PracticeUpdate Cardiology March 2019

VOL. 4 • NO. 1 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4672

More Top Stories 2018 Aspirin Primary Prevention Trials Cardiovascular Outcome Studies: REDUCE-IT Expert Opinion Practical Considerations and Utility of SGLT2 Inhibitors in Improving CV Outcomes Interviewwith Silvio E. Inzucchi MD My Approach to StemCell Therapy for Heart Failure Patients By Eugenio Cingolani MD

International Stroke Conference 2019

JOURNAL SCANS Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome: A Systematic Review and Meta-Regression Study

Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial

Workplace Bullying and Workplace Violence as Risk Factors for Cardiovascular Disease: A Multi-Cohort Study

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FH: Familial hypercholesterolaemia; LDL-C: Low-density lipoprotein cholesterol.

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PBS Information: Authority Required. Familial heterozygous and homozygous hypercholesterolaemia. Refer to PBS Schedule for full Authority Required information. PLEASE REFER TO FULL PRODUCT INFORMATION BEFORE PRESCRIBING. AVAILABLE FROM AMGEN AUSTRALIA PTY LTD, PH: 1800 803 638 OR AT WWW.AMGEN.COM.AU/REPATHA.PI For more information on Repatha ® , or to report an adverse event or product complaint involving Repatha ® , please contact Amgen Medical Information on 1800 803 638. Indication: Prevention of cardiovascular events (CVD) (myocardial infarction, stroke and coronary revascularisation) in adults given in combination with an optimally dosed statin and/or other lipid-lowering therapies; Primary hypercholesterolaemia (heterozygous familial hypercholesterolaemia and non-familial hypercholesterolaemia) in adults, given in combination with diet, exercise and a statin, or statin with other lipid-lowering therapies or alone in statin-intolerant patients; Homozygous familial hypercholesterolaemia (HoFH) 12 years and above given in combination with diet, exercise and other lipid-lowering therapies. Contraindications: Sensitivity to evolocumab or excipients. Precautions: Hypersensitivity reactions. Concomitant lipid-lowering therapies – check all relevant prescribing information. Effect of long term Low LDL-C levels unknown. Immunogenic potential. Pregnancy Category: B1. Caution – breastfeeding. Drug interactions – approx. 20% increase in clearance of Repatha co-administered with statins with no adverse impact on pharmacodynamic effect of Repatha. Adverse Reactions: Common – nasopharyngitis, upper respiratory tract infection, influenza, back pain, arthralgia, nausea, sinusitis, upper abdominal pain, gastroesophageal reflux disease, gout, insomnia, blood creatine phosphokinase increased, diarrhoea, dizziness, gastroenteritis, rash, palpitations, injection site reactions. Dosage & Administration: Subcutaneous. Aim:decrease low-density lipoprotein – cholesterol (LDL-C).Primary hypercholesterolaemia and prevention of CVD:140 mg every 2 weeks or 420 mg monthly.HoFH: Initial dose 420mg monthly. Increase to 420mg fortnightly if meaningful response not achieved in 12 weeks. Patients on apheresis may initiate at 420mg fortnightly with apheresis schedule. Min PI based on full PI dated 6 August 2018 and available on request. Reference: 1. Repatha Product Information. Available at www.amgen.com.au/Repatha.PI. 2. Raal FJ et al. Lancet 2015;385:331-40. 3. Pharmaceutical Benefits Scheme. Available at: www.pbs.gov.au.

Amgen Australia Pty Ltd. ABN 31 051 057 428. Level 7, 123 Epping Road, North Ryde NSW 2113. ©2018 Amgen Inc. All rights reserved. AU-10386. Date of preparation: November 2018. AMG3393/FP

CONTENTS 3

TOP STORIES 2018 5 Aspirin Primary Prevention Trials By Joerg Herrmann MD 6 Are Omega-3 Fatty Acids Cardioprotective? It Depends…. By Peter Libby MD 7 Cardiovascular Outcome Studies: REDUCE-IT By Benjamin Morgan Scirica MD

RESEARCH Editor’s picks 8 Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome

