USC 12.2 by Radcliffe Cardiology

US Cardiology Review

Volume 12 • Issue 2 • Winter 2018

www.USCjournal.com

Volume 12 • Issue 2 • Winter 2018

Renal Denervation: Paradise Lost? Paradise Regained? Deepak Padmanabhan, DM, Ameesh Isath, MBBS, and Bernard Gersh, MB, ChB, D Phil, FRCP, MACC

Coronary Bioresorbable Scaffolds in Interventional Cardiology: Lessons Learnt and Future Perspectives Bill Gogas, MD, PhD, FACC, Jun-Jie Zhang, MD, FSCAI, and Shao-Liang Chen, MD, PhD, FACC, FSCAI

Fluoroless Catheter Ablation of Cardiac Arrhythmias Sandeep K Goyal, MD, FHRS and Bruce S Stambler, MD, FHRS

Management of Cardiovascular Disease During Pregnancy Nandita S Scott, MD, FACC

ISSN: 1758-3896 • eISSN: 1758-390X

Vector Isolated Heart

Transthoracic Echocardiogram for a Patient with Biopsy-Proven Amyloidosis

Differences and Disparities in AF

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Volume 12 • Issue 2 • Winter 2018

www.USCjournal.com

Editor in Chief Dr Ankur Kalra Case Western Reserve University School of Medicine, Cleveland, OH

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Heart Failure)

Carey Kimmelstiel, MD

Warren Manning, MD

Leway Chen, MD, MPH

Tufts Medical Center, Boston, MA

Harvard Medical School, Boston, MA

University of Rochester, Rochester, NY

Deputy Editors Kashish Goel, MBBS

Ronnie Ramadan, MD

Bruce Stambler, MD

Mayo Clinic, Rochester, MN

Harvard Medical School, Boston, MA

Piedmont Healthcare, Atlanta, GA

Chad A Kliger, MD, MS, FACC, FSCAID

Rajalakshmi Santhanakrishnan, MBBS

Lenox Hill Heart and Vascular Institute, New York, NY

Wright State University, Dayton, OH

Editorial Board Uma Mahesh R Avula, MD

Bernard J Gersh, MB, ChB, DPhil

Roberto M Lang, MD

Columbia University, New York, NY

Mayo Clinic, Rochester, MN

University of Chicago, Chicago, IL

Ralph G Brindis, MD

C Michael Gibson, MS, MD

University of California, San Francisco, CA

Beth Israel Deaconess Medical Center, Boston, MA

Todd Brown, MD, MSPH

Bill Gogas, MD, PhD

University of Alabama, Birmingham, AL

Emory University School of Medicine, Atlanta, GA

Leo Buckley, PharmD

Michael R Gold, MD

Virginia Commonwealth University, Richmond, VA

Medical University of South Carolina, Charleston, SC

Robert Chait, MD, FACC, FACP

University of California San Diego School of Medicine, La Jolla, CA

Barry H Greenberg, MD

JFK Medical Center, Atlantis, FL

Thomas A Haffey, MD, DO

Donald E Cutlip, MD Harvard Medical School, Boston, MA

Western University of Health Sciences, Pomona, CA

Gregory J Dehmer, MD, MACC, FACP, FAHA, MSCAI

Case Western Reserve University, Cleveland, OH

Texas A&M University College of Medicine, Bryan, TX

NA Mark Estes III, MD Tufts University School of Medicine, Boston, MA

Elizabeth Kaufman, MD Morton J Kern, MD University of California at Irvine, Orange, CA

Jackson J Liang, MD, DO Hospital of the University of Pennsylvania, Philadelphia, PA

Sylvia Mamby, MD, FACC, FASE Emeritus Staff, Mayo Clinic, MN

Patrick T O’Gara, MD Brigham and Women's Hospital, Boston, MA

Duane Pinto, MD, MSc Harvard Medical School, Boston, MA

Krishna Pothineni, MD University of Arkansas for Medical Sciences, Little Rock, AR

Elizabeth Ross, MD, FACC

Richard Kones, MD, FAHA, FESC, FCCP, FRSM, FAGS

Emeritus Member, American College of Cardiology, WA

Cardiometabolic Research Institute, Houston, TX

Wayne State University, Detroit, MI

W Douglas Weaver, MD

Managing Editor Rosie Scott • Production Aashni Shah • Design Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Key Account Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O'Neill •••••••••••••••••••••••••

Editorial Contact rosie.scott@radcliffe-group.com Circulation & Commercial Contact david.ramsey@radcliffe-group.com •

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Cardiology

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End Buckinghamshire SL8 5AS, UK © 2018 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 Frequency: Bi-annual Current issue: Winter 2018

Aims and Scope • US Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiac failure practice. • US Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • US 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 • US Cardiology Review is a bi-annual journal comprising review articles and editorials. • The structure and degree of coverage 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 US Cardiology Review is replicated in full online at www.USCjournal.com

• 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.USCjournal.com.

Reprints Editorial Expertise US 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 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.

All articles included in US Cardiology Review are available as reprints. Please contact Rob Barclay at rob.barclay@radcliffe-group.com

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

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in US 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, Rosie Scott at rosie.scott@radcliffe-group.com

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

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Contents

76 Foreword Ankur Kalra, MD, FACP, FACC, FSCAI

Editorial

A Message From the Outgoing Editor-in-Chief Donald E Cutlip, MD

Interventional Cardiology

Renal Denervation: Paradise Lost? Paradise Regained?

Left Atrial Appendage Closure Devices for Stroke Prevention in Patients with Non-Valvular AF

Deepak Padmanabhan, DM, Ameesh Isath, MBBS, and Bernard Gersh, MB, ChB, D Phil, FRCP, MACC

Daniel A McBride, MD, Timothy M Markman, MD, Jackson J Liang, DO, and Pasquale Santangeli, MD, PhD

Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: Is Less More? Rik Rozemeijer, MD, PharmD, Wijnand P van Bezouwen, MD, Michiel Voskuil, MD, PhD, and Pieter R Stella, MD, PhD

Coronary Bioresorbable Scaffolds in Interventional Cardiology: Lessons Learnt and Future Perspectives Bill Gogas, MD, PhD, FACC, Jun-Jie Zhang, MD, FSCAI, and Shao-Liang Chen, MD, PhD, FACC, FSCAI

Electrophysiology

103

Gender and AF: Differences and Disparities

107

Fluoroless Catheter Ablation of Cardiac Arrhythmias

Naga Venkata Pothineni, MD, and Srikanth Vallurupalli, MD

Sandeep K Goyal, MD, FHRS and Bruce S Stambler, MD, FHRS

Advanced Heart Failure

110

Understanding Iron Deficiency in Heart Failure: Clinical Significance and Management Rajalakshmi Santhanakrishnan, MBBS

113

Amyloid Heart Disease Yaser Nemshah, MBBS, Alex Clavijo, MD, and Gyanendra Sharma, MD, FACC, FASE

Editor’s Pick

119

Management of Cardiovascular Disease During Pregnancy Nandita S Scott, MD, FACC

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Foreword

Ankur Kalra, MD, FACP, FACC, FSCAI is the Editor-in-Chief of US Cardiology Review journal, a staff cardiologist at the Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, and Clinical Assistant Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, OH, USA.

t is with great energy and enthusiasm that I draft the Foreword of this issue of US Cardiology Review (USC) as its newly appointed Editor-in-Chief. I have immense responsibility on my shoulders, as I have been passed the baton by none other than Prof. Donald E. Cutlip, Professor of Medicine at Harvard Medical School and Vice Chair for Clinical Care in the Community at Beth Israel Deaconess Medical Center, both in Boston, Massachusetts. I have had the privilege to work closely with Prof. Cutlip as his former interventional cardiology fellow. Personally, it’s very special to be at the helm of USC, and to have the opportunity to follow Don’s footsteps; it was Don who recruited me to the Beth Israel Deaconess Medical Center interventional fellowship class in 2015. As Don has assumed new responsibilities at the Alma Mater, I wish him continued success in his administrative role at the Beth Israel Deaconess Medical Center. I can only hope I do a good job in carrying forward his legacy, and what he has accomplished as Editor-in-Chief for USC. This issue of USC has four traditional sections: interventional cardiology, electrophysiology, advanced heart failure, and general cardiovascular disease. We’ve worked hard in compiling topics that capture recent and relevant science in these respective subspecialties of cardiovascular medicine. In the interventional cardiology section, Drs Padmanaban and Gersh discuss renal denervation and its current relevance in the management of resistant hypertension, Dr McBride and co-authors discuss the role of left atrial appendage occlusion devices for stroke prevention in AF, Dr Rozemeijer and colleagues discuss contemporary practices with regard to duration of dual antiplatelet therapy following percutaneous coronary intervention, and Dr Gogas and co-authors discuss the future of coronary bioresorbable scaffolds. In the electrophysiology section, Dr Pothineni and co-authors discuss gender differences and disparities in AF, and Drs Goyal and Stambler discuss fluoroless catheter ablation of cardiac arrhythmias. In the advanced heart failure and cardiac transplantation section, Dr Santhanakrishnan discusses the etiology and management of functional iron deficiency in heart failure, and Drs Nemshah and colleagues discuss amyloid heart disease. The Editor’s Pick for this issue of USC is a special article by Dr Nandita Scott (Massachusetts General Hospital, Harvard Medical School) on the management of cardiovascular disease during pregnancy. I hope you enjoy reading this issue as much as we have enjoyed putting it together for our readers. The next issue of USC will be my inaugural issue as Editor-in-Chief. Season’s Greetings, Merry Christmas, and a very Happy New Year.

DOI: https://doi.org/10.15420/usc.2018.15.1

Access at: www.USCjournal.com

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Editorial

A Message From the Outgoing Editor-in-Chief

Donald E Cutlip MD is the outgoing Editor-in-Chief of US Cardiology Review. He is a Vice-Chair of Medicine, Beth Israel Deaconess Medical Center, and Professor of Medicine at Harvard Medical School, Boston, MA, USA.

t has been my pleasure to serve as Editor-in-Chief during the relaunch of US Cardiology Review. Due to the efforts of an excellent editorial staff and the contributions from a number of dedicated authors and reviewers, the journal has made considerable strides to meet our mandate of providing timely and informative reviews and expert perspectives on current topics within the broad field of cardiovascular medicine. Cardiology practice continues to evolve rapidly within all of its subspecialties and the need for a format that provides current reviews of the topics impacted by the latest research is greater than ever. It has been our intent to direct these reviews to the clinicians who are faced with the challenge of providing the highest quality care to their patients and are perhaps overwhelmed by the rapid changes and the volume of published literature. Informative reviews that provide both detailed background information and timely updates of current research and clinical perspective are ideal tools for assisting the busy practitioner in their daily tasks of taking care of patients. As I end my tenure as Editor-in-Chief, I wish to express my gratitude to the journal staff who do an amazing job of taking ideas and working with prospective authors to develop these ideas into outstanding manuscripts. I am especially grateful to the authors, many of whom are the leaders in their fields, who took the time to write the informative reviews that make the journal a success. I look forward to the work Dr Kalra and the Editorial Board will accomplish as they bring the journal to the next phase.

DOI: https://doi.org/10.15420/usc.2018.14.1

ÂŠ RADCLIFFE CARDIOLOGY 2018

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26/11/2018 21:22

Interventional Cardiology

Renal Denervation: Paradise Lost? Paradise Regained? Deepak Padmanabhan, DM, 1 Ameesh Isath, MBBS, 1,2 and Bernard Gersh, MB, ChB, D Phil, FRCP, MACC 1 1. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; 2. Department of Internal Medicine, Mount Sinai St Luke’s Hospital, New York, NY

Abstract Renal denervation is a relatively recent concept whose initial promising results suffered a setback following the SYMPLICITY 3 trial, which did not show a significant blood pressure-lowering effect in comparison to sham. In this review article, we begin with the history including the physiological basis behind the concept of renal denervation. Furthermore, we review the literature in support of renal denervation, including the recently published SPYRAL HTN-OFF MED, which demonstrated significant blood pressure reduction in the absence of antihypertensive medication. We further touch upon the potential pitfalls and possible future directions of renal denervation.

Keywords Renal denervation, trials, hypertension, electroporation, blood pressure, review Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: We wish to thank Kevin M Youel of the media department for help with the illustrations. Received: January 6, 2018 Accepted: April 5, 2018 Citation: US Cardiology Review 2018;12(2):78–86. DOI: https://doi.org/10.15420/usc.2018.1.2 Correspondence: Dr Bernard Gersh, Professor of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E: gersh.bernard@mayo.edu

Endovascular techniques for renal denervation (RDN) as a treatment for hypertension were initially highly encouraging with reductions in blood pressure (BP) in the range of 30 mmHg.1 However, these high expectations received a major setback following the unexpected results of the sham-controlled Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN-3) trial. This promising procedure was faced with a major roadblock and, in general, the expectations that this would stand the test of time were markedly tempered.2 Like all good trials, SYMPLICITY HTN-3 provided answers, but also generated new questions, particularly in regard to procedural and technical issues. This, in turn, has led to a series of new and ongoing trials, which hopefully will resolve the issue of whether this procedure will become a routine aspect of hypertension management. In the present article, we review the literature in support of the RDN concept as well as emphasize the potential pitfalls and possible future direction of RDN.

Proof of Concept: A Historical Perspective The renal system, through the maintenance of fluid–electrolyte balance and its interplay with the autonomic nervous system, plays an essential role in the pathophysiology of hypertension. Increased sympathetic nervous system activity as a cause and result of hypertension has been proven in various human experiments.3 The activation of the efferent sympathetic system via the postganglionic sympathetic neuronal chain relayed to the kidneys over the renal vasculature results in one or all of three effects; increased renin secretion from the juxtaglomerular apparatus; renal vasoconstriction decreasing renal blood flow; and enhanced sodium and water absorption. This contributes to an increased intravascular volume and arteriolar vasoconstriction adding to hypertension.4,5

Access at: www.USCjournal.com

USC_Padmanaban_FINAL.indd 78

Renal structures are also richly innervated with baroreceptors and chemoreceptors. Stimulation of these nerves by metabolites like adenosine, which form under conditions of ischemia and oxidative stress, result in increased input into the hypothalamus augmenting the sympathetic outflow, not only to the kidneys, but also to other structures like the heart and peripheral arteries, resulting in neurogenic hypertension.5–7 Interruption of this neural traffic underlies the concept of RDN for the treatment of hypertension. Esler et al. demonstrated increased renal sympathetic nervous activity in adults with essential hypertension. His assessment of renal norepinephrine spillover using isotope dilution measurements showed elevated levels in comparison to normal individuals.8 Also, this increase was higher in young adults (<40 years) with essential hypertension compared to older individuals. On comparison of 34 patients with essential hypertension and 23 normal patients, Esler et al. demonstrated than in those with hypertension, plasma concentration of noradrenaline and rate of release of noradrenaline into plasma was 32 % and 38 % higher, respectively, than in normal individuals.9 Schlaich further demonstrated a sustained decrease in BP from 161/107 to 127/81 mmHg at 12 months following bilateral renal artery ablation (Figure 1).10 One of the earliest treatment modalities for hypertension preceding the use of medications was surgical RDN. Smithwick and Thompson followed up 1,266 cases of thoracolumbar sympathetic splanchnicectomy over a minimum of 5 years. They compared the management of hypertension in these patients with that of in 467 medically treated controls to assess the mortality and efficacy of surgery as treatment for hypertension.11 Sympathetic splanchnicectomy decreased all-cause mortality in contrast to medically treated controls. However, this nonselective sympathectomy technique resulted in very severe debilitating

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Renal Denervation side-effects, including orthostatic hypotension, palpitations, peripheral vasoconstriction, gastrointestinal dysfunction and sexual dysfunction as varying accompaniments. The introduction of the newer potent antihypertensive drugs soon drove surgical denervation into near extinction given the risk of potential complications as well as the efficacy of the newer medications.12,13

Figure 1: Physiology of Renal Sympathetic Control Hypoxia/ischemia/ oxidative stress

Renal efferent

Renal afferent sympathetic activity

Sympathetic activity

Catheter-based Renal Denervation Ablation using radiofrequency (RF) has been the subject of multiple trials (Figure 2) using different catheter-based systems among which the majority used the SYMPLICITY RDN catheter (Medtronic Inc). This had unipolar platinum-iridium electrodes at the tip and the catheter was introduced percutaneously into the renal artery.14 Multiple (four to six) RF ablations of 8 W for up to 2 minutes applied in a helical manner to the arterial endothelium were used to ablate the sympathetic nerves; this was then replicated in the other renal artery to achieve RDN. Measures to confirm the completeness of this procedure were variably used. SYMPLICITY HTN-1, published in 2009, was the first trial to establish that catheter-based RDN reduced BP (−27/−17 mmHg at 12 months) in patients with rHTN with a reduction of sympathetic activity measured by renal noradrenaline spillover.1 Considering the major, although not unexpected, critical limitation of the study, like the absence of the control group, a new randomized prospective, single-blind, multicenter trial called the SYMPLICITY HTN-2 was initiated.15 The impressive positive results (–32/–12 mmHg) led to great enthusiasm for the procedure (Figure 3). However, a reality check in the form of the results of the SYMPLICITY HTN-3 prevailed. This sham-controlled trial designed to adjust for the effects of a sham procedure showed no significant difference in BP between the target groups at the end of 6 months. The difference in BP between the denervation group compared with the sham-procedure group was only −2.39 mmHg, which was not statistically significant (p=0.26).14 The unexpected results of a trial that was presumed to provide a definitive statement led to a number of trials being discontinued and several possibilities continue to be considered as to why the results were disparate in comparison to the earlier trials.16 Renal Denervation for Hypertension (DENERHTN) was an open-label, prospective, randomized trial that compared RDN to a standardized stepped-care antihypertensive treatment with a blinded endpoint evaluation in patients with rHTN performed in 15 tertiary centers in France.17 However, in comparison to the SYMPLICITY trials, the primary endpoint was the ambulatory BP. Both groups showed a reduction in daytime ambulatory systolic BP, with a greater significant reduction in the RDN group (−15.8 mmHg versus −9.9 mmHg; p=0.0329). However, the small change in BP compared to non-sham controlled groups did not do much to alleviate the fears that RDN had failed as the results of the SYMPLICITY HTN-3 implied.

Limitations of Current Techniques: Behind the Reality Check? The techniques used in various trials as well as the ones in SYMPLICITY HTN-3 trial had various shortcomings.

US CARDIOLOGY REVIEW

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Renal denervation

+ Renal vasculature

TG apparatus

Renal tubular epithelial cells

↓ RBF

↑ Renin serum

↑ Na + H2O reabsorption

Increased stimulation to hypothalamus + Sympathetic outflow to heart, kidney and artery

Vasoconstriction, ↑ cardiac output

↑ Vascular volume Hypertension

The Role of renal denervation on renal physiology to control blood pressure. RBF = renal blood flow; TG = tubulo glomerular.

Variation in Renal Anatomy Histological assessment of the renal vessels at autopsy demonstrated that the maximum mean nerve density was observed in the proximal and middle segments of the renal artery, whereas the least average number of nerves was seen in the distal segment. However, the nerves converge in proximity toward the distal renal arteries and thus the energy delivered by the ablation catheter is most effective here. The mean distance from the lumen to nerves was lowest in this region.18 Further variability in the form of accessory renal arteries with their smaller caliber makes it difficult to ablate within this vessel. Current endovascular techniques of ablation may not account for these anatomical changes thereby partly explaining the variability in results.19 The SYMPLICITY HTN-3 trial was also affected, as the energy delivered by the catheter was concentrated on the proximal renal arteries as per protocol.

Non-contiguous Lesions The anatomical separation between the lumen of the vessel and the adventitia (containing nerves) is also variable along the length of the vessel with the thinnest wall being present distally (50th percentile values = 1.81 mm distally) causing the nerves to converge on the vessel near the renal hilum. Therefore, there is the need for a transmural lesion creation over a minimum depth of 2 mm.19 This, accompanied by a wide variation in nerve distribution patterns and an inability to map electrical nerve signals necessitates a circumferential ablation technique for RDN. While the site of the ablation could be debated, continuity and transmurality need to be present, like the lesions needed to isolate pulmonary veins in AF. This may necessitate the use of electrophysiological mapping systems to ensure the absence of gaps when creating transmural lesions in addition to use of imaging

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Interventional Cardiology Figure 2: Summary of Key Features of the Renal Denervation Trials 100

Age Number of anti-HT drugs 64.5

57.9

57.1

59.5

55.2

58.6

59.9

5.1

5.2

4.4

5.1

4.9

5.3

5.1

REDUCE HTN (n=146)

RAPID (n=50)

4.5

4.1

0 SYMPLICITY HTN-3 (n=535)

Desch et al (n=79)

SYMPLICITY SYMPLICITY DENERHTN HTN-2 HTN-1 (n=106) (n=106) (n=144)

Prague-15 (n=106)

Sham-controlled trials

Global SYMPLICITY HTN-Japan SYMPLICITY (n=998) registry (n=998)

EnligHTN-1 (n=46)

Non-sham-controlled trials Baseline systolic blood pressure Change in ambulatory blood pressure at 6 months Mean (ÂąSD) change in systolic blood pressure at 6 months

200 180

178

181

175.1 159.3

150

181.6

182.4

176

163.5

159

140.2

100

50 32

14.13

6.75

21.9 7 9.9

0 SYMPLICITY HTN-3 (n=535)

Desch et al (n=79)

15.8 12.4

SYMPLICITY HTN-2 (n=106)

SYMPLICITY HTN-1 (n=144)

DENERHTN (n=106)

Sham-controlled trials

8.6

12.4

Prague-15 (n=106)

7.5

24.7

16.6

SYMPLICITY HTN-Japan (n=998)

6.6

11.6

Global SYMPLICITY registry (n=998)

8.4

REDUCE HTN (n=146)

RAPID (n=50)

EnligHTN-1 (n=46)

Non-sham-controlled trials

Comparison of baseline characterisitics and results of key renal denervation trials.

techniques like intracardiac echo to view lesion formation at the time of ablation (Figure 4).

Improper Energy Delivery The renal artery is near the renal vein distally and to the para-aortic vessels proximally. RF energy delivery depends on resistive heating to cause lesions. The presence of these vessels increases the washout of thermal energy created in the local region during RF energy delivery. The inadequate lesions created due to the washout of thermal energy maybe responsible for the limiting results.

Limitations of Radiofrequency Energy Delivery Radiofrequency energy causes thermal damage to the endothelial tissue and carries with it the potential of char and coagulum when delivered

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using non-irrigated catheters and stem pops when delivered using irrigated catheters. Studies using optical coherence tomography have demonstrated endothelial damage at sites of ablation.20 Given that distal vessel lesions may be of potential benefit in achieving neural damage, the use of alternative energy sources that may have a lesser propensity of endothelial damage may be useful. In addition, the more distal the lesion, the greater the chances for complete vessel occlusion, thereby necessitating avoidance of endothelial damage as much as possible.

Absence of an Endpoint for Procedural Efficacy A lack of procedural endpoint has been a limitation in several studies. In addition, norepinephrine spillover has not been a consistent procedural endpoint to evaluate the procedure. Krum et al. used this to evaluate the efficacy of their denervation, which correlated with the

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Renal Denervation long-term reduction in the BP over 6 months.21 However, this extremely time-consuming and laborious process cannot be a used on a routine basis clinically.

Figure 3: Comparison of Changes in Systolic Blood Pressure at 6 Months in SYMPLICITY Trials Denervation

Absence of a procedural endpoint is an Achilles heel, specifically to the SYMPLICITY HTN-3 trial where the proceduralist had no prior experience with RDN technique.14 De Jong et al. proposed that the difference between acute renal nerve stimulation-induced BP rise before and after RDN is a significant predictor of outcome after RDN.22 Gal et al. reported an acute, temporary rise in BP with intrarenal electrical stimulation of the renal artery, which was significantly blunted following RDN. This, however, has not been widely investigated and is limited by the need for general anesthesia as renal nerve stimulation causes pain.23 The design of a catheter in the future that can potentially carry out both stimulation as well as ablation as used for the ablation of arrhythmias could be helpful. The recording of electrograms from renal sympathetic nerves which could record bursts of renal nerve activity in the periarterial nerves has also been hypothesized as a technique for assessing the success of denervation procedure.24

Proceduralist Learning Curve Much has been written about the effects of the proceduralist learning curve on the efficacy of the RDN procedures. Potentially better results may be expected in more experienced hands.25

SYMPLICITY 1

Denervation SYMPLICITY 2

Unblinded control

Denervation SYMPLICITY 3

Sham control

â&#x20AC;&#x201C;10

Mean reduction in SBP-mmHg (and 95 % CI) The difference in blood pressure attained in SYMPLICITY-2 and SYMPLICITY-3 trials. Source: Pocock et al., 2014,27 with permission from Elsevier.

Figure 4: Role of Electrophysiolgical Mapping During Renal Denervation A

Patient Selection Patients with hypertension are the targets in whom the procedure is thought to deliver substantial benefit. However, given that the etiology is multifactorial, the response may be varied. A pooled data of 1103 patients from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry showed the reduction in BP among patients with isolated systolic hypertension was less pronounced than the reduction in patients with combined hypertension. Ewen et al. also demonstrated similar effects in reduction of BP in 126 patients undergoing bilateral RDN with resistant HTN.26 This could be possibly explained by the less-pronounced sympathetic activity in older patients with isolated systolic hypertension. Also, as isolated systolic BP is characterized by stiffness of the arteries with increased pulse pressure, the hypothesized concept behind RDN would not be applicable. This in fact could partly explain the subsets in SYMPLICITY HTN-3 where patients aged <65 years tended to respond better to RDN when compared to patients aged >65 years.14

Placebo Effect, Regression to the Mean, and the Hawthorne Effect The powerful effect of placebo cannot be ruled out given that the initial trials did not compare endovascular RDN against sham procedures. Researchers in the early SYMPLICITY trials and the DENERHTN trial used physician-based BP measurements and automated 24-hour BP measurements, respectively, as endpoints for the trials. Despite these efforts, there were no effective means to counter the bias arising from a regression to the mean (RTM). Since enrollment into trials is when there is patient contact with the caregiver, it is likely that the initial contact was made at the height of the patient symptoms and primed for variability

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A: Renal angiogram using contrast to visualize anatomy; B: 3D image of the renal artery to help guide lesion delivery and avoid gaps. Source: Pocock et al., 2014,27 with permission from Elsevier.

orfall. Pocock et al. using analysis of covariance demonstrated that RTM was found in both the RDN and sham control arms of SYMPLICITY-3 HTN trial, but was not responsible for the neutral findings.27 To estimate if this change is secondary to the therapeutic procedure or merely a variation, it is important to have a randomized control group. Since none of the initial trials were designed to accommodate for this bias,

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Interventional Cardiology Figure 5: Effect of Bias on Outcomes

Results of individual denervation trials, grouped by trial design 60

Blood pressure reduction (mmHg)

Unblinded office single arm

Unblinded office randomized

Unblinded ambulatory

Blinded

Blood pressure documented by machine

Blinded

Trial type Single-arm

Randomized

Blood pressure documented by human Patient aware of allocation (unblinded)

Blood pressure reduction (mmHg)

60 Regression to the mean

Asymmetrical data handling

Non-denervation effect

−1.01 mmHg (95 % CI: −6.27 mmHg to 4.24 mmHg)

−10.82 mmHg (95 % CI: −12.87 mmHg to −8.24 mmHg)

−8.28 mmHg (95 % CI: −4.73 mmHg to −11.83 mmHg)

Open label RCTs (active arm analysed)

Open label RCTs (active versus control)

Open label trials measuring office and ambulatory pressures (office)

Open label trials measuring office and ambulatory pressures (ambulatory)

Open trials (ambulatory pressure drops)

Blinded trials

Trial type A: Relationship between trial design and the reductions in office and ambulatory pressures; B: quantification of three biases contributing to apparent antihypertensive effects. Source: Howard, et al. 2016,28 with permission from Wolters Kluwer Health.

