol , 2002;90:216–21.

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Joynt KE, Blumenthal DM, Orav EJ, et al., Association of public reporting for percutaneous coronary intervention with utilization and outcomes among medicare beneficiaries with acute myocardial infarction, JAMA , 2012;308:1460–8.

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Laskey WK, Yancy CW, Maisel WH, et al., Thrombosis in coronary drug-eluting stents: report from the meeting of the circulatory system medical devices advisory panel of the food and drug administration center for devices and radiologic health, December 7–8, 2006, Circulation , 2007;115:2352–7.

Win HK, Caldera AE, Maresh K, et al., for the EVENT Registry Investigators. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents, JAMA , 2007;297:2001–9.

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.

Serruys PW, Onuma Y, Garg S, et al., Assessment of the SYNTAX score in the Syntax study, EuroIntervention, 2009;5:50–6.

Serruys PW, Morice MC, Kappetein AP, et al., Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease, N Engl J Med , 2009;360:961–72.

Lopez JJ, Keyes MJ, Nathan S, et al., Rapid adoption of drugeluting stents: clinical practices and outcomes from the early drug-eluting stent era, Am Heart J , 2010;160(4):767–74.

Baber U, Kini AS, Sharma SK, Stenting of complex lesions: An overview, Nat Rev Cardiol , 2010;7:485–96.

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19. Lefevre T, Louvard Y, Morice MC, et al., Stenting of bifurcation lesions: classification, treatments, and results, Catheter Cardiovasc Interv , 2000;49:274–83.

20. Movahed MR, Coronary artery bifurcation lesion classifications, interventional techniques and clinical outcome, Expert Rev Cardiovasc Ther , 2008;6(2):261–74.

21. Louvard Y, Thomas M, Dzavik V, et al., Classification of coronary artery bifurcation lesions and treatments: Time for a consensus!, Catheter Cardiovasc Interv , 2008;71:175–83.

22. Louvard Y, Morice MC, Hovasse T, et al., Percutaneous coronary intervention for complex bifurcation lesions.

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23. Zhang F, Dong L, Ge J, et al., Simple versus complex stenting strategy for coronary artery bifurcation lesions in the drug-eluting stent era: a meta-analysis of randomised trials, Heart , 2009;95:1676–81.

24. Brar SS, Gray WA, Dangas G, et al., Bifurcation stenting with drug-eluting stents: a systematic review and meta-analysis of randomised trials, EuroIntervention , 2009;5:475–84.

25. Hakeem A, Khan FM, Bhatti S, et al., Provisional vs. complex stenting strategy for coronary bifurcation lesions: meta-analysis of randomized trials, J Invasive Cardiol , 2009;21(11):589–95.

26. Katritsis DG, Siontis GC, Ioannidis JP, et al., Double versus single stenting for coronary bifurcation lesions: A metaanalysis, Circ Cardiovasc Interv , 2009;2:409–15.

27. Athappan G, Ponniah T, Jeyaseelan L, et al., True coronary bifurcation lesions: meta-analysis and review of literature, J Cardiovasc Med (Hagerstown), 2010;11:103–10.

28. Niccoli G, Ferrante G, Porto I, et al., Coronary bifurcation lesions: To stent one branch or both? A meta-analysis of patients treated with drug eluting stents, Int J Cardiol , 2010;139:80–91.

29. Behan MW, Holm NR, Curzen NP, et al., Simple or complex stenting for bifurcation coronary lesions: a patient-level pooled-analysis of the Nordic Bifurcation Study and the British Bifurcation Coronary Study, Circ Cardiovasc Interv , 2011;4:57–64.

30. Zimarino M, Corazzini A, Ricci F, et al., Late thrombosis after double versus single drug-eluting stent in the treatment of coronary bifurcations: a meta-analysis of randomized and observational Studies, JACC Cardiovasc Interv , 2013;6:687–95.

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Bioresorbable Stents

The Bioresorbable Stent in Perspective— How Much of an Advance is It? V i k t o r Ko č k a a n d Pe t r Wi d i m s k ý Cardiocenter, Third Faculty of Medicine, Charles University, Prague, University Hospital Kralovske Vinohrady, Czech Republic

Abstract The novel idea of bioresorbable stent technology continues to fascinate the interventional community. This article aims to provide a concise and balanced overview of the available technology and clinical evidence. Both potentially positive and negative aspects of bioresorbable stents in different lesion subsets and clinical situations are discussed.

Keywords Bioresorbable vascular scaffold, biodegradable stent Disclosure: Viktor Kočka, MD, FESC, and Petr Widimský, MD, PhD, FESC, FACC, have received occasional speaker’s honoraria from Abbott Vascular.

Received: 8 January 2014 Accepted: 18 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):23–5 Correspondence: Viktor Kočka,MD, FESC, Srobarova 50, 100 34 Prague 10, Czech Republic. E: viktor.kocka@fnkv.cz; petr.widimsky@fnkv.cz

Terminology When the first-in-human implantation of a bioresorbable device into the coronary artery was reported in 2007, the term ‘fully bioabsorbable stent’ was used.1 Later, in 2011, Onuma and colleagues explained that the term ‘bioresorbable’ provides a more precise description of the complete cleavage of macromolecules to small molecules with total elimination and the term ‘scaffold’ was introduced.2 However, the structure looks and behaves exactly like a stent, which is a commonly used term, understood by both medical professionals and patients. Thus, to prevent possible confusion we believe that the term ‘bioresorbable stent’ would be most fitting.

Technology In 2014, there are many bioresorbable stents in different stages of development of which three are described in more detail below.

The most clinical literature currently available is with two generations of the balloon expandable Absorb® device (Abbott Vascular, Santa Clara, California, US). This is formed by a poly-l-lactic-acid polymer backbone (processed for an increased radial strength in the 1.1 version) and a thin amorphous everolimus/poly-lactic-acid matrix coating for controlled drug release. The implant is radiolucent but two platinum markers at each end allow easy visualization with angiography. The single strut thickness is 156 microns. According to preclinical studies the polymer backbone is fully resorbed in 2–3 years; the polymer coating is absorbed more quickly.3 The Absorb stent is commercially available in Europe.

The Dreams® device (Biotronic, Bulach, Switzerland) is a balloon expandable, paclitaxel-eluting magnesium alloy-based bioresorbable coronary stent. 4 The implant is radiolucent with no markers and has a single strut thickness of 125 microns. The absorption process takes 9–12 months. Mechanical properties are similar to the current generation of metallic stents including safe overdilatation. The Dreams stent has not yet received a CE mark.

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The DESolve® stent (Elixir Medical, Sunnyvale, California, US) is also a balloon expandable scaffold made of a poly-l-lactic-acid-based polymer with a strut thickness of 150 microns. It provides sufficient radial strength for over 3 months and is fully bioresorbed in 1–2 years. Interestingly, self-apposing properties have been described and the stent can also be overexpanded by at least 1 mm without evidence of strut fracture in laboratory conditions. The DESolve stent received a CE mark in May 2013.

Evidence First-in-human Studies The ABSORB A study enrolled 30 stable patients with single de novo native short lesions of 3.0 mm calibre and tested the first generation of Absorb stent version 1.0.5 In-stent angiographic late lumen loss was 0.44 ± 0.35 mm at 6 months. Intravascular ultrasound (IVUS) analysis revealed a small neointimal area but also a significant reduction in stent area, probably due to recoil of the Absorb stent version 1.0.

Four-year clinical results with complete follow-up are excellent with only one cardiac event (non-ST elevation acute coronary syndrome) and no stent thrombosis.6 The ABSORB B study enrolled 101 stable patients, again with single de novo lesions, suitable for the implantation of the Absorb stent version 1.1 sized 3.0/18 mm. Excellent clinical results were reported up to four years and, again, there was no stent thrombosis. Planned 6 month invasive assessment of cohort B1 (45 patients) revealed late lumen loss 0.19 ± 1.18 mm and optical coherence tomography (OCT) subanalysis (25 patients) demonstrated 96.8 % strut coverage.7 Similar invasive results were documented at 12, 24, and 36 months.8,9 The BIOSOLVE-I study enrolled 46 patients with stable or unstable angina with one or two de novo short (12 mm or less) and simple lesions with a reference vessel diameter between 3.0 and 3.5 mm for implantation of Dreams stents (3.25/16 mm or 3.5/16 mm).

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Bioresorbable Stents Late lumen loss at 6 months was 0.65 ± 0.50 mm. OCT subanalysis (seven patients) demonstrated 97.2 % of struts to be well apposed at 6 months follow-up. The 12-month rate of clinically driven target lesion revascularization was 4.6 %.4 No further events were reported at the 3-year follow-up, no stent thrombosis occurred.

The DESolve Nx study enrolled 126 patients with mostly stable coronary artery disease with a single de novo short lesion (12 mm or less) and reference vessel diameter between 3.0 and 3.5 mm.

Angiographic late lumen loss was 0.21 ± 0.34 mm at 6 months.

OCT subanalysis (38 patients) demonstrated 98.9 % of struts to be covered. The major adverse cardiac event rate at 12 months was 5.7 % and there was one case of stent thrombosis.

In summary, the first-in-man studies of selected three bioresorbable stents have included a total of 303 patients with mostly stable coronary artery disease. Patients with de novo, short, and ‘simple’ lesions were selected. Acute procedural results were excellent and the angiographic outcomes at 6 months were acceptable. Most importantly, the safety profile seems to be outstanding.

Randomized Studies No results from randomized studies are available. ABSORB II started enrollment in 2011 and compares Absorb stent version 1.1 with the Xience Prime (Abbott Vascular, Santa Clara, California, US) stent in a 2:1 randomized fashion in patients with stable or unstable angina (myocardial infarction is an exclusion criterion). The larger ABSORB III study started enrollment in 2012 in the same fashion and should be sufficiently powered to prove clinical noninferiority. The estimated date of the primary outcome measure completion is August 2015.

Further Reported Data Quantitative coronary angiography analysis demonstrated that the Absorb stent version 1.1 acute recoil is not different, and has better conformability, from metallic stents (Multi-Link or Xience V, Abbott Vascular, Santa Clara, California, US).10,11 Description of strut resorption and surrounding plaque composition by IVUS after Absorb 1.0 and Absorb 1.1 implantation has been reported.12–14 OCT provides excellent resolution but analysis of polymeric structures is different in comparison from metallic stents. The optically translucent polymeric struts appear as a black central core framed by light-scattering borders that do not shadow the vessel wall thus allowing excellent visualization of the vessel wall behind the struts and evaluation of stent apposition.

Stent strut apposition was 95 % at baseline and 98 % at 6 months. A lack of tissue coverage was present in only 1.6 % of struts at 6 months.15 Normalization of local vascular compliance was demonstrated at 6 months.16 The use of online quantitative coronary angiography and especially measurement of maximal diameter of reference segment as a guide to stent size results in more favorable post implantation OCT findings.17,18 Absorb stent version 1.1 implantation was associated with a higher incidence of postprocedural side branch occlusion compared with the everolimus-eluting metallic stent Xience V. This effect was more pronounced with small side branches with a calibre of ≤0.5 mm.19 As far as expanding the use of bioresorbable stents into more challenging clinical scenarios, first case reports or small cohort studies have been reported, generally with encouraging results including: ST segment elevation myocardial infarction (STEMI),20–22 retrograde approach to chronic total occlusion,23 stenting of left main bifurcation,24 vein graft,25 or cardiac allograft vasculopathy intervention.26

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The metal-free struts of Absorb stent version 1.1 (and likely all other polymer-based stents) allow unrestricted coronary computed tomography angiography. 27

Opinions The currently available evidence, as summarized above, does not allow us to reach definitive conclusions. By contrast, two opposing views can often be argued. We present a hypothetical structured debate between a bioresorbable enthusiast and a sceptic.

1) Overall situation. Bioresorbable enthusiast: Revolutionary bioresorbable stents are supported by encouraging data and will expand and dominate in the future. Bioresorbable sceptic: Bioresorbable stents have no proven benefit over currently available drug eluting stents (DES) and should not be routinely used yet.

2) Side branches and bifurcations. Entusiast: Bioresorbable stents are optimal for interventions involving side branches as struts will be resorbed and access to branches restored.28 Sceptic: Bioresorbable stents should not be used in bifurcations—struts may fracture during side branch dilatation and struts are thicker, i.e. more difficult to cross. More side-branch occlusions have been reported.19,29 3) Long lesions. Enthusiast: The longer the lesion, the bigger the potential benefit of resorbable stent with possible elimination of late stent thrombosis and technically possible performance of bypass anastomosis at a later time. Sceptic: Overlaps with struts stacking and resulting thickness over 300 microns present a possible risk for delayed endothelialization.30 4) Imaging. Enthusiast: Polymeric bioresorbable stents allow the evaluation of the coronary artery by computer tomography angiography at any time post implantation. Sceptic: The bioresorbable stent structure is not visualized and optimal expansion cannot be confirmed by angiography thus making the use of intracoronary imaging technology, such as IVUS or OCT, more frequent and thus increasing the complexity and cost of intervention.

5) Myocardial infarction. Enthusiast: Patients with STEMI are ideal candidates for the use of bioresorbable stents as they are typically younger and have soft thrombotic plaques. The first encouraging data have already been presented. Sceptic: There is not enough safety data regarding the use of bioresorbable stents in the highly thrombogenic milieu of acute coronary lesions and there is no proven clinical benefit yet.

6) Vasomotion. Enthusiast: Restoration of normal vasomotion is desirable and could result in a lower rate of future cardiovascular events. Sceptic: Restoration of normal vasomotion could increase the incidence of future vasospasm.

7) Antiplatelet therapy. Enthusiast: If needed, antiplatelet therapy might be safely interrupted once resorption of stent struts is complete and the risk for late stent thrombosis eliminated. Sceptic: Thicker struts of bioresorbable stents might mandate a longer duration of dual antiplatelet therapy than the current generation of DES (all reported studies so far have mandated 12-month dual antiplatelet therapy).

Authors’ Personal View Both authors have been actively involved in the Prague 19 study with the use of Absorb 1.1 stents in patients with STEMI and both

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The Bioresorbable Stent in Perspective

support the use of bioresorbable stent technology. However, there are some remaining concerns. Scientific evidence of superiority over current-generation DES might be achieved in surrogate endpoints, such as vasomotion and vessel remodeling, but evaluation of clinical superiority would require large patient cohorts and long follow-up times (significantly longer than the resorption time of the stent).

This is not likely in the near future. There is no clearly established relationship between the above-mentioned surrogate endpoints and clinical outcomes. On the other hand, evidence of noninferiority could be achievable with a medium-sized randomized study and given the immensely attractive and logical idea of bioresorbable stent, this might

1. Ormiston JA, Webster MW, Armstrong G, First-in-human implantation of a fully bioabsorbable drug-eluting stent: the BVS poly-L-lactic acid everolimus-eluting coronary stent, Catheter Cardiovasc Interv , 2007;69(1):128–31.

2. Onuma Y, Serruys PW, Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization?, Circulation , 2011;123(7):779–97.

3. Onuma Y, Serruys PW, Perkins LE, et al., Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial, Circulation , 2010;122(22):2288– 300.

4. 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(9869):836–44.

5. 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.

6. Dudek D, Onuma Y, Ormiston JA, et al., Four-year clinical follow-up of the ABSORB everolimus-eluting bioresorbable vascular scaffold in patients with de novo coronary artery disease: the ABSORB trial, EuroIntervention , 2012;7(9):1060–1.

7. Serruys PW, Onuma Y, Ormiston JA, et al., Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes, Circulation , 2010;122(22):2301–12.

8. 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.

9. Serruys PW, Onuma Y, Garcia-Garcia HM, et al., Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months, EuroIntervention . 2013 [Epub ahead of print].

10. Onuma Y, Serruys PW, Gomez J, et al., Comparison of in vivo acute stent recoil between the bioresorbable everolimuseluting coronary scaffolds (revision 1.0 and 1.1) and the metallic everolimus-eluting stent, Catheter Cardiovasc Interv , 2011;78(1):3–12.

11. Gomez-Lara J, Garcia-Garcia HM, Onuma Y, et al., A

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be enough to justify widespread use of this technology. From an even more philosophical perspective, this novel technology might lead our community to question the concept of mortality as the only valid and important endpoint. The matter of quality of life with individual patient feelings and, also, interventionalist preference might become more important and result in more diversity in our medical practice. As far as safety is concerned, it is reassuring to note that long-term (over 10 years) clinical outcomes of Igaki-Tamai poly-l-lactic acid coronary stents are excellent with no evidence of harm.31 This particular, first-inhuman bioresorbable stent is not in clinical use anymore but paves the way for future safe clinical use. n

comparison of the conformability of everolimus-eluting bioresorbable vascular scaffolds to metal platform coronary stents, JACC Cardiovasc Interv , 2010;3(11):1190–8.

12. Garcia-Garcia HM, Gonzalo N, Pawar R, et al., Assessment of the absorption process following bioabsorbable everolimuseluting stent implantation: temporal changes in strain values and tissue composition using intravascular ultrasound radiofrequency data analysis. A substudy of the ABSORB clinical trial, EuroIntervention , 2009;4(4):443–8.

13. 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.

14. Brugaletta S, Gomez-Lara J, Bruining N, et al., Head to head comparison of optical coherence tomography, intravascular ultrasound echogenicity and virtual histology for the detection of changes in polymeric struts over time: insights from the ABSORB trial, EuroIntervention , 2012;8(3):352–8.

15. Gomez-Lara J, Radu M, Brugaletta S, et al., Serial analysis of the malapposed and uncovered struts of the new generation of everolimus-eluting bioresorbable scaffold with optical coherence tomography, JACC Cardiovasc Interv , 2011;4(9):992–1001.

16. Brugaletta S, Gogas BD, Garcia-Garcia HM, et al., Vascular compliance changes of the coronary vessel wall after bioresorbable vascular scaffold implantation in the treated and adjacent segments, Circ J , 2012;76(7):1616–23.

17. Farooq V, Gomez-Lara J, Brugaletta S, et al., Proximal and distal maximal luminal diameters as a guide to appropriate deployment of the ABSORB everolimus-eluting bioresorbable vascular scaffold: a sub-study of the ABSORB Cohort B and the on-going ABSORB EXTEND Single Arm Study, Catheter Cardiovasc Interv , 2012;79(6):880–8.

18. Gomez-Lara J, Diletti R, Brugaletta S, et al., Angiographic maximal luminal diameter and appropriate deployment of the everolimus-eluting bioresorbable vascular scaffold as assessed by optical coherence tomography: an ABSORB cohort B trial sub-study, EuroIntervention, 2012;8(2):214–24.

19. Muramatsu T, Onuma Y, Garcia-Garcia HM, et al., Incidence and short-term clinical outcomes of small side branch occlusion after implantation of an everolimus-eluting bioresorbable vascular scaffold: an interim report of 435 patients in the ABSORB-EXTEND single-arm trial in comparison with an everolimus-eluting metallic stent in the SPIRIT first and II trials, JACC Cardiovasc Interv , 2013;6(3):247–57.

20. Wiebe J, Mollmann H, Most A, et al., Short-term outcome of patients with ST-segment elevation myocardial infarction

(STEMI) treated with an everolimus-eluting bioresorbable vascular scaffold, Clin Res Cardiol, 2014;103(2):141–8.

21. Kocka V, Lisa L, Tousek P, et al., ST elevation myocardial infarction treated with bioresorbable vascular scaffold: rationale and first cases, Eur Heart J , 2013;34(27):2073.

22. Kajiya T, Liang M, Sharma RK, et al., Everolimus-eluting bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI), EuroIntervention , 2013;9(4):501–4.

23. La Manna A, Ohno Y, Attizzani GF, Tamburino C, Successful retrograde recanalization of chronic total coronary occlusion with multiple bioresorbable vascular scaffolds (‘full polymer jacket’): initial experience and rationale, Eur Heart J , 2013;34(37):2925.

24. Grundeken MJ, Kraak RP, de Bruin DM, Wykrzykowska JJ, Threedimensional optical coherence tomography evaluation of a left main bifurcation lesion treated with ABSORB(R) bioresorbable vascular scaffold including fenestration and dilatation of the side branch, Int J Cardiol, 2013;168(3):e107–8.

25. Ong PJ, Jafary FH, Ho HH, “First-in-man” use of bioresorbable vascular scaffold in saphenous vein graft, EuroIntervention , 2013;9(1):165.

26. Ribichini F, Pighi M, Faggian G, Vassanelli C, Bioresorbable vascular scaffolds in cardiac allograft vasculopathy: a new therapeutic option, Am J Med , 2013;126(11):e11–4.

27. Nieman K, Serruys PW, Onuma Y, et al., Multislice computed tomography angiography for noninvasive assessment of the 18-month performance of a novel radiolucent bioresorbable vascular scaffolding device: the ABSORB trial (a clinical evaluation of the bioabsorbable everolimus eluting coronary stent system in the treatment of patients with de novo native coronary artery lesions), J Am Coll Cardiol , 2013;62(19):1813–4.

28. Okamura T, Onuma Y, Garcia-Garcia 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.

29. Okamura T, Serruys PW, Regar E, Cardiovascular flashlight.

The fate of bioresorbable struts located at a side branch ostium: serial three-dimensional optical coherence tomography assessment, Eur Heart J , 2010;31(17):2179.

30. Farooq V, Onuma Y, Radu M, et al., Optical coherence tomography (OCT) of overlapping bioresorbable scaffolds: from benchwork to clinical application, EuroIntervention , 2011;7(3):386–99.

31. Nishio S, Kosuga K, Igaki K, et al., Long-term (>10 Years) clinical outcomes of first-in-human biodegradable poly-llactic acid coronary stents: Igaki-Tamai stents, Circulation , 2012;125(19):2343–53.

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Structural

Trans-catheter Aortic Valve Implantation Guidelines – Does the Latest Evidence Change our Views?

Ha nna h Z R M c Co n k e y 1 a n d B e r n a r d Pr e n d e r g a s t 2 1. Oxford Deanery, Oxford, 2. John Radcliffe Hospital, Oxford

Abstract From the wealth of recent registries and trials scrutinising its performance, trans-catheter aortic valve implantation (TAVI) emerges as a viable and rapidly established option, both when compared to medical treatment in inoperable patients and when compared to conventional surgical treatment in high-risk patients. Results consistently demonstrate improvement in functional status and outcome; however, appropriate patient selection remains crucial as high-risk cohorts become apparent.

Keywords Trans-catheter aortic valve implantation (TAVI), aortic stenosis Disclosure: The authors have no conflicts of interest to declare.

Received: 10 January 2014 Accepted: 18 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):26–31 Correspondence: Bernard Prendergast, Consultant Cardiologist, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK. E: Bernard.prendergast@ouh.nhs.uk

Alain Cribier’s determination in the 1980s to provide a definitive solution for high-risk surgical candidates with severe aortic stenosis was met with significant resistance. However, over many years transcatheter aortic valve implantation (TAVI) was developed and refined, leading to the first human procedure in April 2002 in France. Since this first description by Cribier et al.,1 there are now more than 2,000 TAVIrelated articles in peer-reviewed journals. Currently, there are two main devices used in routine practice: the Sapien XT (Edwards Lifesciences, California, US), and the CoreValve (Medtronic Inc., Minneapolis, US), both of which consist of a trileaflet valve: the former delivered using a balloon expandable cobalt chromium open-cell stent and made from bovine pericardial tissue; the latter using a self-expandable nitinol stent and made from porcine tissue.

Valve disease strongly correlates with the phenomenon of population ageing.2 The UK over-65 population has increased by 1.7 million in the last 15 years and by projection it is estimated that by 2034, 23 % of the population will be aged 65 or over. Moreover, the 2010 to 2011 adult cardiac surgery audit has noted that the population of patients being put forward for cardiac surgery is increasingly high risk, where the overall predicted mortality of the population as assessed by the mean logistic European System for Cardiac Operative Risk Evaluation (euroSCORE) has increased from 3.7 % in 2001 to 4.6 % in 2010.3 The treatment of valvular heart disease will therefore continue to be an increasing burden on healthcare resources, with clinicians often facing a dilemma of suitability for surgical intervention.