Comment by Francesco Pelliccia MD, PhD

20 Target: Stroke Phase II Improves Door-to- Needle Times in Acute Ischemic Stroke 21 Late Thrombectomy for Stroke Linked With Better Quality of Life Outcomes in DEFUSE 3 21 Some Stroke Patients May Benefit From Thrombolysis Beyond Standard 4.5-Hour Time Window 22 Minimally Invasive Surgery May be Option for Intracranial Hemorrhage 9 Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation Comment by Gervasio A. Lamas MD, FACC, FAHA, FESC 10 Circulating Blood-Based Biomarkers Associated With Prevalent Atrial Fibrillation Comment by Emile G. Daoud MD, FACC 11 Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study Comment by Stephan Achenbach Prof. Dr. med. 12 Intensive Blood Pressure Control Does Not Decrease Dementia Risk Comment by Clyde W. Yancy MD, MSc, MACC, FAHA, MACP, FHFSA 13 Impact of Atrial Fibrillation Ablation on Recurrent Hospitalization By Douglas P. Zipes MD 14 His Resynchronization vs Biventricular Pacing in Patients With Heart Failure and Left Bundle Branch Block Comment by Douglas P. Zipes MD 15 Workplace Bullying and Workplace Violence as Risk Factors for Cardiovascular Disease Comment by Viola Vaccarino MD, PhD

EXPERT OPINION 16

18 My Approach to Stem Cell Therapy for Heart Failure Patients: Not All Cells Are Created Equally By Eugenio Cingolani MD

Practical Considerations and Utility of SGLT2 Inhibitors in Improving CV Outcomes Interview with Silvio E. Inzucchi MD

19 Getting a B (as in Apolipoprotein B) Is Good Enough By Paul D. Thompson MD

CONFERENCE COVERAGE 20 International Stroke Conference 2019 By the PracticeUpdate Editorial Team

VOL. 4 • NO. 1 • 2019

PRACTICEUPDATE CARDIOLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Douglas Zipes MD Distinguished Associate Editors Joerg Herrmann MD Associate Professor

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ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-HomeMessage designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Cardiology provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Cardiology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Cardiology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The printing and distribution of this publication has been made possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It containscontentpublished inaccordancewith theeditorialpoliciesofElsevier’s PracticeUpdate.com. All content printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission to MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLMassumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Fish oil supplements/gettyimages.com PracticeUpdate Cardiology is published by Elsevier Australia ISSN 2206-4672 (Print) ISSN 2208-0228 (Online)

Benjamin Scirica MD Cardiologist and Director, Innovation, Cardiovascular Division, Brigham and Women’s

Professor, Professor Emeritus of Medicine,

of Medicine, Mayo Graduate School of Medicine, Rochester, Minnesota

Pharmacology and Toxicology; Emeritus Director, Division of Cardiology and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana

Hospital; Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Advisory Board

Deepak Bhatt MD, MPH, FACC, FAHA, FSCAI, FESC Professor of Medicine, Harvard Medical School; Executive Director, Interventional Cardiovascular Programs, Brigham and Women’s Hospital Heart & Vascular Center; Senior Physician, Brigham and Women’s Hospital, Boston, Massachusetts Peter Libby MD Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts J WilliamMcEvoy MB BCh BAO, MEHP, MHS, FRCPI Professor of Preventive Cardiology, National University of Ireland; Medical and Research Director, National Institute for Preventive Cardiology, Ireland; Adjunct Faculty Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins, Baltimore, Maryland

Paul Thompson MD Physician Co-Director, Hartford Healthcare Cardiovascular Institute, Hartford, Connecticut; Professor of Medicine, University of Connecticut, Storrs, Connecticut James Udelson MD Chief, Division of Cardiology; Director, Nuclear Cardiology Laboratory; Professor, Medicine and Radiology, Tufts University School of Medicine, Boston, Massachusetts Gary Webb MD Editor-in-Chief, ChiP Network and ACHD Learning Center; Consultant, Cincinnati Adult Congenital Heart Program; Emeritus Professor, Department of Pediatrics, University of Cincinnati, Ohio Clyde Yancy MD, MSc, MACC, FAHA, MACP, FHFSA Chief of Cardiology, Northwestern University, Feinberg School of Medicine; Associate Director, Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois

Editorial Contributors

Ashish Aggarwal MD Staff Physician, Interventional Cardiology, Providence Holy Cross Medical Center, Mission Hills, California

Samer Ajam MD Clinical Cardiac Electrophysiologist, Community Care Network Inc, Munster, Indiana

Jason Garlie MD Staff Cardiologist; Electrophysiologist, Metropolitan Heart and Vascular Institute, Minneapolis, Minnesota