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Renal Denervation it is likely that there must have been some contribution of the same to the impressive results.14 Howard et al. conducted a meta-analysis of the various randomized and non-randomized trials of RDN to study the disparate results and demonstrated that the disparity may be due to asymmetrical data handling and confounding which can only be reduced by randomization and importantly blinding28 (Figure 5a,b). However, in SYMPLICITY HTN-3, despite accounting for this there was a neutral trial result in both the groups. The observer effect, or the Hawthorne effect, which describes the change in the behavior in subjects when under observation, accounts for some of the improvement seen in the placebo arms of trials. A potential ‘reverse Hawthorne’ effect was noted in the SYMPLICITY HTN-2 trial. Patients anxious to undergo RDN after having known about the results of the initial SYMPLICITY trial may have had reduced compliance with medications. This remains open to speculation. However, a urine analysis-based prospective evaluation of adherence to prescribed medications did show a decrease in compliance in a group of patients who underwent RDN. This noncompliance was maximal for the vasodilator class of medications.29

of the total ablation lesions in the RDN group were delivered to the branch vessels within the kidney and 88.6 % patients did not have any anti-hypertension drugs at baseline and at 3 months in the RDN group (82.9 % in the sham group). When reviewed at 3 months, a significant difference (−5/4.4 mmHg; p-value 0.04/0.002) was noted on the 24-hour ambulatory BP monitoring between the RDN and the sham control groups. Similar significant differences between the two groups were also noted on the office BP recordings (−7.7/−4.9 mmHg; p=0.02/0.008) with the safety results suggesting no complications from the procedure. The results of the SPYRAL HTN-ON MED arm purported to obtain an assessment of the efficacy and safety of RDN in the presence of three standard antihypertensive medications are still awaited (NCT02439775). This is a sham-controlled, randomized, parallel assignment, single blinded, treatment driven trial, having safety outcomes at 36 months post procedure and change in the systolic BP measured by 24-hour ambulatory BP monitoring as the primary outcomes.31,32

Future Directions Ethnic Considerations

Selective Versus Broad Denervation

There was a difference between population cohort recruited to the initial SYMPLICITY trials and the SYMPLICITY HTN-3 trial. Although underpowered subgroup analyses of the fall in BP in the non-AfricanAmerican cohort showed a difference, these findings remain hypotheses generating. In addition, the large magnitude changes seen within the early trials were absent.30

Deciding between ablation of nociceptive afferent fibers selectively versus total ablation including efferent fibers is important intra-procedurally given that their proximity to the adventitia varies as the distance from the aorta varies.19 In case of selective afferent fiber damage, proximity to the aorta is beneficial for the ablation, whereas for the efferent fibers, ablation needs to be performed more distally. It is unclear whether selective afferent fiber damage is beneficial for antihypertensive effect, particularly given that centrally acting medications do not decrease the BP more than what has been seen in patients undergoing RDN.33 Hedging the bets on one or the other is the current paradigm but an answer is still elusive.

SPYRAL HTN-OFF MED Trial The SPYRAL HTN trial with two arms to assess the efficacy of the procedure alone (SPYRAL HTN OFF-MED) and in comparison, to antihypertensive drugs (SPYRAL HTN ON-MED) aimed to address these concerns.31 These were designed to be proof-of-concept trials to demonstrate the ability of RDN to influence BP in uncontrolled hypertension. Twenty-one recruiting sites across the world were used to recruit 80 patients randomized to RDN with a new SPYRAL catheter (n=38) or a sham procedure (n=42) in the SPYRAL HTN-OFF MED arm of the study. Patients were followed up to 3 months and the primary endpoint was the change in 24-hour BP at the end of the follow-up period. Drug surveillance was done to ensure patient compliance with the absence of anti-hypertensive medication. The differences in the study design between the SYMPLICITY-3 trial and the SPYRAL HTN-OFF MED arm included the absence of anti-hypertension drugs at the time of the randomization, the inclusion of patients with moderate hypertension, the exclusion of patients with isolated systolic hypertension and the use of a new catheter designed to ablate distally within the branches of the renal artery. Highly experienced operators were involved in conducting and proctoring the trial. In addition, a standardized approach based on advances in the understanding of renal nerve anatomy to target the renal artery along with its accessory branches was followed. A blinding index of 0.65 (CI [0.56–0.75]) at discharge and 0.59 (CI [0.49–0.70]) at 3 months after the procedure was attained. Near 60 %

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Procedural Efficacy Endpoint Despite the promising results of the recent trials, there remains the looming question of evaluating the procedural efficacy acutely. Given the inability to use norepinephrine spillover values acutely in a routine clinical setting, the search for the endpoint remains ongoing. Efforts to use an electrogram-based endpoint need further data before they can be used. In addition, translational research pertaining to the provocative maneuvers targeting afferent sympathetic nerves to evaluate if there is an acute response to the procedure needs further development and human validation. Inability to find this piece of the puzzle is a major stumbling block in current technology.

Prediction of Response There remains wide variability in the response to the RDN procedure. Even in the SPYRAL HTN trial, there was a significant drop in BP in some with no response in the others. Evaluation of the same to find predictors of response remains a focus of investigation to better identify patients who can benefit from this technology.

Sympathetic Re-innervation Denervation is mainly an axonotmesis, not neuronotmesis. Potential sparing of the autonomic sympathetic ganglia allows for the possibility of re-innervation. Data from porcine and ovine models lends support

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Interventional Cardiology Table 1: Potential Benefits of Renal Denervation Potential Uses of Renal Denervation Cardiovascular • Ventricular arrhythmias • AF • Cardiomyopathy • Gestational hypertension Pulmonary • Pulmonary hypertension Endocrine • Type 2 diabetes Neurological • Stroke Miscellaneous • Obstructive sleep apnea

Use of capsaicin via micro-needles, and use of guanethidine to cause sympathetic destruction via an immune mechanism are still experimental methods which need evaluation.41,42

Non-endovascular Techniques Whereas most of the efforts are directed towards endovascular RDN, there remains a niche for the use of minimally invasive techniques for the delivery of neurotoxic substances for RDN. Laparoscopy as a technique for RDN for the treatment of renal hypertension has not been studied well enough. However, the number, three-dimensional arrangement, and location of the peri-arterial nerves were the main limiting factors when laparoscopic RDN was tried for intractable polycystic kidney disease pain.43 These are also limited by the need for local fat dissection, inadequate delivery methods, intra-abdominal adhesions and possibly longer recovery times.

Other Benefits for Renal Denervation to this hypothesis.34,35 This has always been found to be incomplete and patchy. Similarly, data from other denervation models in humans (post cardiac transplantation) have always shown incomplete neural re-innervation and limited functionality leading to skepticism of its contribution in the long term.36 The results of The Australian SHAM Controlled Clinical Trial of Renal DeNervation in Patients With Resistant Hypertension (AUSHAM-RDN-01) study are awaited to shed some more light on this matter.

Alternate Energy Sources Given the potential shortcomings of RF energy, cryoenergy has been evaluated in animal models and has found some success. However, it remains investigational without any human clinical data at present.37 The PARADISE catheter system uses a non-contact catheter system emitting sound waves circumferentially to cause sympathetic nerve damage via their conversion to thermal energy. Preliminary results in the REDUCE HTN trial using PARADISE catheter system were comparable to published data on RF RDN with a mean reduction in office and home BP of −36/−17 mmHg and −22/−12 mmHg, respectively.38 The Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE HTN) is a sham-controlled, randomized, double-blind study currently evaluating this concept in human trials. Due to the thermal nature of tissue destruction with both these modalities, there are still challenges, such as endothelial damage and heat sink phenomenon. Application of direct current energy in varying pulses can be used to cause tissue destruction via electroporation.39,40 As the mechanism of tissue damage is via the formation of large pores within the cell membrane causing apoptotic cell death, it is unlikely to be affected by the heat sink phenomenon. Coagulum formation leading to distal renal embolization and local inflammation are challenges that may not be avoided by use of this energy source. In addition, the virtual electrode properties of the electric field make it very attractive for use given the wide variability in the anatomy of the nerves. Non-selective neural ablation may also be facilitated. However, this needs evaluation for efficacy and feasibility.

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Besides the obvious benefits on the management of hypertension, RDN also has the potential to offer other systemic benefits that are purely investigational at its present stage (Table 1).

Managing Arrhythmias Premature Ventricular Contraction-mediated Cardiomyopathy Renal denervation inhibits the development of cardiac fibrosis and the risk of VF by inhibiting the renin angiotensin aldosterone system (RAAS) and sympathetic activity. Yamada et al. demonstrated RDN has a protective effect on the development of left ventricular enlargement and biventricular fibrosis in rabbits with high PVC burden.44

Ventricular Tachycardia Storm Following RDN, ventricular tachyarrhythmias were significantly reduced in two patients with therapy-resistant electrical storm.45

Atrial Arrhythmias L inz et al. demonstrated attenuation in the incidence and duration of spontaneous AF on RDN in an obstructive sleep apnea (OSA) model, which was comparable to pharmacological therapy.46 Hou et al. also showed a similar effect of RDN in reducing AF inducibility and reversing the atrial electrophysiological changes induced by sympathetic hyperactivity.47

Reduction in Stroke Risk RDN was shown to decrease the incidence of stroke in hypertensive rats, not just by the reduction of BP, but by the attenuation of oxidative stress and inflammatory effects in brain, the improvement of cerebral blood flow and the inhibition of the blood brain barrier disruption. The suppression of RAAS has shown to decrease the incidence of stroke independent of the BP as angiotensin II alone is involved in stroke. However, further studies are needed to evaluate this concept.48,49

Treatment of Type 2 Diabetes The effect of RDN on glucose metabolism and insulin resistance was studied by Mahfoud et al. demonstrating a significant improvement.50 RDN in the management of T2DM can emerge a synergistic measure to medication perhaps by improving the sensitivity to circulating insulin. This bears evaluation in further studies.

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Renal Denervation Obstructive Sleep Apnea

Cardio-renal Syndrome: Reduction in Renal Fibrosis

Obstructive sleep apnea affects up to 80 % of patients with rHTN with OSA being considered as both a consequence and cause of increased sympathetic tone.51 In one study, RDN was shown to decrease the severity of OSA and attenuate apnea/hypopnea index, thus suggesting RDN as treatment for OSA.52

Chronic activation of RAAS resulting in increased sodium reabsorption has been linked to myocardial and renal fibrosis.55 RDN significantly decreased the sympathetic nervous system activity and RAAS, thereby lowering collagen synthesis biomarkers concentration in plasma and reduction of cardio-renal collagen volume fraction in histopathology in rats with isoproterenol-induced cardiomyopathy.56

P ulmonary Hypertension RDN by the attenuation of RAAS and sympathetic outflow was demonstrated to improve pulmonary vascular remodeling and reduce right ventricular afterload and decreased right ventricular stiffness.53

Gestational Hypertension The enhanced pressor responses to angiotensin II by upregulation of mRNA expression of several RAAS components in offspring of rats with gestational hypertension is reversed by RDN.54

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Conclusion Renal denervation remains a concept with a robust burden of surgical data backing its efficacy, the benefit of which remains lost in translation with the endovascular approach. It is important to continue investigating these techniques, particularly given the wide-ranging impact of this intervention on autonomic homeostasis, with due care given to accuracy and reproducibility of benefits. Recent trials like the SPYRAL HTN OFF-MED have indeed given hope that the paradise deemed to have been lost, may in fact have shown signs of being regained. n

renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet 2015;385:1957–65. https://doi.org/10.1016/S01406736(14)61942-5; PMID: 25631070. Mahfoud F, Lüscher TF. Renal denervation: symply trapped by complexity? Eur Heart J 2015;36:199–202. https://doi.org/10.1093/ eurheartj/ehu450; PMID: 25400163. Sakakura K, Ladich E, Cheng Q, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol 2014;64:635–43. https://doi.org/10.1016/j.jacc.2014.03.059; PMID: 25125292. Templin C, Jaguszewski M, Ghadri JR, et al. Vascular lesions induced by renal nerve ablation as assessed by optical coherence tomography: pre- and post-procedural comparison with the SYMPLICITY catheter system and the EnligHTN multielectrode renal denervation catheter. Eur Heart J 2013;34:2141–8b. https://doi.org/10.1093/eurheartj/eht141; PMID: 23620498. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the SYMPLICITY HTN-1 study. Lancet 2014;383:622–9. https://doi.org/10.1016/S0140-6736(13)62192-3; PMID: 24210779. de Jong MR, Adiyaman A, Gal P, Smit JJ, et al. Renal nerve stimulation–induced blood pressure changes predict ambulatory blood pressure response after renal denervation. Hypertension 2016;68:707–14. https://doi.org/10.1161/ HYPERTENSIONAHA.116.07492; PMID: 27432864. Gal P, de Jong MR, Smit JJJ, et al. Blood pressure response to renal nerve stimulation in patients undergoing renal denervation: a feasibility study. J Hum Hypertens 2014;29:292. https://doi.org/10.1038/jhh.2014.91; PMID: 25339295. Madhavan M, Desimone CV, Ebrille E, et al. Transvenous stimulation of the renal sympathetic nerves increases systemic blood pressure: a potential new treatment option for neurocardiogenic syncope. J Cardiovasc Electrophysiol 2014;25:1115–8. https://doi.org/10.1111/jce.12466; PMID: 24902981. Esler M. Illusions of truths in the SYMPLICITY HTN-3 trial: generic design strengths but neuroscience failings. J Am Soc Hypertens 2014;8:593–8. https://doi.org/10.1016/j. jash.2014.06.001; PMID: 25151320. Ewen S, Ukena C, Linz D, et al. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension. Hypertension 2015;65:193–9. https://doi. org/10.1161/HYPERTENSIONAHA.114.04336; PMID: 25331843. Pocock SJ, Gersh BJ. Do current clinical trials meet society’s needs?: A critical review of recent evidence. J Am Coll Cardiol 2014;64:1615–28. https://doi.org/10.1016/j. jacc.2014.08.008; PMID: 25301467. Howard JP, Shun-Shin MJ, Hartley A, et al. Quantifying the 3 biases that lead to unintentional overestimation of the blood pressure-lowering effect of renal denervation. Circ Cardiovasc Qual Outcomes 2016;9:14–22. https://doi.org/10.1161/ CIRCOUTCOMES.115.002533; PMID: 26758193. Ewen S, Meyer MR, Cremers B, et al. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis. Clin Res Cardiol 2015;104:1097–105. https://doi.org/10.1007/s00392-015-0905-5; PMID: 26306594. Kandzari DE, Bhatt DL, Brar S, et al. Predictors of blood

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pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J 2015;36:219–27. https://doi.org/10.1093/eurheartj/ehu441; PMID: 25400162. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTNOFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet 2017;390:2160–70. https://doi.org/10.1016/S01406736(17)32281-X; PMID: 28859944. Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J 2016;171:82–91. https://doi.org/10.1016/j. ahj.2015.08.021; PMID: 26699604. Esler M, Lux A, Jennings G, et al. [Rilmenidine sympatholytic activity preserves mental and orthostatic sympathetic response and epinephrine secretion]. Arch Mal Coeur Vaiss 2004;97:786–92 [in French]. PMID: 15506067. Rousselle SD, Brants IK, Sakaoka A, et al. Neuromatous regeneration as a nerve response after catheterbased renal denervation therapy in a large animal model: immunohistochemical study. Circ Cardiovasc Interven 2015;8: e002293. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.002293; PMID: 25940523. Booth LC, Nishi EE, Yao ST, et al. Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheepnovelty and significance. Hypertension 2015;65:393–400. https://doi.org/10.1161/HYPERTENSIONAHA.114.04176; PMID: 25403610. Kaye DM, Esler M, Kingwell B, et al. Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans. Circulation 1993;88:1110–8. https://doi.org/10.1161/01.CIR.88.3.1110; PMID: 8353872. Prochnau D, Figulla HR, Romeike BF, et al. Percutaneous catheter-based cryoablation of the renal artery is effective for sympathetic denervation in a sheep model. Int J Cardiol 2011;152:268–70. https://doi.org/10.1016/j.ijcard.2011.08.001; PMID: 21872350. Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012;8:57–61. https://doi.org/10.4244/EIJV8I1A10; PMID: 22580249. Li W, Fan Q, Ji Z, et al. The effects of irreversible electroporation (IRE) on nerves. PLoS One 2011;6:e18831. https://doi.org/10.1371/ journal.pone.0018831; PMID: 21533143. DeSimone CV, Kapa S, Asirvatham SJ. Electroporation: past and future of catheter ablation. Circ Arrhythm Electrophysiol 2014;7:573–5. https://doi.org/10.1161/CIRCEP.114.001999; PMID: 25140018. Manning P, Powers C, Schmidt R, Johnson E. Guanethidineinduced destruction of peripheral sympathetic neurons occurs by an immune-mediated mechanism. J Neurosci 1983;3:714–24. PMID: 6131947. Foss JD, Wainford RD, Engeland WC, et al. A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin. Am J Physiol Regul Integr Comp Physiol 2015;308:R112–22. https://doi.org/10.1152/ajpregu.00427.2014; PMID: 25411365.

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Interventional Cardiology 43. V alente JF, Dreyer DR, Breda MA, Bennett WM. Laparoscopic renal denervation for intractable ADPKD‐related pain. Nephrol Dial Transplant 2001;16:160. PMID: 11209012. 44. Yamada S, Lo LW, Chou YH, et al. Beneficial effect of renal denervation on ventricular premature complex induced cardiomyopathy. J Am Heart Assoc 2017;6. e004479. 45. Ukena C, Bauer A, Mahfoud F, et al. Renal sympathetic denervation for treatment of electrical storm: first-inman experience. Clin Res Cardiol 2012;101:63–7. https://doi. org/10.1007/s00392-011-0365-5; PMID: 21960416. 46. Linz D, Hohl M, Nickel A, et al. Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension 2013;62:767–74. https://doi.org/10.1161/HYPERTENSIONAHA.113.01728; PMID: 23959548. 47. Hou Y, Hu J, Po SS, et al. Catheter-based renal sympathetic denervation significantly inhibits atrial fibrillation induced by electrical stimulation of the left stellate ganglion and rapid atrial pacing. PLoS One 2013;8:e78218. https://doi.org/10.1371/journal. pone.0078218; PMID: 24223140. 48. Nakagawa T, Hasegawa Y, Uekawa K, et al. Renal denervation

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prevents stroke and brain injury via attenuation of oxidative stress in hypertensive rats. J Am Heart Assoc 2013;2:e000375. https://doi.org/10.1161/JAHA.113.000375; PMID: 24125845. Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012;60:1163–70. https://doi.org/10.1016/j. jacc.2012.05.036; PMID: 22958958. Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011;123:1940–6. https://doi.org/10.1161/ CIRCULATIONAHA.110.991869; PMID: 21518978. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271–7. PMID: 11725173. Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011;58:559–65.

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Interventional Cardiology

Left Atrial Appendage Closure Devices for Stroke Prevention in Patients with Non-Valvular AF Daniel A McBride, MD, 1 Timothy M Markman, MD, 2 Jackson J Liang, DO, 2 and Pasquale Santangeli, MD, PhD 2 1. Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA; 2. Division of Cardiology, Electrophysiology Section, Hospital of the University of Pennsylvania, Philadelphia, PA

Abstract The left atrial appendage (LAA) may be involved in offloading atrial pressure during left ventricular systole. As ventricular rate increases, LAA emptying decreases during early diastole causing increased risk of thrombus formation particularly in patients with non-valvular AF (NVAF). The LAA is the site of thrombus formation in more than 90 % of patients with NVAF, so is an important target for thromboembolic prophylaxis in these patients. Anticoagulation therapy is used to treat NVAF, but it has long-term complications and may be contraindicated in some patients. Therefore, alternative strategies to reduce embolic risk in patients with AF have been developed. These include percutaneous, thoracoscopic, and open closure strategies. This study reviews the safety and efficacy of these strategies, comparing these approaches and devices with pharmacological strategies. There is little data to endorse one strategy over another. Given the minimal evidence available, recommendations in support of LAA occlusion remain weak and guidelines have called for more research and coding of endpoints for this emerging technology.

Keywords Left atrial appendage, left atrial appendage occlusion, thrombus, stroke, non-valvular AF, thromboembolic prophylaxis Disclosure: The authors have no conflicts of interest to declare. Submitted: July 1, 2018 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;12(2):87–90. DOI: https://doi.org/10.15420/usc.2018.6.1 Correspondence: Pasquale Santangeli, Hospital of the University of Pennsylvania, 9 Founders Pavilion – Cardiology, 3400 Spruce St, Philadelphia, PA, 19104, USA. E: pasquale.santangeli@uphs.upenn.edu

The left atrial appendage (LAA) is a trabeculated structure with variable anatomy comprised of pectinate muscle, which grows out of the primary atrium before the left atrium (LA) develops. This outcropping joins the venous component of the LA by way of a bottlenecked junction, in contrast to the anatomy of the right atrial appendage which, although trabeculated, joins the atrium via a wider neck.1 Although the exact function of the LAA is unknown, morphologic studies suggest it may play a role in offloading atrial pressure during left ventricular systole.2 Left ventricular rate is inversely correlated with LAA emptying during early diastole, which is hypothesized to play a role in the development of thrombus in the LAA in patients with non-valvular AF (NVAF).3 Transesophageal echocardiography (TEE) is the standard method of evaluating the size and shape of the LAA and to exclude thrombus within it. The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) trial demonstrated that using TEE results in decreased time to cardioversion and the incidence of both major and minor hemorrhagic events in patients with NVAF found to have no LAA thrombus. The reduction in hemorrhagic events was attributed to a lack pre-cardioversion anticoagulation in the no-thrombus population.4 Significantly, even if pre-cardioversion TEE shows no thrombus,

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post-cardioversion anticoagulation remains essential to prevent embolic complications, possibly due to fibrillatory-induced atrial and appendageal myopathies.5,6 TEE findings of increased LAA size and irregular orifice flow patterns are associated with an increased risk of LAA thrombus.7,8 Thrombus characteristics such as size, mobility and shape can also be assessed on TEE and correlated with embolic risk.9 The LAA is the site of thrombus formation in more than 90 % of patients with NVAF, making it an important therapeutic target to reduce embolic stroke risk.10 Unfortunately, pharmacological and catheter-based interventional strategies to abort AF have not been shown to reduce stroke risk.11 Meta-analysis supports the use of anticoagulation therapy in patients with NVAF, especially in subgroups determined to be at high risk based on the CHA2DS2–VASc score.12 Given the potential complications of long-term anticoagulation medication, there are patients in whom the risks of anticoagulation therapy outweigh the potential benefits of ischemic stroke prevention, such as those with prior intracerebral hemorrhage. As a result, nonpharmacological strategies aimed at reducing embolic risk in patients with AF have been developed.

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Interventional Cardiology Closure Strategies: Percutaneous, Thoracoscopic, and Open The Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) study in 2002 was the first to demonstrate that a device could be used to close the LAA.13 Five-year follow-up data showed that percutaneous devices were effective in reducing stroke risk in patients with NVAF by 2.8 % per year compared to the cumulative risk predicted by CHADS2 score, and provided the impetus for further development of percutaneous closure devices.14 The most widely used endovascular percutaneous devices are the WATCHMAN (Boston Scientific) and Amplatzer Amulet (St Jude Medical). Only the WATCHMAN has obtained FDA approval for implantation in the US, although multiple devices are in varying stages of development. The placement of these devices requires femoral venous access with transseptal puncture to access the LAA for implantation. Other closure devices may be placed via the pericardium, some of which require surgical thoracotomy incision to deploy the device. The LARIAT (SentreHEART), AtriClip (AtriCure) and Tiger Paw II (Maquet Cardiovascular) all have FDA approval for transpericardial LAA closure, with the latter two requiring surgical thoracotomy. Surgical ligation or amputation of the LAA when performing other cardiac surgery is an invasive method of LAA exclusion. The efficacy of surgical LAA exclusion/removal has been called into question, however. A 2008 retrospective analysis of 137 patients undergoing surgical exclusion or excision of the LAA found that follow-up TEE (approximately 8–20 months postoperatively) demonstrated a failure rate of up to 60 % assessed by Doppler flow within the appendage or remnant. Notably, there was no significant difference in stroke risk between the successful and the non-successful surgical closure groups.15 A more recent study from the Mayo Clinic found in a large, propensity-matched analysis that prophylactic surgical LAA exclusion during cardiac surgery had no effect on long-term risk of stroke or mortality during follow-up.16

Percutaneous Left Atrial Appendage Occlusion Devices WATCHMAN The Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) trial was a non-inferiority trial comparing warfarin therapy to WATCHMAN implantation in patients with permanent or paroxysmal NVAF who had no contraindications to oral anticoagulation. The trial randomized patients to either oral warfarin or WATCHMAN implantation, followed by a 45-day course of warfarin, and then clopidogrel and aspirin for 6 months, followed by indefinite aspirin monotherapy. A composite primary efficacy endpoint of stroke, cardiovascular death, and systemic embolism was measured in addition to the primary composite safety endpoint of major bleeding, pericardial effusion, and device embolization. At the 1,065 patient-year follow-up, WATCHMAN was found to be noninferior, as measured by the primary efficacy endpoint (3.0/100 patientyears in the intervention group versus 4.9/100 patient-years in the control group). Notably, the primary safety endpoint was significantly

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more frequent in the intervention group (7.4/100 patient years in the intervention group versus 4.4/100 patient years in the control group).17 Four-year follow-up data confirmed the primary endpoint noninferiority and superiority and suggested a significantly lower rate of cardiovascular and all-cause mortality in the intervention group.18 A subsequent analysis compared the PROTECT AF cohort to the open label Continued Access Protocol registry and noted significant decline in the primary safety endpoint within 7 days of the implantation procedure (7.7 % and 3.7 %, respectively).19 The same analysis showed that the intra-trial primary safety endpoint declined between the first and second half of the trials, implying that increased operator experience improved the safety of WATCHMAN implantation. This finding was again suggested in a comparison to the EWOLUTION registry, in which device deployment was successful in 98.5 % of high-risk patients and 30–day periprocedural mortality was 0.7 %.20 The Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy (PREVAIL) trial was another randomized evaluation of the WATCHMAN device, which used the same post-implantation anticoagulation regimen in a similar population to the PROTECT AF trial. The trial found the WATCHMAN device was non-inferior to warfarin in preventing stroke or systemic embolism within 7 days of implantation but did not meet statistical significance with regards to the combined primary efficacy noninferiority endpoint of stroke, systemic embolism and cardiovascular/unexplained death. The trial also found safety was better than in the PROTECT AF trial.21 Based on these findings, the WATCHMAN was granted FDA approval in March 2015. A recent meta-analysis of the PREVAIL and PROTECT AF trials with 5-year follow-up found statistically significant reductions in hemorrhagic stroke, post-procedure bleeding and both cardiovascular and all-cause mortality in the groups that underwent LAA occlusion.22 The ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology (ASAP) study was designed to assess the effectiveness of the WATCHMAN implant in patients with stronger contraindications to anticoagulation with warfarin (noted as hemorrhagic/ bleeding tendencies, blood dyscrasias, senility, high fall risk and other documented reasons such as hypersensitivity). Device implantation was followed by 6 months of a thienopyridine antiplatelet agent and lifelong aspirin. The study found a reduction in stroke rate to 1.7 % from the 7.3 % predicted by the mean CHADS2 score of patients in the ASAP registry (2.8 ± 1.2), suggesting that implantation can be safe without warfarin transition.23 One substudy of the PROTECT AF study reported a 32 % incidence of flow seen around the device at 12 months.24 The presence of peridevice flow at 1 year was not associated with increased risk of clinical thromboembolic events. Stroke patients with peridevice flow leak were more likely to have continued on anticoagulation therapy. Device-associated thrombus (DAT) was a rare complication and was related to AF burden, size of implanted device and adherence to the postprocedural anticoagulant regimen. Warfarin therapy after the discovery of device-related thrombus achieved complete resolution in retrospective analysis.25 Table 1 summarizes several of the large WATCHMAN trials.