The current recommendations from the British Cardiovascular Intervention Society (BCIS) and the Society of Cardiothoracic Surgeons (SCTS) are that TAVI should be reserved for patients who have been

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assessed by a multidisciplinary team (MDT) comprising two cardiac surgeons and two interventional cardiologists, and whose risk of open heart surgery is assessed to be too great (usually euroSCORE >20 and Society of Thoracic Surgeons (STS) score >10).4 Patients should have severe symptomatic aortic stenosis, and the procedure should be performed by an experienced team including interventional cardiologists, cardiac surgeons, cardiac anaesthetists and cardiac imaging specialists.5 TAVI has quickly evolved and programmes have grown considerably, and while TAVI is now considered a viable alternative to surgical aortic valve replacement (sAVR) where an open heart operation would be too precarious, careful consideration is required before proposing percutaneous valve implantation for a high-risk surgical patient. The longterm results are only beginning to emerge, and TAVI is not without risk.

Evidence From cohort B of the Placement of AoRtic TraNscathetER Valves (PARTNER) trial,6 we appreciate that the outcome after TAVI compared with medical therapy in a very high-risk patient group is favourable with significant improved 1-year survival and cardiac symptoms.

The Trans-catheter Valve Treatment Sentinel Pilot Registry7 prospectively collected patient data from 4,571 procedures carried out between January 2011 and May 2012, in 137 centres across 10 European countries, using both Sapien XT and CoreValve prostheses. The average age was 81.4 ± 7.1 years, logistic euroSCORE 20.2 ± 13.3 and New York Heart Association (NYHA) class III or IV was present in 76.9 % of patients.

The left ventricular ejection fraction (LVEF) prior to undergoing TAVI was preserved in the majority of cases (mean 54.1 ± 13.8 %) (see Figure 1), with only 8.2 % of patients having significantly impaired LVEF ≤30 %.

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The 1-year outcomes of the SAPIEN Aortic Bioprosthesis European Outcome-XT (SOURCE) study were presented on behalf of the investigators by Dr Stephan Windecker during the European Association of Percutaneous Cardiovascular Interventions (EuroPCR) congress in 2013.8 This is a prospective, observational registry to assess the effectiveness and major adverse events in all patients implanted with a Sapien XT valve (Edwards Lifesciences), via trans-femoral or transapical access and worth noting that the patients included had a slightly lower mean euroSCORE when compared with the patients enrolled in the earlier SOURCE registry of recipients of the predecessor Sapien valve. From 93 centres in 17 countries, 2,688 patients were included in the study. Procedural complication risks (within 48 hours) were as follows: death 2.3 %, stroke 2.2 %, cardiac tamponade 0.9 %, permanent pacemaker implantation 5.7 %, major/life-threatening bleeding 10.8 % and vascular access-related complications 11 %.

Again, a significant disparity between vascular access and mortality was noted, with the highest 1-year survival in the trans-femorally treated patients (85 %), and other routes carrying apparent increased risk (trans-apical and trans-aortic 1-year survival 72.8 % and 73.9 %, respectively). However, the patients requiring an alternative to femoral access are likely to have comorbidities that make this route unsafe (severe peripheral vascular disease with associated cerebrovascular and coronary artery disease), and may therefore be considered inherently higher-risk patients.

The all-cause mortality at 1 year was 19.5 %, and cardiac mortality 10.8 %, which is encouraging in showing a downward trend in mortality rates after TAVI, and also demonstrating a lower incidence of para-valvular regurgitation (PAR) at 1 year than previously reported (6.2 % versus 10.5 % in the PARTNER B trial).6 In multivariate analyses, only porcelain aorta, liver disease, renal impairment, significant tricuspid regurgitation and coronary artery disease (not PAR) emerged as predictors of mortality.

Substantial symptomatic benefit is achieved one year after TAVI with the proportion of patients in NYHA class III or IV reducing from 75.3 % to 9.7 %. Similarly, quality of life (assessed by the EuroQoL 5D [EQ-

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Prendergast_AMc1.indd 27

A. Aortic valve area

B. Aortic regurgitation 1.81

2

Percentage

cm2

1.0

16.5

18

1.5 0.68

0.5

12 7.7 6 1.7

0

Pre

0

Post

1.3

Pre

Post

Grade 2

C. LVEF

60

55.2

54.1

55

Grade 3

D. LV/AO gradient

60 50 45

40 30

40

20

35

10

30

Pre

49.1

50 mmHg

Percentage

This registry has highlighted that, in Europe, TAVI is still reserved for older patients, and is rarely used in patients under the age of 70 (where special circumstances and/or prohibitive comorbidities may exist).

Figure 1: Haemodynamic Changes after Trans-catheter Aortic Valve Implantation

11.2

0

Post

Pre

Post

LV/AO = left ventricle/ascending aorta; LVEF = left ventricular ejection fraction.

Figure 2: PARTNER A – All-cause Mortality 10 70 All-cause mortality (percentage)

Valve deployment was successful in 96.5 % of patients, although a second valve was required in 2.4 % of cases, and surgical conversion occurred in 4.3 %. Analysis of in-hospital mortality demonstrated a sizeable difference between approaches – total mortality reached 7.4 %, the transfemoral approach was associated with a notably lower risk at 5.9 %, while transapical (12.8 %) and trans-subclavian and other approaches (9.7 %) were associated with adverse outcomes (most likely as a consequence of differing clinical characteristics). A significant difference in permanent pacing requirements was also observed between devices used – the CoreValve resulting in 23.4 % versus 6 % for Sapien XT valves. Similarly, a lower rate of aortic regurgitation (AR) was associated with use of Sapien XT valve (3.8 % versus 6.7 % in the CoreValve valve for both grade 2 and 3 AR). The duration of hospital stay varied between countries (mean 9.3 ± 8.1 days), being more prolonged if general anaesthesia had been administered (10.2 ± 8.7 days versus 7.9 ± 6.1 days) and if a trans-apical or another surgical approach had been used (43.8 % and 39.5 % stayed in hospital >10 days versus 22.0 % of patients treated trans-femorally).

HR [95 % Cl] = 0.93 [0.74, 1.15] p (log rank) = 0.483

60

44.8

50 34.6

40

44.2

26.8

30 20

33.7

24.3

10 0

0

6

12

18

24

30

36

Months post randomisation AVR

TAVR Number at risk TAVR

348

298

261

239

222

187

149

AVR

351

252

236

223

202

174

142

AVR = aortic valve replacement; CI = confidence interval; HR = hazard ratio; TAVR = transcatheter aortic valve replacement.

5D] scale) improved from 49.3 to 69.5, and the proportion of patients with angina reduced from 45 % at baseline to 20.6 %.9 Women fared better than men with 90.6 % versus 87.6 % free from cardiac events, and 82.5 % versus 77.9 % freedom from all-cause events at 1 year.

The 3-year outcome of the PARTNER cohort A trial in 699 operable high-risk patients with severe aortic stenosis after TAVI or sAVR was presented by Dr Vinod Thourani at the American College of Cardiology Scientific Session Summit in March 201310 and revealed similar all-cause mortality (44.2 % versus 44.8 %, respectively; p=0.483) and stroke rates (8.2 % versus 9.3 %; p=0.763) between the two procedures (see Figure 2); therefore, very importantly confirming TAVI as a non-inferior treatment option in this high-risk group.

Baseline outcome predictors for the two procedures differed when

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Structural Table 1: PARTNER A – Multivariate Baseline Predictors of Mortality 10 TAVI

Hazard Ratio (95 % CI)

p Value

sAVR

Hazard Ratio (95 % CI)

p Value

Body mass index (lbs/in2)

0.95 (0.92, 0.98)

0.0003

CABG

0.67 (0.49, 0.92)

0.0139

Atrial fibrillation

1.62 (1.15, 2.27)

0.0056

Pacemaker

1.46 (1.03, 2.08)

0.0353

Mean gradient (baseline)

0.98 (0.97, 0.99)

0.0033

Moderate/severe MR at baseline

1.52 (1.03, 2.23)

0.0330

Liver disease

2.39 (1.11, 5.14)

0.0254

Liver disease

2.34 (1.09, 5.04)

0.0302

Renal disease (CR ≥ 2)

1.61 (1.11, 2.35)

0.0131

STS risk score

1.07 (1.02, 1.12)

0.0048

CABG = coronary artery bypass graft; CI = confidence interval; CR = creatinine; MR = Mitral Regurgitation; sAVR = surgical aortic valve replacement; STS = Society of Thoracic Surgeons; TAVI = trans-catheter aortic valve implantation.

Table 2: PARTNER A – Clinical Outcomes at 1, 2 and 3 years 10

1 Year

2 Years

3 Years

Outcome

sAVR TAVI p Value (n=351) (n=348)

sAVR TAVI p Value (n=351) (n=348)

sAVR TAVI (n=351) (n=348)

p Value

Major vascular complications – no. (%) 13 (3.8)

42 (12.1)

<0.001

13 (3.8)

43 (12.5)

<0.001

13 (3.8)

43 (12.5)

<0.001

Major bleeding – no. (%)

88 (26.7)

52 (15.7)

<0.001

95 (29.5)

61 (19.3)

0.003

99 (31.5)

64 (20.8)

0.003

New PM – no. (%)

16 (5.0)

21 (6.4)

0.44

19 (6.3)

24 (7.6)

0.54

20 (6.8)

25 (8.1)

0.56

Endocarditis – no. (%)

3 (1.0)

2 (0.6)

0.63

3 (1.0)

4 (1.5)

0.62

6 (2.6)

4 (1.5)

0.37

Valve failure requiring AVR

0

0

0

0

0

0

Myocardial infarction – no. (%)

2 (0.6)

0

0.16

4 (1.5)

0

0.05

6 (2.7)

2 (1.1)

0.23

Renal replacement therapy – no. (%)

20 (6.5)

18 (5.4)

0.57

22 (7.3)

20 (6.2)

0.59

23 (7.9)

22 (7.2)

0.76

AVR = aortic valve replacement; PM = permanent pacemaker; sAVR = surgical aortic valve replacement; TAVI = trans-catheter aortic valve implantation.

Figure 3: PARTNER A – Impact of Aortic Regurgitation on Mortality in Transcatheter Aortic Valve Replacement Patients 10

Table 3: The UK TAVI Registry Long-term Outcomes – Predictors of Mortality at 1 Year 12

70 60.8

Mortality (percentage)

60

53.7

50

44.6

38.2

40

32.5

26.0

30

35.3

20

25.6

10 0

12.3 0

6

12

24

18

30

36

Months post procedure Mild

None–trace

Variables Route, trans-femoral

Univariate Model 0.65 (0.48–0.88)

p Value 0.006

Route, other

1.00

AR moderate/severe

1.49 (1.00–2.21)

0.048

LVEF 30%–49%

1.93 (1.40–2.66)

<0.001

LVEF <30%

1.89 (1.16–3.07)

0.01

Coronary disease

1.38 (1.01–1.87)

0.04

Any previous cardiac surgery

1.04 (0.75–1.43)

0.83

Peripheral vascular disease

1.28 (0.91–1.75)

0.16

Diabetes mellitus

1.36 (0.98–1.89)

0.07

COPD

1.40 (1.02–1.93)

0.04

Creatinine >200 mmol/l

1.84 (1.14–2.97)

0.012

AR = aortic regurgitation; COPD = chronic obstructive pulmonary disease; LVEF = left ventricular ejection fraction.

Moderate–severe

Number at risk None– trace

131

121

114

102

93

80

63

Mild 171 Moderate– 34 severe

146 24

125 21

117 18

110 15

94 12

62 9

assessed with multivariate analysis (see Table 1), and complications are shown in Table 2. There was a higher burden of moderate or severe PAR after TAVI than sAVR at 1, 2 and 3 years, which conferred a higher risk of mortality – this adverse effect was demonstrable even in patients with mild PAR (see Figure 3).

Repositionable percutaneous replacement of a stenotic aortic valve through implantation of the Lotus Valve System (REPRISE II) is a prospective registry of 120 patients evaluating the efficacy and safety of the Lotus Valve System, a differentiated second-generation TAVI technology which consists of a pre-loaded, stent-mounted tissue valve prosthesis and catheter for delivery and placement of the valve. Initial data presented by Dr Ian Meredith at EuroPCR in 2013,11 demonstrated low 30-day mortality and stroke rates (1.7 % and 3.4 %, respectively) with a further 5.2 % suffering a non-disabling stroke. There was minimal aortic

28

Prendergast_AMc1.indd 28

regurgitation and mean aortic gradient improved significantly from 47.5 ± 17.2 mmHg to 11.3 ± 5.2 mmHg at 30 days. There was, however, a need for permanent pacing in 29.3 % of patients.

The UK TAVI registry12 followed the outcomes of all patients with severe symptomatic aortic stenosis undergoing TAVI with the CoreValve and Edwards Sapien valves in England and Wales between the first implant in January 2007 to December 2009 (877 implants in 870 patients).

Here, 69 % of cases were carried out via the trans-femoral route, whereas patients with peripheral vascular disease, coronary artery disease, prior cardiac surgery, renal dysfunction, and NYHA class III or IV were more likely to have the procedure carried out through alternative access. The median age was 81.9 ± 7.1 years and median logistic euroSCORE 18.5 %. Eight cases were unsuccessful (0.9 %) and emergency conversion to sAVR occurred in 6 patients (0.7 %). Again, there was a higher need for permanent pacing following CoreValve implantation when compared with Sapien (24.4 % versus 7.4 %; p<0.0001).

Survival at 30 days, 1 year and 2 years was 92.9 %, 78.6 % and 73.7 %, respectively, with no statistical difference between the Sapien and CoreValve cohort. However, a maintained survival benefit was noted with

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Trans-catheter Aortic Valve Implantation Guidelines – Does the Latest Evidence Change our Views?

Figure 4: Long-term Survival after Transcatheter Aortic Valve Implantation and the Outcome Affected by the Presence and Absence of Chronic Obstructive Pulmonary Disease and Physical Activity 14

Figure 5: The UK TAVI Registry Long-Term Outcomes – Survival Curves by Log euroSCORE 12 1.00

p=0.0001

1.00 0.75 74 % 53 %

60

42 % 35 %

40 20 0

0.50

0.25

0

Number at risk 88 73

65

47

37

29

0

2

3

4

5

1

Log euroSCORE

Cumulative survival (%)

83 % 80

0

Cumulative survival (%)

Log rank p<0.01

80 60 40 20 0

0

1

2

3

4

5

12

18

24

30

36

42

48

Follow up (months) >40

Years post TAVI 1.00

6

20–40

0–20

associated with a higher risk of mortality (hazard ratio 2.17 [95 % confidence interval 1.18 to 3.70] and 2.98 [95 % confidence interval 1.44 to 6.17] respectively) (Figure 4). Post-procedure, 25 % of patients had no PAR, 63 % had mild PAR and 11.4 % had at least moderate PAR. Predictors of mortality at 1 year are listed in Table 3, and the survival curves according to logistic euroSCORE plotted in Figure 5.

Although there is significantly worse prognosis for the patients with euroSCOREs >40 after 30 days, no survival difference emerged among lower-risk cohorts.

Years post TAVI None/trace/mild PAP post TAVI ≥ Moderate PAR post TAVI

Cumulative survival (%)

1.00

Log rank p<0.01

80 60

Haemodynamic benefits were impressive and sustained. There was a significant improvement in aortic valve area from 0.62 ± 0.17 cm2 to 1.67 ± 0.41 cm2, with persistence of this benefit 5 years post procedure (1.40 ± 0.25 cm2). The same trend was seen with mean aortic valve gradient from 46 ± 18 mmHg to 10 ± 4.5 mmHg pre and immediately post procedure, to 11.8 ± 5.7 mmHg at 5 years. At 4 years, there were no features of prosthetic valve failure, although three patients (3.4 %) developed moderate trans-valvular regurgitation and/or stenosis at 5 years.

40

Interestingly, nearly half of the patients (48 %) had concomitant moderate/severe mitral regurgitation (MR) at the time of TAVI which improved to no/mild MR in 57 % of cases post-operatively.

20 0

0

1

2

3

4

5

Stroke

Years post TAVI COPD -

COPD +

COPD = chronic obstructive pulmonary disease; PAP = pulmonary arterial pressure; PAR = paravalvular regurgitation; TAVI = transcatheter aortic valve implantation.

the trans-femoral route compared with alternative access (81.5 % versus 72.3 % at 1 year; p=0.002; 77.5 % versus 65.3 % at 2 years; p=value <0.001). The UK TAVI investigators also noted that these survival rates are consistent with outcomes in the UK surgical database for octogenarians undergoing sAVR or sAVR with coronary artery bypass grafting.13 A 5-year outcome analysis of the first 111 TAVIs performed between 2005 and 2007 using the Cribier-Edwards or Edwards SAPIEN valve in a single centre in Canada14, reported unsuccessful implantation in 8 cases and 15 deaths occurred within 30 days. Of the remaining 88, 84 (median age 83 ± 7 years) were followed up with a median survival time of 3.4 years (survival rates at 1 to 5 years were 83 %, 74 %, 53 %, 42 % and 35 %, respectively). The presence of chronic obstructive pulmonary disease (COPD) and at least moderate PAR post-TAVI were

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Prendergast_AMc1.indd 29

Neurological sequelae following TAVI remain highly debated, and the adverse event most feared by patients and their families.

Thromboembolic events with cerebrovascular injury may occur at various stages during the TAVI procedure itself (retrograde crossing of the calcified aortic valve, preliminary valvuloplasty, manipulation of the delivery catheter through the aortic arch and valve deployment)15 and may also arise as a result of other post-procedural influences (e.g. atrial fibrillation [AF]). As yet, there is no accepted or evidence-based guidance as to the optimal peri- and post-procedural anti-platelet or anticoagulant regime. However, the ongoing Aspirin versus aspirin and clopidogRel following Transcatheter aortic valvE implantation (ARTE) pilot trial will provide some useful data.

The PARTNER A trial of TAVI versus surgical AVR in high-risk patients with symptomatic aortic stenosis16 showed that the incidence of all stroke and transient ischaemic attack (TIA) following TAVI was 5.5 % at 30 days and 8.3 % at 1 year, and 3.8 % and 5.1 %, respectively, for major stroke. In the surgical arm, all stroke and TIA incidence

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Structural Table 4: Risk of stroke – a meta-analysis of 10,037 TAVI patients 20

Procedural stroke (<24h)

Number of publications with available data (n) 24

Overall number of patients with available data (n) 3041

Number of events (n) 47

Weighted mean ± SD 1.5 ± 1.4 %

30-day stroke/TIA

53

10037

334

3.3 ± 1.8 %

30-day major stroke

42

5514

158

2.9 ± 1.8 %

30-day minor stroke/TIA

42

5514

53

1.0 ± 1.3 %

30-day overall mortality

52

10022

812

8.1 ± 3.9 %

30-day mortality in patients suffering stroke

29

4430

41

25.5 ± 21.9 %

30-day mortality in patients without stroke

29

4430

312

6.9 ± 4.2 %

6-month stroke

9

669

29

4.3 ± 1.6 %

12-month stroke

7

1507

78

5.2 ± 3.4 %

was 2.4 % and 4.3 % at 30 days and 1 year, respectively, and 2.1 % and 2.4 % for major stroke. These data, suggesting an early excess of stroke following TAVI, were balanced by longer-term follow-up data showing equivalent stroke rates at 36 months (8.2 % versus 9.3 %, respectively, p=0.763).

In the PARTNER B trial,6 patients deemed unsuitable for surgery due to comorbidities associated with a predicted probability of ≥50 % of death after surgery, were randomised to undergo TAVI or continue with medical therapy. There was a significant reduction in mortality associated with TAVI at 1-year follow up (30.7 % versus 50.7 %, hazard ratio [HR] 0.58; 95 % confidence interval [CI] 0.43 to 0.78; p<0.001) although major strokes were more common in the TAVI group (5.0 % versus 1.1 % at 30 days; p=0.06; 7.8 % versus 3.9 % at 1 year; p=0.18).

A small study conducting diffusion-weighted magnetic resonance imaging (MRI) scans to detect subclinical cerebral ischaemic post-TAVI with CoreValve valves identified that silent cerebral embolism is frequent (73 %) compared with the incidence of clinically apparent cerebral embolism (3.6 %).17 This high subclinical uncovering was again shown in a small study that carried out neurological testing and serial cerebral diffusion weighted MRI at baseline, at 3.4 days (2.5–4.4) post-procedure and at 3 months. New ischaemic lesions were identified in 84 % of cases, which is considerably more when compared with 48 % of sAVR patients, and were usually multiple but smaller than after sAVR. No patients were symptomatic, there was no demonstrable neurocognitive impairment and no further events were reported at 3 months.18 A meta-analysis of TAVI versus sAVR derived from 14 studies found no significant difference in stroke risk, either at the time of the procedure (2.6 % versus 2.3 %, relative risk [RR] 1.16, 95 % CI 0.72–1.87; p=0.54) or at 1-year follow up (4.5 % versus 3.4 %, RR 1.27, 95 % CI 0.68–2.37; p=0.46).19 However, a subgroup analysis of two randomised controlled trials did identify higher incidence of stroke/TIAs associated with TAVI (5.8 % versus 2.3 %; p=0.02).

In a prospective single-centre registry (Bern TAVI registry) of 389 high-risk elderly patients with severe symptomatic aortic stenosis undergoing TAVI from August 2007 to October 2011, 14 patients (3.6 %) experienced at least one stroke (major in 3.1 %; minor in 0.5 %) and 71.4 % of these occurred within 1 day of the procedure.15 Smaller body mass index (BMI ≥25 adjusted odds ratio [AOR] 0.78 compared with BMI <25), previous stroke (AOR 1.87) and chronic obstructive pulmonary disease (COPD) (AOR 4.73) were all risk factors for cerebrovascular complications. However, conventional risk factors for stroke including age, hypertension, male gender, diabetes

30

Prendergast_AMc1.indd 30

mellitus, smoking and AF were not found to have an effect, nor antithrombotic treatment at baseline. Surprisingly, the number of aortic valve pre-dilatations was not associated with a higher incidence of stroke, whereas the converse is true with post-dilatation (AOR 2.00).

Significant risk was also associated with more than one implantation attempt (AOR 8.32). All-cause mortality at 30 days was significantly higher in the group who suffered a stroke (42.3 % versus 5.1 %, OR 11.7, 95 % CI 3.4–40.3; p<0.001) with cardiovascular mortality accounting for 38.4 % in the stroke group, and 4.6 % in the group with no neurological consequences.

Similarly, a higher 30-day mortality was associated with stroke in a meta-analysis including 10,037 patients undergoing TAVI between January 2004 and November 2011.20 Here, procedural stroke (<24 hours) occurred in 1.5 ± 1.4 %, increasing to 3.3 ± 1.8 % at 30 days, 4.3 ± 1.6 % at 6 months and 5.2 ± 3.4 % at 1 year. Table 4 shows the incidence of stroke and associated mortality.

In a 5-year follow-up period, cumulative major ischaemic stroke rates were 9.7 % and haemorrhagic stroke rates 7.3 % (50 % fatal). The calculated annual risk of ischaemic stroke was consistently around 2 %, whereas the risk of haemorrhagic stroke increased each year, being 2.8 % in the first year, and reaching 7.3 % in years 4 and 5.14

Conclusion From the wealth of registries and trials scrutinising its performance, TAVI emerges as a viable and rapidly established option, both when compared with medical treatment in inoperable patients and when compared with conventional surgical treatment in high-risk patients. It has revolutionised the treatment of high-risk patients with severe calcific aortic stenosis, and results continue to improve as operator experience grows and technology develops.