Editor-in-Chief CENTERS OF EXCELLENCE Our centers of excellence in the treatment of cardiometabolic disease & diabetes and congenital heart disease leverage technology to create a collaborative and comprehensive way to improve patient care. These unique centers have the key advantage of a real world academic center as well as the features and enhancements that only PracticeUpdate and Elsevier can provide to foster an expert-led team approach that helps you stay ahead. CARDIOMETABOLIC DISEASE AND DIABETES FACULTY Associate Editors Richard E. Pratley MD Senior Investigator, Florida Hospital/Sanford–Burnham Silvio E. Inzucchi MD Professor of Medicine

(Endocrinology); Clinical Director, Section of Endocrinology; Director, Yale Diabetes Center; Director, Endocrinology and Metabolism Fellowship, Yale School of Medicine, New Haven, Connecticut

Translational Research Institute for Metabolism and Diabetes; Medical Director, Florida Hospital Diabetes Institute, Orlando, Florida Deborah Wexler MD, MSc Associate Professor of Medicine, Harvard Medical School; Associate Clinical Chief of the Diabetes Unit, Clinical Director, Massachusetts General Hospital Diabetes Center; Associate Program Director for Clinical Research, Internal Medicine Residency Program, Massachusetts General Hospital, Boston, Massachusetts

CONGENITAL HEART DISEASE FACULTY Editor-in-Chief Gary Webb MD

Associate Editors

George Ofori- Amanfo MD Chief, Division of Pediatric Critical Care Medicine, Mount Sinai Health System, Kravis Children’s Hospital, New York, New York

Christopher Spurney MD Associate Professor of Pediatrics, Children’s National Health System, Washington, DC

Editor-in-Chief, ChiP Network and ACHD Learning Center; Consultant, Cincinnati Adult Congenital

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Heart Program; Emeritus Professor, Department of Pediatrics, University of Cincinnati, Ohio

TOP STORIES 2018 5

Aspirin Primary Prevention Trials By Joerg Herrmann MD

Aspirin is an integral component of secondary prevention guidelines for patients with established cardiovascular diseases (CVD). Based results of meta-analyses, such as the ones by the Antithrombotic Trialists’ Collaboration over a decade ago, it reduces the risk of myocardial infarction (MI), stroke, and vascular death by 35%, 25%, and 15%, respectively. Following stroke and MI, the use of aspirin leads to 36 fewer events of recurrent MI, stroke, or vascular death per 1000 patients treated, outweighing the risk of 1 to 2 major bleeds per 1000 patients treated.

I n 2016, two systematic reviews/ meta-analyses conducted by the US Preventive Services Task Force (USP- STF) indicated that the efficacy of primary prevention with aspirin may be of the same magnitude, a 20% risk reduction, at a nearly 60% higher risk of major bleeding events and a 30% higher risk of hemorrhagic stroke. 1,2 A second systematic review further- more concluded on a 20% to 24% reduction in the incidence of colorectal cancer (CRC) and a 33% reduction in CRC mortality. These data fueled the grade B USPSTF recommendation for low-dose aspirin for primary prevention of CVD and CRC in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. For those aged 60 to 69 years with similar characteristics, the decision was to be an individual one. No recommendations could be given for those outside these age ranges. The 2012 American College of Chest Physicians evi- dence-based clinical practice guidelines suggest low-dose aspirin for primary pre- vention for individuals aged 50 and older. 3 The 2002 American Heart Association pri- mary prevention guidelines recommended the consideration of low-dose aspirin in persons at higher risk (especially those with 10-year CVD risk of 10%). 4 On the contrary, the 2016 European Society of Cardiology primary prevention guidelines recom- mended against it (class III). 5 Hence, not much of a surprise, there has been consid- erable uncertainty whether to pursue or not pursue aspirin for the purpose of primary prevention of CVD (and CRC).

In 2018, three randomized clinical trials pro- vided an answer to this pressing question. The three trials were ASCEND in diabetics, ARRIVE in patients at moderate calculated CV risk (an approximate 15% 10-year risk), and ASPREE in patients aged 70 years or older. 6-8 All three trials compared low- dose aspirin (100 mg daily) with placebo over 5 (ARRIVE and ASPREE) to 7.5 years (ASCEND), and their collective findings are as following: 1. no difference in MI and stroke rates; 2. no difference in CV mortality; 3. no difference in all-cause mortality in ASCEND and ARRIVE, and a small increase in risk with aspirin in ASPREE; and 4. higher risk of gastrointestinal malignancy among aspirin users in the ASPREE trial and a numerically higher but still overall small risk with aspirin in the ARRIVE trial. This is a “three strikes out” scenario for primary prevention aspirin all in a single year. Undoubtedly, the ASCEND, ARRIVE, ASPREE trial trio has changed the land- scape in preventive cardiology forever. These results are reinforcing some, while challenging a re-write of other, guidelines as much as they most likely will influence practice directly. When patients ask, or are confronted with the question in other ways, providers now know how to respond. The answer is found in three randomized con- trolled trials carefully conducted in nearly 50,000 patients across a wide range of possible scenarios that might have justi- fied primary prevention aspirin in the past, but no longer will – 2018, a major game changer, if you will.