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Left Atrial Appendage Closure Amulet The Amulet device is an alternative to the WATCHMAN and has gained CE marking but no FDA approval. It has a different occluder structure from the WATCHMAN. The Amulet has been found to significantly reduce the annual rate of systemic thromboembolism in patients with NVAF compared to the rate predicted by their CHA2DS2–VASc score.26

Device-associated Thrombus One recent pooled meta-analysis suggests that DAT prevalence affects all devices at a rate of 3.9 % and can be broken down by device – 3.4 % for WATCHMAN (40/1,184), 4.6 % for ACP/Amulet (35/757), 4.8 % for ACP (34/707).27 Recent multicenter data from 1–2 years follow-up suggest that DAT has a strong association with risk of ischemic stroke (HR 4.39, 95 % CI [1.05–18.43]), and that protective factors include dual antiplatelet therapy (HR 0.10, 95 % CI [0.01–0.76]) and oral anticoagulation (HR 0.26 95 % CI [0.09–0.77]).28 Further randomized controlled trials are necessary to determine the optimal post-implantation anticoagulation regimen for better characterization of device-associated risk as to best avoid iatrogenic complication of device implantation.29

Table 1: Summary of the WATCHMAN Trials Trial

Study design

Key takeaway

Prospective, non-randomized multicenter trial

Successful implantation demonstrated in 108/111 patients (97.3 %, 95 % CI [92.3–99.4 %]); percutaneous closure is feasible

PROTECT AF17

Prospective, randomized, unblinded multicenter trial

Percutaneous LAA closure met criteria for both noninferiority and superiority compared with warfarin for combined outcome of stroke, systemic embolism, cardiovascular death (rate ratio, 0.60; [95 % CI [0.41–1.05])

PREVAIL21

Prospective, randomized, unblinded multicenter trial

LAA occlusion was noninferior to warfarin for ischemic stroke prevention or system embolism >7 days post procedure (risk difference 0.0053, 95 % CI [−0.0190–0.0273])

ASAP23

Prospective, non-randomized, unblinded multicenter trial

LAA closure with the WATCHMAN device can be safely performed without a warfarin transition based on ischemic stroke rate lower than expected based on CHADS score (1.7 % versus 7.3 % 1-sided exact upper 95 % bound rate of 4.4 %)

PLAATO

Percutaneous Epicardial Left Atrial Appendage Exclusion Devices LARIAT The LARIAT device requires epicardial access and an endovascularly placed magnetic guidewire to ultimately provide suture ligation of the most anterior lobe of the LAA. This device has FDA approval as a tissue closure device, and has been used as a LAA exclusion device. However, retrospective multicenter data have shown a high periprocedural major complication rate (9.7 %) and a significant rate of pericardial effusion (10.4 %) in patients undergoing the LARIAT ligation procedure.30,31 At present, this device is the only nonsurgical option for patients who have an absolute contraindication to oral anticoagulation even for a short duration post-implant. The LARIAT is associated with significant reduction in annual stroke rate compared to what would be expected for the studied population (1 % observed event rate versus 6.2 % expected in one multicenter trial).32 Addition of LARIAT ligation to conventional catheter ablation has been shown in one observational study to reduce persistent NVAF, assessed by the primary endpoint of freedom from antiarrhythmic medication after a single ablation procedure (65 % in the LARIAT ligation group versus 27 39 % undergoing ablation only; p=0.002), possibly due to reduced substrate for propagation of reentry.33

Standalone Thoracoscopic Approaches Novel thoracoscopic approaches have been developed to achieve minimally invasive surgical LAA exclusion. Ohtsuka et al.34 carried out a standalone thoracoscopic LAA appendectomy in 30 patients with contraindications to standard anticoagulation therapy. The study used 3D CT to assess successful closure of the LAA and there were no thromboembolic events in up to 38 months of follow-up. A similar procedure for exclusion of the LAA with the AtriClip device demonstrated effective exclusion in up to 93.9 % in one single-center

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trial. The authors of this study acknowledge that the significance of a remnant stump seen in this procedure remains unknown and TEE evidence of complete occlusion should be obtained before cessation of oral anticoagulant therapy.35 The data on surgical closure of the LAA to prevent thromboembolism are mostly observational and non-randomized. The on-going Left Atrial Appendage Occlusion Study (LAAOS) III will end its enrollment in 2018 and should have a sufficient number of patients to detect any significant reduction in primary outcomes using open surgical closure.36

Conclusion The LAA remains an important target for thromboembolic prophylaxis in patients with NVAF. There are few multicenter randomized controlled trial data to endorse one strategy over another as the number of options to achieve LAA exclusion continues to grow. Given the minimal evidence available at present, consensus guidelines make only weak recommendations in support of LAA occlusion.37 The 2012 focused update to the European Society of Cardiology Guidelines for the Management of Atrial Fibrillation gave a class IIb level B recommendation for the use of LAA occlusion devices in patients who have contraindications to long-term oral anticoagulant therapy.38 However, these guidelines were called into question in a 2015 update, which noted that such recommendations were built on studies where patients did not have oral anticoagulant therapy contraindications.39 It is worth noting that both the PROTECT AF and PREVAIL trials were designed as non-inferiority trials in comparison to standard medical anticoagulant therapies. By achieving non-inferiority, these devices show a comparable effectiveness in preventing the known complications of NVAF; however, the decision to use such a device

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Interventional Cardiology must remain at the level of the patient and provider taking into account bleeding risk and compliance.

Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial.41

Since this update, the WATCHMAN has gained FDA approval, but there has been no consensus statement in the US with recommendations for LAA occlusion with the closure devices described above. Instead, there is a growing number of guidelines calling for more trials and codification of valuable endpoints in keeping with this new, growing technology.40

There may be a role for intervention if it can be shown in large trials that implant devices benefit patients with risks for anticoagulation. It remains to be shown whether combined therapy with non-vitamin K antagonists and LAA occlusion can provide superior results to either method independently.

Another significant consideration is the expanded use of non-vitamin K antagonist anticoagulant therapy, which may be appropriate for patients with contraindications to warfarin anticoagulation. This was suggested in the 2011 Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial

As strategies for occlusion improve and periprocedural risks decline, outcome measures must be assessed at the level of the individual patient. Stroke risk ought to be reduced in a way that promotes good compliance and has meaningful quality-of-life benefits to patients with NVAF.

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l-Saady NA, Obel O, Camm A. Left atrial appendage: structure, A function, and role in thromboembolism. Heart 1999;82:547–54. https://doi.org/10.1136/hrt.82.5.547; PMID: 10525506. Davis CA 3rd, Rembert JC, Greenfield JC Jr. Compliance of left atrium with and without left atrium appendage, Am J Physiol 1990;259:H1006–8. https://doi.org/10.1152/ ajpheart.1990.259.4.H1006; PMID: 2221109. Akosah KO, Funai JT, Porter TR, et al. Left atrial appendage contractile function in atrial fibrillation. Influence of heart rate and cardioversion to sinus rhythm. Chest 1995;107:690–6. https://doi.org/10.1378/chest.107.3.690; PMID: 7874938. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344:1411–20. https://doi. org/10.1056/NEJM200105103441901; PMID: 11346805. Grimm RA, Leung DY, Black IW, Stewart WJ, et al. Left atrial appendage ‘stunning’ after spontaneous conversion of atrial fibrillation demonstrated by transesophageal Doppler echocardiography. Am Heart J 1995;130:174–6. https://doi. org/10.1016/0002-8703(95)90253-8; PMID: 7611109. Black IW, Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial-fibrillation. A multicenter study. Circulation 1994;89:2509–13. https://doi.org/10.1161/01. CIR.89.6.2509; PMID: 8205657. Pollick C, Taylor D. Assessment of left atrial appendage function by transesophageal echocardiography. Implications for the development of thrombus. Circulation 1991;84:223–31. https://doi. org/10.1161/01.CIR.84.1.223; PMID: 2060098. Li YH, Hwang JJ, Tseng YZ, et al. Clinical significance of fibrillatory wave amplitude. A clue to left atrial appendage function in nonrheumatic atrial fibrillation. Chest 1995;108:359– 63. https://doi.org/10.1378/chest.108.2.359; PMID: 7634867. Leung DY, Black IW, Cranney GB, et al. Prognostic implications of left atrial spontaneous echo contrast in nonvalvular atrial fibrillation. J Am Coll Cardiol 1994;24:755–62. https://doi. org/10.1016/0735-1097(94)90025-6; PMID: 8077549. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996;61:755–59. https://doi.org/10.1016/0003-4975(95)00887-X; PMID: 8572814. Zheng YR, Chen ZY, Ye LF, Wang LH. Long-term stroke rates after catheter ablation or antiarrhythmic drug therapy for atrial fibrillation: a meta-analysis of randomized trials. J Geriatr Cardiol 2015;12:507–14. https://doi.org/10.11909/j.issn.16715411.2015.05.012; PMID: 26512242. Hart RG, Pearce LA, Aguilar MA. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. https://doi. org/10.7326/0003-4819-146-12-200706190-00007; PMID: 17577005. Sievert H, Lesh MD, Trepels T, et al. Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in highrisk patients with atrial fibrillation: early clinical experience. Circulation 2002;105:1887–9. https://doi.org/10.1161/01. CIR.0000015698.54752.6D; PMID: 11997272. Block PC, Burstein S, Casale PN, et al. Percutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5–year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) study. JACC Cardiovasc Interv 2009;2:594–600. https://doi. org/10.1016/j.jcin.2009.05.005; PMID: 19628179. Kanderian AS, Gillinov AM, Pettersson GB, et al. Success of surgical left atrial appendage closure: assessment by transesophageal echocardiography. J Am Coll Cardiol 2008;52:924–

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9. https://doi.org/10.1016/j.jacc.2008.03.067; PMID: 18772063. 16. M elduni RM, Schaff HV, Lee HC, et al. Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality: a propensity score-matched analysis of 10 633 patients. Circulation 2017;135:366–78. https://doi.org/10.1161/ CIRCULATIONAHA.116.021952; PMID: 27903589. 17. Holmes DR, Reddy VY, Turi ZG, et al., Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised noninferiority trial. Lancet 2009;374:534–42. https://doi.org/10.1016/ S0140-6736(09)61343-X; PMID: 19683639. 18. Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988–98. https://doi. org/10.1001/jama.2014.15192; PMID: 25399274. 19. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123:417–24. https://doi.org/10.1161/ CIRCULATIONAHA.110.976449; PMID: 21242484. 20. Boersma LV, Schmidt B, Betts TR, et al. Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur Heart J 2016;37:2465–74. https://doi.org/10.1093/eurheartj/ ehv730; PMID: 26822918. 21. Holmes DR Jr, Kar S, Price MJ. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. https://doi.org/10.1016/j.jacc.2014.04.029; PMID: 24998121. 22. Reddy VY, Doshi SK, Kar S, et al. 5–year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF Trials. J Am Coll Cardiol 2017;70:2964–75. https://doi.org/10.1016/ j.jacc.2017.10.021; PMID: 29103847. 23. Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551–6. https://doi. org/10.1016/j.jacc.2013.03.035; PMID: 23583249. 24. Viles-Gonzalez JF, Kar S, Douglas P, Dukkipati S, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J Am Coll Cardiol 2012;59:923–9. https://doi. org/10.1016/j.jacc.2011.11.028; PMID: 22381428. 25. Kubo S, Mizutani Y, Meemook K, et al. Incidence, characteristics, and clinical course of device-related thrombus after watchman left atrial appendage occlusion device implantation in atrial fibrillation patients. JACC Clin Electrophysiol 2017;3:1380–6. https:// doi.org/10.1016/j.jacep.2017.05.006; PMID: 29759668. 26. Tzikas A, Shakir S, Gafoor S, et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 2016;11:1170–9. https://doi.org/10.4244/EIJY15M01_06; PMID: 25604089. 27. Lempereur M, Aminian A, Freixa X, et al. Device-associated thrombus formation after left atrial appendage occlusion: a systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter Cardiovasc Interv 2017;90:E111–21. https://doi.org/10.1002/ccd.26903; PMID: 28145040.

28. F auchier L, Cinaud A, Brigadeau F. Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. J Am Coll Cardiol 2018;71:1528–36. https://doi. org/10.1016/j.jacc.2018.01.076; PMID: 29622159. 29. Valderrábano M. Left atrial appendage occlusion devicerelated thrombus: certainties and uncertainties. J Am Coll Cardiol 2018;71:1537–9. https://doi.org/10.1016/j.jacc.2018.01.077; PMID: 29622160. 30. Price MJ, Gibson DN, Yakubov SJ, et al. Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium. J Am Coll Cardiol 2014;64:565–72. https://doi.org/10.1016/j. jacc.2014.03.057; PMID: 25104525. 31. Chatterjee S, Herrmann HC, Wilensky RL. Safety and procedural success of left atrial appendage exclusion with the Lariat device: a systematic review of published reports and analytic review of the FDA MAUDE Database. JAMA Intern Med 2015;175:1104–9. https://doi.org/10.1001/ jamainternmed.2015.1513; PMID: 25938303. 32. Sievert H, Rasekh A, Bartus K, et al. Left atrial appendage ligation in nonvalvular atrial fibrillation patients at high risk for embolic events with ineligibility for oral anticoagulation: initial report of clinical outcomes. JACC Clin Electrophysiol 2015;1: 465–74. https://doi.org/10.1016/j.jacep.2015.08.005; PMID: 29759399. 33. Lakkireddy D, Sridhar Mahankali A, Kanmanthareddy A, et al. Left atrial appendage ligation and ablation for persistent atrial fibrillation: the LAALA–AF registry. JACC Clin Electrophysiol 2015;1:153–60. https://doi.org/10.1016/j.jacep.2015.04.006; PMID: 29759358. 34. Ohtsuka T, Ninomiya M, Nonaka T, et al. Thoracoscopic stand-alone left atrial appendectomy for thromboembolism prevention in nonvalvular atrial fibrillation. Am Coll Cardiol 2013;62:103–107. https://doi.org/10.1016/j.jacc.2013.01.017; PMID: 23433566. 35. Ellis CR, Aznaurov SG, Patel NJ, et al. Angiographic efficacy of the atriclip left atrial appendage exclusion device placed by minimally invasive thoracoscopic approach. JACC Clin Electrophysiol 2017;3:1356–65. https://doi.org/10.1016/j.jacep.2017.03.008; PMID: 29759664. 36. Whitlock R, Healey J2, Vincent J, et al. Rationale and design of the Left Atrial Appendage Occlusion Study (LAAOS) III. Ann Cardiothorac Surg 2014;3:45–54. https://doi.org/10.3978/ j.issn.2225-319X.2013.12.06; PMID: 24516797. 37. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893–962. https://doi. org/10.1093/eurheartj/ehw210; PMID: 27567408. 38. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;33:2719–47. https://doi.org/10.1093/ eurheartj/ehs253; PMID: 22922413. 39. Masoudi FA, Calkins H, Kavinsky CJ, et al. 2015 ACC/HRS/SCAI left atrial appendage occlusion device societal overview. J Am Coll Cardiol 2015;66:1497–513. https://doi.org/10.1016/ j.jacc.2015.06.028; PMID: 26133570. 40. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017;14:e275–444. https://doi.org/10.1016/j.hrthm.2017.05.012; PMID: 28506916. 41. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17. https://doi. org/10.1056/NEJMoa1007432; PMID: 21309657.

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Interventional Cardiology

Abstract The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) using the latest-generation drug-eluting stents remains a matter of debate. Evidence suggests short regimens of DAPT are favorable for patients with a low ischemic risk, while those at a high risk of ischemia may benefit from taking DAPT for a long duration. An individually assessed risk profile is pivotal in guiding DAPT duration. Risk scores may aid individual patient DAPT decisions, but the value they add to clinical outcomes still needs to be established in a prospective randomized trial. This review aims to provide an overview on DAPT, evaluate the available evidence on DAPT duration with a description of common pitfalls of trial interpretation, and assess available tools for individual risk assessment in patients scheduled for PCI with the latest-generation DES.

Keywords Coronary artery disease, ischemic heart disease, percutaneous coronary intervention, drug-eluting stent, dual antiplatelet therapy Disclosure: The authors have no conflicts of interest to declare. Submitted: June 29, 2018 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;12(2):91–7. DOI: https://doi.org/10.15420/usc.2018.4.2 Correspondence: Pieter R Stella, University Medical Center Utrecht, Department of Cardiology, Heidelberglaan 100, Room E.04.201, 3584 CX, Utrecht, the Netherlands. E: p.stella@umcutrecht.nl

Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is prescribed in the treatment of acute coronary syndrome (ACS) or following percutaneous coronary intervention (PCI) for drug-eluting stent (DES) implantation. An important misconception remains that DAPT should be prescribed to prevent stent thrombosis. Although this may seem obvious, it should be emphasized that the incidence of stent thrombosis is below 1.0 % in second-generation DES and recurrent adverse events are equally attributable to culprit lesions or non-culprit lesions which can also be prevented by DAPT.1,2 Current guidelines recommend at least 12 months of DAPT for patients with ACS who have a low bleeding risk (class 1, level A).3,4 It is advised to treat patients with a low bleeding risk for at least 6 months for stable coronary artery disease (class 1, level A). Optimal DAPT duration remains a matter of debate. Risk assessment is key in this decision, and the higher bleeding risk with longer DAPT duration must be balanced with the benefits of prolonged DAPT duration for patients with increased ischemic risk.3-5 The authors therefore aimed to evaluate current evidence regarding antiplatelet agents, DAPT duration and risk assessment of patients scheduled for PCI with implantation of a latest-generation DES.

Antiplatelet therapy Thrombocytes, or platelets, are anucleate cell fragments that are essential for primary hemostasis and repair of the endothelium.6 Platelet

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adhesion, activation and aggregation are considered key elements in the formation of arterial thrombi, and are targets of antiplatelet therapy in the treatment of ACS or DES implantation.7,8 At present, several distinct antiplatelet agents are used in routine practice: aspirin; clopidogrel; prasugrel and ticagrelor.9–11 Aspirin irreversibly inhibits the cyclooxygenase (COX-1) enzyme, reducing the formation of thromboxane A2 and prostaglandins from arachidonic acid, which leads to decreased platelet activation. Several trials have demonstrated that aspirin reduces cardiovascular events.12 However, blocking COX-1 with aspirin also leads to a dose-dependent increased risk of bleeding, mainly in the upper gastrointestinal tract.13 Clopidogrel is the only agent of the purigernic G-protein-coupled P2Y12 receptor inhibitors that is currently recommended for stable coronary artery disease, and is one of the most widely investigated antiplatelet agents. A synergistic effect of clopidogrel on top of aspirin has been established.14 As a prodrug, this thienopyridine requires a two-step oxidation process that contributes to the non-uniform inter-individual clopidogrel response,which has led to high-on platelet reactivity in 30–40 % of patients; this has prompted further research into other potent P2Y12 inhibitors.15 In contrast to clopidogrel, prasugrel requires single-step oxidation by the hepatic cytochrome P450 iso-enzyme family, leading to a rapidonset, highly potent antiplatelet effect with less variability between

Access at: www.USCjournal.com

04/12/2018 19:31

Interventional Cardiology Table 1: Characteristics of Major Studies Investigating Short Dual Antiplatelet Therapy Study (year)

Size

S-DAPT

L-DAPT

(n)

(months)

RESET (2012)25

2,117

OPTIMIZE (2013)27

3,119

EXCELLENT (2012)24

1,443

SECURITY (2015)23

1,399

ISAR-SAFE (2015)22

Non-inferiority

Time of

ACS

margin (%)

randomization

(%)

4.0

At time of index

Cardiovascular death, MI, ST, TVR, major or minor bleeding

TIMI

2.7

At time of index

All-cause death, MI, stroke, major bleeding

Modified REPLACE–2 and GUSTO

4.0

At time of index

Cardiac death, MI, TVR

TIMI

2.0

At time of index

Cardiac death, MI, stroke, ST, major bleeding

BARC

4,005

2.0

6 months after PCI

All-cause death, MI, ST, stroke, major bleeding

TIMI

I-LOVE-IT 2 (2016)21

1,829

3.7

At time of index

Cardiac death, TV–MI, TLR

BARC

IVUS-XPL (2016)

1,400

N/A

At time of index

Cardiac death, MI, stroke, major bleeding

TIMI

SMART-DATE (2018)20

2,712

2.0

At time of index

100

All-cause death, MI, stroke

BARC

NIPPON (2017)

3,773

2.0

At time of index

All-cause death, MI, stroke, major bleeding

BARC

PRODIGY (2012)34

2,013

N/A

30 days after PCI

All-cause death, MI, stroke

BARC

ITALIC (2017)36

1,850

2.0

At time of index

All-cause death, MI, TVR, stroke, major bleeding

TIMI

Design

Primary endpoint

Bleeding criteria

Abbreviations: ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; GUSTO = Global Use of Strategies to Open Occluded Arteries; L-DAPT = long dual antiplatelet therapy; NI = non-inferiority; REPLACE = Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events; S = superiority; S-DAPT = short dual antiplatelet therapy; ST = stent thrombosis; TIMI = thrombolysis in myocardial infarction; TLR = target lesion revascularization; TVR = target vessel revascularization; TV-MI = target vessel myocardial infarction. Study acronyms: EXCELLENT = the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting; I–LOVE–IT 2 = Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization; ISAR–SAFE = Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC = Is There a Life for DES After Discontinuation of Clopidogrel; IVUS–XPL = Impact of Intravascular Ultra-sound Guidance on Outcomes of XIENCE PRIME Stents in Long Lesions; NIPPON = Nobori Dual Antiplatelet Therapy as Appropriate Duration; OPTIMIZE = Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice; PRODIGY = Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study; RESET = REal Safety and Efficacy of 3–month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation; SMART–DATE = Smart Angioplasty Research Team: Safety of 6-month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes; SECURITY = Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy.

individuals than clopidogrel.16,17 Prasugrel should be administered only after the coronary anatomy of a patient has been established, except for those with ST-elevation myocardial infarction (STEMI), who will undergo primary PCI. Notably, prasugrel is associated with significantly higher rates of TIMI (thrombolysis in MI) major bleeding, life-threatening bleeding and fatal bleeding, and should not be administered to those with a history of stroke or transient ischemic attack.10 Ticagrelor, as a first-in-class cyclopentyltriazolopyrimidine, can be administered before assessment of the coronary anatomy and acts by reversible and direct inhibition of platelets by allostatic modulation of the P2Y12 receptor, leading to a highly potent, rapid-onset and more predictable antiplatelet effect compared to clopidogrel.11,18 With a plasma half-life of 8–12 hours, ticagrelor requires administration twice daily, which may be unattractive to patients with poor compliance. An important adverse effect of ticagrelor is dyspnea (usually self-limiting), which occurred in roughly 20 % of patients in major trials and accounted for a substantial number of withdrawals.11 Ever since the introduction of DAPT, extensive research has tried to establish the optimal duration of DAPT. This has led the adoption of two main strategies for patients scheduled for PCI: abbreviated, or short DAPT; and prolonged DAPT.