Long-term results in well-selected patients are excellent, although choosing the right patient is vital. From the trials mentioned, the independent predictors of outcome are BMI, COPD, post-TAVI AR, porcelain aorta, liver disease, AF, renal disease and impaired LVEF, many of which are not accounted for within currently available risk stratification tools. A more recent publication assessing predictors of 6-month poor clinical outcome after TAVI has shown AF, severe baseline pulmonary hypertension and right ventricular dysfunction to be associated with poor outcome, and baseline AR to be protective.21 While TAVI is an excellent option, it is important to consider which patients are least likely to benefit, including those with a euroSCORE >40, severe left or right ventricular systolic dysfunction, severe respiratory disease and restricted mobility.

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Trans-femoral access is associated with improved overall survival, although it is clear that the cohort of patients treated via an alternative route already have a more adverse risk profile. Advances in technology will hopefully address areas of concern such as paravalvular AR and pacing requirements.

1. Cribier A, Eltchaninoff H, Bash A, et al., Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description, Circulation , 2002;106(24):3006–8.

2. Nkomo VT, Gardin JM, Skelton TN, et al., Burden of valvular heart diseases: a population-based study, Lancet , 2006;368:1005–11.

3. The National Adult Cardiac Surgery Audit Report, Annual Report 2010–2011. Available at: http://www.ucl.ac.uk/nicor/ audits/Adultcardiacsurgery/publications/pdfs/NACSA_ annual_report_FINAL (accessed 20 February 2014).

4. Transcatheter Aortic Valve Implantation (TAVI), A position statement of the British Cardiovascular Intervention Society (BCIS) and the Society of Cardiothoracic Surgeons (SCTS). December 2008. Available at: http://www.bcis.org. uk/resources/documents/BCIS%20SCTS%20position%20 statement.pdf (accessed 20 February 2014).

5. Vahanian A, Alfieri O, Andreotti F, et al., ESC/EACTS Guidelines on the management of valvular heart disease, Eur Heart J , 2012;33:2451–96.

6. Leon MB, Smith CR, Mack M, et al.; PARTNER Trial Investigators, Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med , 2010;363:1597–1607.

7. Di Mario C, Eltchaninoff H, Moat N, et al.; Transcatheter Valve Treatment Sentinel Registry (TCVT) Investigators of the EURObservational Research Programme (EORP) of the European Society of Cardiology. The 2011–12 pilot European Sentinel Registry of Transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients, EuroIntervention ,

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Current risk scores have good discrimination (low versus high risk), but poor calibration (predicted versus observed risk)22 and we need more rigorous risk stratification tools. However, the role of the heart team remains central in optimal patient selection. Nearly 12 years since the first procedure, TAVI is flourishing, and with ongoing development, will continue to do so. n

2013;8:1362–71.

8. SOURCE XT Post-Approval Study, presented at EuroPCR 2013. Available at: http://www.pcronline.com/About/DailyNews/2013/EuroPCR/Wrap-up/Late-breaking-trials (accessed 20 February 2014).

9. Available at: http://www.medscape.com/viewarticle/804576 (accessed 5 January 2014).

10. Three-Year Outcomes after Transcatheter or Surgical Aortic Valve Replacement in High-Risk Patients with Severe Aortic Stenosis, presented at ACC 2013. Available at: http:// clinicaltrialresults.org/Slides/ACC%202013/Thourani_ PARTNER%20Cohort%20A_ACC%202013.ppt (accessed 20 February 2014).

11. Repositionable Percutaneous Replacement of a Stenotic Aortic Valve through Implantation of the Lotus Valve System. 30-day Outcomes for the first 60 patients in the REPRISE II Study, presented at EuroPCR 2013. Available at: http://solaci.org/en/ ian_meredith_europcr.php (accessed 20 February 2014).

12. Moat NE, Ludman P, de Belder, et al., Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry, J Am Coll Cardiol , 2011;58:2130–8.

13. Bridgewater B, Keogh B, Sixth National Adult Cardiac Surgical Database Report, Society for Cardiothoracic Surgery, 2008. Available at: http://www.e-dendrite.com/ files/13/file/Pages%20from%20NACSD%202008.pdf (accessed 20 February 2014).

14. Toggweiler S, Humphries KH, Lee M, et al., 5-year outcome after transcatheter aortic valve implantation, J Am Coll Cardiol ,

2013;61:413–19.

15. Stortecky S, Windecker S, Pilgrim T, et al., Cerebrovascular accidents complicating transcatheter aortic valve implantation: frequency, timing and impact on outcomes, EuroIntervention , 2012;8:62–70.

16. Smith CR, Leon MB, Mack MJ, et al., for the PARTNER Trial Investigators Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients, N Engl J Med, 2011; 364:2187–98.

17. Ghanem A, Müller A, Nähle CP, et al., Risk and fate of cerebral embolism after transfemoral aortic valve implantation: a prospective pilot study with diffusion-weighted magnetic resonance imaging, J Am Coll Cardiol , 2010;55:1427–32.

18. Kahlert P, Knipp SC, Schlamann M, et al.,Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic resonance imaging study, Circulation , 2010;121:870–8.

19. Cao C, Ang SC, Indraratna P, et al., Systematic review and meta-analysis of transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis, Ann Cardiothorac Surg , 2013;2(1):10–23.

20. Eggebrecht H, Schmermund A, Voigtländer T, et al., Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients, EuroIntervention , 2012;8:129–38.

21. Auffret V, Boulmier D, Oger E, et al., Predictors of 6-month poor clinical outcomes after transcatheter aortic valve implantation. Arch Cardiovasc Dis, 2013;S1875-2136(13)00331–8.

22. Kovac J, Baron JH, Chin DT, Are the standard criteria for TAVI too lax or too strict?, Heart , 2010;96(1):5–6.

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LE ATION.

Surgical Approaches to Aortic Valve Replacement and Repair— Insights and Challenges Ba sel R a mla wi , M a h e s h R a m c h a n d a n i a n d M i c h a e l J R e a r d o n Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas, US

Abstract Since 1960, surgical aortic valve replacement (sAVR) had been the only effective treatment for symptomatic severe aortic stenosis until the recent development of transcatheter aortic valve replacement (TAVR). TAVR has offered an alternative, minimally invasive treatment approach particularly for patients whose age or co-morbidities make them unsuitable for sAVR. The rapid and enthusiastic utilization of this new technique has triggered some speculation about the imminent demise of sAVR. We believe that despite the recent advances in TAVR, surgical approach to aortic valve replacement has continued to develop and will continue to be highly relevant in the future.

This article will discuss the recent developments and current approaches for sAVR, and how these approaches will keep pace with catheter-based technologies.

Keywords Aortic stenosis, surgical aortic valve replacement (sAVR), mini thoracotomy, mini sternotomy, aortic regurgitation Disclosure: Basel Ramlawi, MD, is a Consultant for Atricure, Inc. Mahesh Ramchandani, MD, has no conflicts of interest to declare. Michael J Reardon, MD, is a Consultant for and sits on the Advisory Board of Medtronic, Inc. Acknowledgment(s): The authors would like to thank Maitreyi Muralidhar, B.Pharm, MS Pharmacology, employee of Houston Methodist DeBakey Heart & Vascular Center, for critically reviewing and editing the manuscript.

Received: 5 February 2014 Accepted: 16 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):32–6 Correspondence: Michael J Reardon, MD, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas, US. E: MReardon@houstonmethodist.org

Symptomatic severe aortic stenosis or insufficiency have no effective medical treatments and carry a dismal prognosis if left untreated. Since the first aortic valve replacement in 1960, hundreds of thousands of lives have been saved and improved by this procedure. Until recently, surgical aortic valve replacement (sAVR) was the only effective therapy for severe aortic valve stenosis. The recent introduction of transcatheter aortic valve replacement (TAVR) has offered an alternative in specific high-risk patients with symptomatic severe aortic stenosis. The rapid adoption and dissemination of TAVR have led some to speculate on the demise of sAVR. Although TAVR has and will continue to cater to a portion of patients with aortic valve disease, in the meantime, the field of sAVR has not stood stagnant but rather continues to advance and improve in tandem with TAVR. In addition to surgical valve replacement techniques, repair principles have been adopted from the mitral valve to the aortic valve with growing success leading to the standardization of regurgitant aortic valve repair approaches. This article will examine the current surgical approaches for aortic valve replacement with insights into the challenges faced and how these approaches will remain competitive with catheterbased technologies. We will focus on minimally invasive approaches to sAVR, new valve technologies, and aortic valve repair techniques.

Minimally Invasive Surgical Aortic Valve Replacement sAVR requires the use of the heart lung machine to stop the heart and to allow access to the aortic valve within the heart. The traditional approach to exposing the heart for bypass and to gain access to the

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aortic valve has been via median sternotomy. Median sternotomy allows excellent access to all cardiac structures but requires complete division of the sternum and sternal spreading. This disrupts the integrity of the chest wall in the early recovery phase. Surgeons therefore decided to look for less invasive ways of performing sAVR to see if this would lead to easy recovery and possibly improved results for patients. The parasternal approach to sAVR was first reported by Cosgrove in 1996, but has been largely abandoned due to chest wall hernias.1 The right mini thoracotomy approach was introduced by Benetti in 19972 and the mini sternotomy approach

by Gundry in 1998.3 At the Houston Methodist Hospital, we began our minimally invasive valve program in 1999 when we performed anatomic studies on cadavers. In these studies, we examined the relationship of the cardiac valve structures to the chest wall to help plan potential surgical approaches.4 From these early studies in our program, we have employed two minimally invasive approaches to sAVR: mini sternotomy and mini thoracotomy (see Figure 1).

Right Anterior Mini Thoracotomy Right anterior mini thoracotomy is performed with the patient in the supine position with femoral cannulation, most commonly for both the venous and arterial cannulae. In cases where retrograde aortic blood flow is not desired (e.g. peripheral vascular disease), direct cannulation of the distal ascending aorta or right axillary can be performed along with percutaneous femoral venous cannulation. An incision is made over the right third intercostal space and the fourth

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costal cartilage is divided to allow exposure. Cardioplegia can be performed by direct antegrade coronary infusion through the aortic root or a retrograde coronary sinus catheter can be placed via the right jugular vein under transesophageal echocardiographic (TEE) and/or fluoroscopic guidance. It is also possible for the surgeon to place a retrograde catheter directly through the right atrium with echo guidance. A malleable aortic clamp is used for cross-clamping the aorta and aortotomy exposure is standard. Left ventricular vent (right superior pulmonary vein [RSPV]), replacement of the aortic valve, and suture placement is similar to standard sternotomy approach. Care must be taken to ensure the far corner of the aortotomy closure is secure before coming off cardiopulmonary bypass (CPB), as this area can be difficult to see in some patients after separation from bypass. The advantage of this approach is that it does not destabilize the sternum and the chest wall. Disadvantages can include occasional decreased exposure and the need to divide the right mammary artery in all cases. A preoperative chest computed tomography (CT) scan can be helpful for preoperative planning and delineation of aortic anatomy/orientation.

Figure 1: Placement of Incision for Mini Thoracotomy and Mini Sternotomy A

B

A. Incision for mini thoracotomy. B. Incision for mini sternotomy.

Figure 2: Trifecta Pericardial Valve

Mini Sternotomy Mini sternotomy is carried out with the patient supine. A skin incision is made over the upper sternum. The third or fourth right intercostal space is exposed and opened next to the sternum.

The sternum is divided from the sternal notch to this level and then ‘Jed’ off into the right interspace. Cannulation for bypass can be performed completely centrally or, more commonly, we use percutaneous femoral venous drainage and central aortic arterial return. This affords excellent exposure of the ascending aorta and aortic root similar to full sternotomy. Cardioplegia can be administered via direct antegrade infusion through the aortic root or combined with retrograde infusion via the coronary sinus.

We can generally cannulate the coronary sinus under TEE guidance through the right atrium and the RSPV can be used to decompress the left ventricle. Both mini thoracotomy and mini sternotomy offer limited access, which can complicate de-airing, therefore, we use CO2 insufflation. The advantage of the sternotomy approach is that it is familiar to more cardiac surgeons who are used to full median sternotomy, affords excellent exposure of the ascending aorta and aortic root, can be used with central cannulation, does not violate the pleural space, and is easily converted into a full sternotomy if needed. The fact that part of the sternum is divided is considered by some to be a disadvantage of this approach.

Outcomes for Minimally Invasive Surgical Aortic Valve Replacement For minimally invasive sAVR to be successful, it should, at a minimum, pose no safety hazards and allow the same technical valve procedure as full sternotomy AVR. Additionally, it would be hoped that these approaches would improve mortality, morbidity, and cause less pain and faster recovery. A number of observation studies of minimally invasive sAVR have shown less blood loss and blood usage, shorter hospital stays, less atrial fibrillation, and faster return to functional activity.5–7 Propensity matched studies of minimally invasive versus full sternotomy sAVR have confirmed the safety of these approaches, but have not shown a survival advantage in average risk patients.8–10 The safety of this approach has even been shown in reoperative sAVR,11 the elderly,12 and high-risk patients.13 Small randomized studies have also started to appear in the literature.14 The overall consensus is that a minimal approach provides the same safety as the conventional

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approach, and offers some advantages including less blood loss, shorter hospital stay, faster recovery in the early phase, and better patient acceptance.

Valves Currently, two main groups of artificial valves or prosthesis are available for aortic valve replacement. These are mechanical valves and tissue/bioprosthetic valves. The main advantage of mechanical valves is their excellent durability. Their principal disadvantage is the need for lifelong anticoagulation therapy due to increased risk for blood clots. Tissue valves, on the other hand, have less durability and tend to wear out sooner than mechanical valves.

However, they do not require lifelong anticoagulation. Over the last 2 decades, there has been a growing trend to implant more tissue aortic valves as opposed to mechanical valves. 15 Tissue aortic valves (e.g. bovine, porcine, and homografts/human cadaveric aortic valves) can be stented or stentless. One major concern with stented (tissue mounted on a stent) bioprosthesis has been the less-than-optimal systolic hemodynamic performance with the smaller sizes. Stentless bioprosthesis have excellent hemodynamics but are generally more complex to implant in the subcoronary position or are carried out as a root replacement, which is a longer and more complex procedure. In this review, we will focus on the more commonly used stented bioprosthesis. TAVR series have shown excellent systolic hemodynamic function in all annular sizes thus presenting a challenge for sAVR using stented bioprosthesis.16,17 Valve innovation is fortunately still occurring and one answer to improving the systolic hemodynamics of the stented bioprosthesis is the new St Jude Medical Trifecta valve (St Paul, Minnesota, US).

The Trifecta valve is an externally wrapped, stented pericardial valve designed to allow a larger effective orifice area (EOA) (see Figure 2).

A clinical trial with this valve was conducted from 2007 to 2009 at 31 centers and published in 2014.18 The question of poor hemodynamic performance in the smaller sizes did not appear in this series. All valves

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Structural Figure 3: McGovern-Cromie Valve

reducing operative time and because these are known to carry the risk for postoperative mortality and morbidity, especially in higher risk patients, or when combined procedures need to be performed (AVR/ coronary artery bypass surgery [CABG] or multiple valves).19

Figure 4: New Sutureless Aortic Valves A

B

C

A. Enable valve. B. Perceval S valve. C. Intuity valve.

from 19 mm to 29 mm had single digit mean gradients at discharge. At 1 year, this still held true for all but the 19 mm size, which had a mean gradient of 10.7 mm Hg, which is still highly desirable. Mean indexed EOA at 1 month did not show any patient prosthetic mismatch (PPM) and only the 19 mm size gave an indexed EOA of 0.85 cm2/m2, which is the absolute upper end of moderate PPM. Early results with the Trifecta valve are promising, with indications of improved systolic hemodynamics and potential advantages of lower transvalvular gradients. However we would like to point out that, currently, this is one of the several options available and that longer term follow-up data are necessary to evaluate the effectiveness and durability of this design. Further, if this valve does undergo structural valve deterioration necessitating a new valve, the external pericardial wrap may make coronary occlusion a greater risk if the TAVR valve-in-valve method is chosen and this remains to be tested.

Sutureless Valves The concept of an aortic valve that could be placed without sutures is not new and in fact originated with the McGovern-Cromie valve in 1964 (see Figure 3). The success of TAVR has refocused attention in this area and currently three sutureless aortic valves are either available outside of the US or being tested here (see Figure 4). The 3f Enable bioprosthesis by Medtronic (Medtronic, Inc., Minneapolis, Minnesota, US) and the Perceval S by Sorin (Sorin Biomedica Cardio Srl, Saluggia, Italy) are self-expanding with Nitinol frames and pericardial leaflets. The Intuity by Edwards (Edwards Lifesciences, Irvine, California, US) has a balloon-expandable frame and pericardial leaflets. Although termed sutureless valves, guiding sutures are often used to seat the valve properly and a better term for them might be rapid deployment valves. These valves are placed when the patient is on CPB with aortic cross-clamp (ACC) under cardioplegic arrest.

The native stenotic leaflets are removed, but without the meticulous decalcification normally carried out for a sAVR, as some remaining calcium will help hold the valve in place. The concept for these valves is that they would simplify valve implantation by shortening both cross-clamp time and cardiopulmonary bypass times and maintain the excellent hemodynamics seen in TAVR, but with a decreased incidence of paravalvular leak (PVL), and thus will allow increased adoption of minimally invasive surgical approaches to sAVR. Shortening cross-clamp and CBP times is appealing in terms of

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Sutureless aortic valves are still early in their development and a number of smaller trials with these exist. One of the larger trials was reported by Kocher and involved 146 patients in six European centers using the Intuity valve.20 The 1-year hemodynamic performance was good but two early and two late valve explants were required. The ACC time was 41.1 minutes and only 31.1 % of the cases were performed via a minimally invasive approach. A propensity matched study between 519 patients having TAVR or sAVR using the Perceval S valve and then matched to 38 pairs has been presented by D’Onofrio.21 Hemodynamic performance, complications, and pacemaker insertion rates were similar between the groups.

Differences were seen in a greater rate of atrial fibrillation in the sAVR group (42 % versus 16 %) and a lesser rate of at least mild PVL in the sAVR group (16 % versus 45 %), though PVL results along the same lines may not be representative of all studies. Current data on sutureless aortic valves would suggest that they can be used safely, with good hemodynamics and with acceptable complication rates. It is however unknown if this will increase the adoption of minimally invasive approaches to sAVR or improve patient outcomes. Also unknown is the long-term durability of these valves. Despite these areas of concern, these valves offer the potential for a simplified and reproducible technique for sAVR, provide another tool in the toolbox of aortic surgeons, and deserve further study.

Aortic Valve Repair The success of mitral valve repair in treating mitral regurgitation has prompted the development of repair techniques for aortic regurgitation. Successful aortic valve repair as opposed to sAVR would allow the patient to avoid anticoagulation as well as structural valve deterioration. Successful aortic valve repair, like mitral valve repair, requires an understanding of the mechanisms leading to aortic insufficiency (AI). A functional classification of AI similar to the Carpentier classification for mitral regurgitation has been presented

by El Khoury22 (see Figure 5). Type I AI shows central regurgitation. This can occur from dilatation of the annulus or the sinotubular junction.

Dilatation of the sinuses alone does not lead to AI. Additionally a perforation of the valve cusp can lead to a Type I central regurgitation.

An eccentric regurgitation from cusp prolapse is seen in Type II and from cusp restriction in Type III. Repair techniques, as with mitral valve repair, are dependent on the mechanism causing the regurgitation.

Type I Aortic Regurgitation Central regurgitation due to cusp perforation can occur in endocarditis or trauma. If the regurgitation is limited, it can be repaired by pericardial patch closure. The more common causes of Type I AI are annular and sinotubular junction dilatation. Occasionally, the AI is due to dilatation of the sinotubular junction when an ascending aortic aneurysm is the only pathology. The aortic aneurysm can be repaired by graft replacement of the ascending aorta. The diameter of the graph is equal to the free margin (annular diameter) of the cusps or slightly undersized. This brings the commissural posts back into alignment and allows proper coaptation of the valve cusps to eliminate AI. Annular dilatation requires reducing the annular diameter. Although there are subannular rings being developed for this purpose similar to mitral rings, they are still early in their development. This is more commonly performed using a valve sparing

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Figure 5: Functional Classification of Aortic Insufficiency AI Class

Type I

Type II

Type III

Normal cusp motion with FAA dilatation or cusp perforation Ia

Ib

Ic

Id

Cusp Prolapse

Cusp Restriction

STJ Remodeling Ascending aortic graft

Aortic Valve Sparing Reimplantation or remodeling with SCA

SCA

Patch Repair Autologous or bovine pericardium

Prolapse Repair Plication Triangular resection Free margin Resuspension Patch

Leaflet Repair Shaving Decalcification patch

SCA

SCA

SCA

Mechanism

Repair Techniques (Primary)

(Secondary)

SCA

STJ Annuloplasty

AI = aortic insufficiency; FAA = functional aortic annulus; SCA = subcommissural annuloplasty; STJ = sinotubular junction. Source: Boodhwani M et al.,

root replacement (VSRR) technique. Two common approaches have been used for fixing annular dilatation: remodeling introduced by Sarsam et al.23 and the reimplantation technique introduced by David et al.24 (see Figure 6) The remodeling technique removes the sinuses and coronaries are freed up as buttons, leaving the aortic valve and a several millimeter rim of sinus above the annulus. A graft is then fashioned with tongues that extend down to replace the sinuses and the coronary buttons are then reimplanted. The reimplantation technique differs in that the graft is brought over the remaining valve and rim of the sinus tissue. The graft is loosely sewn with subannular sutures extending out through the graft to hold it in place. The valve complex is then sewn inside the graft forming the hemostatic sealing suture line. The coronaries are then reimplanted in a standard fashion. The reimplantation technique allows stabilization of the annulus unlike remodeling. Reimplantation may potentially be a better approach for a patient subject to recurring annular dilatation like patients with connective tissue disorders or bicuspid valves.

Type II Aortic Regurgitation Cusp prolapse may occur with Type I anatomy or in isolation. The base of the valve cusp is generally about 1.5 times longer than the free margin of the cusp. If the free margin elongates and approaches the length of the base, then the cusp will prolapse into the ventricle during diastole and allow AI. The surgical solution to this is to shorten the free margin length of the cusp. This can be performed by resection of the center point of the elongated cusp or just suture imbrication of this area. The cusps can also be shortened by imbrication at the aortic wall or by placing a free margin suture of fine polytetrafluoroethylene (PTFE).

Type III Aortic Regurgitation Like restricted leaflets in mitral regurgitation, cuspal restriction in AI does not lend itself well to repair using current techniques and generally requires valve replacement.

1. Cosgrove DM, 3rd, Sabik JF, Minimally invasive approach for aortic valve operations, Ann Thorac Surg , 1996;62(2):596–7.

2. Benetti FJ, Mariani MA, Rizzardi JL, et al., Minimally invasive aortic valve replacement, J Thorac Cardiovasc Surg , 1997;113(4):806–7.

3. Gundry SR, Shattuck OH, Razzouk, et al., Facile minimally invasive cardiac surgery via ministernotomy, Ann Thorac Surg , 1998;65(4):1100–4.

4. Reardon MJ, Conklin LD, Philo R, et al., The anatomical aspects of minimally invasive cardiac valve operations, Ann Thorac Surg , 1999;67(1):266–8.

5. Johnston DR, Atik FA, Rajeswaran J, et al., Outcomes of less

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2009.29

Reprinted with permission.

Figure 6: Valve Sparing Root Replacement Techniques

A

B

A. Diagrammatic representation of reimplantation. B. Diagrammatic representation of remodeling. Both figures reprinted with permission. Source: David TE, Korean J Thorac Cardiovasc Surg, 2012;45:207 (Figure B); 208 (Figure A).