References 1. Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016;164(12):836-845. 2. Dehmer SP, Maciosek MV, Flottemesch TJ, et al. Aspirin for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2016;164(12):777-786. 3. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e637S-e668S. 4. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002 Jul 16;106(3):388-391. 5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37(29):2315-2381. 6. ASCEND Study Collaborative Group, Bowman L, MafhamM, Wallendszus K, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379(16):1529-1539. 7. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo- controlled trial. Lancet 2018;392(10152):1036-1046. 8. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379(16):1509-1518. www.practiceupdate.com/c/76724

VOL. 4 • NO. 1 • 2019

Are Omega-3 Fatty Acids Cardioprotective? It Depends…. By Peter Libby MD TOP STORIES 2018 6

S ince the days of the eccentric Oxford Don Hugh Sinclair, many have ascribed cardioprotective and other benefits to diets enriched in omega-3 fatty acids. 1 Despite generations of observational stud- ies, and the heroic auto-experimentation of Sinclair, who consumed seal meat for 100 days and monitored his own bleeding time, many intervention studies with omega-3 fatty acids have proven disappointing. Among the exceptions, the GISSI-Prevenzione study showed a 15% reduction in cardiovascular endpoints driven primarily by sudden car- diac death in individuals taking 850 mg daily of a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 2 The Japan EPA Lipid Intervention Study (JELIS) led by Mitsuhiro Yokoyama exam- ined the effect of a higher dose of purified EPA (1800 mg/day) in Japanese individu- als receiving statin therapy. JELIS showed a 19% reduction in the primary cardiovascu- lar endpoint. 3 Yet, a number of other studies showed no benefit of omega-3 fatty acids, often administered as diet supplements rather than quality-controlled, pharmaceu- tical-grade products of known composition, and often in lower doses than employed in JELIS. 4 Two very recent studies involv- ing low doses of omega-3 fatty acids (1 g/ day, ASCEND and VITAL) showed no ben- efit of administration of a mixture of DHA and EPA. 5,6 In striking contrast to these recent null results, Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), presented by Dr. Deepak L. Bhatt at the American Heart Association

Scientific Sessions in November 2018, showed amarked reduction in cardiovascular events of 25% in the primary endpoint. 7 This study followed over 8000 individuals with median triglyceride concentrations at baseline of 216 mg/dL. The enrolled population had established cardiovascular disease, diabetes, or other risk factors for atherosclerosis. The participants randomly received 4 g daily of purified EPA ethyl esters or a mineral oil control. Most participants received statin therapy at baseline. The study followed patients for a median of almost 5 years. The participants receiving EPA had a decline in triglyceride concentrations of over 18%. Their baseline LDL was around 75 mg/ dL, and the median baseline high-sensitivity C-reactive protein (hsCRP) was about 2.2 mg/L. The omega-3 fatty acid treatment reduced all components of the primary and secondary composite endpoints significantly, save for all-cause mortality. The intervention did not cause excess serious bleeding, but it was associated with a slight but statistically significant increase in the reports of atrial fibrillation. Yet, there was a decrease in fatal or nonfatal stroke that was greater than or equal to the other components of the composite endpoints. Why did REDUCE-IT show a striking ben- efit while other recent and extremely well-conducted studies were null? First, the enrolled population in REDUCE-IT had hypertriglyceridemia. Evidence has snow- balled that triglyceride-rich lipoproteins, for which triglyceride concentrations serve as a biomarker, play a causal role in athero- thrombosis. 8 Secondly, the dose of EPA

used was substantially higher than in the recent null trials (4 vs 1 g/day). The mix- ture of pharmaceutical-grade EPA and DHA ethyl esters in VITAL and ASCEND differed from the purified EPA used in REDUCE-IT. Many of the trials included in the recent null meta-analysis used dietary supplements rather than pharmaceutical-grade omega-3 fatty acids. 4 These over-the-counter prepa- rations have uncertain quality control and may contain toxins or contaminants. Another well designed study, Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH), uses a mixture of EPA and DHA (4 g/day) in a population similar to that studied in REDUCE-IT. 9 STRENGTH may provide insight into whether the benefit observed in REDUCE-IT depends on the high EPA content of the treatment. What mechanisms may contribute to the striking reduction in atherothrombotic events observed in REDUCE-IT? Triglyceride lowering likely contributed part of the benefit. An anti-inflammatory effect, manifest by the reduction in hsCRP from about 2.2 to 1.8 mg/L, might also contribute to the event reduction. Alterations in prostaglandin metabolism and that of other lipid mediators including pro-resolving molecules might mediate some of the anti- inflammatory actions of EPA in high doses. Membrane stabilization may account for part of the apparent anti-arrhythmic benefit, manifest by the decline in sudden cardiac death. Altered metabolism of lipid mediators might also contribute to the