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Evidence on Short Duration of Dual Antiplatelet Therapy The primary motivators to study short DAPT (S-DAPT; 3–6 months) or ultra-short DAPT (US-DAPT; 3 months or less) are the increased risk of major bleedings caused by DAPT and the improved safety profile of the latest generation DES,which reduces the risks for late and very late stent thrombosis (ST).19 To date, eight trials have investigated S-DAPT (n=6) or US-DAPT (n=2) and compared these to 12 months of therapy (Table 1). All trials demonstrated S-DAPT or US-DAPT to be non-inferior to 12 months of therapy in a comparison of primary composite outcomes (Table 2).20–27 When interpreting the evidence, several aspects should be kept in mind. First, most trials investigating S-DAPT or US-DAPT had a non-inferiority design. Accompanying non-inferiority margins range from 2 % in three trials to up to 4 %,which is rather wide to conclude non-inferiority.20,22–25 Second, the trials were not powered for individual endpoints like ST, but for composite primary endpoints, which were differently composed, complicating interpretation and compatibility. For example, three trials did not include major bleeding in the primary endpoint.20,21,24 Patient selection is the third and probably most important consideration when interpreting different trials. Most trials included a variety of patient groups or at least combined people with stable coronary artery disease and ACS, thereby limiting translation to individual patients. Two trials investigating S-DAPT had stricter inclusion criteria, including only patients

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Towards Tailored Dual Antiplatelet Therapy Table 2: Results of Major Studies Investigating Short Dual Antiplatelet Therapy Study (year)

Effect

Primary

estimate

endpoint

All-cause death

RESET (2012)25

RD (95 % CI)

0.0 % (−2.5–2.5)

−0.5 % (−1.4–0.4)

−0.2 % (−0.7–0.3)

OPTIMIZE (2013)27

HR (95 % CI)

1.03 (0.77–1.38)

0.95 (0.63–1.45)

1.17 (0.77–1.76)

ST (definite or

Stroke

Major bleeding

−0.1 % (−0.5–0.3)

0.1 % (−0.1–1.0)

−0.4 % (−0.9–0.1)

1.08 (0.49–2.36)

0.99 (0.29–3.44)

0.71 (0.32–1.60)

probable)

HR (95 % CI)

1.14 (0.70–1.86)

0.57 (0.17–1.95)

1.86 (0.74–4.67)

6.02 (0.72–49.96)

0.60 (0.14–2.51)

0.50 (0.09–2.73)

SECURITY (2015)23

RD (95 % CI)

0.8 % (−2.4–1.7)

−0.1 % (−0.7–0.5)

0.2 % (−1.2–1.7)

−0.1 % (−0.7–0.4)

0.6 % (−0.2–1.3)

−0.5 (−1.4–0.4)

ISAR-SAFE (2015)22

HR (95 % CI)

0.91 (0.55–1.50)

0.66 (0.27–1.63)

0.93 (0.44–1.97)

1.25 (0.33–4.65)

1.40 (0.44–4.41)

0.80 (0.21–2.98)

I-LOVE-IT 2 (2016)

Cumulative incidence, log-rank p-value

7.2 % versus 6.4 % p=0.53

1.1 % versus 1.4 % p=0.57

4.4 % versus 3.9 % p=0.53

0.6 % versus 0.2 % p=0.25

1.2 % versus 1.4 % p=0.71

1.2 % versus 0.7 % p=0.21

IVUS-XPL (2016)26

HR (95 % CI)

1.07 (0.52–2.22)

0.50 (0.17–1.45)

N/A

1.00 (0.14–7.11)

2.00 (0.50–7.99)

0.71 (0.23–2.25)

SMART-DATE (2018)20

HR (95 % CI)

1.13 (0.79–1.62)

0.9 (0.57–1.42)

2.41 (1.15–5.05)

1.5 (0.68–3.35)

0.92 (0.41–20.8)

0.6 (0.22–1.65)

NIPPON (2017)

EXCELLENT (2012)

RD (95 % CI)

−0.6 % (−1.5–0.3)

−0.5 (−1.2–0.0)

−0.2 (−0.6–0.1)

−0.1 (−0.4–0.2)

−0.1 (−0.6–0.4)

0.1 % (−0.6–0.7)

PRODIGY (2012)34

HR (95 % CI)

0.98 (0.74–1.29)

1.00 (0.72–1.40)

1.06 (0.69–1.63)

1.15 (0.55–2.41)

0.60 (0.29–1.23)

0.56 (0.32–0.98)

ITALIC (2017)36

HR (95 % CI)

0.94 (0.58–1.52)

0.55 (0.26–1.15)

1.34 (0.56–3.17)

2.00 (0.50–7.98)

0.85 (0.29–2.53)

N/A

Abbreviations: N/A = not available; RD = risk difference; ST = stent thrombosis. Study acronyms: EXCELLENT = Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting; I–LOVE–IT 2 = Evaluate Safety and Effectiveness of the Tivoli DES and the Firebird DES for Treatment of Coronary Revascularization; ISAR–SAFE = Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC = Is There a Life for DES After Discontinuation of Clopidogrel; IVUS–XPL = Impact of Intravascular Ultrasound Guidance on Outcomes of XIENCE PRIME Stents in Long Lesions; NIPPON = Nobori Dual Antiplatelet Therapy as Appropriate Duration; OPTIMIZE = Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice; PRODIGY = Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study; RESET = REal Safety and Efficacy of 3–month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation; SMART–DATE = Smart Angioplasty Research Team: Safety of 6– month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndromes; SECURITY = Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy.

with stable angina, silent ischemia or unstable angina or studied only those with biomarker positive ACS.20,23 Overall, mostly patients with a relatively low ischemic risk (stable coronary artery disease or biomarker negative ACS) were included in the majority of these trials. Finally, trials used homogeneous and different bleeding endpoint criteria, which complicates the interpretation of results. Multiple meta-analyses have attempted to compare the outcomes of trials investigating S-DAPT.28–33 The results of these meta-analyses are consistent and none of them show a difference in mortality. Importantly, the risks for ST, MI and stroke were not increased in the S-DAPT arm, while an increased risk for major bleeding events was observed with 12 months’ treatment. Three trials compared S-DAPT to prolonged DAPT (>12 months of treatment).34–36 Two trials concluded S-DAPT to be non-inferior to prolonged DAPT, and one trial noted a trend of more complications in the arm who were treated for 24 months.35,36 The only trial powered for superiority did not find 24 months of therapy to be superior to S-DAPT, but did notice a significant increase in BARC 3 or 5 bleeding events (HR 0.56, 95 % CI [0.32–0.98], p=0.037).34 It seems likely that S-DAPT may be beneficial to selected patients with a high risk of bleeding. Major bleeding events are an important complication because of the association between major bleedis and a poor prognosis,in addition to the negative impact these events have on a patient’s quality of life.37 Notably, a recent individual patient data meta-analysis found an association between bleeding-related deaths and DAPT duration after PCI.38 More specifically, S-DAPT was associated with a reduction of bleeding-related deaths compared to long DAPT (L-DAPT; 12 months of treatment) and prolonged DAPT. When interpreting these

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results, it is important to address the definition used for bleeding-related death, where death was considered to be possibly bleeding related if occurring within 1 year of the bleeding episode, which is a rather liberal definition, leading to an overestimated result. On the other hand, most patients were treated with clopidogrel. With the availability of more potent P2Y12 inhibitors in current practice, the effects on bleeding events or even mortality in these trials may be underestimated. Of course, causality cannot be established, but the impact of bleeding should not be underestimated. More studies have found bleedings associated with an increased risk of recurrent bleeding and all-cause mortality.39,40

Evidence on Prolonged Duration of Dual Antiplatelet Therapy To date, four trials compared prolonged DAPT (>12 months of treatment) to a standard regimen of DAPT (12 months of treatment).41–44 The trials’ characteristics are shown in Table 3, and the main results are summarized in Table 4. The Dual Antiplatelet Trial (DAPT) is the largest study and was powered for superiority for the primary endpoints of definite or probable ST and a composite endpoint of death, MI and stroke.41 For both ST (definite and probable) and the composite primary endpoint, a significant decrease was found when prolonging DAPT (ST: HR 0.29, 95 % CI [0.17–0.48], p<0.001, composite endpoint: HR 0.71, 95 % CI [0.59– 0.85], p<0.001). Notably, all-cause deaths were higher in the prolonged DAPT arm (HR 1.36, 95 % CI [1.00–1.85], p=0.05), as a result of to the larger occurrence of non-cardiovascular deaths in the prolonged DAPT arm (HR 2.23, 95 % CI [1.32–3.78], p=0.002). This difference in mortality was explained by a between-group imbalance of patients diagnosed with cancer. Not surprisingly, prolonged DAPT caused an increase in bleeding complications (HR 1.61, 95 % CI [1.21–2.16], p=0.001). In their individual patient data analysis, Palmerini et al.38 observed numerically more bleeding-related deaths in the DAPT trial.

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Interventional Cardiology Table 3: Characteristics of Major Studies Investigating Long Dual Antiplatelet Therapy Study (year)

Size (n)

ARCTIC (2014)43 DAPT (2014)41 DESLATE (2014)

OPTIDUAL (2016)44

Standard

L–DAPT

DAPT (months)

(months)

2440

18–30

9961

5045 1799

Design

Time of

ACS

randomisation

(%)

Primary endpoint

Bleeding criteria

Superiority

12 months after index

All-cause death, MI, ST, stroke, revascularization

STEEPLE

Superiority

12 months after index

ST and death, MI, stroke

BARC and GUSTO

Superiority

12 months after index

Cardiac death, MI, stroke

TIMI

Superiority

12 months after index

All-cause death, MI, stroke major bleeding

ISTH

ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; GUSTO = Global Use of Strategies to Open Occluded Arteries; ISTH = International Society on Thrombosis and Haemostasis; L–DAPT = long dual antiplatelet therapy; S–DAPT = short dual antiplatelet therapy; ST = stent thrombosis; STEEPLE = Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients: an International Randomized Evaluation; TIMI = Thrombolysis In MI. Study acronyms: ARCTIC = Assessment by a double Randomisation of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting; DAPT = Dual Antiplatelet Therapy; DES–LATE = Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary Arterial Thrombotic Event; OPTIDUAL = OPTImal DUAL Antiplatelet Therapy.

Table 4: Results of Major Studies Investigating Long Dual Antiplatelet Therapy Study (year)

Effect estimate

Primary

All-cause death

endpoint

ST (definite or

Stroke

Major bleeding

probable)

ARCTIC (2014)43

HR (95 % CI)

0.94 (0.66–1.35)

0.71 (0.45–1.10)

1.43 (0.80–2.58)

1.59 (0.61–4.09)

1.01 (0.55–1.85)

0.71 (0.42–1.20)

DAPT (2014)

HR (95 % CI)

0.71 (0.59–0.85)

1.36 (1.00–1.85)

0.47 (0.37–0.61)

0.29 (0.17–0.48)

0.68 (0.40–1.17)

*RD 1.0 % (0.4–1.5)

DESLATE (2014)42

HR (95 % CI)

1.17 (0.68–2.03)

1.32 (0.49–3.55)

1.04 (0.41–2.62)

N/A

0.69 (0.19–2.44)

0.15 (0.02–1.20)

OPTIDUAL (2016)44

HR (95 % CI)

0.75 (0.50–1.28)

0.65 (0.34–1.22)

0.67 (0.31–2.18)

2.97 (0.31–28.53)

0.69 (0.22–2.18)

0.98 (0.47–2.05)

*Major bleedings reported as risk difference. N/A = not available; RD = risk difference; ST = stent thrombosis. Study acronyms: ARCTIC = Assessment by a double Randomisation of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption versus Continuation 1 year after stenting; DAPT = Dual Antiplatelet Therapy; DES–LATE = Optimal Duration of Clopidogrel Therapy With DES to Reduce Late Coronary Arterial Thrombotic Event; OPTIDUAL = OPTImal DUAL Antiplatelet Therapy.

The Assessment by a double Randomization of a Conventional antiplatelet strategy versus a monitoring-guided strategy for drugeluting stent implantation and of Treatment Interruption versus Continuation 1 year after stenting (ARCTIC)-Interruption trial did not find a difference in the composite primary endpoint (death, MI, ST, stroke or transient ischemic attack, and urgent revascularization).43 However, it should be emphasized that this study was prematurely terminated, and the event rates were lower than anticipated. The prolonged DAPT arm did, however, show a significant increase in STEEPLE (Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients: An International Randomized Evaluation) bleeding (HR 0.26, 95 % CI [0.07–0.91], p=0.04). Therefore, the ARCTIC-Interruption authors concluded that prolonging DAPT has no apparent benefit and could harm patients. Both the Optimal Duration of Clopidogrel Therapy with DES to Reduce Late Coronary Arterial Thrombotic Event (DES-LATE) trial and the OPTImal DUAL Antiplatelet Therapy (OPTIDUAL) trial did not observe any potential harm from prolonging DAPT nor a beneficial effect.42,44 This is explained by the fact that these studies were powered to detect major differences only. Several meta-analyses have combined these trials. The results for all-cause death and cardiac death are conflicting. 29,30,32,33,45 One showed prolonged DAPT reduced cardiac death,while another indicated non-cardiac death to be increased by prolonged DAPT.29,45 Evidence also showed prolonged DAPT reduced ischemic events at the cost of more major bleedings.29,30,32,33,45 Patients with a high ischemic burden are most likely to benefit from prolonged DAPT or maybe even life-long DAPT.

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Patient-tailored Duration of Dual Antiplatelet Therapy The European Society of Cardiology’s focused update on DAPT3 states that the use of risk scores to guide DAPT duration may be considered (class IIB recommendation). Multiple risk scores to assess a patient’s ischemic or bleeding risk have been proposed: the DAPT score,the PARIS registry risk scores, PRECISE-DAPT, and CREDO-Kyoto (Tables 5–7 and Figure 1).46–49 The first risk assessment tool was the DAPT score,which was derived from the DAPT trial to aid clinical decision-making regarding DAPT duration.46 This score aims to predict who would benefit from prolonged DAPT at 12 months after PCI after an event-free period of 12 months. Including eight variables (age, smoking, diabetes, MI at presentation, prior PCI or MI, paclitaxel-eluting stent, stent diameter, chronic heart failure and vein graft stent), the score ranges from −2 to 10. Any score below 2 is associated with a bleeding risk that exceeds ischemic risk, indicating DAPT cessation at 12 months. High scores (≥2) are associated with an increased ischemic risk, leading to an increased net clinical benefit from continuing DAPT treatment. Important limitations of the DAPT score are: a limited external validity because it is derived from the DAPT study cohort, which included ischemic patients and those who were bleeding event free after 12 months; and the reduced effect when correcting for paclitaxel-eluting stents, which are no longer used. The PARIS registry risk scores are two scores to predict bleeding and ischemic risk after PCI.47 The ischemic score is composed solely of clinical characteristics (diabetes, ACS type, smoking, creatinine clearance, prior PCI, and prior coronary artery bypass graft), although procedural and

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Towards Tailored Dual Antiplatelet Therapy Table 5: Duration of Dual Antiplatelet Therapy Risk Score Parameter

Score

Age (years)

Table 6: PARIS Risk Scores PARIS ischemic risk score

PARIS bleeding risk score

Parameter

≥75

−2

65 to <75

−1

Score

Diabetes

Parameter

Score

Age (years)

None

<50

Type 2 diabetes

50–59

Type 1 diabetes

60–69

Acute coronary syndrome

MI at presentation

Prior PCI or prior MI

Paclitaxel-eluting stent Stent diameter <3 mm CHF or LVEF <30 %

Vein graft stent

Yes

<65

Cigarette smoking Diabetes

70–79

≥80

Yes, troponin negative

BMI, kg/m2

Yes, troponin positive

<25

Current smoking

25–34.9

≥35

Current smoking

Total score range: −2–10 CHF = congestive heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention.

CrCl <60ml/min

The CREDO-Kyoto risk scores aim to assess thrombotic and bleeding risks using two scores: an eight-item ischemic risk score and a seven-item bleeding risk score.49 Four parameters are included in both scores. This raises questions about clinical applicability, as patients with a high ischemic score are likely to have an increased bleeding score too, leaving the question whether to prolong or shorten DAPT duration unanswered. Unlike other scoring systems, in CREDO-Kyoto, the procedural parameters were tested and included chronic total occlusion in the final ischemic score. In the first validation studies, the DAPT score was retrospectively replicated in the PRODIGY study, but failed to discriminate the risk on bleeding and ischemic events using data from the ISAR-SAFE cohort.51,52 Hereafter, both the DAPT score and PARIS registry scores were retrospectively validated and compared in a Chinese population (n=5,709).53 Only the DAPT score showed modest accuracy for predicting major bleedings. Both scores showed poor discriminative capacity predicting ischemic events. Therefore, the DAPT score and risk scores from PARIS may not be applicable in a Chinese population. In the Spanish

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Absent

Yes

Anemia Absent

Present

Yes

CrCl <60ml/min Absent

Present

Yes

Triple therapy on discharge

Prior CABG

Total score range: 0–12

The PRECISE-DAPT score was developed as a standardized tool to weight bleeding risk before selecting DAPT treatment duration and aims to predict out-of-hospital bleeding events with a five-item score. The external validation in two validation cohorts (PLATelet inhibition and patient Outcomes [PLATO] and the BernPCI registry) indicated replicable moderate discriminative ability. Its clinical utility is, however, lower than those of other risk scores since the score is primarily based on laboratory results.48

Present Prior PCI

angiographic characteristics also influence patients’ ischemic risk.50 The bleeding score includes age, BMI, smoking, anemia, creatinine clearance and triple therapy. Smoking and reduced creatinine increase a patient’s ischemic risk as well as bleeding risk, according to the derivation cohort. Retrospective validation of the PARIS risk scores using data from the platelet reactivity and clinical outcomes after coronary artery implantation of DES (ADAPT-DES) registry resulted in moderate discrimination of both the thrombotic and bleeding risk scores.

Yes

Total score range: 0–15

CrCl = creatinine clearance; CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention.

Table 7: CREDO-Kyoto Risk Scores CREDO ischemic risk score

CREDO bleeding risk score

Parameter

Score

Parameter

Score

Severe chronic kidney disease

Platelet count <100/ml

Severe chronic kidney disease

Peripheral vascular disease

Anemia

Heart failure

Age ≥75 years

Prior MI

Heart failure

Malignancy

Diabetes

Chronic total occlusion

Total score range: 0–12

Total score range: 0–11

CardioCHUVI (Cardiologia del Complejo Hospitalario Universitario de Vigo) cohort (n=1,926),PARIS bleeding score and PRECISE-DAPT score were retrospectively validated.54 For major bleedings, PARIS and PRECISE-DAPT showed a moderate discriminative power and, using decision curve analyses, it was concluded that the PARIS bleeding score had a superior performance. Recently, the DAPT score was successfully validated in a pooled Japanese cohort (n=12,223).55 One year after PCI, the DAPT

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Interventional Cardiology Clinical Perspectives and Future Research

Figure 1: PRECISE–DAPT Score Bleeding score 0

Points ≥12.0

11.5

11.0

10.5

≤10.0

Hemoglobin (g/dl) ≤5

≥20

White blood cell count (x10 cells/µl) ≤50

≥90

Age (years) ≥100

Creatinine clearance (ml/min) No

Yes Previous bleed

score successfully stratified ischemic and bleeding risks. However, the investigators observed low ischemic event rates in patients with a high DAPT score. Therefore, questions remain over the clinical utility of the score and the benefit of prolonging DAPT treatment. Last, in a nationwide Swedish registry (n=41,101) the DAPT score had poor discriminative capacity for ischemic events and did not discriminate bleeding risk.35 Results of these validation studies are conflicting, but differences between the validation cohorts need to be taken into account. Cohort size and geographical background in particular may differ substantially between derivation cohorts.

almerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis P with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 2012;379:1393– 402. https://doi.org/10.1016/S0140-6736(12)60324-9; PMID: 22445239. 2. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226–35. https://doi.org/10.1056/NEJMoa1002358; PMID: 21247313. 3. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2017;39:213–60. https://doi.org/10.1093/eurheartj/ehx419; PMID: 28886622. 4. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082–115. https://doi.org/10.1016/j.jacc.2016.03.513; PMID: 27036918. 5. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800. https://doi.org/10.1056/NEJMoa1500857; PMID: 25773268. 6. Cuisset T, Verheugt FWA, Mauri L. Update on antithrombotic therapy after percutaneous coronary revascularisation. Lancet 2017;390:810–20. https://doi.org/10.1016/S0140-6736(17)319360; PMID: 28831996. 7. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013;368:2004–13. https:// doi.org/10.1056/NEJMra1216063; PMID: 23697515. 8. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94. https://doi.org/10.1056/ NEJMra071014; PMID: 18077812. 9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. https://doi.org/10.1056/NEJMoa010746; PMID: 11519503. 10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus

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11.

12.

13.

14.

15.

16.

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18.

Several randomized trials have established the pivotal role of DAPT following PCI for latest-generation DES implantation. Individual assessment of a patient’s risk profile will be essential to optimize DAPT duration. A substantial proportion of patients have stable coronary artery disease. Especially for stable patients with a low ischemic risk profile, the authors believe short durations of DAPT may be beneficial, given the improved safety profile of currently available DES. On the other hand, it seems obvious that patients with a high ischemic risk profile may need prolonged or even lifelong DAPT. Regarding the currently available risk scores, any clinical value they add needs to be determined in a prospective randomized trial. Although the authors believe risk scores are likely to improve in aiding individual patient-tailored DAPT, physicians should acknowledge the limitations of existing risk scores, and fully assess the patient’s risk profile and coronary angiographic characteristics. Since optimal durations of DAPT have been investigated for more than a decade, many clinicians believe simplification may be required regarding pharmacotherapy after PCI. Future research may examine de-escalation of DAPT. For example, the ongoing Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT) study (NCT02270242) challenges the concept of DAPT as ticagrelor monotherapy for long-term platelet inhibition in a broad population of patients undergoing PCI with DES. As the latest-generation DES with enhanced safety profiles are likely to reduce adverse events even further, a paradigm shift to de-escalation of DAPT should be evaluated in future dedicated trials.

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36.

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38.

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43.

44.

45.

drug-eluting stent implantation. JACC Cardiovasc Interv 2017;10:1189–98. https://doi.org/10.1016/j.jcin.2017.04.019; PMID: 28641838. Didier R, Morice MC, Barragan P, et al. 6– versus 24–month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: final results of the ITALIC Trial (Is There a Life for DES After Discontinuation of Clopidogrel). JACC Cardiovasc Interv 2017;10:1202–10. https://doi.org/10.1016/j. jcin.2017.03.049; PMID: 28641840. Genereux P, Giustino G, Witzenbichler B, et al. Incidence, predictors, and impact of post-discharge bleeding after percutaneous coronary intervention. J Am Coll Cardiol 2015;66:1036–45. https://doi.org/10.1016/j.jacc.2015.06.1323; PMID: 26314532. Palmerini T, Bacchi Reggiani L, Della Riva D, et al. bleedingrelated deaths in relation to the duration of dual-antiplatelet therapy after coronary stenting. J Am Coll Cardiol 2017;69:2011–22. https://doi.org/10.1016/j.jacc.2017.02.029; PMID: 28427576. Rao SV, Dai D, Subherwal S, et al. Association between periprocedural bleeding and long-term outcomes following percutaneous coronary intervention in older patients. JACC Cardiovasc Interv 2012;5:958–65. https://doi.org/10.1016/j. jcin.2012.05.010; PMID: 22995883. Kwok CS, Khan MA, Rao SV, et al. Access and non-access site bleeding after percutaneous coronary intervention and risk of subsequent mortality and major adverse cardiovascular events: systematic review and meta-analysis. Circ Cardiovasc Interv 2015;8: e001645. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.001645; PMID: 25825007. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–66. https://doi.org/10.1056/NEJMoa1409312; PMID: 25399658. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014;129:304–12. https:// doi.org/10.1161/CIRCULATIONAHA.113.003303; PMID: 24097439. Collet J-P, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC– Interruption): a randomised trial. Lancet 2014;384:1577–85. https:// doi.org/10.1016/S0140-6736(14)60612-7; PMID: 25037988. Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J 2016;37:365–74. https:// doi.org/10.1093/eurheartj/ehv481; PMID: 26364288. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016;37:390–9. https://doi.org/10.1093/eurheartj/ehv443; PMID:

26324537. 46. Y eh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735–49. https://doi.org/10.1001/ jama.2016.3775; PMID: 27022822. 47. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol 2016;67:2224–34. https://doi.org/10.1016/j.jacc.2016.02.064; PMID: 27079334. 48. Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE–DAPT) score: a pooled analysis of individualpatient datasets from clinical trials. Lancet. 2017;389:1025–34. https://doi.org/10.1016/S0140-6736(17)30397-5; PMID: 28290994. 49. Natsuaki M, Morimoto T, Yamaji K, et al. Prediction of thrombotic and bleeding events after percutaneous coronary intervention: CREDO-Kyoto Thrombotic and Bleeding Risk Scores. J Am Heart Assoc 2018;7:e008708. https://doi.org/10.1161/JAHA.118.008708; PMID: 29789335. 50. Dangas GD, Claessen BE, Mehran R, et al. Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes. JACC Cardiovasc Interv 2012;5:1097– 105. https://doi.org/10.1016/j.jcin.2012.07.012; PMID:23174632. 51. Piccolo R, Gargiulo G, Franzone A, et al. Use of the dualantiplatelet therapy score to guide treatment duration after percutaneous coronary intervention. Ann Intern Med 2017;167:17– 25. https://doi.org/10.7326/M16-2389; PMID: 28605779. 52. Harada Y, Michel J, Lohaus R, et al. Validation of the DAPT score in patients randomized to 6 or 12 months clopidogrel after predominantly second-generation drug-eluting stents. Thromb Haemost 2017;117:1989–99. https://doi.org/10.1160/TH17-020101; PMID: 28783201. 53. Song L, Guan C, Yan H, et al. Validation of contemporary risk scores in predicting coronary thrombotic events and major bleeding in patients with acute coronary syndrome after drug-eluting stent implantations. Catheter Cardiovasc Interv 2018;91(S1):573–81. https://doi.org/10.1002/ccd.27468; PMID: 29322612. 54. Abu-Assi E, Raposeiras-Roubin S, Cobas-Paz R, et al. Assessing the performance of the PRECISE-DAPT and PARIS risk scores for predicting one-year out-of-hospital bleeding in acute coronary syndrome patients. EuroIntervention 2018;13:1914–22. https://doi.org/10.4244/EIJ-D-17-00550; PMID: 29131804. 55. Yoshikawa Y, Shiomi H, Watanabe H, et al. Validating utility of dual antiplatelet therapy score in a large pooled cohort from 3 Japanese percutaneous coronary intervention studies. Circulation 2018;137:551–62. https://doi.org/10.1161/ CIRCULATIONAHA.117.028924; PMID: 28982692.

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Interventional Cardiology

Coronary Bioresorbable Scaffolds in Interventional Cardiology: Lessons Learnt and Future Perspectives Bill Gogas, MD, PhD, FACC, Jun-Jie Zhang, MD, FSCAI, and Shao-Liang Chen, MD, PhD, FACC, FSCAI Nanjing First Hospital, Nanjing Medical University, Jiangsu Province, Nanjing, China

Abstract Polymer- and magnesium-based bioresorbable scaffolds were developed with the intention of restoring a functionally intact arterial wall following the scaffold’s biodegradation, avoiding the limitations of coronary stenting associated with persistent vasomotor dysfunction and sustained inflammation leading to in-stent neo-atherosclerosis. Although initial experimental observations encouraged the development of first-in-man registries and the execution of larger randomized trials, clinical results from treating relatively non-complex lesions with these technologies failed to demonstrate any incremental benefit. Furthermore, the significantly higher rates of scaffold thrombosis with the current generation scaffolds led to existing polymer-based technologies being withdrawn from the US clinical market. This article provides an overview of the preclinical and clinical lessons learnt from the recently conducted ABSORB trials using the first-generation Absorb bioresorbable vascular scaffold (Abbott Vascular), which is the most investigated coronary scaffold in clinical trials, and reflects on whether these technologies are a viable alternative to contemporary metal stents for coronary revascularization.

Keywords Coronary bioresorbable scaffolds, mechanisms of failure, target lesion failure, scaffold thrombosis, stents Disclosure: The authors have no conflicts of interest to declare. Submitted: July 14, 2018 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;12(2):98–102. DOI: https://doi.org/10.15420/usc.2018.11.1 Correspondence: Bill D Gogas, Division of Cardiology, Interventional Cardiology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China. E: bill.d.gogas@outlook.com

The current generation of drug-eluting stents (DES) that are clinically available in the US represent significant advancements compared to angioplasty, bare metal stents, and the first generation of DES. The Xience everolimus-eluting stents (Abbott Vascular), Promus everolimus-eluting stents (Boston Scientific) and Resolute zotarolimuseluting stents (Medtronic) demonstrate the optimal balance of safety and efficacy. More recently, the SYNERGY platinum-chromium everolimus-eluting stent, a thin strut platform with bioresorbable polylactide-co-glycolide polymer, became clinically available and shows significantly lower rates of stent thrombosis than other durable polymer DESs. Despite these advances, the durable metallic platform and/or permanent polymer coating that remains in the arterial wall induces persistent vasomotor dysfunction and sustained inflammation enabling the development of in-stent neo-atherosclerosis.1 Phenotypic (anatomic and physiologic) as well as genotypic (gene expression) arterial restoration over the course of scaffold’s biodegradation have been described in porcine coronary arterial segments, with translational implications of transforming coronary angioplasty with contemporary stenting to coronary angioplasticity with a bioresorbable scaffold (BRS, Figure 1).2 However, evidence from large-scale randomized trials and metaanalyses has highlighted the lack of any incremental benefit with firstgeneration BRS for coronary revascularisation due to significantly higher rates of target lesion failure (TLF) and scaffold thrombosis (ScT).3

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This article gives an overview of the preclinical/clinical mismatch observed with current generation BRS and expands on the mechanisms of failure of the first-generation ABSORB bioresorbable vascular scaffold (BVS) that led the technology being withdrawn. It discusses the evolving innovations needed to develop scaffolds with more biocompatible physical properties that, under optimal deployment techniques, will provide a suitable alternative to metal stents for coronary revascularisation.