Outcomes for Aortic Valve Repair and Valve Sparing Aortic Root Procedures Long-term results have been reported for several studies that have used the remodeling or reimplantation approach. Following remodeling, freedom from moderate or severe AI at 10 years was 64 % in the study

by Yacoub et al.,25 96 % for bicuspid valves, and 87 % for tricuspid valves as reported by Aicher et al.26 Following reimplantation, freedom from reoperation at 10 years was 93 % for David et al.27 and 88 % for De Paulis et al.28 Aortic valve sparing operations have been shown to have good long-term outcomes in experienced centers and offer the ability to maintain the patient’s native valve.

Conclusion Surgical approaches to aortic valve disease continue to advance and improve. We agree that TAVR technology is an exciting and useful addition to the surgeon’s toolkit for treating aortic valve disease but also believe that surgical improvements will keep sAVR highly relevant and necessary for a large portion of patients with specific aortic valve pathologies. n

invasive J-incision approach to aortic valve surgery, J Thorac Cardiovasc Surg , 2012;144(4):852–8 e3.

6. Korach A, Shemin RJ, Hunter CT, Bao Y, Shapira OM, Minimally invasive versus conventional aortic valve replacement: a 10-year experience, J Cardiovasc Surg (Torino), 2010;51(3):417–21.

7. Brown ML, McKellar SH, Sundt TM, Schaff HV, Ministernotomy versus conventional sternotomy for aortic valve replacement: a systematic review and meta-analysis, J Thorac Cardiovasc Surg , 2009;137(3):670– 9 e5.

8. Gilmanov D, Bevilacqua S, Murzi M, et al., Minimally invasive and conventional aortic valve replacement: a propensity

score analysis, Ann Thorac Surg , 2013;96(3):837–43.

9. Furukawa N, Kuss O, Aboud A, et al., Ministernotomy versus conventional sternotomy for aortic valve replacement: matched propensity score analysis of 808 patients, Eur J Cardiothorac Surg , 2014 [Epub ahead of print].

10. Glauber M, Miceli A, Gilmanov D, et al., Right anterior minithoracotomy versus conventional aortic valve replacement: a propensity score matched study, J Thorac Cardiovasc Surg , 2013;145(5):1222–6.

11. Tabata M, Khalpey Z, Shekar PS, Cohn LH, Reoperative minimal access aortic valve surgery: minimal mediastinal dissection and minimal injury risk, J Thorac Cardiovasc Surg ,

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Structural 2008;136(6):1564–8.

12. Mihaljevic T, Cohn LH, Unic D, et al., One thousand minimally invasive valve operations: early and late results, Ann Surg , 2004;240(3):529– 34; discussion 34.

13. Schmitto JD, Mohr FW, Cohn LH, Minimally invasive aortic valve replacement: how does this perform in high-risk patients?, Curr Opin Cardiol , 2011;26(2):118–22.

14. Moustafa MA, Abdelsamad AA, Zakaria G, Omarah MM, Minimal vs median sternotomy for aortic valve replacement, Asian Cardiovasc Thorac Ann , 2007;15(6):472– 5.

15. Brown JM, O’Brien SM, Wu C, et al., Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons National Database, J Thorac Cardiovasc Surg, 2009;137(1):82–90.

16. Leon MB, Smith CR, Mack M, et al., Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med , 2010;363(17):1597–607.

17. Smith CR, Leon MB, Mack MJ, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Engl J Med , 2011;364(23):2187–98.

18. Bavaria JE, Desai ND, Cheung A, et al., The St Jude Medical Trifecta aortic pericardial valve: Results from a global,

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multicenter, prospective clinical study, J Thorac Cardiovasc Surg , 2014;147(2):590–7.

19. Flameng WJ, Herijgers P, Szecsi J, et al., Determinants of early and late results of combined valve operations and coronary artery bypass grafting, Ann Thorac Surg , 1996;61(2):621–8.

20. Kocher AA, Laufer G, Haverich A, et al., One-year outcomes of the Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve (TRITON) trial: a prospective multicenter study of rapid-deployment aortic valve replacement with the EDWARDS INTUITY Valve System, J Thorac Cardiovasc Surg , 2013;145(1):110–5; discussion 5–6.

21. D’Onofrio A, Messina A, Lorusso R, et al., Sutureless aortic valve replacement as an alternative treatment for patients belonging to the “gray zone” between transcatheter aortic valve implantation and conventional surgery: a propensitymatched, multicenter analysis, J Thorac Cardiovasc Surg , 2012;144(5):1010–6.

22. El Khoury G, Glineur D, Rubay J, et al., Functional classification of aortic root/valve abnormalities and their correlation with etiologies and surgical procedures, Curr Opin Cardiol , 2005;20(2):115–21.

23. Sarsam MA, Yacoub M, Remodeling of the aortic valve

anulus, J Thorac Cardiovasc Surg , 1993;105(3):435–8.

24. David TE, Feindel CM, An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta, J Thorac Cardiovasc Surg , 1992;103(4):617–21; discussion 22.

25. Yacoub MH, Gehle P, Chandrasekaran V, et al., Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root, J Thorac Cardiovasc Surg , 1998;115(5):1080–90.

26. Aicher D, Langer F, Lausberg H, et al., Aortic root remodeling: ten-year experience with 274 patients, J Thorac Cardiovasc Surg , 2007;134(4):909–15.

27. David TE, Armstrong S, Manlhiot C, et al., Long-term results of aortic root repair using the reimplantation technique, J Thorac Cardiovasc Surg , 2013;145(Suppl. 3):S22–5.

28. De Paulis R, Scaffa R, Nardella S, et al., Use of the Valsalva graft and long-term follow-up, J Thorac Cardiovasc Surg , 2010;140(6 Suppl):S23–7; discussion S45–51.

29. Boodhwani M, de Kerchove L, Glineur D, et al., Repair of aortic valve cusp prolapse, Multimed Man Cardiothorac Surg , 2009;2009(702):mmcts.2008.003806.

30. David TE, Aortic valve sparing operations: a review, Korean J Thorac Cardiovasc Surg , 2012;45(4):205–12.

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Adoption of Transcatheter Aortic Valve Implantation in Western Europe Da rren My lot te, 1 , 2 R uben L J O s n a b r u g g e , 3 G i u s e p p e M a r t u c c i , 1 R u e d i g e r L a n g e , 4 Arie P i e t e r K a p p e t e i n , 3 a n d N i c o l o P i a z z a 1, 4 1. Department of Interventional Cardiology, McGill University Health Centre, Montreal, Quebec, Canada; 2. Department of Cardiology, University Hospital Galway, Galway, Ireland; 3. Erasmus University Medical Center, Rotterdam, The Netherlands; 4. German Heart Centre, Munich, Germany

Abstract Transcatheter aortic valve implantation (TAVI) is a novel therapeutic option for patients with severe symptomatic aortic stenosis (AS) at excessive or high surgical risk for conventional surgical aortic valve replacement. First commercialised in Europe in 2007, TAVI growth has been exponential among some Western European nations, though recent evidence suggests heterogeneous adoption of this new and expensive therapy. Herein, we review the evidence describing the utilisation of TAVI in Western Europe.

Keywords Transcatheter aortic valve implantation, aortic stenosis Disclosure: Nicolo Piazza is a proctor and consultant for Medtronic. The remaining authors have no other conflicts of interest to declare.

Received: 30 November 2013 Accepted: 19 February 2014 Citation: Interventional Cardiology Review, 2013;9(1):37–40 Correspondence: Nicolo Piazza, Department of Interventional Cardiology, McGill University Health Centre, Montreal, Quebec, Canada and Department of Cardiac Surgery, German Heart Centre, Lazarettstrasse 36, 80636 Munich, Germany. E: nicolopiazza@mac.com

Transcatheter aortic valve implantation (TAVI) has emerged as a safe and efficacious treatment in patients with symptomatic severe aortic stenosis (AS) at high- or excessive-risk for surgical aortic valve replacement.1,2 More recently, TAVI technology has been extended to treating high-risk patients with failing aortic or mitral surgical bioprosthetic valves, bicuspid aortic stenosis, pure aortic regurgitation, and lower-risk aortic stenosis patients.3–8 Thus, TAVI technology is increasingly being applied worldwide since Conformité Européenne mark approval of the Edwards SAPIEN (Edwards Lifesciences Inc, Irvine, California, US) and Medtronic CoreValve (Medtronic Inc, Minneapolis, Minnesota, US) systems in 2007.

Importantly, few studies report the adoption of TAVI across nations.

Anecdotal evidence of TAVI practice in Europe, and studies describing the adoption of other novel medical devices, such as drug-eluting stents (DES) and implantable cardioverter defibrillators (ICDs), suggest that the use of expensive new technologies may be inconsistent across nations.9,10 Indeed, such is the inequality in the adoption of DES and ICD technology that societal initiatives have been established in an attempt to level the playing field between nations.11

of Ireland.12 The number of TAVI implants and TAVI centres in each nation were retrieved from national databases that were submitted by a selected group of investigators. These data were cross-referenced with TAVI use estimates derived by BIBA MedTech (London, UK), a cardiovascular market analysis group.

Between 2007 and 2011, 34,317 patients underwent TAVI in the 11 study nations. TAVI implants increased 33-fold from 445 in 2007 to 14,946 in 2011 (see Figure 1). Most implants were performed in Germany (45.9 %), Italy (14.9 %) and France (12.9 %) (see Figure 2). Portugal (0.6 %) and Ireland (0.4 %) accounted for the smallest proportion of implants.

When the cumulative TAVI implant numbers were applied to year-end national population estimates, we observed considerable disparity in TAVI utilisation among nations (see Figure 3). In 2011, Germany (961), Switzerland (797) and Denmark (611) had the highest TAVI implant rates per million of population ≥75 years of age. Portugal (71) and Ireland (127) had the lowest TAVI implant rates.

Transcatheter Aortic Valve Implantation Centres Herein, we profile the adoption of TAVI in Western Europe, highlight some factors that may account for the disparate adoption of TAVI between nations, and present evidence that suggests that this therapy remains greatly underutilised in Europe.

Adoption of Transcatheter Aortic Valve Implantation We evaluated TAVI adoption among 11 Western European Nations – Germany, France, Italy, UK (including Northern Ireland), Spain, the Netherlands, Switzerland, Belgium, Portugal, Denmark and the Republic

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The number of TAVI centres increased ninefold from 37 in 2007 to 342 in 2011 (see Figure 4). On average, there were 0.9 ± 0.6 TAVI centres per million of population. In 2011, the number of TAVI centres ranged from 0.3 per million in Portugal to 2.1 per million in Belgium.

A high number of TAVI centres per million of population can result in fewer procedures being performed in each centre. Hence, guidelines recommend that TAVI procedures be centralised in high-volume regional centres to ensure adequate operator and centre experience.13,14 These volume-based recommendations suggest that a minimum of 24 TAVI procedures be performed in each centre per annum.13,14 Despite

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Structural Figure 1: Cumulative European Transcatheter Aortic Valve Implantation Implants (2007–2011)

Figure 3: Variability in Transcatheter Aortic Valve Implantation Utilisation 1,000

2007

Implants per million (≥75)

2008 2009 2010 2011 30,000

500 400 300 200 100

40,000

lg iu m Po rtu ga l D en m ar k Ire la nd

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la nd

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rla nd

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he et

Transcatheter aortic valve implant rates per million of population ≥75 years of age in 2011 among 11 European nations. TAVI = transcatheter aortic valve implantation.

Figure 4: Number of Transcatheter Aortic Valve Implantation Centres in Europe

16,000 14,000 12,000

2007 10,000

2008

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Year

Cumulative number of TAVI implants

N

Figure 2: Nation Specific Cumulative Transcatheter Aortic Valve Implants (2007–2011)

Sp

an y m G

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Cumulative implants per annum Total number of TAVI implants among 11 European nations from 2007 to 2011.

e

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Mean: 398 ± 283 TAVI implants per million ≥75 years of age

900

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nd

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Ire

ar m

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rtu Po

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Total number of TAVI implants in each study nation from 2007 to 2011. TAVI = transcatheter aortic valve implantation.

Total number of centres performing transcatheter aortic valve implantation in 11 European nations from 2007 to 2011.

a European average of 41 ± 28 TAVI implants per centre in 2011, Ireland, Belgium and Spain all had TAVI centres that performed <20 TAVI implants annually. The low number of implants per centre may be explained by the low procedural volume in Ireland and by a high number of TAVI centres in Belgium and Spain. National administration and funding agencies should be encouraged to centralise TAVI in designated TAVI centres and ensure that the recommended minimal implant volume is achieved.

(SAVR), 5.2 % were at high operative risk (Society of Thoracic Surgeons risk of mortality >10 %). Finally, 40.3 % of inoperable patients and 80.0% of high-risk patients were deemed to be potential TAVI candidates.

Number of Potential Transcatheter Aortic Valve Implantation Candidates Recently, Osnabrugge et al. evaluated the potential number of TAVI candidates in 19 European nations and in North America.15 These authors estimated the prevalence of severe aortic stenosis in the elderly (≥75 years) to be 3.4 % (95 % confidence interval [CI], 1.1–5.7 %). To calculate the number of potential TAVI candidates in each nation, a meta-analysis was performed, which focused on published data describing the treatment pathway of high-risk aortic stenosis patients. It was estimated that 75.6 % of patients with severe aortic stenosis were symptomatic, 40.5 % were inoperable due to excessive surgical risk, and among patients that undergo surgical aortic valve replacement

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Extrapolating these data, Osnabrugge et al. estimated that there are 189,836 (95 % CI, 80,281–347,372) TAVI candidates in the Europe and 102,558 (95 % CI, 43,612–187,002) in North America. Annually, there are 17,712 (95 % CI, 7,590–32,691) new TAVI candidates in Europe and 9,189 (95 % CI, 3,898–16,682) in North America (see Figure 5). Like all meta-analyses and modelling studies, this study has limitations, such as differences in the definition of aortic stenosis used among the included studies and more importantly, the difficulty associated with determining the number of inoperable or high-risk patients that are truly suitable for TAVI.16 In the future, more comprehensive prospective national and international registries detailing the actual treatment of high-risk aortic stenosis patients (medical therapy, SAVR, TAVI) will provide invaluable insights into the management of aortic stenosis patients. In the meantime, the study by Osnabrugge et al. reflects the best available evidence detailing the prevalence of severe aortic stenosis in the elderly, and provides the only estimate of the number of potential of TAVI candidates.

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Adoption of Transcatheter Aortic Valve Implantation in Western Europe

Figure 5: Annual Number of Transcatheter Aortic Valve Implantation Candidates Under the Current Treatment Indications

Annual number of transcatheter aortic valve implantation candidates in different countries under the current treatment indications. CI = confidence interval; TAVR = transcatheter aortic valve replacement. Reprinted with permission from Osnabrugge, et al., 2013.15

Estimated Transcatheter Aortic Valve Implantation Penetration The penetration of a therapy describes actual use relative to potential use. Applying the 2011 TAVI implant data to the number of potential TAVI candidates, one can approximate the penetration of TAVI in each nation (see Figure 6). In Germany, the estimated TAVI penetration rate was 36.2 %; that is, 36.2 % of TAVI eligible patients went on to receive TAVI in 2011. This contrasts considerably with the estimated penetration rate in Portugal (6.4 %). The weighted average TAVI penetration was calculated according to the weight (number of TAVI cases performed) or relative contribution of each individual nation to the average). Overall, the weighted average penetration rate for the 11 European nations was only 17.9 %.

Figure 6: Estimated European Transcatheter Aortic Valve Implantation Penetration 2011

Germany France Italy UK

Weighted average TAVI penetration: 17.9 %

Spain Netherlands Switzerland Belgium Portugal Denmark Ireland

It is important to note that the denominator for estimating TAVI penetration is based on the number of potential TAVI candidates described by Osnabrugge et al. As such, the TAVI penetration calculation is subject to the limitations of this study. As noted by Webb et al., a more conservative estimation of the number of potential TAVI candidates would have altered the penetration calculation significantly.17 For example, a commercial analysis of the US TAVI market has suggested that TAVI penetration is already at approximately 45 %, despite the delayed and highly restrictive introduction of TAVI in that country.18 With ongoing trials in intermediate-risk patients, it is generally expected that TAVI use will continue to rise worldwide. Device iteration, documentation of long-term efficacy, and reduced costs will

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0

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Estimated TAVI penetration 2011 (%)

Estimated transcatheter aortic valve implantation penetration among 11 European nations in 2011.

TAVI = transcatheter aortic valve implantation.

drive the adoption of this therapy. Furthermore, as patient selection and procedural outcomes improve, the currently underappreciated morbidity and mortality advantages of TAVI are likely to become apparent, and it is likely that TAVI utilisation will increase further.

Transcatheter Aortic Valve Implantation Funding and Reimbursement Issues Given the prevalence of aortic stenosis in the elderly, the ageing global population, and the absence of effective preventative therapies,

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Structural the economic burden of aortic stenosis is increasing. Of course, the adoption of TAVI is affected by economic conditions: more prosperous nations that spend more on healthcare tend to perform more TAVIs.12 Implant rates are also affected by reimbursement strategies – nations with TAVI-specific diagnosis-related groups that cover all of the costs of TAVI tend to perform more TAVI than nations where the cost of TAVI is reimbursed and constrained at local level.12 Importantly, these differences in reimbursement may also have the potential to impact patient outcomes; as in nations

1. Leon MB, Smith CR, Mack M, et al., Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med, 2010;363(17):1597–607.

2. Smith CR, Leon MB, Mack MJ, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Engl J Med, 2011;364(23):2187–98.

3. Dvir D, Webb J, Brecker S, et al., Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: results from the global valve-in-valve registry, Circulation , 2012;126(19):2335–44.

4. Mylotte D, Lange R, Martucci G, Piazza N, Transcatheter heart valve implantation for failing surgical bioprostheses: technical considerations and evidence for valve-in-valve procedures, Heart , 2013;99(13):960–7.

5. Hayashida K, Bouvier E, Lefèvre T, et al., Transcatheter aortic valve implantation for patients with severe bicuspid aortic valve stenosis, Circ Cardiovasc Interv , 2013;6(3):284–91.

6. Lange R, Bleiziffer S, Mazzitelli D, et al., Improvements in transcatheter aortic valve implantation outcomes in lower surgical risk patients: a glimpse into the future, J Am Coll Cardiol, 2012;59(3):280–7.

7. Wenaweser P, Stortecky S, Schwander S, et al., Clinical outcomes of patients with estimated low or intermediate surgical risk undergoing transcatheter aortic valve

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with more constrained local reimbursement, less experience with the procedure is developed.

Conclusions There are a large number of potential TAVI candidates in Western Europe and the concomitant economic burden is considerable. Adoption of TAVI in Europe is heterogeneous and varies according to nation-specific economic situations, healthcare policies and reimbursement strategies.

Current evidence suggests that TAVI remains underutilised in Europe. n

implantation, Eur Heart J, 2013;34(25):1894–905.

8. Roy DA, Schaefer U, Guetta V, et al., Transcatheter aortic valve implantation for pure severe native aortic valve regurgitation, J Am Coll Cardiol, 2013;61(15):1577–84.

9. Lubinski A, Bissinger A, Boersma L, et al., Determinants of geographic variations in implantation of cardiac defibrillators in the European Society of Cardiology member countries-data from the European Heart Rhythm Association White Book, Europace, 2011;13(5):654–62.

10. Ramcharitar S, Hochadel M, Gaster AL, et al., An insight into the current use of drug eluting stents in acute and elective percutaneous coronary interventions in Europe. A report on the EuroPCI Survey, EuroIntervention, 2008;3(4):429–41.

11. Kristensen SD, Fajadet J, Di Mario C, et al., Implementation of primary angioplasty in Europe: stent for life initiative progress report, EuroIntervention, 2012;8(1):35–42.

12. Mylotte D, Osnabrugge RL, Windecker S, et al., Transcatheter aortic valve replacement in Europe: adoption trends and factors influencing device utilization, J Am Coll Cardiol, 2013;62(3):210–9.

13. Vahanian A, Alfieri O, Al-Attar N, et al., Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European Association of Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology

(ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI), Eur Heart J , 2008;29(11):1463–70.

14. Tommaso CL, Bolman RM 3rd, Feldman T, et al., Multisociety (AATS, ACCF, SCAI, and STS) expert consensus statement: operator and institutional requirements for transcatheter valve repair and replacement, part 1: transcatheter aortic valve replacement, J Am Coll Cardiol, 2012;59(22):2028–42.

15. Osnabrugge RL, Mylotte D, Head SJ, et al., Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study, J Am Coll Cardiol, 2013;62(11):1002–12.

16. Vahanian A, Iung B, Himbert D, Transcatheter aortic valve implantation: a treatment we are going to need!, J Am Coll Cardiol , 2013;62(11):1013–4.

17. Webb JG, Barbanti M, Transcatheter aortic valve adoption rates, J Am Coll Cardiol, 2013;62(3):220–1.

18. J.P. Morgan, Edwards Lifesciences, The US TAVR Market: What We Learned from this Weekend’s Publication, North American Equity Research, 2013.

Available at: ftp://115.113.198.66/DOC%20&%20IR/2013/ DECEMBER/13%20DEC/SWETA_EW/20131118_EW_HQ_1.PDF (accesssed 21 February 2014).

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LE ATION.

Transcatheter Aortic Valve Replacement in Moderate-risk Aortic Stenosis Patients Lars G Svensson Department of Cardiothoracic Surgery, Aorta Center and Heart and Vascular Institute, Cleveland, US

Abstract The Placement of Aortic Transcatheter Valves (PARTNER) trial showed the effectiveness of transcatheter aortic valve replacement (TAVR) for inoperable patients and non-inferiority for mortality versus open valve replacement. There are three questions concerning the role of TAVR for intermediate-risk patients. These relate to: institutional and surgeon results, physician and hospital alignments, and who will pay.

Keywords Transcatheter aortic valve replacement, transcatheter aortic valve implantation, aortic valve stenosis, aortic valve replacement Disclosure: The author has no conflicts of interest to declare.

Received: 24 January 2014 Accepted: 10 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):41–3 Correspondence: Lars G Svensson, Aorta Center and Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave/Desk J4-1, Cleveland, OH 44915, US. E: svenssl@ccf.org

If you can look into the seeds of time and say which grain will grow and which will not speak then to me. Macbeth; William Shakespeare.

question for greater society of what should we pay for and should healthcare be ‘rationed’ for the moderate-risk and high-risk elderly?

Predictions of the role of transcatheter aortic valve replacement (TAVR) in moderate-risk patients is fraught with potential pitfalls. The matrix of outcomes is interlinked and changes in one cell may have consequences beyond currently observable measures. For example, the Congressional Budget Office (CBO) options for cost reductions (‘caps on spending’) being presented to lawmakers, reads like rationing for healthcare and new technologies. Moreover, neither Europe, Canada nor Scandinavia are immune and if anything, many are more restricted, such as Belgium.

It is thus incumbent upon us physicians to consider options both locally and more globally for the management of our patients.

Results

The previous randomised study of the Placement of Aortic Transcatheter Valves (PARTNER) trial showed that TAVR was superior to medical treatment and that TAVR was equivalent to open aortic valve replacement (AVR) for mortality, although the stroke or transient ischaemic attack (TIA) rate was three times higher. Long-term data are, however, not available for valve durability, particularly in younger patients with longer expected survival. Open surgical treatment is established, highly successful and safe treatment for aortic valve stenosis that both relieves symptoms and very markedly extends survival. The seed of TAVR has been planted, is growing, and only time will tell how TAVR compares with AVR. Thus the use of TAVR in lower risk, and hence younger patients, needs to address safety and durability and also the trade-off of less invasive procedure for greater risk of stroke.