PRACTICEUPDATE CARDIOLOGY

TOP STORIES 2018 7

Cardiovascular Outcome Studies: REDUCE-IT By Benjamin Morgan Scirica MD

F or cardiovascular outcome studies, 2018 was a banner year. Many of the large tri- als of novel strategies for lipids, diabetes, inflammation, anticoagulation, and devices that reported last year truly deserve the label “land- mark,” and will change practice. But, among themall, my choice for the story of the year is the

Reduction of Cardiovascular Eventswith Icosapent Ethyl–Intervention (REDUCE-IT) trial, 1 which demonstrated that this purified formulation of eicosapentaenoic acid (EPA) markedly reduced cardiovascular events in 8179 patients whose fasting triglyceride levels were 135– 499 mg/dL and LDL levels were 41–100 mg/dL, as either a primary or secondary prevention strategy. EPA lowers triglycerides, and several formulations, including the one used in REDUCE-IT, are approved for use to lower triglycerides in patients with triglycerides >500 mg/dL. Before REDUCE-IT, though, no study ever demonstrated a cardiovascular benefit with targeted triglyceride-lowering, despite the clear association between elevated triglycerides and poor outcomes. The effect of EPA on cardiovascular events was greater than expected (HR, 0.75; P < .001 for the primary composite endpoint of CV death, MI, stroke, coronary revasculari- zation, and unstable angina) and was remarkably consistent among the individual components, including MI (HR, 0.69; P < .001), stroke (HR, 0.72; P = .01), coronary urgent or emergent revascularization (HR, 0.65; P < .001), and cardiovascular death (HR, 0.80; P = .03). Notably, the cardiovascular benefit of EPA was consistent regard- less of baseline LDL and triglyceride levels. EPA also lowered hsCRP by almost 40% compared with placebo, indicating that, in addition to lowering triglycerides, a reduction in inflammation may also be part of the mechanism by which EPA improves out- comes. There was some talk about the potential that the placebo, which contained mineral oil in order to maintain blinding, may have increased LDL and thus tilted the scale for EPA; however, the 5-mg/dL difference in LDL between the two groups would not explain the divergent rates of clinical events. How EPA will be incorporated into clinical guidelines and practice is still not clear. For the first time, there is now strong evidence for cardiovascular benefit with a non-LDL lowering lipid strat- egy. The triglyceride entry criteria of REDUCE-IT (135–499 mg/ dL) is much lower than the typical threshold for initiating triglycer- ide-lowering therapy and thus increases the size of the potentially eligible population. The LDL levels at baseline were lower in the REDUCE-IT trial compared with the two pivotal PCSK9 inhibitor outcome studies; however, the prioritization of further triglycer- ide- or LDL-lowering therapy after high-intensity statin/ezetimibe therapy remains to be determined in a population with mild to moderately elevated triglycerides and an LDL level between 50 and 100 mg/dL. In the search for reducing the residual risk of ath- erosclerotic cardiovascular disease, the compelling data from REDUCE-IT must broaden the focus of lipid therapy from only LDL to include triglycerides as well. Reference 1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018 Nov 10. doi: 10.1056/NEJMoa1812792. [Epub ahead of print.] www.practiceupdate.com/c/77103