Mismatch Between Experimental and Clinical Observations Large animals are the standard experimental models for the preclinical assessment of safety and efficacy of coronary stents. BRS such as the first-generation BVS underwent extensive translational in vivo and ex vivo testing with angiographic, invasive imaging and genetic evaluation at different time points over periods of up to 4 years. The most remarkable example of experimental/clinical mismatch was the discordance in vasomotor responses of non-atherosclerotic porcine coronary arteries and human arterial segments treated with either the ABSORB BVS or Xience V stent. The gradual loss of the scaffold’s mechanical integrity at 1 and 2 years was associated with restoration of the vasomotor responses (constrictive and expansive) following vasomotor challenge with endothelial and non-endothelial dependent agents in large animals.4 In contrast, evidence derived from the

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Coronary Bioresorbable Scaffolds Figure 1: Chronologic Insights From the Absorb BVS Translational Assessment in Healthy Porcine Coronary Arteries Up to 4 Years Strut coverage is delayed in segments treated with overlapping Absorb scaffolds

Lumen and vessel enlargement initiation Scaffold’s strut core sites remain acellular

Scaffold’s strut core sites have ‘preserved box’ appearance and polymer is being replaced by matrix

Light intensity of strut core sites surges due to gradual cellularisation by connective tissue

Thinning of vessel wall attributed to late lumen enlargement Restored vasomotor function of Absorbtreated segments

90 days

1 year

2 years

3 years

4 years

Strut coverage is comparable among segments treated with overlapping Absorb scaffolds and metallic stents

Restored vasomotor function of Absorbtreated segments Restored pulsatility of Absorb-treated segments

Gene levels of Cx43 are increased in Absorb-treated arterial segments

The Absorb BVS is completely degraded Late lumen enlargement

Resorption sites have >50 % of collegen-rich tissue fully integrated in the vessel wall

28 days

Reproduced from Gogas and Samady, 2016,2 with permission from Elsevier.

ABSORB II randomized clinical trial, where non-endothelial dependent vasoreactivity was investigated, demonstrated greater expansive responses in the cohort treated with a metallic stent at 3 years.5 It has been specualted that the greater interstrut distance of metallic stent rings or late metal strut malapposition associated with expansive remodelling may be the most relevant mechanisms behind this mismatch. Although there was no direct impact on clinical outcomes, this finding certainly raised concerns as to whether vascular restoration occurs in the clinical setting. The clinical observations related to novel modes of failure with the Absorb BVS that were not observed during animal testing, involving late intraluminal scaffold dismantling and scaffold discontinuity, raised questions over the validity of non-atherosclerotic large animals as suitable models for assessing the safety and efficacy of these technologies. In non-atherosclerotic coronary arteries, the absence of atherosclerotic plaque at the selected site of stent/scaffold deployment eliminates the need for optimal lesion pre-dilatation; and stent deployment requires a stent/artery ratio of at least 1.1:1 to avoid device dislodgement as opposed to the 1:1 stent/artery ratio in the clinical setting. The critical components of optimal lesion preparation (P), 1:1 stent sizing (S) and mandatory pre-dilatation, which improve clinical endpoints when properly applied in the clinical setting, have little significance in the preclinical stage. Despite these fundamental differences, large animals remain the gold standard for phase I testing of interventional devices.

Inferior Safety with First Generation Absorb Bioresorbable Vascular Scaffold Concerning signs of increased rates of ScT with first generation BVS were initially reported in real-world registries such as the GHOST-EU registry and selected case reports, and were confirmed when the AIDA randomized trial was published.7 In this study, 1,845 patients undergoing PCI were randomized to either the first generation BVS (n=924) or contemporary metallic stents (n=921). The trial was halted and reported

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at an early stage because of safety concerns related to the threefold increase in the risk of definite or probable ScT over 2 years. Similarly, cumulative evidence from small registries with intracoronary imaging follow-up consistently reported the presence of novel mechanisms of scaffold failure leading to ScT. Furthermore, in a recent network meta-analysis where the authors analyzed 105,842 patients who had undergone implantation of metallic stents or BRS from 91 randomized trials after a mean follow-up of 3.7 years, ScT rates were consistently and significantly higher in the early (≤30 days), late (31 days–1 year) and very late (>1 year) time points after BVS deployment with the trend increasing after the first year (Figure 2).3 A combination of etiologic factors involving the scaffold’s bulky and nonstreamlined strut design, suboptimal deployment techniques and novel modes of scaffold failure were the leading safety problems that caused the technology to be withdrawn. An examination of these mechanisms of failure below would enable optimal design iteration of the next generation scaffolds with more biocompatible profiles. This should lead to non-inferior clinical outcomes when compared with contemporary DESs.

Non-Streamlined and Bulky Strut Design The bulky strut design of the first-generation scaffolds such as the ABSORB BVS induced solid- and fluid-mechanical alterations after deployment, leading to excessive mechanical loading over the arterial circumference and recirculation zones around the strut surface (Figure 3).8 Mechanical stretch is sensed by mechanoreceptors such as stretchactivated channels and integrins, enabling the activation of downstream signaling pathways, which promote inflammation, apoptosis and angiogenesis.9,10 Although mechanical loading over the arterial circumference is temporary and declines dramatically 6 months after BRS deployment as opposed to the permanent stretch induced by metallic stents, the combination of increased circumferential stress and

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Interventional Cardiology Figure 2: Forest Plot of Definite and Probable ScT at Early, Late and Very Late Time Points From the ABSORB Trials Definite or Probable ScT BVS

CoCr–EES

Odds ratios (95 % CI) for stent thrombosis

Events

Total

Events

Total

ABSORB II

335

166

2.50 (0.12–52.3)

ABSORB Japan

265

133

1.52 (0.16–14.7)

ABSORB China

238

237

3.00 (0.12–74.0)

ABSORB–STEMI TROFI II

3.06 (0.12–76.2)

ABSORB III

1,322

686

1.46 (0.52–4.06)

AIDA

924

921

2.61 (0.93–7.36)

Overall (fixed)

3,179

2,239

2.01 (1.05–3.85)

0.034

2.00 (1.05–3.82)

0.036

Early ST

(random) 2

Heterogeneity: I =0 %, τ =0, p=0.975

Late ST ABSORB II

335

166

1.49 (0.06–36.9)

ABSORB Japan

265

133

0.50 (0.03–8.06)

ABSORB China

238

237

ABSORB–STEMI TROFI II

ABSORB III

1,322

686

6.78 (0.38–121)

AIDA

924

921

8.03 (1.00–64.4)

3,179

2,239

3.87 (1.15–13.0)

0.029

3.13 (0.93–11.8)

0.092

Overall (fixed) (random)

Heterogeneity: I2=1.3 %, τ2=0.025, p=0.386

Very late ST ABSORB II

335

166

6.57 (0.37–117)

ABSORB Japan

265

133

5.64 (0.31–103)

ABSORB China

238

237

3.00 (0.12–74.0)

ABSORB–STEMI TROFI II

1.01 (0.06–16.4)

1,322

686

11.0 (0.64–188)

ABSORB III AIDA

924

921

5.03 (1.10–23.0)

Overall (fixed)

3,179

2,239

5.09 (1.94–13.3)

<0.001

4.50 (1.67–12.1)

0.003

3.59 (2.11–6.09)

<0.001

3.49 (2.05–5.93)

<0.001

(random) 2

Heterogeneity: I =0 %, τ =0, p=0.887

Overall ST (all studies) 83

Fixed effects model

3,179

2,239

Random effects model 2

Heterogeneity: I =0 %, τ =0, p=0.948

0.01

0.1 Favors BVS

100

Favors CoCr–EES

Reproduced from Kang et al. 2018, with permission from EuroIntervention. 3

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Coronary Bioresorbable Scaffolds Figure 3: Computational Modelling Derived From Fusion of Angiographic and Optical Coherence Tomographic Acquisitions for the Assessment of Local Fluid Mechanics After Scaffold Deployment 2D angiographic projections Pre

3D OCT derived vessel and Absorb BVS reconstructions post implantation

Post

Proximal (inflow)

3D OCT derived strut level wall shear stress (WSS) assessment following Absorb BVS deployment E1

A2 3D angiographic projections

Pre

Inflow

Post

4 3

E2 B1

Outflow

Distribution of WSS magnitude over the five different strut surfaces

2D OCT post-Absorb BVS implantation

F 5. Outflow strut: 14.5±6.8

4. Outflow ditch: 3.5±3.6

D Distal (outflow) mm

Proximal Distal (outflow) (inflow)

Distal (outflow) 3. Top surface: 70.3±29.7

Proximal (inflow)

2. Infow ditch: 7.7±7.3

1. Inflow strut: 22.3±14.2

dynes/ cm2

Reproduced from Gogas et al. 2016,8 with permission from Elsevier.

low endothelial shear stress induced by the thicker struts triggered the development of greater neointimal hyperplasia and late lumen loss over time compared to contemporary metal DES. Next generation scaffolds have been developed with thinner strut profiles in the range of ~90 μm and a circular rather than rectangular design, potentially eliminating rheological and mechanical issues, which could reduce the development of TLF and ScT.

Suboptimal Deployment Techniques Optimal lesion preparation (P), correct scaffold sizing (S) and proper postdilation (P) are essential for good clinical outcomes. Suboptimal PSP techniques in the acute phase of scaffold deployment, which were not included in the manufacturer’s initial instructions, generated only modest strut embedment in the arterial wall, leading to strut underexpansion or malapposition. The cumulative observations from the ABSORB trials clearly showed that BVS implantation in properly sized vessels was an independent

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predictor of freedom from: TLF for 1 year (HR 0.67; p=0.01) and for 3 years (HR 0.72; p=0.01); and ScT for 1 year (HR 0.36; p=0.004). Aggressive pre-dilatation was an independent predictor of freedom from ScT between 1 and 3 years (HR: 0.44; p=0.03), and optimal postdilatation was an independent predictor of freedom from TLF between 1 and 3 years (HR: 0.55; p=0.05).11

Optical Coherence Tomographic Guidance Optical coherence tomographic (OCT) guidance is essential for vessel sizing and assessment of novel modes of late and very late scaffold failure. Accurate vessel sizing for BVS implantation can be performed only with OCT. Although experienced operators are able to correctly size the vessel by ‘eyeballing’, this approach is significantly subjective. In addition, quantitative coronary angiography consistently underestimates the actual reference vessel diameter (RVD) while intravascular ultrasound slightly overestimates vessel size. Although initial instructions by the manufacturer did not alert operators that they should avoid implantation of BRS in vessels with a RVD of <2.5 mm, it soon became evident that BVS deployment in small vessels led to a fourfold increase

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Interventional Cardiology in the ScT rates. In the ABSORB III trial, BRS deployment in vessels with RVD <2.25 mm measured by quantitative coronary analysis resulted in increased rates of TLF (12.9 % versus 8.3 %) and device thrombosis (4.6 % versus 1.5 %) when compared to metallic DES.11 Although OCT-guided BVS implantation was performed in only a small percentage of cases in the ABSORB trials, future studies using next generation BRS are designed with mandatory OCT-guidance for scaffold deployment. Recently, novel mechanisms of scaffold failure were described with OCT imaging at follow-up, such as scaffold discontinuity associated with late intraluminal scaffold dismantling. Other modes of failure similar to those associated with metallic stents involved malapposition, neoatherosclerosis and scaffold shrinkage which, in aggregate, offset the incremental benefits of using this new technology in interventional cardiology.

ogas BD, McDaniel M, Samady H, King SB 3rd. Novel drugG eluting stents for coronary revascularization. Trends Cardiovasc Med 2014;24:305–13. https://doi.org/10.1016/j.tcm.2014.07.004; PMID: 25240980. Gogas BD, Samady H. Coronary angioplasticity. JACC Cardiovasc Interv 2016;9:852–5. https://doi.org/10.1016/j.jcin.2016.03.002; PMID: 27101911. Kang SH, Gogas BD, Jeon KH, et al. Long-term safety of bioresorbable scaffolds: insights from a network meta-analysis including 91 trials. EuroIntervention 2018;13:1904–13. https://doi. org/10.4244/EIJ-D-17-00646; PMID: 29278353. Gogas BD, Benham JJ, Hsu S, et al. Vasomotor function comparative assessment at 1 and 2 years following implantation of the Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold and the Xience V Everolimus-Eluting Metallic Stent in porcine coronary arteries: insights from in vivo angiography, ex vivo assessment, and gene analysis at the stented/scaffolded segments and the proximal and distal edges. JACC Cardiovasc Interv 2016;9:728–41. https://doi.org/10.1016/j. jcin.2015.12.018; PMID: 27056313.

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Future Perspectives Improved scaffold designs will need to make implantation as user friendly as metal stent implantation, so that they can be inserted not only by the most experienced operators but also by less skilled operators, matching the high bar established by metal DES. The reason to persevere is not because of any expectation that scaffolds can beat metal stents in the intermediate term, but the concern that metal stents may begin to produce significant adverse events many years after implantation. That will have to become a demonstrated reality rather than a hypothetical speculation for BRS to replace metal stents. For the time being, although the ABSORB scaffold has gone, the authors believe that these disappearing technologies will eventually reappear in an improved form; questions remain over whether they will be competitive with current and future coronary stents.12

erruys PW, Chevalier B, Sotomi Y, et al. Comparison of an S everolimus-eluting bioresorbable scaffold with an everolimuseluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, singleblind, multicentre clinical trial. Lancet 2016;388:2479–91. https://doi.org/10.1016/S0140-6736(16)32050-5; PMID:27806897. Capodanno D, Gori T, Nef H, et al. Percutaneous coronary intervention with everolimus-eluting bioresorbable vascular scaffolds in routine clinical practice: early and midterm outcomes from the European multicentre GHOST-EU registry. EuroIntervention 2015;10:1144-53. https://doi.org/10.4244/ EIJY14M07_11; PMID: 25042421. Wykrzykowska JJ, Kraak RP, Hofma SH, et al. Bioresorbable scaffolds versus metallic stents in routine PCI. N Engl J Med 2017;376:2319–28. https://doi.org/10.1056/NEJMoa1614954; PMID: 28402237. Gogas BD, Yang B, Piccinelli M, et al. Novel 3-dimensional vessel and scaffold reconstruction methodology for the assessment of strut-level wall shear stress after deployment of bioresorbable

vascular scaffolds from the ABSORB III Imaging Substudy. JACC Cardiovasc Interv 2016;9:501–3. https://doi.org/10.1016/j. jcin.2016.01.008; PMID: 26965940. 9. Jufri NF, Mohamedali A, Avolio A, Baker MS. Mechanical stretch: physiological and pathological implications for human vascular endothelial cells. Vasc Cell 2015;7:8. https://doi.org/10.1186/ s13221-015-0033-z; PMID: 26388991. 10. Wang PJ, Ferralis N, Conway C, Grossman JC, Edelman ER. Strain-induced accelerated asymmetric spatial degradation of polymeric vascular scaffolds. Proc Natl Acad Sci USA 2018;115:2640-2645. https://doi.org/10.1073/pnas.1716420115; PMID: 29483243. 11. Stone GW, Abizaid A, Onuma Y, et al. Effect of technique on outcomes following bioresorbable vascular scaffold implantation: analysis from the ABSORB Trials. J Am Coll Cardiol 2017;70:2863–74. https://doi.org/10.1016/j.jacc.2017.09.1106; PMID: 29100704. 12. King SB, 3rd, Gogas BD. Can the Vanishing stent reappear?: Fix the technique, or fix the device? J Am Coll Cardiol 2017;70:2875–7. https://doi.org/10.1016/j.jacc.2017.10.009; PMID:29100703.

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Electrophysiology

Gender and AF: Differences and Disparities Naga Venkata Pothineni, MD, and Srikanth Vallurupalli, MD Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR

Abstract AF is the most common clinical arrhythmia encountered. A wealth of evidence has improved our ability to diagnose and effectively treat AF. An intriguing aspect of this common disease – gender-based differences – is well recognized, but poorly understood. In this brief review, we will explore the accumulating evidence suggesting a gender-based disparity in the prevalence, pathogenesis and management of AF.

Keywords AF, stroke, gender differences, health disparities, anticoagulants Disclosure: The authors have no conflicts of interest to declare. Received: December 21, 2017 Accepted: January 12, 2018 Citation: US Cardiology Review 2018;12(2):103–6. DOI: https://doi.org/10.15420/usc.2017:39:1 Correspondence: Naga Venkata Pothineni, 4301 W Markham Street, #532, Little Rock, AR 72205, USA. E: nvpothineni@uams.edu

AF is the most common clinically relevant supraventricular arrhythmia. AF is a leading risk factor for stroke and accounts for about one-third of all ischemic cerebrovascular events.1 The last two decades have witnessed a paradigm shift in the management of AF with the development of catheter ablation and improvements in anticoagulant therapies. In this review, we discuss gender-related differences and disparities in the pathophysiology, clinical presentation, and management of AF.

Gender Differences in the Pathophysiology of AF Men are more susceptible to the development of AF. However, since women live longer than men, the cumulative lifetime risk of AF is similar in men and women, at about 30 %.2 On average, women develop AF 10 years later than men.2 Differences in atrial effective refractory period (ERP) in response to rapid atrial pacing have been reported in men and women. The degree of shortening of atrial ERP was significantly less in premenopausal women compared with postmenopausal women and age-matched men, suggesting the protective role of estrogen.3 In addition, non-pulmonary vein triggers are more frequent in women with AF compared with men.4 More recent evidence points to genetic disparities in ion channel expression between men and women. Ambrosi et al. investigated the mRNA expression of 89 ion channel subunits, calcium handling proteins, and transcription factors important in cardiac conduction and arrhythmogenesis. 5 Gender-specific analysis showed lower expression levels in transcripts encoding for Kv4.3, KChIP2, Kv1.5, and Kir3.1 in the failing female left atrium compared with the male left atrium. Gender differences in autonomic control of the cardiovascular system have been described as well. Sympathetic-mediated responses predominate in men, while women have higher degrees of parasympathetic activation, which has been associated with an increased propensity of AF due to extensive vagal innervation of the atrial muscle sleeves extending into the pulmonary veins.6

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Morphologically, significant gender-based differences in AF-related atrial remodeling have been observed. Fibrotic remodeling of the left atrium leads to electrical dissociation of atrial cells that contributes to higher incidence and recurrence rates of AF. Li et al. analyzed tissue samples from men and women with long-standing, persistent AF and showed that women have a significantly higher degree of fibrotic remodeling compared with men.7 This morphological difference was driven by differential expression of fibrosis-related genes and proteins, such as transforming growth factor-beta, which were upregulated in women with persistent AF. Cochet et al. reported that female gender was independently associated with delayed gadolinium enhancement in patients with AF, as well as in patients with no AF or structural heart disease.8 In a subanalysis of the AF Follow-up Investigation of Rhythm Management (AFFIRM) trial, female gender was significantly associated with higher rates of left atrial remodeling and adverse cardiovascular endpoints.9 Gender modulates how various risk factors contribute to AF.10 Obesity appears to impart a higher risk of AF in men compared with women (hazard ratio [HR] per standard deviation increase 1.18; 95 % CI [1.12– 1.23] in women versus 1.31; 95 % CI [1.25–1.38] in men; Pinteraction<0.001). Women with AF have a lower prevalence of coronary disease and sleep apnea compared with men. However, hypertension and heart failure with preserved ejection fraction are more prevalent in women with AF, likely reflecting the later age of onset.

Gender Differences in the Clinical Presentation of AF Substantial differences in clinical symptomatology of AF exist between men and women. In the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry, women with AF experienced more symptoms and worse quality of life in comparison with men.10 Similarly, in the Euro Observational Research Program on AF (EORP-AF) pilot survey, women

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Electrophysiology experienced a significantly higher rate of palpitations and fear and anxiety compared with men.11 A similar pattern of AF-related symptoms was also reported in the Prevention of Thromboembolic Events European Registry in AF (PREFER in AF) registry. In this analysis of 7,243 patients, 95 % of women with AF were symptomatic compared with 90 % of men.12 In addition to variations in symptomatology, there are important prognostic differences between women and men with AF. A metaanalysis of 30 studies from 1996 to 2015, including >4 million participants, indicated that female gender is an independent risk factor for all-cause and cardiovascular mortality, incident heart failure, and stroke in patients with AF.13 There are significant disparities in AF-related stroke risk, with women experiencing more strokes as well as more disabling strokes compared with men, as discussed below.

Gender Differences in AF Management Rate Control Gender bias is apparent in the choice of medications for rate control of AF. In the ORBIT-AF registry, women were less likely to receive betablocker therapy (62.0 % versus 65.5 %) and were more likely to receive digoxin (24.6 % versus 22.6 %).10 In the EORP-AF registry, use of digoxin as a rate-control agent was significantly more common in women (25 % versus 19.8 %), while there was no difference in prescription rates of betablockers.11 In the Rivaroxaban Once-Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF (ROCKET-AF) trial, digoxin was used in 42 % of female participants compared with 38 % of males, and digoxin use was associated with increased all-cause mortality, vascular death and sudden death.14 Other studies have also revealed an association between digoxin and higher rates of cardiac death.15 In this context, the consistently higher rates of use of digoxin as a rate-control agent is women is concerning. Whether this reflects poor tolerability to commonly used rate-control medications is unknown. Gender-specific differences also appear to exist in the use of nonpharmacological rate-control measures. In the ORBIT-AF registry, women had significantly higher rates of atrioventricular nodal ablation and pacemaker implantation (adjusted HR 1.97; 95 % CI [1.30–2.97]) compared with men over a median follow-up of 2.3 years.10

Rhythm Control Gender differences in rates of prescription of anti-arrhythmic medications for AF have been debated. In the EORP-AF survey, rhythm control was less commonly utilized in women, despite a higher rate of symptomatic AF and lower quality of life. Rates of electrical cardioversion were 18.9 % in women compared to 25.5 % in men.11 In the PREFER in AF observational cohort, women were more likely to receive pharmacological cardioversion while men had higher rates of electrical cardioversion.12 However, in the ORBIT-AF registry, there was no difference in rates of anti-arrhythmic medication use in women compared with men.10 In a nationwide analysis of all in-patient cardioversions in the US, we have previously reported that in-hospital rates of electrical cardioversion were significantly higher in men compared with women (58.4 % versus 48.6 %).16 Rates of AF recurrence following cardioversion have also been reported to be higher in women.17 In this context, it is important to understand that women appear to have a higher risk of side-effects with rhythm-control strategies. Women with

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AF on Class IA and Class III anti-arrhythmic medications have higher rates of torsades de pointes and bradyarrhythmias requiring a pacemaker. In the Fibrillation Registry Assessing Costs, Therapies, Adverse Events, and Lifestyle (FRACTAL) registry, Essebag et al. have reported that female gender was an independent risk factor that determines the need for a pacemaker in patients taking amiodarone for AF.18

Catheter Ablation Catheter ablation has emerged as an important therapeutic strategy in the management of AF. Significant gender disparities in utilization of catheter ablation, in which women are referred late and less frequently for catheter ablation of AF compared with men, have been identified. Women referred for ablation are older, and have larger indexed left atrial dimensions.19 In a nationwide analysis of AF ablation procedures, women were 17 % less likely to undergo catheter ablation compared with men.20 Another analysis of AF care strategies in Medicare beneficiaries demonstrated significantly lower referral rates for catheter ablation in women (HR 0.65; 95 % CI [0.63–0.68]), even after adjusting for multiple confounding variables.21 There is similar under-representation of women in randomized trial data of AF ablation (Table 1). A meta-analysis of all AF ablation clinical trials reported that women constitute only one-fifth of the study population.31 In addition to disparities in utilization, gender-based differences in efficacy and safety of AF ablation also exist. Women suffered from a higher risk of complications after AF ablation in multiple studies. Patel et al. reported that women undergoing catheter ablation more often had persistent AF, a higher proportion of non-pulmonary vein triggers, lower ablation success rates, and significantly higher complication rates, the latter driven primarily by vascular complications.32 In a nationwide analysis of AF ablation complications, overall, women had higher in-hospital complication rates than men (7.51 % versus 5.49 %; p<0.001).33 A more recent study reported that women undergoing AF ablation had a higher risk of vascular-related complications, hemorrhage, and perforation or tamponade, and that overall, women had an increased risk of all-cause hospitalization compared with men (9.4 % versus 8.6 %; p=0.07).34 Various patient-related factors could explain the higher rates of vascular and hemorrhagic complications in women. Female patients tend to have smaller vessel calibers compared with men, which may increase the risk of vascular injury. In AF ablation studies, women have been shown to have higher activated partial thromboplastin times compared with men, even when lower doses of heparin are administered.35 However, although these are interesting hypotheses, the underlying mechanism leading to higher complication rates in women is yet to be deciphered.

Gender Differences in Stroke Risk AF is a well-recognized risk factor for stroke. In a retrospective Swedish AF cohort study of 100,802 patients with AF, female gender was an independent risk factor for stroke (HR 1.18; 95 % CI [1.12–1.24]), even after adjusting for multiple confounding variables.36 As described earlier, women with AF tend to have larger left atrial volumes and reduced atrial contractility compared with men, which can increase the risk of atrial thrombi. Elderly postmenopausal women also have higher rates of diastolic dysfunction and elevated systolic blood pressure compared with men, which can lead to accelerated cardiovascular remodeling and endothelial dysfunction that translates into a higher risk of stroke.37

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Gender and AF Table 1: Representation of Women in Major Randomized Clinical Trials of AF Ablation Authors

Trial

Year

Ablations

Female Participants (n)

Stabile et al.22

CACAF

2003

31 (45.5 %)

Wazni et al.23

RAAFT

2005

Not reported

Oral et al.24

2006

10 (12.9 %)

Pappone et al.25

APAF

2006

30 (30.3 %)

Jais et al.26

2008

8 (15.1 %)

Forleo et al.27

2009

14 (42.9 %)

Wilber et al.28

Thermocool AF

2010

106

33 (31.1 %)

Nielsen et al.29

MANTRA PAF

2012

146

46 (32 %)

Packer et al.30

STOP AF

2013

163

38 (22.3 %)

APAF = Ablation for Paroxysmal AF; CACAF = Catheter Ablation for the Cure of AF; MANTRA PAF = Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal AF; RAAFT = Radiofrequency Ablation versus Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal AF.