Questions to Address There are three scenarios to consider. Firstly, the ethical question of what are your institutional results with AVR and TAVR? Secondly, what are your physician and hospital alignments? Thirdly, is the moral

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What are your results? This question should be relatively easy to answer yet it surprises me when we are asked to review cardiovascular programmes how scanty the data can be. Nevertheless, both institutional outcomes and individual surgeon’s outcomes should be known based on the Society of Thoracic Surgeons (STS) data or collection of state data such as in New York, Pennsylvania or Massachusetts. In a broader US context, for July 2011 to June 2012, 92,514 aortic valves were sold at a cost of US$472 million, and in 2010 on average a cardiac surgeon did eight AVRs and an institution 21.1,2 To illustrate the point, at the Cleveland Clinic in the year 2011 we did 479 isolated AVRs (we do in total about 1,500 AVRs combined with other procedures), including reoperations, emergencies and endocarditis with a predicted STS mortality score of 3.48 %, but observed mortality was in fact 0.60 % and stroke 1.50 %.3 For 2012 we did 539 patients, STS predicted death was 3.96 %, actual deaths 0.40 % and stroke 1.10 %. From 2001 to December 2007 (before potential influence of TAVR) it was only after the age of 80 years that mortality increased for reoperations to 5.6 %. However, based on careful patient selection no patient operated on over the age of 90 years died during that period.

For root sparing procedures, including aortic dissections, it was 1.4 % (n=418) and for minimally invasive approaches for AVR 0.5 % (n=1,572, stroke 0.8 %). For patients <70 years old and primary operations (n=720) it was 0.28 %. Thus, because our operative results are so good this would be a considerable equipoise challenge to perform a prospective randomised study for the use of TAVR in our population.

Certainly, for enrolment in the PARTNER 2A trial, this raised an ethical question of equipoise until we analysed our data in December 2012.

For 257 transfemoral TAVRs there were 11 conversions (five to transapical [TA], two open AVR for ruptured roots, 4.2 %), one death

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Structural (0.4 %) and two strokes (0.8 %). Up to May 2013 for 150 TA patients there were five deaths (3.3 %) and one death out of 85 patients since January 2011 (1.2 %). This compares favourably to the PARTNER A results.4 Hence, based on the data, we had the equipoise to enrol in the PARTNER 2A trial in which moderate-risk patients were required to have a STS score of 4–8 %, although later the upper limit was removed at the Food and Drug Administration’s (FDA) request. Nevertheless, this is a trial of moderate-risk and also high-risk patients with a new device (Sapien XT) that will help inform patient selection for AVR versus TAVR. Whether the lessons learnt from the PARTNER A trial will apply to the moderate-risk patients, such as the finding that transfemoral (TF) is better for high-risk patients with significant co-morbid disease, at the cost of 4.6 % stroke or TIA versus 1.4 % for open AVR (p=0.04), and that AVR or TA is better for more complex cardiovascular cases (like reoperations [p<0.05] or with males [p<0.05]) remains to be seen.5 The STS score has proven to be very accurate for prediction of deaths for the mature and technological plateaued procedure of AVR, even for STS >10 % but with wider confidence limits and receiver operating characteristic (ROC) curve c-statistics of better than 0.8.6 However, our attempts at finding a reliable ROC score for TAVR has not been as effective (c-statistic <0.6).7 Why should this be? AVR has become a mature technology for which random unpredicted events are rare, such as coronary occlusion (a good surgeon should mostly prevent this) or aortic dissection, and hence patient-related factors can be used in a predictive formula with greater reliability. For TAVR, as with other new innovative and disruptive technologies there are greater risks of both unpredictable and frequent random events. These include: failure to place the valve accurately, sizing problems, conversions, valve embolization, root rupture, ventricular perforation, aortic dissection, vascular access injury, ventricular tears, pacing wire perforations, heart block, entrapped wires or catheters, severe mitral valve regurgitation, severe perivalvular leaks, etc.4,8 In the PARTNER A trial, 9.5 % had a failure of successful TAVR insertion based on Valve Academic Research Consortium (VARC) definitions and 10.5 % had severe or moderate perivalvular leak, also a failure by VARC; thus in total, approximately 20 % had a failed procedure. Indeed, there is some evidence that if all complications related to a TAVR procedure are combined and because transapical TAVR is associated with less bleeding and less perivalvular severe leaks, the transfemoral approach has an overall greater risk of complications for all comers. Thus, based on current known outcomes, until TAVR further matures, TAVR in moderate-risk patients should be used with caution but would depend on institutional experience and AVR outcomes.

salary and the perception is for the greater good, accommodation of TAVR is more based on medical imperatives and less influenced by financial potential arbitrations. On the contrary, however, it is likely in the latter scenario that surgeons will be more prepared to give up complex reoperations for TAVR if there are no rewards to do the complex cases, even though previous coronary artery bypass grafting (CABG) patients in the PARTNER A trial did much better (p<0.05) with open AVR.

Who Will Pay The moral question of whether society will pay? Centers for Medicare & Medicaid Services (CMS) posed the question of whether “the evidence (is) adequate to conclude that transcatheter aortic valve replacement improves health… for Medicare beneficiaries with severe aortic stenosis”? It is worth noting that CMS has three departments and the evaluation of effectiveness is done by a group separate from the payment department. The issue is that in 2009 (financial data is a minimum of two years behind) CMS spent US$133 billion on in-hospital patient care (estimate US$170 billion, 2013); while the total estimated expenditure by CMS in 2013 was US$1,125 billion according to the CBO, with 36 % of all US patient care paid for by CMS (Medicare, Medicaid, CHIP, etc.). Currently, 42 % of patients are covered by government insurance but our predication is that in a decade it will be 75 %.

Consequences are that CMS will determine directly or indirectly the level of reimbursement (for example, exchanges will pay physicians 5 % above Medicare rates and hospitals at the Medicare rate). Hence, with the financial problems, poor job growth and the budget deficit, healthcare will be under increasingly severe ‘spending caps’ as recommended by the CBO. In turn, CMS will be under pressure to cut costs. Clearly, while AVR and TAVR are among the most effective cardiovascular treatments to improve symptoms, quality of life, Kansas City Cardiomyopathy Questionnaire (KCCQ) score and long-term survival, both treatments cost more than ‘medical treatment’.9,10 This then is the moral question as to who should receive treatments within the group of patients at increased risk. The determination of CMS for TAVR in high-risk patients was “TAVR provided no mortality benefit but significant risk of harm. … coverage… should be restricted only to clinical trials rather than registries.” Hence, the TVT Registry™/ NCDR® database. Furthermore, based on CMS reimbursement on the valves costing US$32,500, some hospitals lose US$4,000–14,000 per TAVR (average cost was US$78,000 with a mean 1.5 nine-year survival gain) and analysts’ predict that CMS could end up paying a predicated US$2.6–6.0 billion per year for percutaneous valves in contrast to half a billion for AVR.11

Conclusion Alignments What are your alignments? This question addresses the issue of surgeon and interventional cardiologist alignments in either doing open AVR or TAVR. In Germany, one-third of patients are done by TAVR because institutions get paid more for TAVR and surgeons are essentially employed by the institutions, although numbers do count. However, the German healthcare system has realised this and now a senior surgeon is required to approve patients for TAVR. In Belgium, the government will not pay for TAVR and so surgeons and cardiologists do TAVRs for free and hospitals absorb the costs but limit the annual number they permit, to for example 15. In the US the situation varies from institution to institution. If both cardiologist and surgeon are in private practice, there is little support for moderate-risk TAVR. If surgeons are in combined practice plans there is more accommodation since fees are split and a surgeon gets half of the AVR fee. In institutions where both are on

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In conclusion, it is noteworthy that in the recent report published in The Journal of the American Medical Association (JAMA)12 of the first 7,710 patients in the TVT/NCDR registry the STS score was a mean of 7 (for the approval of the device for inoperable patients in the PARTNER B trial it was 11 and also for high-risk patients in PARTNER A it was also 11, and this is the population the device should be commercially used in). Thus, there are already moderate-risk patients (for PARTNER 2A moderate-risk study the Cleveland Clinic mean was STS 7) being done commercially. Furthermore, based on the data shown in their Figure 1, institutions doing small volumes of TAVR, particularly <60 TAVR case volume, were also doing more low-risk STS score patients.

If two surgeons in these low volume institutions are approving these cases, then it is likely they feel less confident to tackle higher risk patients, like reoperations, despite the fact these patients do paradoxically better with open AVR. Indeed, between January 1999

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and mid-2013, at the Cleveland Clinic, we did 329 reoperations of all types for AVR surgery and the mortality rate was 2.4 % and stroke 1.8 %. Furthermore, for our low-risk patients (n=771) with a STS <4 % risk the mortality rate was 0.3 % between 2011 and 2013, and for 74 % intermediate or high-risk there were no deaths (0 %) for a total of 0.2 % death (n=956 patients). The unanswered questions are the long-term durability of TAVR in younger intermediate-risk patients, the stroke risks, and the effect of perivalvular leaks long-term.

PARTNER 2A will likely add information but will show mixed results.

1. Svensson LG, Adams DH, Bonow RO, et al., Aortic valve and ascending aorta guidelines for management and quality measures: executive summary, Ann Thorac Surg , 2013;95(4):1491–505.

2. Svensson LG, Adams DH, Bonow RO, et al., Aortic valve and ascending aorta guidelines for management and quality measures, Ann Thorac Surg , 2013;95(6 Suppl):S1–66.

3. Svensson LG, Evolution and results of aortic valve surgery, and a ‘disruptive’ technology, Cleve Clin J Med, 2008;75(11):802, 804.

4. Smith CR, Leon MB, Mack MJ, et al., Transcatheter versus surgical aortic-valve replacement in high-risk patients, N Engl J Med, 2011;364(23):2187–98.

5. Svensson LG, Leon MB, Blackstone EH, et al., Comprehensive

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It is unlikely that further successful prospective randomised trials will be done in the intermediate-risk patients to clarify selection of patients. At least for high-risk and inoperable patients the results are encouraging in our experience.13 The future use of TAVR for moderate-risk will be determined by your answers to the above questions; and in the US, risk creep, the future decisions of congress, CBO recommendations and CMS reimbursement. n

Analysis of Deaths among Patients in the PARTNER Trial, J Am Coll Cardiol, 2014 (In Press).

6. O’Brien SM, Shahian DM, Filardo G, et al., The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2--isolated valve surgery, Ann Thorac Surg , 2009;88 (1 Suppl):S23–42.

7. Svensson LG, Tuzcu M, Kapadia S, et al., A comprehensive review of the PARTNER trial, J Thorac Cardiovasc Surg, 2013;145(3 Suppl):S11–6.

8. Leon MB, Smith CR, Mack M, et al., Transcatheter aorticvalve implantation for aortic stenosis in patients who cannot undergo surgery, N Engl J Med, 2010;363(17):1597–607 9. Clark MA, Arnold SV, Duhay FG, et al., Five-year clinical and economic outcomes among patients with medically managed

severe aortic stenosis: results from a Medicare claims analysis, Circ Cardiovasc Qual Outcomes, 2012;5(5):697–704.

10. Clark MA, Duhay FG, Thompson AK, et al., Clinical and economic outcomes after surgical aortic valve replacement in Medicare patients, Risk Manag Healthc Policy , 2012;5:117–26.

11. Svensson LG, Aortic valve replacement: options, improvements, and costs, Cleve Clin J Med, 2013;80(4):253–4.

12. Mack MJ, Brennan JM, Brindis R, et al., Outcomes following transcatheter aortic valve replacement in the United States, JAMA , 2013;310(19):2069–77.

13. Kapadia SR, Svensson LG, Roselli E, et al., Single center TAVR experience with a focus on the prevention and management of catastrophic complications, Catheter Cardiovasc Interv , 2014 (In Press).

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Structural

Percutaneous Paravalvular Leak Closure Ama r K rishna swa my, 1 E M u ra t Tu z c u 2 a n d S a m i r R K a p a d i a 3 1. Associate Program Director, Interventional Cardiology Fellowship; 2. Vice Chairman, Department of Cardiovascular Medicine, Heart and Vascular Institute; 3. Director, Sones Cardiac Catheterization Laboratories, Cleveland Clinic, Ohio, US

Abstract Symptomatic paravalvular leak (PVL) complicates up to 12 % of surgical valve replacements. When patients present with congestive heart failure and/or haemolysis, reoperation for repeat valve replacement may be undertaken, but presents greater risk and lower likelihood of success than the initial operation. Therefore, percutaneous approaches to PVL closure have been developed by specialists in structural cardiac intervention. Large series demonstrate high levels of procedural success and promising clinical outcomes for this complex intervention. A thorough understanding of multimodality imaging is necessary for the diagnosis of PVL and the safe and successful performance of these closure procedures.

Keywords Percutaneous paravalvular leak closure, structural cardiac intervention, transoesophageal echocardiography, DynaCT, C-arm computed tomography integration Disclosure: The author has no conflicts of interest to declare.

Received: 27 January 2014 Accepted: 18 February 2014 Citation: Interventional Cardiology Review, 2013;9(1):44–8 Correspondence: Samir R Kapadia, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J2-3, Cleveland, OH 44195, US. E: Kapadis@ccf.org

Among patients undergoing surgical valve replacement, 1–5 % of patients with an aortic valve replacement (AVR) and 2–12 % with a mitral valve replacement (MVR) may develop paravalvular regurgitation or ‘leak’ (PVL).1–3 In the era of transcatheter aortic valve replacement (TAVR) with first-generation balloon expandable valves, up to 17 % of patients may be left with moderate or severe PVL, also referred to as paravalvular aortic regurgitation (PAR).4 Risk factors for PVL in patients undergoing surgical valve replacement include the use of mechanical valves, severe calcification of the valve annulus, or valve replacement for infectious endocarditis. Similar factors contribute to PVL in the post-TAVR setting, as well as improper pre-procedural valve sizing.5

Diagnosis In patients with prior valve replacement, symptoms of CHF or haemolysis should merit further evaluation for PVL. Transthoracic echocardiography (TTE) is important to establish ventricular function and overall valve assessment. It is important to understand, however, that prosthetic valve shielding may not provide an adequate characterisation of PVL and appropriate diagnosis may require further imaging using transoesophageal echocardiography (TOE). In some rare situations, it may be unclear whether the leak is intra- or paravalvular by both TTE and TOE; intracardiac echocardiography (ICE) may be helpful in these situations.

Mitral Paravalvular Leak The majority of patients who have symptomatic PVL present with congestive heart failure (CHF) (85 %), and a significant number may have haemolysis (50 %).6,7 Patients who fail medical therapy directed at CHF and/or haemolysis (erythropoietic agents, blood transfusion) should be considered for redo open-heart surgery (OHS) or percutaneous PVL closure. Re-operation must be approached cautiously, as redo surgery usually carries greater risk than a first operation, and recurrence of PVL may be seen in more than one-third of patients who undergo redo OHS for PVL.6 As a result, percutaneous PVL closure has recently gained greater favour. First reported in 1992, this procedure has been slowly evolving and is now successfully performed in a number of centres with significant experience in structural cardiac intervention.8–12 In this review, we will discuss the imaging diagnosis of PVL and data supporting percutaneous closure, as well as highlight the procedural techniques to accomplish PVL closure.

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The ‘clock face’ nomenclature of the mitral valve (MV) as seen from the left atrium, or ‘surgeon’s view’, facilitates communication among different specialists (see Figure 1). Most PVLs occur anteromedially (10 to 11 o’clock position) and posterolaterally (5 to 6 o’clock position).7,10 As discussed above, TTE may provide the diagnosis and location of PVL (see Figure 2). However, TOE is usually necessary to define the extent of PVL, and understanding the relationship of TOE angles is imperative to an accurate localisation and subsequent treatment (see Figure 3). Three-dimensional (3D) TOE may be beneficial to localise the PVL, but is sometimes limited by shadowing artifact or echo dropout (see Figure 4).

Aortic Paravalvular Leak The clock face of the aortic valve (AV) shares the 12 o’clock position with the MV (see Figure 1). Aortic PVLs are most commonly

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Percutaneous Paravalvular Leak Closure

Figure 1: Clock Face Designation of the Mitral and Aortic Valves from the Left Atrial Side

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Figure 3: Localisation of Paravalvular Leak Using Transoesophageal Echocardiography

6

L

A 90°

135°

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Ao N

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LAA

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9 9

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3 3 6

L = left coronary cusp; LAA = left atrial appendage; N = non-coronary cusp; R = right coronary cusp. Reproduced with permission from Krishnaswamy, et al., 2014.14

Figure 2: TTT Localization of Mitral PVL

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3

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AoV

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9 Medial

LV

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(A) Transthoracic echocardiogram demonstrates mitral paravalvular leak at 10 o’clock in the parasternal short-axis view. (B) Placement of a 6 mm Amplatzer Vascular Plug Device in the paravalvular leak.

AVR = aortic valve replacement; MVR = mitral valve replacement. Reproduced with permission from Krishnaswamy, et al., 2014.14

D

120° Ao 12

30°

E 9

LAA 9

encountered at the 7 to 11 o’clock position (46 %), followed by the 11 to 3 o’clock position (36 %).10 We find it helpful to also identify the location of the PVL with respect to the native coronary cusp, which more easily translates to the fluoroscopic relationships with which interventionists are familiar. Figure 5 demonstrates the AV in fluoroscopic projection and TOE.

Outcomes of Percutaneous Paravalvular Leak Closure While a number of groups have demonstrated successful percutaneous PVL closure in small series’ and case reports, Ruiz and colleagues and Sorajja and colleauges have provided the largest published experiences.9 Ruiz and colleagues performed 57 PVL procedures in 43 patients, with a procedural success of 86.0 % and a 30-day all-cause mortality rate of 5.4 %.11 As a point of reference, surgical series’ have demonstrated a mortality of 6 %.6,10 Haemolysis was a common finding, seen as the reason for the procedure in 14 % and in combination with CHF among 70 %. Despite the fact that 35 % of patients actually developed worsening haemolysis after the procedure, the number

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3 6

3 6

(A) The angles shown refer to the cuts made by a TOE imaging crystal. The numbers correspond to the clock face perspective of the MV (MV is shown from the LV; clock face numbering is as viewed from the LA). (B) TOE 120-degree view. (C) TOE 30-degree short-axis view. (D) The TOE planes are shown on the MV clock face (LV view) with the intersection (arrow) defining the PVL origin. (E) Deployment of the Amplatzer muscular VSD occluder (arrow) confirms the initial leak localisation by TOE (LAO projection).

Ao = aorta; AOV = aortic valve; LA = left atrium; LAA = left atrial appendage; LAO = left anterior oblique; LV = left ventricle; MV = mitral valve; PVL = paravalvular leak; TOE = transoesophageal echocardiography; VSD = ventricular septal defect. Adapted with permission from Krishnaswamy, et al., 2014.14

of patients requiring erythropoietic agents of regular transfusion decreased from 56 to 5 %. In this series, 10 patients required a redo percutaneous procedure, and two required three procedures total. This not only demonstrates the safety of repeat percutaneous procedures, but the idea that continued valve dehiscence may lead to new or worsening leaks.

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Structural Figure 4: Three-dimensional Transoesophageal Echocardiography Localisation of Mitral Paravalvular Leak Closure

AV

A

Figure 6: Use of Intracardiac Echocardiography to Guide Mitral Paravalvular Leak Closure

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B LV

LV

LA

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C (A) Left atrial view with colour Doppler demonstrates the leak (arrow). (B) Two AVP II plugs in place (arrow). AV = aortic valve; AVP = Amplatzer vascular plug; MV = mitral valve. Adapted with permission from Chenier, et al., 2013.16

D LV

LV

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Figure 5: Aortic Paravalvular Leak

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LMCA

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(A) 2D demonstration of the medial PVL; (B) Color Doppler demonstration of the PVL; (C) Wire across the PVL; (D) Minimal residual leak after device closure. Adapted with permission from Krishnaswamy, et al., 2014.14

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Figure 7: Mitral Paravalvular Leak Closure Using Computed Tomography Overlay Guidance

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(A) Aortic root angiogram in the LAO projection demonstrates cusp anatomy. (B) Transoesophageal echocardiogram short-axis view (45째) demonstrates PVL at the junction of right and non-coronary cusps in a patient with prior transcatheter aortic valve replacement.

(C) Aortic root angiography in the same patient (LAO projection). (D) Amplatzer vascular plug II deployed in the PVL. AVP = Amplatzer vascular plug; L = left coronary cusp; LMCA = left main coronary artery; N = non-coronary cusp; R = right coronary cusp; RCA = right coronary artery. Adapted with permission from Krishnaswamy, et al., 2014.14

Sorajja and colleagues published their short-term outcomes of closure for 141 defects (115 patients, 78 % mitral, 22 % aortic) and long-term outcomes on closure of 154 defects (126 patients).11,13 Heart failure outcomes were substantially improved: despite 93 % of patients presenting with CHF, 72 % had none or minimal dyspnoea at three-year follow-up. Procedural success was enjoyed by 77.0 % of patients, and 8.7 % experienced a major adverse event at 30-days.

Importantly, >3+ PVL was seen in only 10 % of patients post-closure.

One patient required emergent surgery due to valve interference by a device that could not be retrieved, there were no procedural deaths, and survival was 64 % at three years.

It is difficult to accurately compare survival in the series of percutaneous PVL closure with those in surgical series. As this is a procedure still in its infancy, with surgery often performed without

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PVL

RA:IVC junction

E

F LA

LV

(A) Pre-procedural MDCT marked with points of interest. (B) C-arm CT acquisition.

(C) MDCT:DynaCT registration. (D) Fluoroscopic overlay of MDCT markings.

(E) Wiring the PVL using CT-mark guidance (arrows). (F) Device in place (arrow).

Ao = aorta; CT = computed tomography; IVC = inferior vena cava; LA = left atrium; LPA = left pulmonary artery; LV = left ventricle; MVA = mitral valve anulus; PVL = paravalvular leak; RA = right atrium.

Reproduced with permission from Krishnaswamy, et al., 2014.15

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consideration of, or access to, percutaneous closure, those patients presenting for percutaneous therapy are often far more co-morbid than their peers who are taken for surgery. Nevertheless, the available data suggest safety of this approach and substantial functional improvement is enjoyed by patients undergoing percutaneous PVL closure. Given the high risks and poor results of reoperation, percutaneous PVL closure presents a promising treatment that is likely to improve with time and innovation.

Procedural Details A more thorough description of percutaneous PVL closure techniques can be found elsewhere.14 Briefly, percutaneous mitral PVL closure can be performed via femoral vein access and transseptal puncture, left ventricular (LV) apical access, or retrograde via the femoral artery.

Closure of aortic PVL is most effectively accomplished retrograde via the femoral artery. Tricuspid PVL can be accomplished via the jugular vein. The choice of access site should be decided on the basis of PVL location, support required for delivery of the bulky closure devices, and presence of other mechanical prostheses that may interfere with wire-snaring/externalisation. As we perform the majority of our PVL closure procedures without general anaesthesia or endotracheal intubation, minimising TOE-probe dwell time is essential for patient comfort. We therefore rely on ICE (see Figure 6) for transseptal puncture and when possible for PVL guidance (see Figure 6). We have also demonstrated previously the feasibility of integrating computed tomography (CT) data onto the realtime fluoroscopic image using a C-arm based CT acquisition (Syngo DynaCT, Siemens Healthcare, Forchheim, Germany) (see Figure 7).15 These techniques allow us to place the TOE probe only after the device is in place to confirm adequate PVL closure.

Choice of Device There are no devices created specifically for percutaneous PVL closure; those that are used are created for other applications, such as closure of septal defects or vascular plugs (see Figure 8). An important part of planning the percutaneous PVL closure is understanding the shape and size of the defect. We find that given the crescentic shape of PVLs, and the generally round shape of the devices, multiple devices are often necessary to adequately close the leak. It is important, especially in the setting of mechanical valve replacements, to be watchful of impingement on the prosthetic valve apparatus.