anti-thrombotic effect, going back to the original observations of Sinclair in the mid-twentieth century. Regardless of the mechanisms, we now possess firm evidence from a superbly conducted and well-powered clinical trial that, on top of contemporary standard of care, the administration of a high dose (4 g/day) of a pharmaceutical-grade EPA can offer many cardiovascular benefits. These results have the potential of advancing the clinical care of individuals with or at high risk of coronary artery disease with hypertriglyceridemia, the population studied in REDUCE-IT. The results of REDUCE-IT offer consid- erable promise to patients in an era when conditions linked to hypertriglyceridemia such as obesity, insulin resistance, and dia- betes have become epidemic and drive considerable remaining risk for cardiovascular disease. References 1. Ewin J. Fine wines and fish oil: the life of Hugh Macdonald Sinclair. J R Soc Med 2002;95(5):263-264. 2. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354(9177):447-455. 3. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369(9567):1090-1098. 4. Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018;3(3):225-234. 5. Group ASC, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-1550. 6. Manson JE, Cook NR, Lee IM, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med 2018 Nov 10. doi: 10.1056/ NEJMoa1811403. [Epub ahead of print.] 7. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2018 Nov 10. doi: 10.1056/ NEJMoa1812792. [Epub ahead of print.] 8. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-776. 9. Nissen S, Lincoff AM, Nicholls S. Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia (STRENGTH). 2017;2017. www.practiceupdate.com/c/76801

VOL. 4 • NO. 1 • 2019

EDITOR’S PICKS 8

Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome JACC: Heart Failure

COMMENT By Francesco Pelliccia MD, PhD P atients with takotsubo syndrome (TTS) are commonly believed to have a good long-term outcome after the index episode. However, a new meta-analysis demonstrates that long-term rates of overall mortality and recurrence in patients discharged after TTS hospitalization are not trivial. The interesting new and important findings of this pooled analysis of 54 studies involving a total of 4679 patients with TTS were that the annual rate of total mortality was 3.5%, with a 1.0% annual rate of recurrence. In addition, meta- regression analysis showed that some presenting features (older age, physical stressor, and atypical ballooning) were significantly associated with an unfavorable long-term prognosis. This study, therefore, will be very useful to clinicians because it will help to iden- tify the subset of patients discharged alive after an episode of TTS who are more likely to experience a worse out- come in the long term. On the basis of the results of the new study, the possi- bility exists that stronger triggers (eg, physical stressor) that occur in more vul- nerable patients (eg, older adults) might result in a larger extent of myocardial damage, which, in turn, could lead to global left ventricular stunning in the acute phase (eg, atypical ballooning) and eventually to a worse outcome in the long term. episode of TTS who are more likely to experience a worse outcome in the long term. " " This study…will help to identify the subset of patients discharged alive after an

Take-home message • This systematic review and meta-regression analysis used data from 4679 patients with takotsubo syndrome (TTS) to examine long-term outcomes. The median fol- low-up was 28 months, and most (4077) of the patients were women. Although only 2.4% of patients died during the index admission, approximately 10% of surviving patients (464) died during the follow-up. The majority of deaths (351) after the index admission were due to noncardiac causes. The annual rate of recurrence was 1.0%. The yearly mortality rate did not vary significantly by length of follow-up, and there was a 3.5% annual rate of total long-term mortality. There were associations between the presence of a physical stressor, older age, and having atypical bal- looning and an increased risk of long-term mortality. • Although TTS is often considered benign, these findings suggest that it may have non-trivial risks of long-term mortality and recurrence that should be the subject of future prospective studies.

Abstract OBJECTIVES This study assessed the incidence of long-term adverse outcomes in patients with Takotsubo syndrome (TTS). BACKGROUND The long-term prognosis of TTS is controversial. It is also unclear whether pre- senting characteristics are associated with the subsequent long-term prognosis. METHODS We searched the PubMed, Embase, and Cochrane databases and reviewed cited references up to March 31, 2018 to identify stud- ies with >6 months of follow-up data. RESULTS Overall, we selected 54 studies that included a total of 4,679 patients (4,077 women and 602 men). Death during admission occurred in 112 patients (2.4%), yielding a frequency of 1.8% (95% confidence interval [CI]: 1.2% to 2.5%), with significant heterogeneity (I2 = 78%; p < 0.001). Dur- ing a median follow-up of 28months (interquartile range: 23 to 34months), 464 of 4,567 patients who the survived index admission died (103 because of cardiac causes and 351 because of noncar- diac issues). The annual rate of total mortality was 3.5% (95% CI: 2.6% to 4.5%), with significant

heterogeneity (I2 = 74%; p < 0.001). Overall, 104 cases of recurrence of TTS were detected during follow-up, yielding a 1.0%annual rate of recurrence (95% CI: 0.7% to 1.3%), without significant heter- ogeneity (I2 = 39%; p = 0.898). Meta-regression analysis showed that long-term total mortality in each study was significantly associated with older age (p = 0.05), physical stressor (p = 0.0001), and the atypical ballooning form of TTS (p = 0.009). CONCLUSIONS Our update analysis of patients discharged alive after TTS showed that long- term rates of overall mortality and recurrence were not trivial, and that some presenting fea- tures (older age, physical stressor, and atypical ballooning) were significantly associated with an unfavorable long-term prognosis. Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome: A Systematic Review and Meta-Regression Study. JACC Heart Fail 2019 Jan 02;[EPub Ahead of Print], F Pelliccia, V Pasceri, G Patti, et al. www.practiceupdate.com/c/78280

Dr. Pelliccia is Professor of Cardiology at Sapienza University School of Medicine in Rome, Italy.