Table 2: Gender Differences in Stroke Risk in Anticoagulation Trials of AF Author

Study

Year

Men (n)

Women (n)

Anticoagulant

Stroke Rate (%)

Men Women

Hart et al.42

SPAF

1999

1,853

1,339 (72.3 %)

514 (27.7 %)

Warfarin

2.1

Fang et al. 43

ATRIA

2005

13,559

7,764 (57.3 %)

5,795 (42.7 %)

Warfarin

1.8

3.5

Rienstra et al.44

RACE

2005

522

330 (63.2 %)

192 (36.8 %)

Warfarin

6.7

6.8

4.4

Gomberg et al.45

SPORTIF

2006

7,329

5,072 (69.2 %)

2,257 (30.8 %)

Warfarin

1.4

2.1

Connolly et al.46

RELY

2009

12,091

7,705 (63.7 %)

4,386 (36.3 %)

Dabigatran

1.4

1.9

Connolly et al.47

AVERROES

2011

2,808

1,660 (59.1 %)

1,148 (40.9 %)

Apixaban

1.4

1.9

Not reported

ROCKET AF 2011 7,131 4,300 (60.3 %) 2,831 (39.7 %) Rivaroxaban Patel et al.48 Granger et al.49

ARISTOTLE

2011

9,120

5,886 (64.5 %)

3,234 (35.5 %)

Apixaban

1.2

1.4

Guigliano et al.50

ENGAGE AF-TIMI 48

2015

21,105

13,065 (61.9 %)

8,040 (38.1 %)

Edoxaban

1.16

1.21

AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management; ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF; ATRIA = Anticoagulation and Risk Factors in AF; AVERROES = Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; ENGAGE AF-TIMI 48 = Effective Anticoagulation with Factor Xa Next Generation in AF – Thrombolysis in Myocardial Infarction 48; RACE = Rate Control versus Electrical Cardioversion for Persistent AF; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy; SPAF = Stroke Prevention in AF; SPORTIF = Stroke Prevention Using Oral Thrombin Inhibitor in AF.

Efficacy of Anticoagulants

Direct-acting Oral Anticoagulants

For many decades, warfarin was the choice of anticoagulant for stroke prophylaxis in AF. Direct-acting oral anticoagulants (DOACs) are now available and have been shown to be non-inferior in stroke prevention. Analysis of trial data demonstrates some gender-specific differences in efficacy and risk of bleeding with the use of these medications.

Gender-based differences in stroke risk are less obvious in trials of DOACs. A meta-analysis of 71,683 participants included in the ROCKETAF, Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY), Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE), and Effective Anticoagulation with Factor Xa Next Generation in AF – Thrombolysis in MI 48 (ENGAGE AF-TIMI 48) trials showed no gender-based differences in stroke or bleeding risk among patients assigned to DOACs.41 In contrast to patients assigned to warfarin, the risk of residual ischemic stroke among those assigned to DOACs did not reveal any gender bias.

Warfarin A meta-analysis of five randomized controlled trials of patients with AF reported that warfarin reduces the risk of ischemic stroke by 84 % (95 % CI [55–95 %]) in women compared with 60 % (95 % CI [35–76 %]) in men.38 However, more recent evidence indicates that women have a higher residual stroke risk compared with men receiving oral anticoagulation. In a post hoc analysis of the AFFIRM trial, Sullivan et al. reported that women were at greater risk of ischemic stroke than men despite similar anticoagulation patterns.39 The difference in ischemic stroke risk was primarily related to a higher proportion of women being outside the therapeutic range for warfarin. Time in therapeutic range is recognized as a major factor determining stroke risk in AF patients on warfarin. A recent meta-analysis also reported similar findings, showing that female patients with AF on warfarin had a significantly higher residual risk of stroke and systemic thromboembolism than men (OR 1.28; 95 % CI [1.11–1.47]).40

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In summary, although prior trials of stroke prevention in AF revealed a higher rate of ischemic stroke in women with AF on warfarin, DOACs appear to not suffer from this gender-based difference in efficacy (Table 2).

Conclusion Multiple studies have shown major gender-based differences in the clinical profile and management of AF. Whether these are related to differences in biology or represent treatment disparities is unknown. This area of cardiac electrophysiology deserves further study. n

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org/10.1161/CIRCULATIONAHA.113.003862; PMID: 24061087. 34. K aiser DW, Fan J, Schmitt S, et al. Gender differences in clinical outcomes after catheter ablation of atrial fibrillation. JACC Clin Electrophysiol 2016;2:703–10. https://doi.org/10.1016/j. jacep.2016.04.014; PMID: 29623299. 35. Winkle RA, Mead RH, Engel G, Patrawala RA. Safety of lower activated clotting times during atrial fibrillation ablation using open irrigated tip catheters and a single transseptal puncture. Am J Cardiol 2011;107:704–8. https://doi.org/10.1016/j. amjcard.2010.10.048; PMID: 21185007. 36. Friberg L, Benson L, Rosenqvist M, Lip GY. Assessment of female sex as a risk factor in atrial fibrillation in Sweden: nationwide retrospective cohort study. BMJ 2012;344:e3522. https://doi. org/10.1136/bmj.e3522; PMID: 22653980. 37. Cove CL, Albert CM, Andreotti F, et al. Female sex as an independent risk factor for stroke in atrial fibrillation: possible mechanisms. Thromb Haemost 2014;111:385–91. https://doi. org/10.1160/TH13-04-0347; PMID: 24305974. 38. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–57. https://doi.org/10.1001/ archinte.1994.00420130036007; PMID:8018000. 39. Sullivan RM, Zhang J, Zamba G, et al. Relation of gender-specific risk of ischemic stroke in patients with atrial fibrillation to differences in warfarin anticoagulation control (from AFFIRM). Am J Cardiol 2012;110:1799–802. https://doi.org/10.1016/j. amjcard.2012.08.014; PMID: 22995971. 40. Pancholy SB, Sharma PS, Pancholy DS, et al. Meta-analysis of gender differences in residual stroke risk and major bleeding in patients with nonvalvular atrial fibrillation treated with oral anticoagulants. Am J Cardiol 2014;113:485–90. https://doi. org/10.1016/j.amjcard.2013.10.035; PMID: 24315113. 41. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. https://doi.org/10.1016/S01406736(13)62343-0; PMID: 24315724. 42. Hart RG, Pearce LA, McBride R, et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III Clinical Trials. Stroke 1999;30:1223–9. PMID: 10356104. 43. Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors in Atrial fibrillation (ATRIA) study. Circulation 2005;112:1687–91. https://doi.org/10.1161/CIRCULATIONAHA.105.553438; PMID: 16157766. 44. Rienstra M, Van Veldhuisen DJ, Hagens VE, et al. Gender-related differences in rhythm control treatment in persistent atrial fibrillation. J Am Coll Cardiol 2005;46:1298–1306. https://doi. org/10.1016/j.jacc.2005.05.078; PMID: 16198847. 45. Gomberg-Maitland M, Wenger NK, Feyzi J, et al. Anticoagulation in women with nonvalvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials. Eur Heart J 2006;27:1947–53. https://doi.org/10.1093/eurheartj/ ehl103; PMID: 16774980. 46. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. https://doi.org/10.1056/NEJMoa0905561; PMID: 19717844. 47. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806–17. https://doi. org/10.1056/NEJMoa1007432; PMID: 21309657. 48. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/NEJMoa1009638; PMID: 21830957. 49. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365: 981–92. https://doi.org/10.1056/NEJMoa1107039; PMID: 21870978. 50. Giugliano RP, O’Donoghue ML, Ruff CT, et al. Efficacy and safety outcomes in 8040 women compared with 13,085 men with atrial fibrillation treated with edoxaban vs warfarin for an average 2.8 years. J Atrial Fibrillation 2015;8(suppl). Available at: http://jafib.com/va_abstract_2015.php?view=full&id=330 (accessed October 6, 2018).

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Electrophysiology

Fluoroless Catheter Ablation of Cardiac Arrhythmias Sandeep K Goyal, MD, FHRS and Bruce S Stambler, MD, FHRS Piedmont Heart Institute Atlanta, GA

Abstract Catheter ablation is the mainstay of cardiac arrhythmia management, and the number of these procedures carried out is continuing to grow. Fluoroscopy has been integral to these procedures to ensure safe catheter manipulation. Unfortunately, exposure to ionizing radiation is associated with several health risks to patients and personnel. The personal protective equipment used to reduce these risks is associated with incomplete protection and orthopedic risks to physicians and other staff. 3D mapping systems and intracardiac echocardiography, if used properly, can significantly reduce the use of fluoroscopy. The study describes a zero-fluoroscopy approach to cardiac ablation of AF and other arrhythmias using 3D mapping and intracardiac echocardiography to reduce or eliminate exposure to ionizing radiation and orthopedic risks to personnel.

Keywords Catheter ablation, fluoroscopy, AF, zero fluoroscopy, 3D mapping, intracardiac echocardiography Disclosure: Dr Goyal is a consultant for Biosense Webster (<US$5,000); Dr Stambler has no relevant conflicts of interest to declare Received: September 27, 2017 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;12(2):107–9. DOI: https://doi.org/10.15420/usc.2018.12.1 Correspondence: Sandeep K Goyal, 275 Collier Road, Suite 500, Atlanta, GA 30309, USA. E: Sandeep.Goyal@piedmont.org

Catheter ablation is the mainstay of treatment in the management of cardiac arrhythmias. The number of catheter ablation procedures performed worldwide in the past 25 years has significantly increased and is expected to increase further. Cardiac ablation requires catheters to be advanced and manipulated within cardiovascular structures. This manipulation has traditionally been performed under fluoroscopic guidance. The advent of 3D electro-anatomic mapping systems (EAM) and intracardiac echocardiography (ICE) has reduced reliance on fluoroscopy. However, fluoroscopy remains an integral part of ablation procedures in the hands of most operators.

Rationale for Eliminating Fluoroscopy When Possible The optimal goal for fluoroscopic exposure is known by the acronym ALARA (as low as reasonably achievable). Ionizing radiation can result in two types of tissue injury: stochastic (carcinogenic and genetic effects); and deterministic (also called tissue reactions). The most commonly used model for stochastic effects is the ‘linear non-threshold’ model, i.e. any small amount of radiation involves an increase in cancer risk with no threshold, and the probability increases linearly with increasing radiation dose.1 For deterministic effects (such as skin injuries or cataracts), there is a minimum threshold of dose for the effect to happen and severity increases with rising dose. The threshold for skin injuries is considered to be 2–3 Gy, but for radiationinduced opacities in the eye lens, the International Commission on Radiological Protection (ICRP) has proposed 500 mGy as the threshold.1 The ICRP gives a dose threshold of 500 mGy for non-cancer effects of ionizing radiation to the heart.1

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Patients can receive a large dose of radiation during complex catheter ablations for AF or ventricular tachycardia (VT). Most experienced cardiac electrophysiologists have an exposure per annum of around 5 mSv with a typical cumulative lifetime attributable risk in the order of magnitude of one cancer (fatal and non-fatal) per 100 exposed subjects.2 Multiple studies have confirmed the increased risks of orthopedic problems associated with the use of lead aprons. The WIN for Safety group’s survey showed that 19.5 % of interventional cardiologists had orthopedic problems.3 Ross et al.4 surveyed three physician groups to study; they compared the effects of standing for long periods while wearing lead aprons (cardiologists) with lengthy standing at an operating table without weights (orthopedic surgeons) and standing for short periods while examining patients (rheumatologists). They found the cardiologists wearing lead aprons had a significantly higher incidence of skeletal complaints and missed more days from work because of back pain than individuals in the control groups.

Fluoroless AF Ablation Technique The advent of 3D mapping and intracardiac echocardiography (ICE) has provided unique opportunities for significant reduction in and potential elimination of fluoroscopy during most ablation procedures. AF ablation is the most commonly performed complex ablation procedure and is traditionally associated with a long duration of fluoroscopy. The authors have adopted a zero-fluoroscopy approach for the majority of AF ablation procedures. SG has personally performed ~200 AF ablation procedures using zero fluoroscopy. The physician and other staff do not wear lead aprons (to eliminate orthopedic risks) and the

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Electrophysiology X-ray system is paused for the whole procedure (eliminating radiationrelated risks to patients and personnel). AF ablations are performed with 3D mapping using the CARTO 3™ system (Biosense Webster). Access to right and, rarely, left femoral veins is obtained under handheld ultrasound guidance and four sheaths are placed. A CARTOSOUND® ICE catheter (Biosense Webster) is advanced from the right femoral vein to the right atrium (RA). This is performed using the live image obtained from the ICE catheter. We ensure that there is always echo-free space at the tip of transducer to avoid inadvertent venous perforation by the catheter. ICE images are obtained from the RA using various deflections of the catheter. The location of the coronary sinus (CS), cavo-tricuspid isthmus, superior vena cava (SVC), interatrial septum (IAS), left atrial appendage and pulmonary veins are drawn in 3D using CARTOSOUND (Biosense Webster). The desirable puncture site on the atrial septum is specifically tagged on this map. The esophagus is visualized using ICE and marked on the CARTOSOUND module. A 10-pole temperature-sensing probe is placed in the esophagus and the position of the probe is confirmed using ICE. Next, a bidirectional, THERMOCOOL™ SmartTouch catheter (Biosense Webster) is advanced to the RA via a steerable sheath, and a limited fast anatomic map (FAM) of the CS, SVC and interatrial septum is obtained using the sound images as a guide. The contact force-sensing technology provides an additional layer of safety for catheter movements without fluoroscopy. A decapolar CS catheter is now placed. Any decapolar catheter can be visualized on the 3D mapping system after creation of the FAM map by the ablation catheter and is quite easily positioned in CS. Heparin is administered to achieve an activated clotting time (ACT) of >350 seconds. A long wire is placed in the SVC from the right femoral vein and the position of the wire in the SVC is confirmed on ICE. An SL–0 sheath and dilator complex are advanced over the wire and is seen in the SVC. The wire is removed, and sheath is flushed. A 71-cm Agilis NxT™ (St Jude Medical) needle is connected to the mapping system via a Duomode™ Cable (Baylis Medical) and advanced via the SL–0 sheath. When the needle tip exits the SL-0 sheath, the tip can be visualized in the SVC as an electrode on 3D mapping system. The needle, dilator and sheath complex are pulled down from the SVC and the needle is directed towards the previously tagged optimal puncture location on the IAS. The position of the needle on the desired site on the IAS is confirmed on ICE and radiofrequency (RF) energy is delivered to cross the IAS. The use of a RF-activated needle allows for transseptal puncture without significant manual pressure and decreases the risk of inadvertent LA perforation from the needle and the sheath ‘jumping’ across the septum. The needle is removed while the tip of the dilator is remains in place across the septum.

LA, the sheath is pulled back into the RA while the wire is maintained in the LA. The ablation catheter is used to access the LA using the same transseptal puncture by using a buddy technique using the existing wire. The Agilis sheath is advanced in the LA over the ablation catheter. The ablation catheter is now stabilized and the SL–0 sheath is re-advanced into the LA over the ProTrack wire. After the SL-0 sheath position has been confirmed in the LA, the wire and dilator are removed and replaced with a multipolar mapping catheter. A previously obtained 3D CT or MRI rendering of the LA and pulmonary veins is merged with the CARTOSOUND map of the LA, and a FAM of the LA is created using the multipolar catheter. A complete bi-antral pulmonary vein isolation is then completed in standard fashion, while the catheters are visualized on the 3D mapping system. The use of contact force sensing eliminates the need to use fluoroscopy to assess catheter to tissue contact. Additional FAM data are collected as needed to refine views of the anatomic structures. Additional linear and focal ablation can also be performed using the same map without any need for fluoroscopy. At the end of the procedure, ICE imaging is performed to confirm a lack of pericardial effusion and the catheters are removed from the body. A similar approach can be taken for other left atrial arrhythmias including atypical flutters and left-sided accessory pathways. Right atrial arrhythmias (such as typical flutter, atrioventricular nodal reentry tachycardia, atrioventricular re-entry tachycardias and atrial tachycardias) are routinely mapped without fluoroscopy. The operator uses the ablation catheter to create a FAM map of the RA then place other catheters, such as the high right atrial catheter, CS catheter and right ventricle (RV) catheter as they can be visualized on CARTO after a FAM has been created. Impedance-based mapping systems such as EnSite™ have the advantage of not needing a sensor-based catheter to visualize the diagnostic catheters; this allows the operator to make a definite diagnosis before deciding which ablation catheter to use. Ablation of VT and premature ventricular contractions can also be easily performed using a fluoroless approach. We routinely use Cartosound to map the anatomy of the LV and RV before placing other catheters in the body. Transseptal access is performed in the same way as described for AF ablation. Retrograde access is facilitated by visualizing the wire in the descending aorta and using a longer sheath (~40 cm) to navigate the tortuosity of femoral and iliac arteries.

Procedure Time We do not see any significant increase in procedure time for right-sided ablations or retrograde VT ablations. The time to transseptal access is increased by approximately 5 minutes for zero fluoroscopy procedures compared to when fluoroscopy is used.

Complications A ProTrack™ 260 cm wire (Baylis Medical) is placed in the left atrium (LA) via the SL–0 sheath. This wire has an atraumatic pigtail loop at the tip, which can be easily visualized in the LA using ICE. The SL–0 sheath and dilator are advanced into the LA over this wire. After the septum is dilated by a to-and-fro movement of the sheath between the RA and the

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There has been no difference in complication rate between procedures performed with or without fluoroscopy. It is important that patients remain in same position for the duration of procedure to maintain accuracy of the EAM-generated map; longer procedures usually require use of general anesthesia to eliminate the risk of patient movement.

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Fluoroless Catheter Ablation Learning the Technique

Limitations and Tips for Troubleshooting

Zero fluoroscopy ablation has a steep learning curve for most operators. Most physicians who are comfortable using EAM and use fluoroscopy only for initial catheter placement or trans-septal puncture can expect to feel confident using the zero-fluoroscopy approach after about 10–15 AF ablations. Operators may choose to wear lead aprons for their initial cases to gain confidence with their technique. Physicians who continue to place significant reliance on fluoroscopy for ablation will benefit from starting with using fluoroscopy for initial catheter placement and transseptal puncture then performing left atrial mapping and ablation with minimal or no fluoroscopy. These operators may require 25–50 cases to feel confident about performing zero fluoroscopy ablation.

Zero-fluoroscopy approach has minor limitations related to the need for ICE for trans-septal and left ventricular procedures, operator learning curve and the necessity to obtain pre-procedural imaging in the initial phases of the learning curve. In our experience, the use of ICE has not changed significantly after the adoption of zero-fluoroscopy technique. The pre-procedural CT/MRI also becomes optional for most operators after approximately 50 cases.

Remaining Need for Fluoroscopy In rare circumstances (<5 % cases), brief use of fluoroscopy is necessary to facilitate some components of the procedure. Most commonly encountered scenarios include: • A thick IAS can rarely require the use of extra force to get the sheath across the IAS, and fluoroscopic visualization can facilitate this process. • We still use fluoroscopy for right atrial catheter placement and transseptal puncture in patients with recently implanted (within the past 6 months) cardiovascular devices to prevent lead dislodgement. Under these circumstances, a lead apron is worn for the necessary amount of time, then removed as soon as fluoroscopy is no longer necessary.

tewart FA, Akleyev AV, Hauer-Jensen M, et al. ICRP publication S 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs – threshold doses for tissue reactions in a radiation protection context. Ann ICRP 2012;41:1–322. https://doi.org/10.1016/j.icrp.2012.02.001; PMID: 22925378.

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The sheaths can not be visualized on mapping system and sheath orientation has to be predicted based on catheter tip movement on operating the steerable mechanism or by visualizing the sheath catheter assembly on the ICE. The approximate position of the sheath can be assessed by slowly advancing the sheath over the ablation catheter and when proximal electrodes turn “black” the sheath has covered those electrodes.

Future Directions The number of cardiac ablation procedures is projected to grow worldwide due to increased safety and access to technology. Improvements in 3D mapping technology will allow operators to perform a greater number of ablations without fluoroscopy. The long guiding sheaths with embedded electrodes near the distal end are in development. This will allow visualization of the distal portion of sheaths on 3D mapping system, increasing safety and efficiency of fluoroless procedures. The authors are hopeful that, in the near future, fluoroscopy will become an adjunct (if not extinct) rather than a necessary tool for cardiac ablation.

enneri L, Rossi F, Botto N, et al. Cancer risk from professional V exposure in staff working in cardiac catheterization laboratory: insights from the National Research Council’s Biological Effects of Ionizing Radiation VII Report. Am Heart J 2009;157:118–24. https://doi.org/10.1016/j.ahj.2008.08.009. PMID: 19081407. Buchanan GL, Chieffo A, Mehilli J, et al. The occupational effects

of interventional cardiology: results from the WIN for Safety survey. EuroIntervention 2012;8:658–63. https://doi.org/10.4244/ EIJV8I6A103; PMID: 23086783. Ross AM, Segal J, Borenstein D, et al. Prevalence of spinal disc disease among interventional cardiologists. Am J Cardiol 1997;79:68– 70. https://doi.org/10.1016/S0002-9149(96)00678-9; PMID: 9024739.

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Advanced Heart Failure

Understanding Iron Deficiency in Heart Failure: Clinical Significance and Management Rajalakshmi Santhanakrishnan, MBBS Biomedical Science Program, College of Science and Mathematics, Wright State University, Dayton, OH

Abstract Iron deficiency (ID) has been increasingly recognized as an important co-morbidity associated with heart failure (HF). ID significantly impairs exercise tolerance and is an independent predictor of poor outcomes in people with HF irrespective of their anemic status. Diagnosis of ID in people with HF is often missed and therefore routine screening for ID is necessary for these patients. IV iron repletion has been recommended in HF treatment guidelines to improve symptoms and exercise capacity. People with ID and HF who are treated with IV iron have an improved quality of life, better 6-minute walk test results and New York Heart Association functional class. The effect of iron therapy on re-hospitalization and mortality rates in people with HF remains unclear. Large-dose oral iron treatment has been found to be ineffective in improving symptoms in people with HF. This review summarizes the current knowledge on prevalence, clinical relevance, and the molecular mechanism of ID in patients with chronic HF and the available evidence for the use of parenteral iron therapy.

Keywords Heart failure, iron deficiency, anemia, prognosis, iron therapy Disclosure: The author has no conflict of interest to declare. Received: November 15, 2017 Accepted: October 8, 2018 Citation: US Cardiology Review 2018;12(2):110–2. DOI: https://doi.org/10.15420/usc.2017.30.2 Correspondence: Rajalakshmi Santhanakrishnan, 235A Biological Sciences, Wright State University, Dayton, OH 45431, USA. E: santhanakrishnan.2@wright.edu

Heart failure (HF) is a major health problem and about 6 million adults are affected in the US alone, at a cost of approximately $20 billion per year.1 Despite the availability of new treatment strategies, the incidence, number of hospitalizations and mortality associated with HF remains a big health burden.1 In addition to increasing age, the factors that contribute to poor prognosis for people with HF are its associated co-morbidities. Iron deficiency (ID) has been increasingly recognized as an important co-morbidity that contributes to increased incidence, re-hospitalization and poor survival in people with HF.2 Anemia is the ultimate consequence of ID, but the conditions are distinct clinical scenarios. Identification of ID in people with chronic diseases such as HF is important as iron repletion has shown to improve patient’s symptoms irrespective of anemic status.

Mechanism of Iron Deficiency in Heart Failure Iron is an essential micronutrient in all types of cells and is particularly important in energy-demanding cells such as cardiomyocytes.3 Iron acts as a co-factor for several enzymes involved in oxidative phosphorylation and plays a key role in oxygen transport through erythropoiesis. The etiology of ID in HF is not clearly understood; it could possibly be due to multiple factors including poor iron absorption due to edema in the gastrointestinal tract, low bioavailability of iron, and a chronic inflammatory state.4 At the molecular level, one possible mechanism of ID is related to hepcidin, an iron regulatory hormone, whose synthesis is stimulated when iron stores or levels of the cytokine interlukin-6 (IL6) are elevated. In chronic inflammatory conditions, hepcidin levels are increased due to an increase in IL-6 and/or fluctuating iron levels. Elevated

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hepcidin results in removal of ferroportin – a protein that increases iron efflux into the bloodstream – from the duodenal surfaces.5 However, in HF, a reverse mechanism exists: initially hepcidin level increases but as HF progresses, hepcidin is downregulated which maintains ferroportin levels thereby increasing iron efflux.6 The reason for this is still not clearly understood. Importantly, lower hepcidin levels have been associated with increased 3-year mortality rate in people with acute HF.7 Another mechanism underlying ID in people with HF is thought to be liver congestion that leads to increased hemosiderin-laden macrophages. 8 Cardiomyocytes have a high-energy demand and are therefore susceptible to ID. In patients referred for cardiac transplantation, myocardial iron stores have been found to be lower compared with patients without HF. 9 HF patients also showed reduced myocardial oxygen respiration and reduction in mitochondrial respiratory enzymes.10 In experimental mice models, the left ventricular cardiomyocytes with depleted iron-regulatory protein (IRP), which maintains intracellular iron availability, showed reduced mitochondrial complex I activity and the mice were unable to increase ventricular systolic function in response to dobutamine stress. 11 Despite there being different possibilities for the mechanism underlying ID in HF disease, its pathophysiology is unclear.

Prevalence of Iron Deficiency in Heart Failure The prevalence of ID has been widely studied in patients with chronic HF with reduced ejection fraction (HFrEF) and ranges between 36 and 69 %

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Iron Deficiency in Heart Failure have been found among different ethnic groups with the Portuguese having the lowest and British having the highest prevalence rates.12 In patients presenting with acute decompensated HF (ADHF), the prevalence of ID is much higher than those with chronic HF.7 A gender difference in the prevalence of ID was shown in a French study of 832 people with ADHF; 66 % of men and 75 % of women had ID.13 Independent correlates of ID in HF include increased age, higher New York Heart Association (NYHA) functional class, being a woman, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein.2 The prevalence of ID in people with HFpEF is still unknown.