We most often use the Amplatzerâ&#x201E;˘ Vascular Plug II (AVP II; St. Jude Medical, Minnesota, US), which consists of a nitinol cylinder with a nitinol disc on either side. The AVP I is a single cylinder design, making it less stable and effective in our experience, and the AVP III is not available in the US. We find that the use of atrial septal defect (ASD) occlusion devices is often complicated by the large discs that can interfere with the prosthetic valve, and ventricular septal defect (VSD) closure devices are quite stiff and often result in worsening haemolysis. Patent ductus arteriosus (PDA) occluders are available in limited sizes, but are sometimes helpful when the AVP II discs interfere with valve leaflet motion.

Complications of Paravalvular Leak Closure Percutaneous PVL closure in trained centres has demonstrated good efficacy and safety. It is important in the performance of these procedures, to be aware of the potential complications in order to plan accordingly.

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Figure 8: Devices Used for Paravalvular Leak Closure

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D

B

LA Disc

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E

RA Disc (A) Amplatzer Vascular Plug I (AVP I). (B) Amplatzer Vascular Plug II (AVP II). (C) Amplatzer patent ductus arteriosus (PDA) occluder. (D) Amplatzer atrial septal defect (ASD) occluder.

(E) Amplatzer Muscular ventricular septal defect (VSD) Occluder. LA = left atrium; RA = right atrium. Reproduced with permission from Krishnaswamy, et al., 2014.14

The atrioventricular node is situated at the junction of the interatrial septum and the interventricular septum. Therefore, closure of PVLs close to this position can be complicated by complete heart block at the time of device implantation. Pre-emptive temporary pacemaker placement may be reasonable in such cases.

Care must be taken to observe mechanical valve function fluoroscopically and by echocardiography to assure that the PVL closure device does not produce valve dysfunction prior to release. In our experience, it is rare that PVL closure cannot be completed due to valve interference, though attempt at different devices and sizes may be necessary for a successful procedure.

In patients for aortic PVL, proximity to the native right and left coronary arteries should be considered, along with the relative size of the aortic sinus. In some cases, it is helpful to take an aortic root angiogram to further define this space prior to the placement of a PVL closure device.

Embolisation of the occluder devices has been reported in <1 % to 5 % of large seriesâ&#x20AC;&#x2122;.10,13 A sudden change in symptoms or atrial or ventricular ectopy may be early clues to device embolisation. When it does occur, percutaneous retrieval is usually performed successfully using snare devices and/or bioptomes. Alternatively, if the device is permanently lodged within the LV without significant risk for further mobilisation, consideration can be given to leaving it in place with monitoring by CT or echocardiography during follow-up.10 Echocardiographic follow-up is also important to reassess device placement and integrity of the valve itself as further valve dehiscence over time has been reported.

Conclusions Patients with cardiac valve replacement may suffer from PVL in the acute, subacute or chronic phases after cardiac surgery. These patients present most commonly with CHF, though a significant number also have debilitating haemolysis. As surgical reoperation carries great risk and chance for PVL recurrence, percutaneous strategies have been developed. These therapies are gaining favour as operators trained in structural cardiac intervention have developed a greater understanding of this procedure and made significant improvements in technique. While no specific trials of percutaneous

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Structural versus surgical closure exist, many high-volume interventional centres have been taking care of larger numbers of these patients,

1. Jindani A, Neville EM, Venn G, Williams BT, Paraprosthetic leak: a complication of cardiac valve replacement, J Cardiovasc Surg (Torino) , 1991;32:503–8.

2. Hammermeister K, Sethi GK, Henderson WG, et al., Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial, J Am Coll Cardiol , 2000;36:1152–8.

3. Ionescu A, Fraser AG, Butchart EG, Prevalence and clinical significance of incidental paraprosthetic valvar regurgitation: a prospective study using transoesophageal echocardiography, Heart , 2003;89:1316–21.

4. Rodes-Cabau J. Transcatheter aortic valve implantation: Current and future approaches, Nature Reviews Cardiology , 2012;9:15–29.

5. Jilaihawi H, Kashif M, Fontana G, et al., Cross-sectional computed tomographic assessment improves accuracy of aortic annular sizing for transcatheter aortic valve replacement and reduces the incidence of paravalvular aortic regurgitation, J Am Coll Cardiol , 2012;59:1275–86.

6. Genoni M, Franzen D, Vogt P, et al., Paravalvular leakage after

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and consideration may be given to the percutaneous approach as the first-line treatment strategy in carefully selected patients. n

mitral valve replacement: Improved long-term survival with aggressive surgery?, Eur J Cardiothorac Surg , 2000;17:14–9.

7. De Cicco G, Russo C, Moreo A, et al., Mitral valve periprosthetic leakage: Anatomical observations in 135 patients from a multicentre study, Eur J Cardiothorac Surg , 2006;30:887–91.

8. Hourihan M, Perry SB, Mandell VS, et al., Transcatheter umbrella closure of valvular and paravalvular leaks, J Am Coll Cardiol, 1992;20:1371–7.

9. Kim MS, Casserly IP, Garcia JA, et al., Percutaneous transcatheter closure of prosthetic mitral paravalvular leaks: are we there yet?, JACC Cardiovasc Interv , 2009;2:81–90.

10. Ruiz CE, Jelnin V, Kronzon I, Dudiy Y, et al., Clinical outcomes in patients undergoing percutaneous closure of periprosthetic paravalvular leaks, J Am Coll Cardiol , 2011;58:2210–7.

11. Sorajja P, Cabalka AK, Hagler DJ, Rihal CS, Long-term follow-up of percutaneous repair of paravalvular prosthetic regurgitation, J Am Coll Cardiol, 2011;58:2218–24.

12. Goel S, Krishnaswamy A, Tuzcu EM, Kapadia SR, Percutaneous

repair of paravalvular regurgitation: Characteristics and outcomes of 45 patients at cleveland clinic, Presented at: Society for Cardiovascular Angiography and Interventions Scientific Sessions, Orlando, Florida, US, 9 May 2013.

13. Sorajja P, Cabalka AK, Hagler DJ, Rihal CS, Percutaneous repair of paravalvular prosthetic regurgitation: Acute and 30-day outcomes in 115 patients. Circulation, Circ Cardiovasc Interv, 2011;4:314–21.

14. Krishnaswamy A, Tuzcu EM, Kapadia SR, Paravalvular leak closure Interventional Procedures for Adult Structural Heart Disease. eds Lasala J & Rogers J. Elsevier, 2014.

15. Krishnaswamy A, Tuzcu EM, Kapadia SR, Integration of MDCT and fluoroscopy using C-arm computed tomography to guide structural cardiac interventions in the cardiac catheterization laboratory, Catheter Cardiovasc Interv , 2014 [Epub ahead of print].

16. Chenier M, Tuzcu EM, Kapadia SR, Krishnaswamy A, Multimodality imaging in the cardiac catheterization laboratory: a new era in sight, Interventional Cardiology , 2013;5:335–44.

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LE ATION.

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declare. o declare.

Transcatheter Mitral Valve Devices – Functional Mechanical Designs Ch a d Kl i g e r Division of Structural and Congenital Heart Disease, Lenox Hill Heart and Vascular Institute – North Shore/LIJ Health System, New York, US

Abstract Mitral regurgitation is a complex disorder involving a multitude of components of the mitral apparatus. With the desire for less invasive treatment approaches, transcatheter mitral valve therapies (TMVT) are directed at these components and available at varying stages of development. Therapeutic advancements and the potential to combine technologies may further improve their efficacy and safety.

Transcatheter mitral valve replacement, while preserving the mitral apparatus, may emerge as an alternative or even a more suitable treatment option. In addition, early data on transcatheter mitral valve-in-valve and valve-in-ring implantation are encouraging and this approach may be an alternative to reoperation in the high-risk patient. This review details the expanding functional mechanical designs of current active TMVT.

Keywords Mitral regurgitation, transcatheter mitral valve therapies, transcatheter mitral valve replacement, valve-in-valve, valve-in-ring Disclosure: The author has received speaking honoraria from St. Jude Medical.

Acknowledgement: Eric Lehto from CVPipeline, MarketMonitors, Inc. for the information on innovative mitral medical technologies in early-stage development.

Received: 3 January 2014 Accepted: 22 January 2014 Citation: Interventional Cardiology Review, 2014;9(1):49–53 Correspondence: Chad Kliger, Lenox Hill Heart and Vascular Institute, 130 East 77th Street, 4th Floor Black Hall, New York, NY 10021-10075, US. E: ckliger@nshs.edu

Mitral regurgitation (MR) is a complex disorder requiring the understanding of mitral anatomy and pathophysiology. With the increasing patient population of mitral regurgitation, both functional and degenerative types, and our desire for less invasive treatment approaches, transcatheter mitral valve therapies (TMVT) have emerged. After more than a decade of advancements, development in TMVT still remains in its infancy. Initial therapies were focused on the surgical predicate of repair rather than replacement; now more recent designs on percutaneous mitral valve replacement and access approaches, in particular transapical, are leading advancements in the field. This review is written for the interventionist to understand the intricate mitral anatomy/ pathophysiology and the associated functional mechanical designs of current active TMVT.

annular size, a geometrically correct orientation of the papillary muscles, appropriate tethering to the tendinous cords, and suitable closing forces generated by LV muscular contraction.3

Mitral Valve Apparatus and Regurgitation

Mitral Annulus

The mitral valve apparatus is a complex structure that requires the integrity of six anatomic components. These components include: the mitral annulus (MA) or left atrioventricular junction, the mitral leaflets, the chordae tendineae, the papillary muscles, the left ventricular myocardium and the posterior left atrial wall.1,2 Contraction of the left ventricle (LV) and papillary muscles during systole results in forces that drive the mitral leaflets into apposition. The elevation in LV pressure, compared with left atrial (LA) pressure, allows for coaptation of the free leaflet margins. The MA acts as the fulcrum for the leaflets and is reduced in size during each ventricular systole. Papillary muscle contraction applies the appropriate counterforces to the chordae tendineae, preventing eversion of the leaflets. During normal closure, both leaflets must align in the same plane during coaptation and require an optimal

The mitral annulus is the D-shaped orifice formed by the convergence of the LA and LV.3,5 It is saddle-shaped with elevated septal and lateral segments, and a depressed medial segment along the central zone of apposition.6 The anterior mitral leaflet is in fibrous continuity with the aortic valve and the posterior mitral leaflet with the musculature of LV inflow. During systole, the MA contracts reducing the area that the opposing leaflets need to coapt by 20–50 %.7 Left ventricular dilatation distends the MA, reducing the ability for the annulus to contract.8 In the setting of significant mitral annular calcification, a loss of annular contraction can also lead to leaflet malapposition.9

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For MR to occur, more than one of these components must be dysfunctional. Dysfunctional components to the mitral valve apparatus help to further categorise this disorder and offer many potential options for mechanical correction. This aids in tailoring TMVT according to functional anatomy and device action.2,4 Current active TMVT focus on the MA, mitral leaflets, chordae tendineae and papillary muscles.

As these technologies improve, so do their applications and the possibilities for combining techniques. When percutaneous mitral valve repair approaches are unlikely to work, transcatheter mitral valve replacement (TMVR) may be a potential option.

The goal of treating the MA when it is dilated is to decrease the septal-lateral diameter by at least 8 millimetres (mm). Annuloplasty techniques are designed to restore annular size and shape,

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Structural subsequently improving leaflet coaptation. Approaches for correction include indirect reshaping or restraining the valvular orifice via the coronary sinus (CS) versus direct via the LA or LV.

Coronary Sinus Indirect Annuloplasty Indirect annuloplasty utilises the CS to reshape the mitral annulus. The close proximity of the CS to the MA allows for the placement of devices that will shorten the posterior annulus and bring it anteriorly, decreasing the septal-lateral dimension and improving leaflet coaptation. The main difficulty with this technique is that the CS only relates to the posterior annulus and that, in many cases, does not course in the atrioventricular groove along the MA. Furthermore as annular dilatation progresses with worsening MR, the distance from the CS to the mitral annulus increases.

Other considerations that would limit the use of these devices include mitral annular calcification that makes it difficult to reshape the MA. In addition, the CS may directly transverse the coronary arteries, most commonly the left circumflex.10–12 Coronary angiography is necessary to confirm the relationship of the coronary arteries to the CS prior to indirect annuloplasty.

The only available CS device is the CARILLON® Mitral Contour System™ (Cardiac Dimensions Inc., Kirkland, WA, US). It consists of two self-expanding nitinol anchors connected by a fixed-length nitinol intervening cable. After the distal anchor is deployed in the great cardiac vein, the bridge is unsheathed and tension is applied to the cable. Tension can be adjusted to achieve optimal results; subsequently, the proximal anchor is deployed in the anterior interventricular vein. The device is retrievable if results are non-optimal. In the Carillon Mitral Annuloplasty Device European Union Study (AMADEUS) and Tighten the Annulus Now (TITAN) trials, successful device implantation was demonstrated in 62 % of patients with a mean grade reduction of MR by ≥1.13,14 This device has CE mark and is awaiting pivotal study in the US.

Mechanical Approach to Direct Annuloplasty Direct annuloplasty reshapes the MA without use of the CS, preserving native leaflet function and restoring leaflet coaptation.

These devices are delivered to the LA or LV and implanted into the MA. The Mitralign device (Mitralign Inc., Tewksbury, MA, US) is delivered retrograde transaortic into the LV periannular space. Two pledgeted anchors are deployed on the posterior mitral annulus at P1P2 and P2P3 locations, connected by a suture. The pledgets are plicated and secured into place by a stainless steel lock, cinching the posterior MA.15 First-in-man (FIM) study is ongoing.

The Accucinch Annuloplasty system (Guided Delivery Systems [GDS], Santa Clara, CA, US) utilises a similar technique; however, it has placement of up to 12 retrievable anchors applied from P1 to P3, extending from the right to left trigones. A suture connects the anchors with direct tension applied to decrease posterior annular size. Enrolment into Cooling in intracerebral Hemorrhage (CINCH) 2 safety and feasibility trial is underway. Moreover, the Cardioband device (Valtech, Or-Yehuda, Israel) is a sutureless technology where supra-annular fixation is made through an antegrade transseptal approach.16 Anchors are implanted individually along the posterior annulus and can be repositioned or retrieved, and adjustments made to fine-tune annular dimensions. FIM is also ongoing.

The major limitation of these devices is that they are partial rings that only affect the posterior MA. Currently, placement of a complete

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mitral annuloplasty ring is being evaluated in preclinical trials using the Millipede (Millipede LLC, Ann Arbor, MI, US) and enCorTC (Micardia Corporation, Irvine, CA, US) systems. Both are delivered via a transseptal approach and fixed into the periannular space. Unlike its surgical counterpart (enCorSQ device [MiCardia Corporation, Irvine, CA, US]) that requires exposure of a subcutaneous atrial lead for radiofrequency activation, the activation of enCorTC is wireless and is adjustable for appropriate MR result by echocardiography.12

Mitral Leaflets The anterior leaflet tends to be the more mobile of the two leaflets, while the posterior leaflet acts as the support structure.17 The anterior mitral leaflet is in fibrous continuity with the aortic valve, bordered on either side by the right and left fibrous trigones. The areas of both leaflets are identical, with the posterior leaflet being broad (occupying nearly two-thirds of the annular circumference) and short.1 Leaflet defects typically include excessive/deficient tissue or unrestrained/ restricted mobility. The goal of treating the mitral leaflets is to improve leaflet coaptation and to reduce the effective regurgitant orifice area.

Leaflet Plication Based on the surgical Alfieri technique, percutaneous leaflet plication re-establishes leaflet coaptation by approximating the anterior and posterior leaflets (A2 and P2 central segments, site of regurgitation) together via a cobalt-chromium clip.18 The MitraClip® system (Abbott Vascular, Redwood City, CA, US) creates an effective double-orifice mitral valve, reducing the overall amount of MR for both functional and degenerative types. The system uses a steerable catheter (24F proximally, 22F distally) to deliver the MitraClip transseptally and allow for grasping of the leaflet free edges.19 The MR jet must be centrally located with sufficient coaptation length of at least 2 mm, a depth from the MA of no more than 11 mm, and if a flail leaflet is present, a gap and flail width not exceeding 10 mm and 15 mm, respectively.

MitraClip implantation is typically guided by conventional fluoroscopy and transoesophageal echocardiography (TOE). The use of live three-dimensional (3D) TOE-fluoroscopy fusion technology (EchoNavigator system [Philips Healthcare, Andover, MA, US]) can potentially further aid in implantation. With this technology, landmarks can be placed at the site of transseptal puncture (3–4 centimetres [cm] above the coaptation plane) and at the central A2P2 coaptation or intended coaptation point (if prolapse or a flail leaflet is present) to guide the intervention (see Figure 1a). The device can be steered until it is aligned over the landmark and advanced into the LV (see Figure 1b). The clip is then retracted for leaflet grasping and device closure. The MitraClip can be repositioned or removed prior to final deployment and multiple clips can be implanted to achieve the desired MR reduction (see Figure 1c).

The Endovascular Valve Edge-to-Edge Repair Study (EVEREST) II study enrolled 279 patients with moderate-severe or severe MR in a 2:1 ratio to undergo either MitraClip implantation or conventional mitral valve repair or replacement.20 Successful reduction in MR by at least 1 grade was achieved in 76 % of patients. Composite endpoint of freedom from death, MV surgery or reoperation, and MR >2+ at one year was 72.4 % and 87.8 % (p=0.02), MitraClip and surgery, respectively, in patients with successful in-hospital results. The MitraClip was associated with a significant improvement in New York Heart Association (NYHA) classification with superiority in safety endpoints, major adverse events occurring in 15 versus 48 % at 30 days (p<0.001), compared with

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Figure 1: Leaflet Plication Using the MitraClip System and Transoesophageal Echocardiography Fluoroscopy Fusion Imaging A

B

C

(A) Landmarks were placed using live transoesophageal echocardiography (TOE) fluoroscopy fusion imaging (Philips Healthcare, Andover, MA, US) and overlayed onto fluoroscopy (transseptal puncture: yellow dot/blue arrow and A2P2 coaptation point: red dot). The delivery system can be visualised across the interatrial septum in the left atrium. The first MitraClip device was released at the site of A2P2 coaptation. (B) Repeat imaging revealed significant residual regurgitation medial to the first MitraClip. A second landmark was placed at the site of regurgitation, medial to the first clip, and the delivery system was advanced into the left ventricle as visualised under three-dimensional (3D) TOE. (C) A second MitraClip was positioned and deployed with minimal residual regurgitation.

surgery. Similar results were achieved regardless of the MR type and were maintained at three years. In those requiring surgery, it usually occurred within six months after implantation and surgical options were preserved with 84 % able to undergo successful mitral valve repair.21

Leaflet Coaptation Providing a sealing surface for the leaflets, the Mitra-Spacer™ (Cardiosolutions Inc., Stoughton, MA, US) is a polyurethane-silicone polymer spacer that positions itself at the zone of coaptation, filling the regurgitant orifice. It is anchored to the apex and can be delivered via a transseptal or transapical approach. Pre-sizing balloons are used to appropriately match the spacer to the dimension of the mitral valve (MV) orifice. The device does not alter the MV apparatus and can be fully removed or maintained permanently. Potential complications with the system include thrombus formation or iatrogenic mitral stenosis. The FIM trial resulted in a 1–2 grade reduction in MR without a significant transmitral gradient.22

Chordae Tendineae/Papillary Muscles The chordae tendineae originate from the papillary muscles and attach to the mitral leaflets, transmitting ventricular contractions.3 The primary and secondary chordae maintain leaflet apposition and facilitate valve closure, whereas the tertiary chordae help to maintain ventricular geometry. 5 Abnormalities of the chordae tendineae typically include rupture and presence of abnormally long or short chordae.1 Papillary dysfunction can occur with fibrosis, ischaemia, or rupture through infarction or trauma. Elongated degenerated papillary muscles can induce prolapse and retracted papillary muscles can make cords vulnerable to disruption.

Chordal Implants/Cinching Chordal implants are synthetic chords or sutures that can be used to correct leaflet prolapse usually due to ruptured or torn chordae.

The implants are attached to the free leaflet margins and anchored to the papillary muscles or LV myocardium. The chords can be delivered either via a transseptal or transapical approach. V-Chordal (Valtech Cardio LTD, Or-Yehuda, Israel), originally designed for an off-pump transatrial approach, allows for chordal implantation with dynamic modulation, able to adjust chordal length under physiological conditions to optimise leaflet coaptation. The device is initially screwed (sutureless) into the papillary muscles; then the chordal length is adjusted by turning a nob; they are subsequently secured to the leaflet margin. FIM trial of seven patients revealed complete procedural

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success with 100 % chronic success at two years.23 The newer transseptal system has a cinching device to secure the chord with two chords allowed for each implant. Preclinical trials are underway.

The NeoChord (NeoChord, Eden Prairie, MN, US) system allows for transapical deployment with fibre optic confirmation of leaflet grasping.24 This device is mentioned due to its off-pump application and potential for percutaneous delivery. Transapical Artificial Chordae Tendineae (TACT) trial enrolled 30 patients with severe MR and isolated posterior leaflet prolapse who underwent placement of at least one artificial NeoChord.25 Acute procedural success was noted in 87 % of patients with 65 % achieving MR reduction to ≤2+ at 30 days. The implantation of multiple chords (2–4 per patient) and fixation to the posterolateral wall translated into higher success rates. All patients requiring subsequent surgery were able to undergo successful repair. NeoChord recently achieved CE mark. Overall, the concern with chordal implants is that aggressive therapy may lead to leaflet restriction and residual MR. Furthermore, the presence of intracardiac material may also predispose the patient to thrombus formation.

Mitral Valve Replacement Despite the desire to repair rather than to replace the mitral valve, TMVT are currently limited. With the ability to preserve the mitral apparatus, TMVR may be an alternative to repair technologies when suboptimal results are achieved or even a more suitable approach.

Unlike the aortic valve and transcatheter aortic valve replacement, the complexities of the mitral apparatus make TMVR a challenge.

Concerns for TMVR include the presence of larger annular sizes and asymmetric MA anatomy, the need for appropriate valve anchoring within the MA, and the potential for developing left ventricular outflow tract (LVOT) obstruction and paravalvular regurgitation. Durability issues dealing with stent fracture, tissue erosion and degeneration require evaluation. Multiple TMVR devices that have been developed are in preclinical testing or FIM trials.

The CardiAQ Prosthesis (CardiAQ Valve Technologies Inc., Irvine, CA, US) is a porcine pericardial, trileaflet valve on a nitinol frame that is transseptally delivered.13 It has two sets of 12 anchors that secure the device within the MA and preserve the chordae and papillary muscles.

It was the first valve to achieve successful FIM in 2012 for severe MR. This patient died on day three due to multisystem organ failure with autopsy not revealing evidence of prosthetic issues. The Cardiovalve® prosthesis (Valtech Cardio Ltd) is also transfemorally delivered

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Structural Figure 2: Transcatheter Mitral Valve-in-Valve Implantation A

C

B

D

initially delivered transatrially via a right thoracotomy.29 The device is made of a foldable nitinol frame that attaches to the native valve through three anchors or grippers, grasping the native leaflets and MA; a Dacron skirt covers the valve. Recent concern over valve fixation has stimulated valve redesign to create an active fixation system where the device is delivered transapically and anchors are attached to a novel transapical closure device, Permaseal™ (Micro Interventional Devices Inc.). Preclinical trials of the newer generation device are still pending.