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Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgitation Circulation Take-home message • Patients with chronic functional mitral regurgitation (MR) secondary to left ventricular (LV) dysfunction receiving standard heart failure therapy were randomized to receive sacubitril/valsartan or valsartan to compare outcomes. There was a significantly greater decrease in the effective regurgitant orifice area in the sacubitril/valsartan group compared with the valsartan group at 12 months. In addition, there was a significant decrease in the regurgitant volume in the sacubitril/valsartan group compared with the valsartan group. The rate of serious adverse events was similar in the two groups. • The use of sacubitril/valsartan among patients with secondary functional MR results in a greater reduction of MR than the use of valsartan. An angiotensin receptor neprilysin inhibitor should be considered when treating patients with functional MR secondary to heart failure.

COMMENT By Gervasio A. Lamas MD, FACC, FAHA, FESC T he PRIME study sheds an interesting light on the use of medical therapy in severe functional mitral regurgitation (MR). This mechanistic comparison of valsartan with sacu- bitril + valsartan in patients with functional MR suggests that that part of the effectiveness of angiotensin receptor–nepri- lysin inhibitors (ARNIs) may be related to reverse remodeling of the LV and subsequent reduction of mitral regurgitation. The study is designed simply and had excellent follow-up and methodology. There were 117 patients with an average EF of 34% and MR (principally nonischemic) with an effective regur- gitant orifice area (EROA) of 0.2 cm 2 . Regurgitant volume was also decreased by a mean difference of −7.3 mL (P = .009) favoring the sacubitril + valsartan group, which demonstrated a within-groups EROA reduction of 30%. Moreover, the difference in EDVI change favoring the sacubitril + valsartan group gives a hint as to the potential physiological underpinning of the MR reduction. That is, an ARNI may not be an MR drug, but rather an LV remodeling drug that secondarily reduces functional MR. An additional strength of this study lies in the concordance of results between the intention-to-treat group and the completers group (n=104). As pointed out, this study was heavily weighted toward nonischemic cardiomyo- pathies, and subgroup analysis of nonischemic vs ischemic myopathies may be considered in the future. Future outcome studies will be helpful in determining whether ARNIs should eventually take the place of ARBs or ACE inhib- itors in the treatment of functional MR. This is, however, an interesting and promising start.

Abstract BACKGROUND The morbidity and mortality of patients with functional mitral regurgitation (MR) remain high, but no pharmacological therapy has been proven effective. The hypothesis of this study was that sacubitril/valsartan would be superior to valsartan alone in improving functional MR via dual inhibition of the renin-angiotensin system and neprilysin. METHODS In this double-blind trial, we randomly assigned 118 heart fail- ure patients with chronic functional MR secondary to left ventricular (LV) dysfunction to receive either sacubitril/valsartan or valsartan, in addition to standard medical therapy for heart failure. The primary end point was the change in effective regurgitant orifice area (EROA) of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, LV end-systolic volume, LV end-diastolic volume and incomplete mitral leaflet closure area. RESULTS The decrease in EROA was significantly greater in the sacubitril/ valsartan group compared to the valsartan group (-0.058±0.095 versus -0.018±0.105 cm2; P=0.032) in an intention-to-treat analysis including 117 (99%) patients. Regurgitant volume was also significantly decreased in the sacubitril/valsartan group compared with the valsartan group (mean dif- ference -7.3 ml, 95% CI -12.6 to -1.9; P=0.009). There were no significant between-group differences regarding the changes in incomplete mitral leaflet closure area and LV volumes except LV end-diastolic volume index (P=0.044). We noted no significant difference in the change of blood pres- sure between the treatment groups and 7 patients (12%) in the sacubitril/ valsartan group and 9 (16%) in the valsartan group had one or more seri- ous adverse events (P=0.54). CONCLUSIONS Among patients with secondary functional MR, sacubitril/ valsartan reduced MR to a greater extent than did valsartan. Our find- ings suggest that an angiotensin receptor neprilysin inhibitor might be considered for optimal medical therapy of patients with heart failure and functional MR.