Table 1: Diagnosis of Iron Deficiency in Heart Failure Non-invasive (routine)

Serum ferritin level <100 µg/1 OR Serum ferritin level 100–300 µg/l AND transferrin saturation <20 %

Invasive (gold standard)

Bone marrow aspiration Prussian blue stain for absence of iron granules

Table 2: Guidelines for the Treatment of Iron Deficiency in Heart Failure

Consequences of Iron Deficiency Heart Failure with Reduced Ejection Fraction ID greatly decreases the quality of life irrespective of the presence of anemia in patients with HFrEF. In one study, patients with concurrent ID and HFrEF had lower peak oxygen consumption (peak VO2) and increased ventilator response to exercise (VE-VCO2 slope) compared with those without concurrent ID with both reflecting poor exercise capacity.14 Quality of life has been shown to be significantly affected in HF patients irrespective of diagnostic criteria using either the European Quality of Life-5D, Kansas City Cardiomyopathy, or the Minnesota Living with Heart Failure questionnaires.15 In one study, of 1,506 HF patients, short-term 6-month follow-up showed a higher risk of death in those with HF and ID compared with patients with HF and no ID (8.7 % versus 3.6 % respectively, p<0.001).16 Similarly, in long-term follow-up over approximately 2.5 years, those with ID had a higher likelihood of dying than those without ID.16 The association with mortality was independent of anemic status. In another study involving 157 people with HF, participants with nonanemic ID had twice the risk of death than anemic patients on iron therapy.17 In a study that used serum-soluble transferrin receptor (sTfR) and hepcidin levels to define ID in people with ADHF, there was a 5 % in-hospital mortality and a strikingly higher risk of death (95 % CI [2.97– 14.62], p<0.001) within 12 months of discharge.12

Guidelines description

COR

American Heart Association1

In patients with NYHA class II and III HF and ID, IV iron replacement might be reasonable to improve functional status and quality of life

IIb

European Society of Cardiology25

IV FCM should be considered in symptomatic patients with HFrEF and ID to alleviate HF symptoms and improve exercise capacity and quality of life

IIa

COR = class of recommendation; FCM = ferrous carboxymaltose; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; ID = iron deficiency; NYHA = New York Heart Association.

the serum ferritin concentration (a marker of iron stores) and saturation level of transferrin – the iron transport protein. In the general population, a serum ferritin cut-off value of 30 µg/l is used for the diagnosis of ID.20 Ferritin is an acute-phase reactant, therefore a higher cut-off serum level is used for diagnosis of ID in people with chronic inflammatory state. Absolute ID is defined as reduced iron stores despite normal iron homeostasis diagnosed as serum ferritin level of <30 µg/l (Table 1). Functional ID is defined as an inability to meet the body’s iron demand despite having normal iron stores. It is measured by a combination of serum ferritin (100–300 µg/l) and transferrin saturation (<20 %) levels.3 The gold standard assay to diagnose ID is the bone marrow Prussian blue stain to identify absence of iron granules. It is an invasive procedure and is not routinely used.

Heart Failure with Preserved Ejection Fraction The definitive role of ID in patients with HF with preserved ejection faction (HFpEF) is poorly understood. In a small study involving 26 HFpEF subjects, neither cardiac function (both systolic and diastolic) nor reduced exercise capacity was dependent on ID.18 In another study involving 40 HFpEF patients, ID was a predictor of decreased exercise tolerance independent of ventricular diastolic function, renal function, hemoglobin and NT-proBNP.19 There was a significant correlation of both transferrin and ferritin levels with peak VO2 in these subjects. The difference in results between the two studies might be because the latter study involved subjects with more advanced disease (higher NT-proBNP, higher NYHA class, previous history of ADHF and relatively lower peak VO2). More studies are required to identify the significance of ID in people with HFpEF.

Diagnosis of Iron Deficiency in Heart Failure Diagnosis of ID in HF is complicated by the fact that the symptoms of fatigue and exercise intolerance associated with ID overlap with the symptoms of HF. ID is defined as absolute and functional depending on

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Iron Therapy in Heart Failure Parenteral Iron Having proven the significant correlation of ID in HF patients, several clinical trials of iron therapy have been conducted. The current treatment guidelines for HF with ID is listed in Table 2 and is based on two large trials: Ferinject® Assessment in Patients With IRon Deficiency and Chronic Heart Failure (FAIR-HF) and A Study to Compare the Use of Ferric Carboxymaltose With Placebo in Patients With Chronic Heart Failure and Iron Deficiency (CONFIRM-HF).21,22 Both trials tested intravenous ferric carboxymaltose (FCM) in patients with ambulatory chronic systolic HF with ID in NYHA classes II and III. The FAIR-HF trial included 459 HFrEF patients (EF <45 %) who completed a self-reported Patient Global Assessment, which improved in 50 % (n=147) of patients in the FCM group compared with 28 % (n=41) of the placebo group, along with improvement in NYHA functional class, 6-minute walk test and qualityof-life assessments. The positive changes were present in patients with ID both with and without anemia. CONFIRM-HF included 304 HFrEF

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Advanced Heart Failure patients and after 6 months of iron treatment, the primary endpoint of a 6-minute walk test significantly improved in the FCM group compared with the placebo group. All secondary endpoints including NYHA class, quality of life, fatigue score and time for first rehospitalization improved significantly in the FCM group. Both trials did not show any adverse side-effects with IV iron therapy. Although individual clinical trials were not tested for major clinical events, a meta-analysis including FAIR-HF, CONFIRM-HF, EFfect of Ferric Carboxymaltose on exercIse CApacity and Cardiac Function in Patients With Iron deficiencY and Chronic Heart Failure (EFFICACY-HF) and FER-CARS-01 assessed the effect of iron therapy in cardiovascular hospitalization, and mortality in patients with HF and ID.23 Treatment with IV FCM had lower rates of combined HF hospitalizations and cardiovascular mortality (rate ratio 0.53, 95 % CI [0.33–0.86], p=0.011). These findings from the meta-analysis need to be validated in randomized clinical trials.

Oral Iron The Iron Repletion Effects on Oxygen Uptake in Heart Failure (IRONOUT HF) study is a large-scale randomized clinical trial that tested the role of high-dose oral iron therapy in 225 patients with HFrEF and

ancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Y Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Card Fail 2017;23:628-651. https://doi.org/10.1016/j. cardfail.2017.04.014; PMID: 28461259. Yeo TJ, Yeo PS, Ching-Chiew WR, et al. Iron deficiency in a multi-ethnic Asian population with and without heart failure: prevalence, clinical correlates, functional significance and prognosis. Eur J Heart Fail 2014;16:1125–32. https://doi. org/10.1002/ejhf.161; PMID: 25208495. Cappellini MD, Comin-Colet J, de Francisco A, et al. Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management. Am J Hematol 2017;92:1068–78. https://doi.org/10.1002/ajh.24820; PMID: 28612425. Jankowska EA, Von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J 2013;34:816–29. https://doi.org/10.1093/ eurheartj/ehs224; PMID: 23100285. Ganz T, Nemeth E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology Am Soc Hematol Educ Program 2011;2011:538–42. https://doi.org/10.1182/asheducation-2011.1.538; PMID: 22160086. Jankowska EA, Malyszko J, Ardehali H, et al. Iron status in patients with chronic heart failure. Eur Heart J 2013;34:827–34. doi:10.1093/eurheartj/ehs377. PMID: 23178646. Jankowska EA, Kasztura M, Sokolski M, et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J 2014;35:2468–76. https://doi.org/10.1093/eurheartj/ ehu235; PMID: 24927731. Suzuki T, Hanawa H, Jiao S, et al. Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency. J Card Fail 2014;20:268–77. https://doi.org/10.1016/j.cardfail.2014.01.008; PMID: 24440572.

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ID.24 The primary endpoint was change in peak VO2 at 16 weeks and secondary endpoints included change in NT-proBNP, 6-minute walk test and quality of life. In contrast to results from trials that used IV iron, the IRONOUT HF trial failed to show improvements in primary and secondary endpoints.

Conclusion ID is more common in patients with HF and is often overlooked because of overlapping clinical symptoms. ID in HF patients is associated with reduced exercise tolerance, poor quality of life and increased rehospitalizations and mortality. Routine screening for ID in patients with HF and treatment with iron is recommended by HF treatment guidelines.1 Parenteral iron improves patient symptoms, quality of life and exercise capacity after iron therapy.26 Despite improvements in HF symptoms, major clinical outcomes were not tested in clinical trials. Further, all trials included only patients with HFrEF and the role of ID in patients with HFpEF is not clearly understood. More randomized clinical trials that might answer the open questions on the effect of iron repletion on long-term symptoms, effects on rehospitalization and survival in patients with concurrent ID and HF are currently underway. n

L eszek P, Sochanowicz B, Szperl M, et al. Myocardial iron homeostasis in advanced chronic heart failure patients. Int J Cardiol 2012;159:47–52. https://doi.org/10.1016/j. ijcard.2011.08.006; PMID: 21899903. Melenovsky V, Petrak J, Mracek T, et al. Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis. Eur J Heart Fail 2017;19:522–30. https://doi. org/10.1002/ejhf.640. PMID: 27647766. Haddad S, Wang Y, Galy B, et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur Heart J 2017;38:362–72. https://doi.org/10.1093/eurheartj/ ehw333; PMID: 27545647. Fitzsimons S, Doughty RN. Iron deficiency in patients with heart failure. Eur Hear J Cardiovasc Pharmacother 2015;1:58-64. https://doi. org/10.1093/ehjcvp/pvu016; PMID: 27533968. Cohen-Solal A, Damy T, Terbah M, et al. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail 2014;16:984–91. https://doi.org/10.1002/ejhf.139; PMID: 25065368. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail 2011;17:899–906. https://doi. org/10.1016/ j.cardfail.2011.08.003; PMID: 22041326. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786–95. https://doi.org/10.1002/ejhf.473; PMID: 26821594. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82.e3. https://doi.org/10.1016/j.ahj.2013.01.017; PMID: 23537975. Okonko DO, Mandal AKJ, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241–51. https://doi.org/10.1016/j.jacc.2011.04.040; PMID: 21903058. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron

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deficiency and diastolic function in heart failure with preserved ejection fraction. Int J Cardiol 2013;168:4652–7. https://doi. org/10.1016/j.ijcard.2013.07.185; PMID: 23968714. Núñez J, Domínguez E, Ramón JM, et al. Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction. Int J Cardiol 2016;207:365–7. https://doi.org/10.1016/j.ijcard.2016.01.187; PMID: 26820369. Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol 2009;15:4638-43. https://doi.org/10.3748/wjg.15.4638; PMID: 19787826 Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48. https://doi. org/10.1056/NEJMoa0908355; PMID: 19920054. Ponikowski P, Van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015;36:657–68. https://doi. org/10.1093/eurheartj/ehu385; PMID: 25176939. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in irondeficient heart failure patients: an individual patient data metaanalysis. Eur J Heart Fail 2017;20:125–33. https://doi.org/10.1002/ ejhf.823. PMID: 28436136. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency. JAMA 2017;317:1958–66. https://doi.org/10.1001/jama.2017.5427; PMID: 28510680. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; PMID: 27206819.

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Advanced Heart Failure

Amyloid Heart Disease Yaser Nemshah, MBBS, 1,2 Alex Clavijo, MD, 1 and Gyanendra Sharma, MD, FACC, FASE 1 1. Medical College of Georgia at Augusta University, Augusta, GA; 2. King Fahad Medical City, Riyadh, Saudi Arabia

Abstract Cardiac amyloidosis is a group of disorders that develop secondary to the deposition of misfolded proteins in the heart. It can occur in isolation or as part of a systemic disease and can be inherited or acquired. Amyloid light chain (AL) and amyloid transthyretin (ATTR) are the two main forms of amyloid proteins that can infiltrate the heart. With the increased use of advanced imaging techniques and protocols, the recognition and diagnosis of cardiac amyloidosis, especially ATTR, has become easier. New therapies intended to improve survival and quality of life in patients with cardiac amyloidosis are emerging. This article provides an up-to-date review of cardiac amyloidosis.

Keywords Cardiac amyloidosis, immunoglobulin light chain amyloidosis, transthyretin amyloidosis, cardiovascular MRI, echocardiography, scintigraphy Disclosure: The authors have no conflicts of interest to declare. Submitted: July 2, 2018 Accepted: July 24, 2018 Citation: US Cardiology Review 2018;12(2):113–8. DOI: https://doi.org/10.15420/usc.2018.5.1 Correspondence: Yaser Nemshah, 1120 15th Street-BBR 6518, Augusta, Georgia 30912, USA. E: ynemshah@gmail.com. Gyanendra Sharma; E: gsharma@augusta.edu

Amyloidosis is a heterogenous group of disorders that develops secondary to the deposition of abnormally folded proteins, amyloid fibrils, in the extracellular space. Amyloidosis is classified according to the type of the precursor protein that results in the formation of amyloid fibrils. It can be inherited or acquired, and can involve multiple organs, including the heart. Amyloidosis that involves the heart is referred to as cardiac amyloidosis (CA) in this review.

Epidemiology Immunoglobulin light chain amyloidosis (AL amyloidosis) and transthyretin amyloidosis (ATTR amyloidosis) are the two most common forms of systemic amyloidosis. AL amyloidosis is a rare disease, with an incidence of approximately 9–15.2 cases per million person-years.1,2 However, autopsy studies have shown that acquired ATTR amyloidosis (formerly called senile cardiac amyloidosis) is not uncommon, affecting 10–25 % of people aged over 80 years, and 50 % of those over 90 years.3–5 The prevalence of ATTR amyloidosis is higher in the US than in Asia.5 CA has a higher prevalence in patients with severe aortic stenosis. Recent published data showed that 13.9–16 % of patients who undergo transcatheter aortic valve replacement have CA.6,7 The median survival of people with AL and ATTR amyloidosis is 211–330 days and 961–2,250 days, respectively.8,9

immunoglobulin while ATTR is derived from misfolded unstable liverbased transthyretin protein. ATTR can be hereditary caused by a mutation in the ATTR gene; known as mutant ATTR (ATTRm). It can also be acquired; the acquired type is known as ATTR wild-type (ATTRwt) and used to be called senile cardiac amyloidosis. Amyloid fibrils can be deposited in any structure in the heart. They can be found in the atria and ventricles, and involve the pericardium, myocardium and endocardium. The valves, the conduction system and the coronary vessels can be affected as well. Depositions vary from small nodules to complete replacement of the cardiac tissue.11 High-grade deposition(>50 % of the myocardium) and frequent (90 %) vascular involvement have been noted in hearts with AL amyloidosis compared with low-grade deposits and infrequent (4 %) vascular involvement in the ATTR type.12 Myocardial deposition can lead to stiff ventricles early in the course of the disease, resulting in diastolic dysfunction and usually followed by left ventricular systolic dysfunction.13,14

Clinical Manifestations The impact of cardiac amyloid deposition can range from being asymptomatic to a rapidly fatal disease. CA tends to be evident clinically when the deposition exceeds 10 % of the myocardium.12 Early recognition can be important to reduce the disease burden and improve survival.

Pathophysiology An amyloid fibril protein is defined as a protein that is deposited as insoluble fibrils, mainly in the extracellular spaces of organs and tissues as a result of sequential changes in protein folding resulting in a condition known as amyloidosis.10 In humans, there are 31 extracellular precursor proteins that can lead to amyloid fibril formation.10 Among those, the AL and ATTR amyloid proteins are those that traditionally involve the heart. AL is an amyloid protein derived from light chain

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AL amyloidosis can affect any organ except the central nervous system leading to variety of symptoms. Outside the heart, it can result in the development of carpal tunnel syndrome, nephrotic syndrome, autonomic neuropathy, malabsorption syndromes, hepatomegaly, macroglossia (27.2 %), and periorbital purpura (12.5 %). Fatigue and weakness are the most common presenting symptoms. AL cardiac amyloidosis is unusual in isolation (3.9 % of patients).15

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Advanced Heart Failure Table 1: Summary of Differences Between AL and ATTR CA, Their Diagnosis and Treatment AL

ATTR

Prevalence

Rare

Common

Median survival

211–330 days

961-2250 days

Diagnosis:

EKG: Low voltage (AL>ATTR) LVH (ATTR >AL) AF/flutter (ATTR >AL) Heart block

Figure 1: EKG for a Patient with Cardiac Amyloidosis Featuring Low Voltage in Limb Leads and Pseudoinfarct Pattern

Biomarkers: Serum-free light chain Serum/urine protein immunofixation Troponin/NT-pro BNP Transthoracic echocardiography: Chambers hypertrophy Pericardial effusion Sparkling appearance LV systolic dysfunction Lower strain values especially at bases (cherry on top) MRI: ↑ LV mass and volume (ATTR > AL) Normal or low EF (ATTR has lower EF) Subendocardial to transmural LGE ↑ Extracellular volume (ECV >0.316) Nuclear: 99mTc-DPD/99mTc-PYP has ↑ uptake by ATTR (useful for subtyping) Tissue Diagnosis: EMB (gold standard, safe, not always needed) Fat pad biopsy Treatment

• • • •

Chemotherapy Alkylating agent Proteasome inhibitor Immunomodulators

• TTR silencer (gene level) e.g. siRNA, antisense oligonucleotides • TTR stabilizer (unstable protein level) e.g. tafamidis • Disruptors (amyloid fibril level)

AL = amyloid light chain; ATTR = amyloid transthyretin, ECV = extracellular volume; EMB = endomyocardial biopsy; EF = ejection fraction; LGE = late gadolinium enhancement; TTR = transthyretin.

ATTRm can cause peripheral and autonomic neuropathy. Around 50 % of affected patients have a positive family history.16 ATTRwt can lead to carpal tunnel syndrome, biceps tendon rupture and spinal stenosis.17,18 It usually takes years before heart failure (HF) develops. AF and heart block can also develop (Tables 1 and 2).

Diagnosis On EKG, around 46–70 % of CA cases have a low voltage (defined as all limb leads ≤0.5 mV, all precordial leads ≤1.0 mV, or Sokolow index ≤1.5 mV) at the time of diagnosis.8,19 Low voltage is more common in the AL than ATTR type (Figure 1).8,20 However, this difference between the subtypes is not consistent and has not been observed in other retrospective studies.21 Of patients with CA, 9–13 % meet the voltage criteria for left ventricular hypertrophy (LVH), and 15–42 % have atrial flutter or AF.8,21 Second degree atrioventricular block, LVH and AF tend to be more common in the ATTR than the AL subtype.8,21 QRS duration tends to be longer in the ATTR type.8

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Biomarkers can be helpful in diagnosis and in determining the prognosis. Serum-free light chain and serum and urine protein immunofixation, which are more sensitive than serum and urine protein electrophoresis and have thus replaced this, are usually positive with AL amyloidosis and important for typing CA. Serum amyloid A, beta2-microglobulin, osteopontin, and osteoprotegerin are other markers that can be elevated early in the course of the disease, but have variable specificity for CA.22 Troponin elevation and elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) levels are late markers and signify cardiac damage.23 NT-proBNP levels elevated out of proportion to left ventricular systolic dysfunction can be a sign of CA.24,25 Imaging studies are helpful in the diagnosis of CA and may be sufficient to establish a diagnosis when combined with biomarker data in ATTR amyloidosis. Echocardiography is a useful screening tool, and findings for patients with proven CA include concentric left ventricular hypertrophy, small to normal left ventricular diameters (>90 %), left atrial enlargement (89–91 %), a granular and sparkling appearance of the myocardium (55–82 %), moderate to large pericardial effusion (64–67 %), and left ventricular systolic dysfunction (44–73 %) (Figure 2).14,20 The transmitral flow velocity is often compatible with abnormal relaxation in all types of CA, and is seen in 57–64 % of patients, usually in the early phase of the disease.13,14 Intracardiac thrombus has also been observed on echocardiograms of patients with AL CA.26 The majority of these findings, while more common in CA, are also seen in patients with hypertrophic cardiomyopathy (HCM). Right ventricular inferior wall thickening (>4 mm) has been seen in 25 % of patients with CA, compared to 15 % of those with HCM, and sparkling myocardium was present in 25 % of people with CA, compared to 12.5 % of those with HCM. Compared to HCM, CA leads to a more advanced stage of diastolic dysfunction and a more impaired ejection fraction.27 CA can also cause left ventricular outflow tract obstruction and be mistaken for hypertrophic obstructive cardiomyopathy. The 2D–speckle tracking strain values, especially at the bases, are consistently lower (i.e. more impaired) in people with CA than in those with HCM, which makes these deformation parameters better differentiating factors than traditional echocardiographic findings.27 The global longitudinal strain typically features preserved apical segments (cherry on the top) and reduced strain in the basal segments. The presence of pleural effusion is associated with a worse prognosis.

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Amyloid Heart Disease Figure 2: Transthoracic Echocardiogram for a Patient with Biopsy-proven Amyloidosis, Showing a Sparkling Appearance with Severe Left Ventricular Hypertrophy and Right Ventricular Hypertrophy

Figure 3: Cardiovascular Magnetic Resonance for a Patient with Cardiac Amyloidosis: True FISP Image Showing Severe LVH and Pericardial Effusion

LVH = left ventricular hypertrophy.

Figure 4: Cardiovascular Magnetic Resonance for a Patient with Cardiac Amyloidosis: Global Gadolinium Enhancement With Lack of Myocardial Nulling

B A: Apical four chamber view. B: Parasternal short axis view. LVH = left ventricular hypertrophy; RVH = right ventricular hypertrophy.

MRI is a valuable modality in evaluating CA. It helps by assessing biventricular function, mass and volume, late gadolinium enhancement (LGE), T1 mapping, extracellular volume (ECV) and strain pattern. Dungu et al. compared ATTR and AL types, and found that ATTR CA has greater LV mass and volume, lower EF, thicker interventricular septum, RV free wall and large atrial areas.28 LGE is thought be an early sign that may precede LV wall thickening (Figures 3 and 4).28 Maceria et al. found that 69 % of patients with CA have global subendocardial LGE with non-coronary distribution. LGE was present in all cases of ATTR CA and in the majority of those of AL CA.29 Dungu et al. and Fontana et al. showed that LGE in ATTR CA has more RV LGE, more transmural LGE and less global subendocardial LGE than AL CA.28,30 Based on these observations, an LGE-based scoring system was created to differentiate between ATTR and AL CA, and this system detected ATTR CA with an 87 % sensitivity and 96 % specificity.28 Furthermore, Barison et al. found that a cut‐off value of myocardial ECV >0.316 has a sensitivity of 79 % and a specificity of 97 % for differentiating between patients with amyloidosis and control subjects. Increased myocardial ECV was also correlated with disease severity.31 Cardiovascular magnetic resonance strain analysis can detect early systolic and diastolic strain impairment in patients with AL CA with and without LGE.32

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The role of nuclear imaging in the typing of CA is increasing. Many radiotracers have been studied to help detect and diagnose CA with limited value. However, technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) and technetium pyrophosphate (99mTc–PYP) have shown great potential in differentiating between the two main types of CA. ATTR CA has high uptake to DPD and PYP in contrast to AL CA. A study by Bokhari et al. on 45 subjects with CA showed that the ATTR subtype has a significant higher myocardial tracer uptake than the AL subtype.

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Advanced Heart Failure Figure 5: Endomyocardial Biopsy Showing Amyloid Deposition

Table 2: Clinical and Diagnostic Findings that Raise the Suspicion for Cardiac Amyloidosis HFpEF with preceding history of carpal tunnel syndrome and peripheral neuropathy HFpEF with autonomic dysfunction/orthostatic hypotension Low voltage on EKG with pseudoinfarct pattern Severe LVH on echo with low-voltage EKG Thick hypo-contractile ventricle on echo (LVH with low EF) LVH with sparkling appearance and pericardial effusion on echo “Cherry on top” on echo strain images HFpEF = heart failure with preserved ejection fraction, LVH = left ventricular; LVH = left ventricular hypertrophy.

A B

there is a suspicion of CA and imaging modalities have not resulted in a diagnosis. It is a generally safe procedure if carried out by an experienced clinician. However, it is an invasive procedure and comes with considerable risks.35 In the right clinical settings and when at least four samples are obtained, EMB has a reported sensitivity of 100 % for detecting CA.36,37 Fat pad biopsy is a safer procedure that can obviate the need for EMB but has sensitivity of only 50–75 % in AL and 12–73 % in ATTR amyloidosis (Figure 5).38–40

Prognosis

AL CA is associated with a poorer prognosis than ATTR CA.21 Low voltage on EKG at the time of presentation is associated with all-cause mortality in AL and ATTR CA.8,21 On echocardiogram, left ventricular strain, an E/A ratio of >2.1, and a dt <150 ms are bad prognostic factors.41 On MRI, LGE was found to be a sign of poor prognosis in a study by Fontana et al. but this was an inconsistent finding.29 The APOLLO 3 study showed that NT-proBNP in ATTR amyloidosis is a strong predictor of survival.42 Patients with NT–proBNP levels of >3,000 ng/l have 19.3-fold greater mortality risk than those with levels below 3,000 ng/l. Other studies have shown NT– proBNP levels have a similar predictive value in AL amyloidosis.25

Management Treatment of Amyloidosis

Using a heart-to-contralateral ratio >1.5, consistent with intensely diffuse myocardial tracer retention, had a 97 % sensitivity and 100 % specificity for identifying ATTR CA.33 Another study on a smaller number of patients showed that 99mTc–DPD uptake, as measured by visual scoring, has 100 % sensitivity and specificity for ATTR CA.34 Various specialized CA centers have started to use this in combination with different biomarkers as a substitute for myocardial biopsy for diagnosing ATTR CA.

Treatment of amyloidosis depends on its type. AL amyloidosis is a plasma cell dyscrasia, and chemotherapy has been used to target the plasma cells with alkylating agents (e.g. cyclophosphamide), proteasome inhibitors (e.g. bortezomib), immunomodulators (e.g. pomalidomide), and anti-CD-38 monoclonal antibodies (IgG1-kappa, e.g. earatumumab). The goal of the therapy is to achieve hematological response, defined as the normalization of serum free light chain, and negative serum and urine monoclonal immunofixation. Triple chemotherapy with bortezomib, dexamethasone and an alkylating agent for AL CA has been shown to improve survival when hematological response was achieved.43,44 Daratumumab, reserved currently for relapsed or refractory cases, yielded rapid hematologic response in 76 % of patients with AL CA in a recent study.45 Monoclonal antibodies targeting amyloid fibrils in AL amyloidosis are in the phase of clinical trials and will hopefully provide a selective, targeted therapy for patients with AL CA.46

Tissue biopsy is the gold standard for diagnosing and subtyping amyloidosis. Endomyocardial biopsy (EMB) is usually carried out if

ATTR amyloidosis therapies are targeted at the gene (TTR silencers), the unstable protein (TTR stabilizers) and the amyloid fibril (disruptors).

A: Low power (2x) image showing diffuse amyloid deposition (arrows). B: High power (20x) image showing eosinophilic, amorphous material amalgamating between cardiac myocytes. C: Congo red staining under standard light confirmed the diagnosis of amyloid deposition. Subsequent polarized light staining also confirmed the diagnosis (image not shown).

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Amyloid Heart Disease TTR silencers are either small interfering RNA (siRNA) or antisense oligonucleotides that target TTR messenger RNA in the hepatocyte, halting the production of TTR protein. Patisiran is a siRNA that was found to improve quality of life in patients with CA in the APOLLO 3 trial. In recent multicenter double-blind, placebo-controlled, clinical trial, Tafamidis, a TTR stabilizer showed improvement in all-cause mortality and quality of life with reduction in cardiovascular hospitalizations in patients with CA treated compared to placebo.47 Amyloid fibril disrupters, such as doxycycline with tauroursodeoxycholic acid, and green tea extracts, have been studied in small, open label studies, and showed no progression of wall thickness or decreased thickening of interventricular septal wall at 1 year.48,49

associated with CA that may lead to hypotension. This complication can be managed with midodrine. Torsemide has greater bioavailability than furosemide and is therefore preferred because of malabsorption syndrome associated with CA, directly from AL amyloidosis or from gut edema from HF. Angiotensin-converting enzyme inhibitors are not tolerated, usually because of autonomic dysfunction. Calcium channel blockers can bind to amyloid fibrils, causing a greater negative inotropic effect. Digoxin can bind to amyloid fibrils but has no role in HF management. Beta-blockers tend to cause fatigue and worsen HF, so are usually avoided. Anticoagulation should be considered in patients with CA, especially those with the AL type, because of their increased risk of thrombosis.26

Treatment of Advanced Heart Block

Conclusion

If heart block develops, permanent pacemaker implantation should be considered.