Finally, the Ventor Embracer prosthesis (Medtronic Inc., Minneapolis, MN, US) is a trileaflet bovine pericardial valve on a self-expanding nitinol frame.30 The device consists of two components: a large inflow portion that seals to the atrial surface of the MA, and a very short LV projection to avoid subannular and LVOT interference. Support arms engage the A2P2 components of the mitral valve, securing the valve in place and creating tension on the atrial portion to improve apposition and reduce paravalvular regurgitation. The device is delivered through a transatrial approach. Preclinical trials are also underway.

Valve-in-Valve/Valve-in-Ring Therapy

A) Three-dimensional (3D) transoesophageal echocardiography (TOE) revealed severe mitral bioprosthetic valve degeneration with thickened and immobile prosthetic leaflets. (B) TOE QLAB (Phillips Healthcare, Andover, MA, US) analysis confirmed the inner diameter of the bioprosthesis prior to valve-in-valve (ViV) implantation. (C) Using a percutaneous transseptal-transapical approach, a 23 mm Edwards SAPIEN valve (red arrows) was implanted within a 25 mm Carpentier-Edwards bioprosthesis under computed tomography angiography (CTA) fluoroscopy fusion imaging guidance (HeartNavigator, Philips Healthcare, Best, The Netherlands). In yellow, the fused CTA outline of the bioprosthesis can be visualised with a virtual valve in red. Directed transseptal puncture is identified by a blue dot. (D) The same technique was applied for a Melody valve (blue arrows) implanted into a 29 mm St. Jude bioprosthesis, inflated to 24 mm. In yellow, the fused CTA outline of the mitral and aortic bioprosthesis is noted below and above, respectively. The interatrial septum was closed using an Amplatzer Septal Occluder (St. Jude Medical Inc., Minneapolis, MN, US, dark blue arrow).

through a transeptal approach.26 The device has separate fixation and sealing, where the sealing skirt is first implanted followed by the valve. The novel fixation design around both the anterior and posterior leaflets is able to generate >50 N of anchoring force. Preclinical trials are promising and ongoing.

On the other hand, the Tiara prosthesis (Neovasc Inc., Vancouver, BC, Canada) is a trileaflet porcine pericardial valve fixed on a self-expanding frame that is delivered transapically.14,15,27 The frame/valvular orifice is D-shaped to mimic the natural shape of the mitral orifice; the flat side of the D is positioned toward the aortic-mitral continuity to prevent interruption with the aortic valve and LVOT. Its atrial lip engages the left atrium and three ventricular anchors secure the valve in place during systole. The ventricular portion of the device has a covered skirt to reduce risk of paravalvular regurgitation. Tiara is repositionable and retrievable, and awaiting FIM later this year. The Lutter prosthesis (Tendyne Medical Inc., Baltimore, MD, US) is a trileaflet bovine pericardial valve fixed on a self-expanding frame.27,28 The device, like the Tiara, is delivered transapically and has an atrial fixation system or flat ring that is connected at a 45, 90 or 110 degree angle (three different iterations of the device) to the tubular ventricular portion of the stent.

In addition, there is a ventricular fixation system where neochords are attached to the apex to secure the valve in place and a covered skirt to reduce paravalvular regurgitation. Preclinical trials are underway.

Next, the Endovalve™ prosthesis (Micro Interventional Devices Inc.™, Bethlehem, PA, US) is a trileaflet bovine pericardial valve that was

52

Kliger_article_edited.indd 52

Although the TMVR technologies remain in its early clinical stages, current transcatheter valves are being implanted successfully within surgical mitral platforms such as degenerative bioprostheses and complete annuloplasty rings. For patients with degenerative bioprostheses or failed repair, reoperative surgical valve replacement often carries a high mortality risk, especially in older patients with multiple co-morbidities.

Transcatheter valve-in-valve (ViV) or valve-in-ring (ViR) implantation is a less invasive option and can be utilised as an alternative to open surgery in the high-risk or inoperable patient.31–33 In the mitral position, the transcatheter valves that are currently utilised ‘off-label’ are the Edwards Sapien (Edwards Lifesciences, Irvine, CA, US) and the Melody® (Medtronic Inc.) valves. The Edwards Sapien valve is a bovine pericardial valve sutured onto a stainless steel balloon-expandable stent that is Food and Drug Administration (FDA) approved and CE marked for transcatheter aortic valve replacement. The Melody valve is that of a bovine jugular valved vein, which is sutured onto a platinum-iridium stent. It is designed for dysfunctional right ventricular outflow tract conduits. To date, the results of seven Melody ViV implantations within a high-pressure, left-sided haemodynamic environment (one mitral, six aortic) revealed complete freedom from regurgitation and an 86 % freedom from significant stenosis at one-year follow-up.24 The Global ViV Registry with nearly 120 patients included for Sapien mitral ViV and ViR, reported 30 day and one-year mortality rates of 12 % and 25 %, respectively.17,34 A majority of implantations, over two-thirds, were performed using a surgical transapical approach. Approximately 5 % had device malpositioning related predominately to the difficulties in achieving coaxial deployment through an antegrade transseptal technique. A newer approach of antegrade transseptal utilising a percutaneous transapical rail provides a complete percutaneous approach to mitral ViV and ViR implantation where creation of the arteriovenous rail has allowed for coaxial deployment and improved fine-tuning of valve positioning within the surgical platform35 (see Figures 2 and 3). Radiopaque fluoroscopic markers of the valve can aid in ViV/ViR positioning. The use of computed tomography angiography (CTA) fluoroscopy (HeartNavigator [Philips Healthcare, Best, The Netherlands]) and TOE-fluoroscopy fusion imaging can

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Transcatheter Mitral Valve Devices – Functional Mechanical Designs

Figure 3: Transcatheter Mitral Valve-in-Ring Implantation A

B

C

(A) Two-dimensional (2D) transoesophageal echocardiography (TOE) revealed a complete annuloplasty ring with severe para-ring and intra-ring regurgitation by colour doppler. (B) With threedimensional (3D) TOE, the mitral valve apparatus can be well-visualised. (C) Using a percutaneous transseptal-transapical approach, closure was performed of the mitral para-ring leak using an Amplatzer Vascular Plug II 8 mm and intra-ring regurgitation using a Melody valve-in-ring. In yellow, the fused computed tomography angiography (CTA) outline of the annuloplasty ring can be visualised as well as the aorta and coronary arteries in red.

provide additional landmarks (i.e. sites of transseptal puncture, transapical puncture, mitral bioprosthesis and mitral ring) to perform guided puncture and valve deployment.

Conclusion Mitral regurgitation is a complex disorder involving a multitude of components of the mitral apparatus. TMVT directed at these components, as described, are available at varying stages of development and able to

1. Perloff JK, Roberts WC, The mitral apparatus: Functional anatomy of mitral regurgitation, Circulation , 1972;46(2):227–39.

2. Kliger C, Ruiz CE, Percutaneous Treatment of Primary and Secondary Mitral Regurgitation: Overall Scope of the Problem, Interventional Cardiology Clinics, 2012;1(1):73–83.

3. Van Mieghem NM, Piazza N, Anderson RH, et al., Anatomy of the mitral valvular complex and its implications for transcatheter interventions for mitral regurgitation, J Am Coll Cardiol, 2010;56(8):617–26.

4. Chiam PT, Ruiz CE, Percutaneous transcatheter mitral valve repair: a classification of the technology, JACC Cardiovasc Interv, 2011;4(1):1–13.

5. Ho SY, Anatomy of the mitral valve, Heart , 2002;88 Suppl 4:iv5–10.

6. Levine RA, Triulzi MO, Harrigan P, Weyman AE, The relationship of mitral annular shape to the diagnosis of mitral valve prolapse, Circulation , 1987;75(4):756–67.

7. Davis PK, Kinmonth JB, The Movements of the Annulus of the Mitral Valve, J Cardiovasc Surg (Torino), 1963;4:427–31.

8. Brolin I, The mitral orifice, Acta Radiol Diagn (Stockh), 1967;6(3):273–95.

9. Korn D, Desanctis RW, Sell S, Massive calcification of the mitral annulus. A clinicopathological study of fourteen cases, N Engl J Med, 1962;267:900–9.

10. Choure AJ, Garcia MJ, Hesse B, et al., In vivo analysis of the anatomical relationship of coronary sinus to mitral annulus and left circumflex coronary artery using cardiac multidetector computed tomography: implications for percutaneous coronary sinus mitral annuloplasty, J Am Coll Cardiol, 2006;48(10):1938–45.

11. Tops LF, Van de Veire NR, Schuijf JD, et al., Noninvasive evaluation of coronary sinus anatomy and its relation to the mitral valve annulus: implications for percutaneous mitral annuloplasty, Circulation , 2007;115(11):1426–32.

12. Buchbinder M, MiCardia: Dynamic Annuloplasty Device Design Concepts, Experimental Insights and First-in-Man, Presented at: TCT 2011, San Francisco, CA, US, 7–11 November 2011.

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treat different pathophysiological substrates. Advancements in therapies and the possibility of combining technologies may further improve their efficacy and safety. TMVR may emerge as an alternative or even a more suitable approach, while preserving the mitral apparatus. Early data on transcatheter mitral ViV and ViR implantation are encouraging, and may be an alternative to reoperation in the high-risk patient. Overall, percutaneous mitral therapies are evolving and options to treat patients with this complicated disorder are expanding. n

13. Sondergaard L, Transcatheter Mitral Valve Implantation: CardiAQ, Presented at: TCT 2012, Miami, Florida, US, 22–26 October 2012.

14. Banai S, TIARA: Catheter-based Mitral Valve Bioprosthesis, Short and Long Term Pre-Clinical Results, Presented at: TCT 2012, Miami, Florida, US, 22–26 October 2012.

15. Banai S, Jolicoeur EM, Schwartz M, et al., Tiara: a novel catheter-based mitral valve bioprosthesis: initial experiments and short-term pre-clinical results, J Am Coll Cardiol , 2012;60(15):1430–1.

16. Schofer J, The Valtech Cardioband, Presented at: CSI 2012, Frankfurt, Germany, 28–30 June 2012.

17. Dvir D, Transcatheter Mitral Valve-in-Valve/Valve-in-Ring Implantations For Degenerative Post Surgical Valves: Results From the Global Valve-in-Valve Registry, Presented at: PCR London Valves 2012, London, UK, 2012.

18. Alfieri O, Maisano F, De Bonis M, et al., The double-orifice technique in mitral valve repair: a simple solution for complex problems. J Thorac Cardiovasc Surg, 2001;122(4):674–81.

19. Feldman T, Wasserman HS, Herrmann HC, et al., Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I Clinical Trial, J Am Coll Cardiol, 2005;46(11):2134–40.

20. Feldman T, Foster E, Glower DD, et al., Percutaneous repair or surgery for mitral regurgitation, N Engl J Med , 2011;364(15):1395–406.

21. Argenziano M, Skipper E, Heimansohn D, et al., Surgical revision after percutaneous mitral repair with the MitraClip device, Ann Thorac Surg , 2010;89(1):72–80; discussion p 80.

22. Ye J, Mitra-Spacer: a novel approach to Mitral Regurgitation, Presented at: TCT 2010, Washington, DC, US, 21–25 September 2010.

23. Maisano F, The Promise and Reality of Surgical and Percutaneous Neochords, Presented at: Transcatheter Valve Therapies (TVT) 2013, Vancouver, Canada, 12–15 June 2013.

24. Hasan BS, McElhinney DB, Brown DW, et al., Short-term performance of the transcatheter Melody valve in high-

pressure hemodynamic environments in the pulmonary and systemic circulations, Circ Cardiovasc Interv, 2011;4(6):615–20.

25. Daly R, Neochord Update: From TACT trial update to percutaneous chords, Presented at: TCT 2012, Miami, Florida, US, 22–26 October 2012.

26. Maisano F, Valtech Cardiovalve: Percutaneous Mitral Valve Replacement System, Presented at: EuroPCR 2013, Paris, France, 21–24 May 2013.

27. Lutter G, Transcatheter Mitral Valve Replacement: Lutter Valve Update, Presented at: TCT 2012, Miami, Florida, US, 22–26 October 2012.

28. Lozonschi L, Bombien R, Osaki S, et al., Transapical mitral valved stent implantation: a survival series in swine. J Thorac Cardiovasc Surg , 2010;140(2):422–6 e1.

29. Herrmann HC, Transcatheter Mitral Valve Replacement, Presented at: CRT 2013, Washington DC, US, 23–26 February 2013.

30. Piazza N, Medtronic Mitral Valve Programme, Presented at: EuroPCR 2013, Paris, France, 21–24 May 2013.

31. Latib A, Ielasi A, Montorfano M, et al., Transcatheter valvein-valve implantation with the Edwards SAPIEN in patients with bioprosthetic heart valve failure: the Milan experience, EuroIntervention, 2012;7(11):1275–84.

32. Cheung A, Webb JG, Barbanti M, et al., 5-year experience with transcatheter transapical mitral valve-in-valve implantation for bioprosthetic valve dysfunction, J Am Coll Cardiol, 2013;61(17):1759–66.

33. Descoutures F, Himbert D, Maisano F, et al., Transcatheter valve-in-ring implantation after failure of surgical mitral repair, Eur J Cardiothorac Surg, 2013;44(1):e8–15.

34. Dvir D, Transcatheter Mitral/Tricuspid Valve Implantation in Failed Surgical Valves: Update from the Global Registry, Presented at: Transcatheter Valve Therapies (TVT) 2013, Vancouver, Canada, 12–15 June 2013.

35. Michelena HI, Alli O, Cabalka AK, Rihal CS, Successful percutaneous transvenous antegrade mitral valve-in-valve implantation, Catheter Cardiovasc Interv , 2013;81(5):E219–24.

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Resistant Hypertension

Renal Sympathetic Denervation – A Review of Applications in Current Practice Vik a s K a p i l , 1 ,2 A j a y K Ja i n 1 ,3 a n d M e l v i n D L o b o 1 ,2 1. William Harvey Heart Centre, NIHR Cardiovascular Biomedical Research Unit, Centre for Clinical Pharmacology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2. Barts Hypertension Clinic, Department of Clinical Pharmacology, Barts Health NHS Trust, London, UK; 3. Department of Cardiology, London Chest Hospital, Barts Health NHS Trust, London, UK

Abstract Resistant hypertension is associated with high morbidity and mortality despite numerous pharmacological strategies. A wealth of preclinical and clinical data have demonstrated that resistant hypertension is associated with elevated renal and central sympathetic tone.

The development of interventional therapies to modulate the sympathetic nervous system potentially represents a paradigm shift in the strategy for blood pressure control in this subset of patients. Initial first-in-man and pivotal, randomised controlled trials of endovascular, radio-frequency renal sympathetic denervation have spawned numerous iterations of similar technology, as well as many novel concepts for achieving effective renal sympatholysis. This review details the current knowledge of these devices and the evidence base behind each technology.

Keywords Hypertension, devices, resistant, renal sympathectomy Disclosure: Vikas Kapil has received funding from the British Heart Foundation. Ajay K Jain is an Advisory board member for Medtronic Inc. Lobo received educational grant funding from Medtronic Inc., is a Consultant to and is on the speakers’ bureau of St Jude Medical and is a Consultant to ROX Medical and Cardiosonic.

Received: 2 December 2013 Accepted: 18 February 2014 Citation: Interventional Cardiology Review, 2014;9(1):54–61 Correspondence: Melvin D Lobo, William Harvey Heart Centre, NIHR Cardiovascular Biomedical Research Unit, Centre for Clinical Pharmacology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ. E: m.d.lobo@qmul.ac.uk

Up to one-in-five treated hypertensive patients are deemed to be treatment resistant1–3 (on at least three different anti-hypertensive medication classes, including a diuretic)4–6 and have high cardiovascular risk.7–9 There is a paucity of high-quality evidence to suggest that the addition of a fourth line (or fifth, sixth line, etc.) medication is likely to bring either hypertension under control or to reduce excess morbidity/mortality in resistant hypertension (RHTN).5 Recently, renal sympathetic denervation (RSD) has been suggested as an effective, evidence-based approach for controlling RHTN.10

The Rationale for Renal Sympathetic Denervation in Human Resistant Hypertension Activation of the sympathetic nervous system (SNS) is now recognised to occur in all stages of hypertension and correlates to the severity of hypertension.11,12 The renal efferent and afferent SNS neural fibres make their own contribution to the maintenance of the hypertensive phenotype. Renal SNS afferents run along the renal artery adventitia and cluster in the renal pelvis13,14 and activity of these renal SNS fibres regulate whole body sympathetic tone by moderating hypothalamic activity.15 Renal SNS efferents innervate the kidneys from the paravertebral ganglia at T10-L2 and also run alongside the renal afferents in the renal artery adventitia.13 Renal SNS efferent activity mediates renal sodium retention, volume expansion16 and stimulates the neuro-humoral renin–angiotensin–aldosterone axis, further elevating blood pressure (BP) though salt/water retention and vasoconstriction.17

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In the first half of the 20th century, surgical thoracolumbar sympathectomy (resulting in renal sympathectomy) was performed to treat malignant hypertension with good results in terms of reducing both BP and mortality. 18,19 However, this radical surgical operation was not without significant operative mortality and post-operative morbidity, including postural hypotension, erectile dysfunction and syncope.

Thus the procedure fell out of favour with the advent of antihypertensive medications that were non-invasive, tolerable and proved to reduce BP and mortality. 20 Preclinical studies have clearly demonstrated that interruption of renal SNS signalling, by either surgical ligation and re-anastomosis or chemical adventitial stripping of the renal artery, prevents the development of hypertension and, furthermore, attenuates established hypertension in numerous animal models of hypertension.21 Further evidence for benefit of renal sympathectomy in the treatment of hypertension comes from a study of patients treated with bilateral nephrectomy for end-stage chronic kidney disease (CKD) maintained on haemodialysis or post-transplantation, which demonstrates sustained BP reduction.22 While these techniques are not suitable for use in humans, the recent development of minimally invasive, catheter-based solutions10,23 to effect selective RSD has re-ignited interest in this field.

© RADCLIFFE CARDIOLOGY 2014

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Renal Sympathetic Denervation – A Review of Applications in Current Practice

Figure 1: Current Renal Sympathetic Denervation Technologies

A

B

D

H

E

I

C

F

G

J

Medtronic Inc. first-generation Symplicity™ (a) and second-generation Symplicity Spyral™ (b) radio-frequency (RF) catheters; St Jude Medical multi-electrode, basket design EnligHTN RF catheter (c); ReCor Medical Paradise™ circumferential irrigated balloon, ultrasound (US) catheter (d); Covidien One-Shot™ spiral RF catheter (e); Biosense ThermoCOOL™ irrigated multielectrode RF catheter (f); CardioSonic TIVUS™ balloon US catheter (g); Verve Medical™ retro-ureteric multi-electrode basket RF catheter (h); Boston Scientific Vessix™ multi-electrode, balloonmounted, bipolar RF catheter (i) and Mercator Bullfrog™ micro-needle catheter for perivascular guanethidine injection (j).

Current Technologies for Renal Sympathetic Denervation The paradigm for a technology that may have utility in renal SNS modulation for hypertension is that it achieves selective RSD with no collateral damage to adjacent/other structures. The different technologies that are currently being tested in both preclinical and clinical studies vary in their potential benefits and pitfalls and these issues are discussed below.

Radio-frequency Neural Ablation Radio-frequency (RF) energy, introduced for ablation of neurovascular tissue more than 25 years ago,24 is an alternating electrical current that produces tissue destruction by both direct resistive heating of the tissue in contact with the catheter tip and by thermal conduction to deeper tissue. The RF electrical current is delivered most frequently in the unipolar mode, with completion of the electrical circuit via another electrode placed on the skin. In bipolar mode, two closely opposed electrodes are placed on the catheter electrode tip. On energy delivery to the target surface, the catheter tip heats subjacent (up to 4 mm) tissues from 50 to 70°C.25 A sudden rise in impedance can suggest over-heating and charring of tissue at the tip and many modern RF catheters are designed with auto-feedback mechanisms to prevent excessive temperature elevations. Other factors that influence tissue destruction include duration of energy application, with at least 35 seconds required for uniform temperature elevations in targeted tissue,26 catheter electrode size and tissue apposition and the level of power applied from the RF generator.

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Anatomical considerations are required before progressing to RF RSD.27–29 Prior renal artery duplex scanning or cross-sectional imaging to rule out significant renal atherosclerotic disease is required, and this is confirmed at the time of endovascular RSD by formal angiography before ablation catheter placement. The main trunk diameter should be >4 mm and the length should be >20 mm to allow both effective blood flow for cooling (see below) and sufficient space for multiple ablations. Furthermore, accessory or dual arteries should be of similar dimensions to allow treatment to be given to all arteries concurrently. To date, RF RSD is not recommended in patients with previous renal artery angioplasty or endovascular stents to treat previous atherosclerotic renal artery stenosis (RAS).

First-generation RF RSD systems utilise flexible RF catheters that are advanced into each renal artery in turn under fluoroscopic guidance.

Energy delivery causes thermal destruction of SNS neural tissue in the perivascular adventitia and using native renal blood flow to cool the intima, endothelial damage is reduced. Intra-procedural utilisation of vasodilators, such as nitroglycerine (glyceryl trinitrate) and non-dihydropyridine calcium channel blockers, are often used to prevent vasospasm that may accompany energy delivery. The perivascular neural bundle also contains sensory C fibres and thus neural destruction is accompanied by significant pain, necessitating conscious sedation and adequate opiate-based analgesia.

Ardian Inc. (later purchased by Medtronic Inc.) developed the first minimally invasive technology to effect selective RSD. The

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Resistant Hypertension Table 1: Radiofrequency Technologies for Renal Sympathetic Denervation Device (Company, CE Mark) Symplicity™

Catheter/Anatomy Details 6 Fr, no guidewire

Technical Details 8 watts

Development Phase Clinical: see text for first-in-man and randomised

Medtronic Inc.

Unipolar, mono-electrode

2 minute/ablation

control trial results10,31

Minneapolis, US

Renal artery: >4 mm

>4 ablation/artery

Double-blind, sham-controlled (Symplicity HTN-3,

Cooling: blood flow

n=530) failed primary efficacy 6 month OBP end-point

CE: February 2008

(NCT01418261)

Symplicity Spyral™

6 Fr, over-the-wire

8 watts

Clinical: [abstract] observational (n=50) to 6 month

Medtronic Inc.

Unipolar, 4-electrode

1 minute/ablation

post RSD

Minneapolis, US

Catheter helically conforms to artery

1 ablation/artery

Severe RHTN, on >2 meds

CE: Not available

Renal artery: 3–8 mm

Cooling: blood flow

Interim results (n=29, 1m); baseline OBP: 182/94 mmHg

↓OBP: 16/7 mmHg88

EnligHTN™

8 Fr, no guidewire

6 watts

Clinical: EnligHTN-1; observational (n=46) to 6 month

St Jude Medical

Unipolar, 4-electrode

90 second/sequential

Severe RHTN, on >2 meds, baseline OBP: 176/96mmHg

St Paul, US

Basket mounted (6 or 8 mm)

ablation per electrode

↓OBP: 26/10 mmHg

CE: December 2011

Renal artery: 4–8 mm

2 ablation/artery

6m Check CTA: no new RAS70

Cooling: blood flow

One-Shot™

7–8 Fr, over-the-wire

25 watts

Clinical: RHAS; observational (n=9) to 12 months

Covidien Ltd

Unipolar, balloon-mounted,

2 minute/ablation

post RSD

CE: February 2012

Low-pressure balloon (<1 atmosphere) Cooling: irrigated (8-hole)

Dublin, Ireland

helical electrode

1 ablation/artery

186/91 mmHg

Withdrawn January 2014

Renal artery: 4–7 mm

catheter tip

↓OBP: 31/10 mmHg (12m), ↓ABP: 3/4 mmHg (6

Treated hypertension, on >1 med, baseline OBP

months) 6 month check CTA: no RAS at 12 months89

ThermoCOOL™

7 Fr, over-the-wire

10–20 watts

Clinical: Observational (n=10) to 6 month post RSD

Biosense Webster

Unipolar, 4-electrode

30 second/ablation

Moderate RHTN, on >2 meds, baseline ABP:

Diamond Bar, US

Renal artery: >4 mm

4–6 ablation/artery

158/88mmHg

CE: May 2012

Cooling: irrigated (6-hole)

↓ABP: 21/10 mmHg

catheter tip

Repeat renal angiography at 3 months: no RAS90

Vessix™

8 Fr, over-the-wire

1 watt

Preclinical: [abstract] porcine (n=17) to 6 months)

Boston Scientific

Bipolar, balloon-mounted,

30 second/ablation

post RSD;

Natick, US

8-electrode pairs

1–2 ablation/artery

Chronic, destructive neural changes at 6 months

CE: May 2012

Non-compliant balloon (3 atmosphere, Cooling: blood flow

Increased small nerve growth at 6 months,

4–7 mm)

uncertain significance91

Renal artery: 3–7 mm

Clinical: reduce HTN; (n=150, NCT01541865)

unpublished data

Iberis™

4 Fr, no guidewire

8 watts

Clinical: case report (n=1) to 2 week post RSD

Terumo Corp.