Cardiac amyloidosis, especially ATTR amyloidosis, is not as rare as previously thought. The advancement in cardiac imaging technologies, especially CMR, facilitated the early diagnosis of this disease and could potentially substitute the need for tissue diagnosis. With the recent development of effective life-prolonging therapies, there is compelling need to early diagnose and treat CA. ■

Treatment of Heart Failure Diuresis is the mainstay of HF management in patients with CA. This is usually a challenge, because there is commonly autonomic dysfunction

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29. M aceira AM, Joshi J, Prasad SK, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111:186–93. https://doi.org/10.1161/01.CIR.0000152819.97857.9D; PMID: 15630027. 30. Fontana M, Chung R, Hawkins PN, Moon JC. Cardiovascular magnetic resonance for amyloidosis. Heart Fail Rev 2015;20:133– 44. https://doi.org/10.1007/s10741-014-9470-7; PMID: 25549885. 31. Barison A, Aquaro GD, Pugliese NR, et al. Measurement of myocardial amyloid deposition in systemic amyloidosis: insights from cardiovascular magnetic resonance imaging. J Intern Med 2015;277:605–14. https://doi.org/10.1111/joim.12324; PMID: 25346163. 32. Kuetting DL, Homsi R, Sprinkart AM, et al. Quantitative assessment of systolic and diastolic function in patients with LGE negative systemic amyloidosis using CMR. Int J Cardiol 2017;232:336–41. https://doi.org/10.1016/j.ijcard.2016.12.054; PMID: 28153537. 33. Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc–pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretinrelated familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6:195–201. https://doi.org/10.1161/ CIRCIMAGING.112.000132; PMID: 23400849. 34. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–84. https://doi.org/10.1016/j.jacc.2005.05.073; PMID: 16168294. 35. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122:900–9. https://doi.org/10.1161/ CIRCULATIONAHA.109.924167; PMID: 20713901. 36. Pellikka PA, Holmes DR Jr, Edwards WD, et al. Endomyocardial biopsy in 30 patients with primary amyloidosis and suspected cardiac involvement. Arch Intern Med 1988;148:662–6. https://doi.org/10.1001/archinte.1988.00380030168027; PMID: 3341867. 37. Ardehali H, Qasim A, Cappola T, et al. Endomyocardial biopsy plays a role in diagnosing patients with unexplained cardiomyopathy. Am Heart J 2004;147:919–23. https://doi. org/10.1016/j.ahj.2003.09.020; PMID: 15131552. 38. Ikeda S, Sekijima Y, Tojo K, Koyama J. Diagnostic value of abdominal wall fat pad biopsy in senile systemic amyloidosis. Amyloid 2011;18:211–5. https://doi.org/10.3109/13506129.2011.6 23199; PMID: 22004460. 39. Garcia Y, Collins AB, Stone JR. Abdominal fat pad excisional biopsy for the diagnosis and typing of systemic amyloidosis. Hum Pathol 2018;72:71–9. https://doi.org/10.1016/j. humpath.2017.11.001; PMID: 29133141. 40. Ansari-Lari MA, Ali SZ. Fine-needle aspiration of abdominal fat pad for amyloid detection: a clinically useful test? Diagn Cytopathol 2004;30:178–81. https://doi.org/10.1002/dc.10370; PMID: 14986298. 41. Klein AL, Hatle LK, Taliercio CP, et al. Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis. A Doppler echocardiography study. Circulation 1991;83:808–16.

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Advanced Heart Failure https://doi.org/10.1161/01.CIR.83.3.808; PMID: 1999031. 42. A dams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11–21. https://doi.org/10.1056/ NEJMoa1716153; PMID: 29972753. 43. Sperry BW, Ikram A, Hachamovitch R, et al. Efficacy of chemotherapy for light-chain amyloidosis in patients presenting with symptomatic heart failure. J Am Coll Cardiol 2016;67:2941–8. https://doi.org/10.1016/j.jacc.2016.03.593; PMID: 27339491. 44. Palladini G, Sachchithanantham S, Milani P, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL

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amyloidosis. Blood 2015;126:612–5. https://doi.org/10.1182/ blood-2015-01-620302; PMID: 25987656. 45. K aufman GP, Schrier SL, Lafayette RA, et al. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood 2017;130:900–2. https://doi.org/10.1182/blood-2017-01-763599; PMID: 28615223. 46. Richards DB, Cookson LM, Berges AC, et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N Engl J Med 2015;373:1106–14. https://doi. org/10.1056/NEJMoa1504942; PMID: 26176329. 47. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis

treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007–1016. https:// doi.org/10.1056/NEJMoa1805689; PMID: 30145929. 48. Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid 2012;19(sup1):34–36. https://doi.org/10. 3109/13506129.2012.678508; PMID: 22551192. 49. aus dem Siepen F, Bauer R, Aurich M, et al. Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an observational study. Drug Des Devel Ther 2015;9:6319–6325. https://doi.org/10.2147/DDDT.S96893; PMID: 26673202.

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Editor’s Pick

Management of Cardiovascular Disease During Pregnancy Nandita S Scott, MD, FACC Division of Cardiology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA

Abstract Cardiovascular disease is a leading cause of maternal death. The normal cardiovascular hemodynamic adaptations to pregnancy are remarkable, but tolerated without difficulty in the majority of women. However, in women with cardiovascular dysfunction, these adaptations may precipitate cardiovascular decompensation. Risk stratification of pregnancy risk should preferably take place before conception. Management of these women requires multidisciplinary involvement of all key areas, including cardiology, nursing, maternal/fetal medicine and obstetric anesthesia. For higher-risk lesions, pregnancy should be managed in centers with expertise in this field.

Keywords Pregnancy, heart disease, pregnancy-associated MI, multidisciplinary care, pre-eclampsia Disclosure: The author has no conflicts of interest to declare Submitted: August 10, 2018 Accepted: October 24, 2018 Citation: US Cardiology Review 2018;13(2):119–23. DOI: https://doi.org/10.15420/usc.2018.8.1 Correspondence: Nandita S Scott, Department of Medicine, Division of Cardiology, Massachusetts General Hospital, 55 Fruit Street, Yawkey 5B, Boston MA 02114. E: nsscott@mgh.harvard.edu

The US has the highest maternal mortality rate in the developed world, at an estimated 26.4 deaths per 100,000 live births. This rate is rising, although it is falling in other wealthy nations.1 Cardiovascular disease is a leading cause of maternal death, so cardiologists need to build on their knowledge and enhance their proficiency on the management of cardiovascular disease during pregnancy.2 There are numerous contributors of this rising risk, including advancing maternal age, pre-existing cardiovascular risk factors, the rise in multifetal pregnancies and survival to fertility age among childhood cancer survivors and women with congenital heart disease. Unlike most cardiovascular conditions, there are no large randomized controlled trials to guide decision-making, and guidelines are based principally on expert consensus. It is increasingly likely that a cardiologist will be called upon to manage these women, so it is incumbent upon them to understand the basic cardiovascular hemodynamics of pregnancy and fundamental risk stratification and management of these conditions.

Hemodynamics of Pregnancy The normal cardiovascular hemodynamic adaptations to pregnancy are remarkable but tolerated without difficulty in the majority of women. In women with cardiovascular dysfunction, however, these adaptations may precipitate cardiovascular decompensation. Hemodynamic changes begin in the first trimester, with a 30–50 % rise in cardiac output, driven by an increase in stroke volume and, to a lesser extent, heart rate. Systemic vascular resistance falls as a result of endogenous vasodilators, as well as flow into the low-resistance

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uteroplacental unit. Red blood cell mass increases because of a rise in erythropoietin levels, though to a lesser extent than plasma volume, causing a dilutional anemia. Heart rate increases in the first trimester and reaches a peak in the early third trimester. Systemic blood pressure falls, reaches a nadir in the second trimester, then slowly increases to term.3 Notably, the supine position can cause a 24 % reduction in cardiac output, due to compression of the enlarging uterus on the inferior vena cava.4 This position can also increase afterload because of aortic compression. This is particularly important to consider during maternal cardiac arrest, at which time manual left lateral uterine displacement should be performed if the uterus can be palpated at or above the umbilicus.5 During labor and delivery, cardiac output is further increased because of auto transfusion from the contracting uterus as well as an increase in heart rate because of maternal pain during labor. Epidural anesthesia can produce transient hypotension resulting from acute venous and arterial dilatation, but then leads to improved hemodynamic stability because of attenuation of the effects on blood pressure and heart rate responses. Despite delivery, the postpartum phase remains an active period for the cardiovascular system and this is often when maternal decompensation occurs. There is further auto transfusion from uterine involution and mobilization of dependent edema. Because of the loss of the low vascular resistance placental unit, afterload increases. These adaptations are more marked in multifetal pregnancies.3 The normal echocardiogram in pregnancy reflects cardiac remodeling secondary to these physiologic changes. Left ventricular mass increases with eccentric hypertrophy and dilatation of all chambers can occur, although absolute values should remain in the normal range. Velocities across the valves increase and physiologic valvular regurgitation is noted

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Editor’s Pick in the tricuspid, pulmonary and mitral valves, but not the aortic valve at term. A small pericardial effusion can be seen in normal pregnancy. Diastolic function, as measured by load-independent indices, such as tissue Doppler imaging, are unchanged during pregnancy despite the increase in preload and physiologic hypertrophy.6–9

Risk Stratification When considering pregnancy in a woman with heart disease, the following factors must be considered: maternal risks of morbidity and mortality; fetal risks of preterm birth, growth restriction or death; risk of congenital heart disease in the baby; and the risk of pregnancy on longterm maternal outcome.3 Patient counseling regarding the risks of pregnancy should ideally take place before conception. This allows informed decision-making about pregnancy risk and the optimization of maternal status, including careful review of potentially teratogenic medications and the use of alternatives. Several risk estimation models exist, notably the CARPREG, Zahara and WHO classification schemes.10–12 The original CARPREG risk score includes four variables: prior cardiac event; New York Heart Association (NYHA) functional classification status; impaired systemic ventricular function; and left-sided obstruction. The Zahara model is based exclusively on women with congenital heart disease and includes eight factors: history of arrhythmia; cardiac medications prior to pregnancy; NYHA status; moderate/severe systemic atrioventricular (AV) valve regurgitation; moderate/severe pulmonary AV valve regurgitation; left heart obstruction; the presence of a mechanical valve; and cyanotic heart disease. The third model, the WHO risk classification, defines specific conditions within a category of 1 through to 4, where women in category 4 are advised against pregnancy. A comparison of these three risk estimation methods demonstrated that all three models were predictors of maternal cardiac risk with the WHO classification having the best discriminatory capabilities.13 More recently, the CARPREG investigators derived an additional comprehensive risk stratification scheme named CARPREG II (Table 1).14 The predicted risk of primary cardiac event was 5 % with a score of 1, 10 % for a score of 2, 15 % with a score of 3, 22 % for a score of 4 and 41 % if the score was greater than 4 points. Maternal cardiac death was rare, occurring in 0.6 % of women, with adverse cardiac events being mostly driven by arrhythmias and congestive heart failure. When all four risk scores were applied to the CARPREG II study group, the CARPREG II score was found to have the highest discriminatory ability. Even women in the lowest risk group had a 5 % risk of cardiac complications, suggesting there should be a low threshold for assessment by a cardiologist with expertise in pregnancy management.14

Multidisciplinary Care The care of pregnant women with heart disease involves several stakeholders with different perspectives but common goals: delivery of a healthy baby and a mother free of cardiac complications. This team should include an obstetric anesthesiologist, maternal fetal medicine specialist, nursing staff and a cardiologist with expertise in the management of pregnant women. This group should meet regularly to discuss, anticipate and plan for any difficulties that could arise, as well as discuss strategy

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for labor, delivery and postpartum care. This multidisciplinary strategy is critical in a field where management often runs in a data-free zone because large randomized controlled trial data are lacking. Depending on maternal and fetal status, this treatment plan could run along the spectrum of usual labor and delivery procedures with no additional monitoring to labor and delivery in the intensive care unit with invasive hemodynamic monitoring. The early postpartum period is a time of particularly high risk for many reasons, including further auto transfusion from uterine involution and mobilization of dependent edema (increasing preload) and loss of the low vascular resistance placental unit (increasing afterload). Therefore, many women would benefit from being monitored postpartum on a cardiology floor where volume overload can be detected and managed promptly and there is access to telemetry monitoring. In centers with no clinical expertise on pregnancy management, women can be referred to a specialized center for initial consultation. Recommendations for treatment can then be made, including whether the patient should deliver locally or at a tertiary care center. The advent of telemedicine should make these consultations more convenient for women in remote locations.

Anticoagulation for Mechanical Heart Valves Women with mechanical heart valves have an elevated risk of complications during pregnancy and only a 58 % chance of a having an uncomplicated pregnancy with a live birth.15 The use of anticoagulants during pregnancy is challenging and influenced by a hypercoagulable state and changes in the volume of distribution and creatinine clearance. Warfarin crosses the placenta and increases the risks of embryopathy, miscarriage and stillbirth, particularly at doses over 5 mg, but has favorable effects for the prevention of valve thrombosis.16 Low molecular weight heparin (LMWH) does not cross the placenta and is therefore safe for the fetus, which suggests that it would be an ideal anticoagulant; however, available data indicates it is linked with a higher risk of valve thrombosis than warfarin.17 This may be related to inadequate and inconsistent monitoring of anti-Xa levels during pregnancy and warrants further investigation. Current guidelines on the management of anticoagulation during pregnancy are based on retrospective series, many which have a large representation of ball and cage heart valves, which is clearly not compatible with the contemporary landscape of pregnancy-aged women with mechanical heart valves. The current American College of Cardiology/American Heart Association (ACC/AHA) 2014 valve guidelines recommend warfarin during the first trimester of pregnancy if the dose is less than 5 mg or alternatively LMWH or unfractionated IV heparin. Warfarin is recommended during the second trimester with aspirin, regardless of warfarin dose, and then there is a transition to IV unfractionated heparin closer to term in anticipation of labor and delivery.18 The transition period of anticoagulant switch during the first trimester is often the time of greatest risk of valve thrombosis, so careful monitoring during that period is required.15 The ACC/AHA guidelines suggest measuring peak anti-Xa levels with a target of anti-Xa level of 0.8–1.2 U/ml 4–6 hours post dose, but there is data suggesting that, even if peak levels are adequate, the trough level is often subtherapeutic.19 Ultimately, the choice of anticoagulant during pregnancy should involve

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Heart disease and pregnancy careful discussion of the risks and benefits of each strategy between the patient and provider.

Acute MI During Pregnancy Fortunately, pregnancy-associated acute MI (PAMI) is uncommon, although its incidence is increasing and in-hospital mortality remains high at 4.5 %. In a recent analysis of pregnancy-related hospitalizations, 8.1 cases per 100,000 hospitalizations were identified, the majority occurring in the postpartum period. Women with PAMI are older and more likely to have traditional cardiovascular risk factors, as well as gestational diabetes or pre-eclampsia, than those without. In-hospital mortality is much higher in PAMI than in MI not associated with pregnancy, with an adjusted odds ratio of 39.9.20 Although acute MI is uncommon among reproductive-aged women, the risk of acute MI is increased three- to fourfold during and immediately following pregnancy compared to nonpregnant women of the same age.21,22 The predominant mechanism of acute MI during pregnancy is felt to be spontaneous coronary artery dissection (SCAD) and, in the largest series to report angiographic findings of pregnant women who had experienced an MI, SCAD was found in 43 %, 27 % had atherosclerosis, 17 % had coronary thrombosis, 3 % had vasospasm and 3 % had takotsubo cardiomyopathy. An additional 9 % had coronary arteries that looked normal at angiography, which could have represented transient spasm, thrombosis with endogenous lysis or unrecognized SCAD.23 Women with pregnancy-associated SCAD are more likely to have ST segment elevation infarctions, left main or multivessel disease and more marked left ventricular systolic dysfunction than those with SCAD unrelated to pregnancy.24 The diagnosis of PAMI is based on symptoms, an EKG suggestive of abnormalities and cardiac biomarkers. CK-MB levels have been shown to increase following labor and delivery in normal pregnancies and may exceed the upper limit of normal during this period. Troponin, as measured by conventional assays, typically remains normal during normal pregnancy and delivery.25 In one study using a high-sensitivity troponin assay, 4.3 % of women had a troponin level above the upper limit of normal for up to 24 hours postpartum, without any correlation to outcomes, so the significance of this troponin elevation is unclear.26 Until there is further data, any troponin elevation during pregnancy should be further investigated. The management of PAMI is individualized. However, in the presence of hemodynamic instability, heart failure or refractory chest pain, angiography is warranted. As a high proportion of PAMI cases are caused by SCAD, in which coronary angiography can propagate dissection, methods to reduce coronary manipulation are recommended such as avoiding deep catheter engagement of the coronary ostia and gentle contrast injections.27 Coronary CT may have an emerging role in the population of patients who are at a lower risk with suspected SCAD, and provides additional data on the vessel wall such as presence of plaque, intramural hematoma or dissection. Women with PAMI who are pregnant should generally be triaged to an intensive care unit with obstetric capabilities and contingency planning for emergent delivery in the event of maternal deterioration.

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Table 1: CARPREG II Risk Predictors Predictor

Points

Prior cardiac events or arrhythmias

Baseline NYHA 3–4 or cyanosis

Mechanical valve

Systemic ventricular dysfunction LVEF<55 %

High-risk valve disease or left ventricular outflow tract

obstruction (aortic valve area <1.5 cm2, subaortic gradient >30, or moderate to severe mitral regurgitation, mitral stenosis < 2.0 cm2) Pulmonary hypertension, RVSP >49 mmHg

High-risk aortopathy

Coronary artery disease

No prior cardiac intervention

Late pregnancy assessment

Primary cardiac event risk: score = 1, 5 % risk, score = 2, 10 % risk, score = 3, 15 % risk, score = 4, 22 % risk and 41 % risk if score greater than 4. NYHA = New York Heart Association Functional Classification; LVEF = left ventricular ejection fraction; RVSP = right ventricular systolic pressure. Source: Silversides et al., 2018, with permission from Elsevier.14

Medical management in those with PAMI includes usual MI care with some caveats. Thrombolytic agents do not cross the placenta but raise the risks of preterm labor, spontaneous abortion, placental abruption and bleeding.28 Glycoprotein IIb/IIIa inhibitors are not advised during pregnancy or lactation because data is limited, and thienopyridines are not recommended for breastfeeding women.27 Beta-blockers have been associated with fetal growth restriction, but should be used in pregnancy when the benefits outweigh the risk. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, renin inhibitors and mineralocorticoid receptor antagonists are contraindicated in pregnancy. ACE inhibitors can be started post partum and are considered safe during lactation, with preference for benazepril, captopril, enalapril, and quinapril.29 Statins are contraindicated during pregnancy and lactation. Epidural anesthesia is an important aspect of the care of women as it limits hemodynamic fluctuations during labor and delivery. However, thienopyridines should be not be administered for 7 days before placement of an epidural anesthesia catheter.30 In general, vaginal delivery is preferred for most women with PAMI, and cesarean delivery is generally reserved for obstetric indications.

Congestive Heart Failure The diagnosis of congestive heart failure (CHF) during pregnancy is challenging, as heart failure symptoms can mimic those of normal pregnancy. Symptoms such as dyspnea, orthopnea, paroxysmal nocturnal dyspnea and peripheral edema do not necessarily represent pathology in pregnant women. Although plasma volume and cardiac output increase during pregnancy, the jugular venous pressure does not, due to increased pulmonary vascular capacitance. Therefore, this is a reliable physical exam tool in the diagnosis of clinical CHF. One would expect, because of the increased plasma volume and chamber stretch during pregnancy, that the values of B-type natriuretic peptide (BNP) and its amino-terminal pro-peptide equivalent would

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Editor’s Pick increase. Current data suggest that they do but they do not rise above the normal range, so they retain their negative predictive value for heart failure in pregnancy.31,32 In one study of 773 healthy women, BNP rose in late pregnancy and the early postpartum period in 6.1 % of these women, who remained asymptomatic and without clinical evidence of cardiovascular pathology.33 Therefore, elevated BNP does not necessarily signify clinically significant cardiovascular dysfunction; however, until supported by further data, an elevated BNP should continue to prompt further clinical evaluation.

Pre-eclampsia and Future Cardiovascular Disease Risk

Once a diagnosis of congestive heart failure and left ventricular systolic dysfunction has been made, the additional challenge is determining the etiology. Pregnancy can often precipitate clinical heart failure in women with pre-existing but unknown cardiovascular disease, because of the increase in cardiovascular demands on the heart during pregnancy. Clues may be found in a family history of cardiomyopathy, previous pregnancy, later presentation during pregnancy and prior non-pregnant imaging. A dilated cardiomyopathy may be clinically indistinguishable from a new peripartum cardiomyopathy initially. However, women with peripartum cardiomyopathy have a significantly better prognosis over time than those with dilated cardiomyopathy.34

Pre-eclampsia and hypertensive disorders of pregnancy are a major cause of maternal and fetal death.36 The management of hypertension during pregnancy balances the risk to the fetus (hypotension, effects on fetal growth and medication exposure) and risk for severe maternal hypertension. It is important to note that the goals of lowering blood pressure are not to reduce the risk for pre-eclampsia. A study evaluating tight (diastolic blood pressure 85 mmHg) versus less tight (diastolic blood pressure 100 mmHg) blood pressure control in pregnancy did not show any significant difference in the risks for pregnancy loss, high level neonatal care and overall maternal complications between the groups. Less tight control was, however, associated with a higher frequency of severe maternal hypertension.36 A subsequent meta-analysis of 15 studies demonstrated similar findings.37 The American College of Obstetricians and Gynecologists recommend treating blood pressure >160/105 mmHg during pregnancy to reduce the risk of maternal complications. For pregnant women without end organ damage and blood pressure <160/105 mmHg, pharmacologic antihypertensive therapy is not recommended. For women being treated for chronic hypertension during pregnancy, blood pressure goals are 120–160/80–105 mmHg.38

Peripartum cardiomyopathy is defined as the development of idiopathic heart failure and a left ventricular ejection fraction of <45 % occurring late in pregnancy or in the months following delivery. Incidence varies geographically, with pockets of greater prevalence in South Africa, Nigeria and Haiti.35 Management during pregnancy is similar to that for non-pregnant patients, with the caveats of avoiding medications that are harmful to the fetus and decision-making surrounding the timing of delivery. Although the decision is individualized, the principle that a longer gestational age is preferred remains true, especially if maternal cardiovascular status can be stabilized. Pre-term delivery is reserved for maternal instability and cardiogenic shock.

Although delivery of the fetus and time resolves the clinical findings of pre-eclampsia, there remains potential long-term sequelae to this disorder. Women who have developed pre-eclampsia are at an increased risk of heart failure, coronary artery disease, death from cardiovascular disease and stroke.39 This is particularly true in those who develop early pre-eclampsia and require pre-term delivery.40 It is therefore important that cardiologists inquire about pregnancy history when considering cardiovascular risk factors. Subsequently, they should counsel women with a history of pre-eclampsia to optimize their cardiovascular risk factors and lifestyle. Future studies should clarify the mechanisms surrounding this increased risk and guide strategies for risk reduction.

Mode of Delivery

Conclusion

Despite the increased hemodynamic burden of labor and delivery, including a further increase in heart rate, stroke volume and cardiac output, vaginal delivery remains the optimal method of delivery. Cesarean section increases the risk of maternal infection, leads to great hemodynamic shifts and blood loss, brings a risk of surgical injury and raises the likelihood of thrombotic events.12 Although there is no consensus over absolute contraindications for vaginal delivery, cesarean section can be considered for some women with certain cardiac conditions, including preterm labor in those receiving full oral anticoagulation, Marfan’s syndrome with an aorta over 45 mm, acute or chronic aortic dissection, and intractable heart failure. Generally, cesarean section is reserved for obstetrical indications.

Cardiovascular disease is a leading cause of maternal death. Cardiovascular training programs are increasingly providing education on the management of cardiovascular disorders during pregnancy and it is increasingly likely that cardiologists will be called upon to manage these women.

BD 2015 Maternal Mortality Collaborators. Global, regional, G and national levels of maternal mortality, 1990–2015: a systemic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1775–812. https://doi.org/10.1016/S01406736(16)31470-2; PMID: 27733286. Building US Capacity to Review and Prevent Maternal Deaths. Report From Maternal Mortality Review Committees: A View Into Their Critical Role. Maternal Mortality Review; 2017. Available at: www. cdcfoundation.org/sites/default/files/upload/pdf/MMRIAReport. pdf (accessed November 2, 2018). Johnson M, von Klemperer K. Cardiovascular changes in normal pregnancy. In: Steer PJ, Gatzoulis MA (eds). Heart Disease and

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There are, however, many unanswered questions on optimal care and clinicians are often working in data-free zones. Fortunately, this field is increasingly being covered at national meetings and research appears to be progressing at a faster pace than in previous decades. It is therefore likely that more data will become available over time on the optimal treatment of these women during pregnancy to improve outcomes for both mother and fetus. n

Pregnancy. Cambridge: Cambridge University Press, 2016;19–28. https://doi.org/10.1017/CBO9781316156063.005. Rossi A, Cornett J, Johnson MR, et al. Quantitative cardiovascular magnetic resonance in pregnant women: a cross-sectional analysis of physiological parameters throughout pregnancy and the impact of the supine position. J Cardiovasc Magn Reson 2011;13:31. https://doi.org/10.1186/1532-429X-13-31; PMID: 21708015. Jeejeebhoy FM, Zelop CM, Lipman S, et al. Cardiac arrest in pregnancy: a scientific statement from the American Heart Association. Circulation 2015;132:1747–73. https://doi. org/10.1161/CIR.0000000000000300; PMID: 26443610.

immons LA, Gillin AG, Jeremy RW. Structural and functional S changes in left ventricle during normotensive and preeclamptic pregnancy. Am J Physiol Heart Circ Physiol 2002;283:H1627–33. https://doi.org/10.1152/ajpheart.00966.2001; PMID: 12234817. Campos O, Andrade JL, Bocanegra J, et al. Physiologic multivalvular regurgitation during pregnancy: a longitudinal Doppler echocardiographic study. Int J Cardiol 1993;40:265–72. https://doi.org/10.1016/0167-5273(93)90010-E; PMID: 8225661. Abduljabbar HS, Marzouki KM, Zawawi TH, Khan AS. Pericardial effusion in normal pregnant women. Acta Obstet Gynecol Scand 1991;70:291–4. https://doi.org/10.3109/00016349109007874; PMID: 1746251.

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