Unipolar, mono-electrode

2 minute/ablation

Severe RHTN on 4 meds, baseline OBP 160/90mmHg

Tokyo, Japan

Radial access

>4 ablation/artery

↓OBP: 15/10mmHg92

CE: April 2013

Renal artery: >4 mm

Cooling: blood flow

Verve™

9 Fr, over-the-wire

Low power

Preclinical: porcine (n=16) study to 30 day post-RSD

Verve Medical

Unipolar, multi-electrode

1 ablation/renal pelvis

Imaging: normal pyelography, angiography 7–30 day

Santa Barbara, US

Retro-ureteric

Cooling: urinary flow

CE: Not available

No systemic contrast

Histology: renal artery safety; SNS neural ablation ↓renal NE by ~60 %40

ABP=ambulatory blood pressure; CTA=computed tomography angiogram; eGFR=estimated glomerular filtration rate; meds=medications; NE=norepinephrine; OBP=office blood pressure; RAS=renal artery stenosis; RHAS=renal hypertension ablation system; RHTN=resistant hypertension; RSD=renal sympathetic denervation; SNS=sympathetic nervous system.

Symplicity™ (Minneapolis, US) catheter consists of a unipolar ablation catheter and a proprietary low-energy RF generator, and is the most widely used and studied device to date. Typically four to seven ablations (5 mm apart; 2 minutes per ablation) are performed sequentially in each artery in a classic helical pattern distally to proximally to prevent potential RAS and cover the full arterial circumference.

Symplicity HTN-1 was a non-randomised, first proof-of-concept study using the Symplicity system in severe RHTN (n=45; office BP=177/101 mmHg; mean anti-hypertensive medications=4.7) demonstrating improvement of office BP by 27/17 mmHg at 12-months10 and by 32/14 mmHg at 36 months.30 Symplicity HTN-2 was a randomised trial of RSD (using the Symplicity catheter) plus current treatment versus current treatment only. In patients randomised to RSD (n=49; office BP=178/97 mmHg; mean anti-hypertensive medications=5.2), 6-month office BP-lowering was 32/12 mmHg compared with 1/0 mmHg in controls (n=51).31

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Since the publication of these initial studies using the Symplicity catheter, other devices have quickly come to the market and tried to establish their own safety and efficacy profiles (see Figure 1; Tables 1–3), with improved technological iterations on the original Ardian Inc. design. Recently, the first dedicated radial-approach RSD device has gained a CE mark (Iberis™, Terumo Corp, Tokyo, Japan) (see Table 1). This is a unipolar electrode similar to the Symplicity system that is introduced via the trans-radial approach rather than the trans-femoral approach. This trans-radial approach has been shown to be associated with reduced access-site complications in percutaneous coronary interventions (PCI) and is recommended as the default site for access in PCI.32 Several companies have designed multi-electrode or elongated, spiral electrode catheters, including a second-generation catheter from Medtronic Inc., which can produce simultaneous energy applications at multiple anatomical sites within the renal artery,

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Table 2: Ultrasound Technologies for Renal Sympathetic Denervation Device (Company, CE Mark) Catheter/Anatomy Details Paradise™ 6 Fr, over-the-wire

Technical Details 25–30 watts, non-focused US

Development Phase Preclinical: [abstract] porcine (n=11) renal artery

ReCor Medical

Cylindrical transducer

Circumferential

safety at 7–28 days post RSD93

Menlo Park, US

Transducer in low-pressure, 5–8 mm

40 second/ablation;

Clinical: REDUCE; observational (n=11) to 3 months

CE: December 2011

cylindrical, centring balloon

<3 ablation/artery

post RSD

Renal artery: 4–8 mm

Cooling: closed circuit

Moderate RHTN on >2 meds, baseline OBP:

irrigated balloon

180/109 mmHg ↓OBP: 36/17 mmHg; ↓HBP:

22/12 mmHg

Stable renal function at 3 months post RSD

(data not provided)94

TIVUS™

6 Fr, over-the-wire

8 watts, high-intensity,

Preclinical: unpublished porcine renal safety data

CardioSonic

Cylindrical transducer

non-focused US

Clinical: unpublished observational (n=17) first-in-

Tel Aviv, Israel

Renal artery: >4 mm

Circumferential

man study

CE: Not available

30 second/ablation;

<3 ablation/artery

Cooling: blood flow

Sound 360™

8 Fr, no guidewire

Low-power, high-intensity,

Clinical: [abstract] sound-interventions;

Sound Interventions

Cylindrical transducer

non-focused US

observational (n=10) to 1 month post-RSD

Stony Brook, US

Transducer in low-pressure,

Circumferential

Severe RHTN on >2 meds, baseline office systolic

CE: Not available

triangular, centring balloon

2 minute/ablation;

blood pressure >160 mmHg ↓OBP: 31/10 mmHg

Renal artery: >5 mm

2 ablation/artery

Post-RSD angiography and IVUS, no change

Cooling: blood flow

arterial size95

Surround Sound™

External applied US energy

Low-intensity, focused US

Clinical: [abstract] WAVE II; observational (n=13) to

Kona Medical

Renal artery: Not available

3 minute/ablation;

6 week post-RSD

Campbell, US

1 ablation/artery

Moderate RHTN on >2 meds

CE: Not available

Cooling: Not available

↓OBP: 18/0 mmHg

No significant adverse events96

HBP=home blood pressure; IVUS=intravascular ultrasound; OBP=office blood pressure; RSD=renal sympathetic denervation; RHTN=resistant hypertension; US=ultrasound.

either mounted externally on a scaffold or inflatable balloon (see Table 1). Not only does this substantially reduce procedure time and contrast load but it may also help achieve complete circumferential nerve ablation, as the catheter does not need to be re-positioned between energy applications. Even more recently, 3D electrical current mapping technology, commonly applied in cardiac electrophysiology (EP) procedures, has been used to further reduce both contrast load and radiation exposure.33 Further iterations of RF RSD devices include integrated cooling mechanisms to prevent local tissue heating to excessive levels (see Table 1). First-generation systems have utilised concurrent renal artery blood flow to aid cooling of the endothelium to prevent thermal damage. Computational modelling has recently indicated that the intrinsic rate of renal artery blood flow, which cannot be easily manipulated peri-procedurally, is crucial in controlling both the direct, local (i.e. thermal effects to arterial wall) and distant (i.e. thermal effect on blood) effects of RF RSD.34 To counteract these effects, saline-irrigated RF catheters have become a standard design for cardiac EP ablations and have been shown to reduce contact-tissue heating without reducing the destruction of deep target tissue.35 Preliminary preclinical data in swine suggest that irrigated RF RSD ablation using the ThermoCOOL™ system (Biosense Webster Inc. [Diamond Bar, US] [see Table 1]) reduced arterial media and peri-arterial collagen damage but produced similar neural destruction compared with non-irrigated RF RSD procedures in arteries harvested 10 days post-procedure.36 Endothelial damage is a serious concern with non-irrigated RF RSD devices as it has been demonstrated with the use of optical coherence tomography (OCT) imaging that first-generation RF RSD

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catheters (Symplicity and EnligHTN™ [St Jude Medical, St Paul, US] systems) caused diffuse renal artery vasospasm, local tissue oedema and thrombus,37,38 suggesting the potential need for concurrent, periprocedural anti-platelet therapy.37 This may well be a temporary phenomenon and the clinical significance of these imaging findings is not currently known. Reassuringly, preclinical porcine studies using the Symplicity catheter showed no significant RAS, smooth muscle hyperplasia or thrombosis angiographically or histologically at 6 months post RF RSD.23 Follow-up renal imaging in the Symplicity trials has indicated only one novel RAS as a sequela of RF RSD in 88 patients followed for up to 3 years.30 Furthermore, renal safety has recently been explored in 15 patients with RHTN and moderate to severe CKD stages 3–4) that would have been excluded from the Symplicity HTN-1 and HTN-2 trials. This study revealed preservation of renal function to 12 months after RSD,39 which provides limited but further encouraging data regarding renal safety.

The potential damage caused by RF energy application direct to the renal artery endothelium means that it may not be the optimal technology for endovascular RSD. Other non-RF technologies, described below, are being developed to overcome some of these concerns. Interestingly, the proximity of the renal nerves to the renal pelvis has led to the development of a non-endovascular approach to RF-mediated RSD. Verve Medical (Santa Barbara, US) have developed an eponymous, retro-ureteric delivered RF device that has been tested in preclinical porcine studies, with reduction in renal tissue norepinephrine (NE) levels and no significant vascular or renal parenchymal damage up to 30 days post-procedure.40 This approach prevents patient exclusion for renal arterial anatomical reasons that was common in the Symplicity RSD clinical studies,10,31 but other urological pathologies may prevent usage of this approach in certain patients.

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Resistant Hypertension Table 3. Chemical Technologies for Renal Sympathetic Denervation Device (Company,CE Mark) Catheter/Anatomy Details Bullfrog™ 6 Fr, over-the-wire

Technical Details Balloon-sheathed micro-needle (30 G)

Development Phase Preclinical: porcine (n=15) to 28 days post RSD

Mercator MedSystems Inc.

Balloon Inflation (2 atmosphere)

Renal nerve rarefaction, reduced renal NE level

San Leandro, US

Renal artery: 2–6 mm

exposes micro-needle

No renal artery morphological changes

CE: Not available

Peri-adventitial delivery of guanethidine Undetectable plasma (guanethidine) 1 day post RSD

50 mg in 6 mL

54 ng guanethidine/g renal tissue 28 days

post RSD97

Peregrine™

7 Fr, over-the-wire

Tube-sheathed micro-needles (3x32 G)

Preclinical: porcine (n=12) to 14–45 days post RSD

Ablative Solutions

3 guide-tubes to centre catheter

Peri-adventitial delivery of 0.15-0.6 mL Dose-dependent reduction in renal NE levels

Kalamazoo, US

Renal artery: not known

dehydrated ethanol

(14 days)

CE: Not available

Histological confirmation of neural injury

Angiography normal (45 days) post RSD98

ApexNano™

Standard catheter

40–80 nM magnetic nanoparticles

No published data

ApexNano Therapeutics

Renal artery: not known

Internal/external magnetic field steer

Herzliya, Israel

particles to renal artery wall

CE: Not available

Modulation of magnetic field releases

Botox®

No name

7 Fr, over-the-wire

0.1 mg vincristine delivered directly

Preclinical: Porcine (n=14–16) to 28 days post RSD

University of Athens

Triple lumen, double-balloon

against renal artery wall

Renal nerve rarefaction and arterial safety54,55

Athens, Greece

catheter

Balloon occludes lumen to prevent

Clinical: Case-report (n=1) to 4 weeks post RSD

CE: Not available

6 side-holes (25 μM)

systemic escape of vincristine

Severe RHTN on 4 meds, baseline OBP 174/102

Renal artery: not known

mmHg

↓OBP: 40/22mmHg; ↓ABP: 23/13mmHg

Stable renal function at 4w (data not provided)56

ABP=ambulatory blood pressure; NE=norepinephrine; OBP=office blood pressure; RSD=renal sympathetic denervation; RHTN=resistant hypertension.

Ultrasound Neural Ablation

Chemical Neural Ablation

Ultrasound (US) energy delivers sound waves >20 Hz. When US is directed against a medium that is able to absorb the energy, it is converted to thermal energy within that medium. It can be delivered without vessel contact, with US waves passing through fluid/ interposing tissue to heat target tissue to generate targeted thermal injury. It has been established as an effective therapy for cardiac EP procedures.41 Different approaches have been developed to harness the potential utility of US for RSD with the proposed benefits over RF ablation being controlled and greater depth of denervation and endothelial sparing (see Table 2). The requisite depth for effective denervation is, however, debatable as the majority of human SNS fibres have been shown to lie within 2 mm of the renal arterial lumen 14 and deeper denervation techniques may pose harm to adjacent structures including the psoas muscle (posteriorly) and bowel within the peritoneal space (anteriorly).

Therapeutic pharmacological neurolysis has been recognised for over a century and several pharmacological agents are being developed for RSD (see Table 3). Targeted drug delivery is an attractive method offering selective neurolysis and obviating endothelial and deeper vascular damage. Alcohol is an effective neurolytic,45 previously used for trigeminal neuralgia,46 and, in fact, more than 20 years ago47 to treat renovascular hypertension through percutaneous injection into the renal artery adventitia. Botulinum toxin type A (commonly known as Botox®) or type B are responsible for the flaccid paralysis associated with Clostridium botulinum poisoning, and have been developed as therapeutic neurolytics to treat muscular dystonias48 and spasticity.49 Similar neurotoxins have been packaged in magnetic nanoparticles that provide a mechanism for targeted drug delivery when combined with an external magnetic field, and have been successfully applied to cardiac SNS ganglionic plexi to treat atrial fibrillation. 50 Guanethidine, one of the first anti-hypertensive medications, reduces norepinephrine (NE) levels in pre-synaptic nerve terminals. At higher systemic doses it has been shown to cause selective SNS neurolysis 51 through an immune-mediated mechanism.52 The anti-neoplastic vinca alkaloid, vincristine, is well recognised to be neurotoxic, especially to peripheral nerves with systemic application,53 and while this can cause disabling peripheral neuropathies in cancer patients, this medication has been re-tasked for therapeutic usage as an RSD agent, and is the only chemicalbased RSD technology that has produced both preclinical and firstin-man data in peer-reviewed publications.54–56

While extra-corporeal high-intensity focused US (HIFU) has long been used to ablate deep, solid tissue tumours through thermal injury42 and has recently been tested in preclinical canine studies of RSD, 43 the use of extra-corporeal, low-intensity focused US (LIFU) for RSD represents an entirely unique and potentially non-invasive strategy that is particularly attractive (see Table 2). The mechanism of tissue damage by LIFU is not entirely characterised and is thought to be predominantly sono-mechanical (i.e. vibration-induced cellular damage) rather than thermal.44 Although the Surround Sound™ system from Kona Medical (Campbell, US) is currently using a targeting catheter in its early phase development, the stated aim of the company is to develop a fully non-invasive technology that applies LIFU without the requirement for endovascular access.

One could imagine such a technology being easily translatable to an ambulant patient setting, which would be the Holy Grail of RHTN therapy.

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Cryoablation to Achieve Renal Sympathetic Denervation Cryotherapy, an effective ablation technology, cools target tissue to ≤40°C, which results in intra-cellular ice crystal formation and cell death57 and has been used to destroy non-epithelial tissue for

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over 50 years.58 Cryoablation has become a mainstay for cardiac EP studies, as there is a reduced frequency of vascular complications 59 and reduced pain 60 compared with standard RF techniques. Standard cardiac EP cryoablation catheters have been used to determine the safety of this approach in preclinical studies that demonstrated effective RSD with no macroscopic evidence of endovascular thrombi, renal parenchymal or vascular damage and endothelial cell preservation by immunohistochemistry. 61 In a small pilot study in patients with RHTN deemed non-responders to RF RSD, cryoablation caused appreciable BP reductions in all three patients to 6 months post-procedure (>22/4 mmHg ambulatory BP).62 This approach is being developed by commercial ventures, including CryoMend Inc. and Cryomedix Inc. (both San Diego, US) although there have been no preclinical or clinical data outputs to date. It is too early to speculate on the long-term potential for cryoablation in RSD and on a cautionary note, higher rates of recurrence after successful index ablation are apparent for certain cardiac arrhythmias compared with RF ablation.60

Ionising Radiation Neural Ablation Radio-ablation is also being developed for endovascular RSD. Although peripheral nerves were initially thought to be relatively radio-resistant, it was established more than 50 years ago that ionising radiation induced neural fibrosis and myelin loss, leading to symptomatic neuropathies in cancer patients treated with radiotherapy.63 Novel, radiation-based therapies that are being developed for RSD include endovascular β-radiation brachytherapy (25–50 Gy delivered by Best Vascular Inc., [Springfield, Virginia] Novoste™ Beta-Cath™ catheter), which has demonstrated effective neural destruction and renal artery safety at 25–50 Gy in swine (n=10) up to 2 months post-procedure,64 and stereotactic, non-invasive, robot-assisted, X-radiation radiosurgery (Cyberheart Inc., [Sunnyvale, US] Cyberheart system™), based on the same company’s Cyberknife™ system, used to treat solid organ tumours. No preclinical data have been presented to date.

Current Controversies and Future Opportunities Technical Failure versus Non-responder One of the main problems with current application of all RSD technologies is the inability to separate technical failure of the procedure from lack of response of patients to effective RSD. This latter problem could arise because either that renal SNS signalling is not paramount to RHTN in that patient (i.e. other mechanisms are driving the RHTN phenotype) or that the patient’s anatomy/ physiology is unable to respond to the reduction in SNS signalling (i.e. large vessel stiffening). Furthermore, a purported cumulative effect to RF RSD in terms of BP lowering over 3 years30 may mean that early lack of BP lowering does not reflect lack of either procedural success or response to RSD. This would seriously complicate decision-making regarding ‘re-do’ procedures (clinicaltrials.gov: NCT01834118) or proceeding to other interventional technologies, such as baroreflex activation therapy (BAT)65,66 or arterio-venous coupling,67 in early non-responders to RSD.68 Furthermore, the recent announcement of the failure of Symplicity HTN-3 to meet its primary efficacy end-point at 6 months with a first-generation sequential ablation catheter system may reflect difficulties in demonstrating effective neural destruction, a primary end-point that was too early in the natural history of the response to RSD, effective guidelinedriven treatment of RHTN in the placebo-sham arm or that RF RSD was truly ineffective in BP lowering in a cohort of patients that had true RHTN in and out of office.

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Further research to determine which patients are suitable/likely to respond to RSD is essential. To date, only baseline BP correlates to the magnitude of BP response to RF RSD across multiple cohorts.10,30,31,69,70 Single-unit muscle sympathetic nerve activity is reduced within 3 months of RF RSD and may predict future BP response but this is not established yet.71 Impaired cardiac baroreflex sensitivity predicts BP response to,72 and improves after,73 RF RSD. More recently, intra-arterial BP response to high-frequency stimulation ([HFS] 20 Hz for 10 seconds) at the renal artery ostium immediately post procedure suggests a potential test of procedural efficacy. 74 In this study, HFS pre-procedure caused an immediate >15 mmHg increase in BP in all patients that was almost entirely blunted (<6 mmHg) post RF RSD. 74 Other investigations that have been utilised in subsets of patients include renal NE spillover 10 and single-unit muscle sympathetic nerve activity. 71 However, both techniques are time consuming, require invasive testing preand post-procedure and are currently only available in specialist centres with expertise of autonomic function assessment. These concerns highlight the growing importance of collaboration with autonomic neurophysiologists and cardiovascular physiologists to develop the means to accurately phenotype individual patients with respect to the role of the SNS and its many subdivisions in their hypertension. In a similar fashion, the clinician already subjects patients to detailed biochemical and imaging characterisation as a pre-requisite to adrenalectomy for patients with adrenal nodules.

Why then should (expensive and invasive) RSD be offered to all patients with RHTN without first determining the involvement of their renal SNS?

Clinical Trials Inadequacies Criticisms of published RSD clinical trials have been widely propagated 75–78 and include lack of sham control; non-blinded design; no per protocol exclusion of both secondary causes of hypertension and non-adherence to therapy; intermediate soft end-points (often 6 month office BP); and lack of ambulatory BP use as standard for both inclusion to exclude white coat effect, and also as a BP outcome and lack of durability and safety beyond 3 years. Ambulatory BP has been included in more recent small studies in moderate RHTN, 79,80 and both sham control (clinicaltrials .gov: NCT01418261) and major adverse cardiovascular events as primary end-points (clinicaltrials.gov: NCT01903187) are included in current large international studies but the results from these studies will not be known for many years, so the current use of RSD technologies is based on low numbers of non-high-quality studies. Durability of BP lowering has recently been demonstrated for at least 3 years, 30 but concerns about renal nerve regrowth remain 81 although the potential impact of any re-innervation on BP is unclear. 30 Reassuringly, denervated renal transplants have preserved functions of solute clearance, electrolyte transport and hormonal function 82 and RF RSD in moderate to severe CKD is both effective and safe up to 1 year post procedure.39

What is the Best Renal Sympathetic Denervation System?

Currently it is difficult to recommend one RSD technology above and beyond any other, as there are no head-to-head comparisons of intra- or inter-class RSD technologies. The majority of clinical trial experience is with the first-generation RF Symplicity catheter, though as outlined previously methodological and technological

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Resistant Hypertension advances in second-generation RF and other non-RF systems give theoretical preference to more recent iterations. A clinical study of four RSD technologies, including one single electrode RF system, two multi-electrode systems and one non-RF system, may help answer this question with respect to BP lowering and procedural and renal artery safety (clinicaltrials.gov: NCT01888315).

Notably, it remains unproven whether any technological form of RSD is equivalent (or superior) to guideline-driven pharmacological management of RHTN5 and specific trials of this type are not currently under way. Until this is the case, RSD should remain a treatment of last resort for RHTN.

Conclusion To date, the majority of clinical studies have evaluated the efficacy of RF (and non-RF) RSD in predominantly severe RHTN. However, given that the pathophysiological basis for RSD therapy is based not on BP level but on the recognition that RHTN is associated with elevated central SNS tone, RSD may be an effective treatment for other conditions that exhibit similar elevated central SNS tone, whether renally mediated or not. As such, RF RSD has been evaluated in other systemic conditions and pleiotropic effects of RF RSD have been reported in both systolic 83 and diastolic 84 heart failure,

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obstructive sleep apnoea,85 glycaemic control in RHTN patients85,86 and both supra-ventricular 74 and ventricular arrhythmias.87 With the proliferation of different technologies and devices for RSD, much more rigorous research is required so that clinicians can confidently and fully inform patients with RHTN which is the most efficacious and safe intervention for them, taking into account the individual pathophysiological basis for RHTN and matching that to available technologies or not as is appropriate. The principles that should guide development of and selection of appropriate RSD technologies should include: minimally/entirely non-invasive device; predictability of injury pattern; selectivity for renal nerves; permanent nerve destruction; minimal injury to renal artery and collateral structures; minimal procedural pain; short procedure time; durable modulation of central SNS tone; and BP lowering. The publication of the Simplicity HTN-3 dataset is now critical so that the full implications of this disappointing result can further inform the most appropriate use of this technology and treatment for RHTN and potentially other disorders as well. The hypertension specialist, and patients, should welcome this paradigm shift in the landscape for treatment of RHTN but a cautious approach should be maintained with newer, novel technologies until evidence emerges to support their use. n

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02/03/2014 19:26