Dr. Lamas is Chairman of Medicine at Mount Sinai Medical Center in Miami Beach, Florida, and Professor of Medicine at Columbia University Medical Center in New York.

Angiotensin Receptor Neprilysin Inhibitor for Functional Mitral Regurgi- tation: The PRIME Study. Circulation 2018 Dec 05;[EPub Ahead of Print], DH Kang, SJ Park, SH Shin, et al. www.practiceupdate.com/c/77281

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Circulating Blood-Based Biomarkers AssociatedWith Prevalent Atrial Fibrillation European Heart Journal

Take-home message • Patients with known atrial fibrillation (AF) and patients without AF but with two or more CHA 2 DS 2 -VASc risk factors underwent measurement of 40 cardiac biomarkers to evaluate their association with AF. AF was associated with age, male gender, BMI, elevated BNP, elevated FGF-23, and reduced TRAIL receptor 2. There was no significant association seen with any other measured biomarkers. The use of biomarkers plus clinical factors was associated with improved AF prediction compared with the use of clinical factors alone. • The risk of AF may be predicted by three clinical factors (age, gender, and BMI) in conjunction with elevation of two biomarkers, BNP and FGF-23. Further study is needed to examine the mechanism by which FGF-23 is associated with AF risk.

COMMENT By Emile G. Daoud MD, FACC T his paper by Chua et al attempts to discern the best combination of clinical variables and serum bio- markers to identify patients with atrial fibrillation (AF). The proposed goal is that, with a reliable algorithm of clini- cal features/biomarkers, prediction of AF will be adequate and may serve as a basis for mass screening for patients with silent, asymptomatic AF. The article is incremental to our knowl- edge base, but the study findings need far more validation. In particu- lar, the study population was patients being hospitalized, and, thus, biomarker results (elevated brain natriuretic pep- tide and elevated fibroblast growth factor-23) and the presence of AF may be altered by the acute illness. Further- more, it is unclear if the biomarkers are only of value if the patient’s rhythm is currently AF, and what is the value of the biomarker for short-lived (<1-hour duration of AF) that occurred several weeks ago? Studies utilizing implanted devices have shown that this is a com- mon pattern of silent AF in patients presenting with stroke. Lastly, in addition to the costs related to mass screening using blood sam- ples and patient chart review, most physicians would likely not have the confidence to start medical therapy such as anticoagulation without ECG confirmation of AF. Certainly, identifica- tion of AF is of great importance, but the cornerstone diagnostic still remains an ECG recording. Hence, the next advances for mass screening may not come from the world of medicine but rather technology: Apple Watch.

Abstract AIMS Undetected atrial fibrillation (AF) is a major health concern. Blood biomarkers associated with AF could simplify patient selection for screening and further inform ongoing research towards stratified prevention and treatment of AF. METHODS AND RESULTS Forty common cardi- ovascular biomarkers were quantified in 638 consecutive patients referred to hospital [mean ± standard deviation age 70 ± 12 years, 398 (62%) male, 294 (46%) with AF] with known AF or ≥2 CHA2DS2-VASc risk factors. Parox- ysmal or silent AF was ruled out by 7-day ECG monitoring. Logistic regression with forward selection and machine learning algorithms were used to determine clinical risk factors, imaging parameters, and biomarkers associ- ated with AF. Atrial fibrillation was significantly associated with age [bootstrapped odds ratio (OR) per year = 1.060, 95% confidence inter- val (1.04-1.10); P = 0.001], male sex [OR = 2.022 (1.28-3.56); P = 0.008], body mass index [BMI, OR per unit = 1.060 (1.02-1.12); P = 0.003], ele- vated brain natriuretic peptide [BNP, OR per

fold change=1.293 (1.11-1.63); P=0.002], elevated fibroblast growth factor-23 [FGF-23, OR= 1.667 (1.36-2.34); P=0.001], and reduced TNF-related apoptosis-induced ligand-receptor 2 [TRAIL-R2, OR=0.242 (0.14-0.32); P=0.001], but not other biomarkers. Biomarkers improved the predic- tion of AF compared with clinical risk factors alone (net reclassification improvement =0.178; P<0.001). Both logistic regression and machine learning predicted AF well during validation [area under the receiver-operator curve=0.684 (0.62-0.75) and 0.697 (0.63-0.76), respectively]. CONCLUSION Three simple clinical risk factors (age, sex, and BMI) and two biomarkers (elevated BNP and elevated FGF-23) identify patients with AF. Further research is warranted to elucidate FGF-23 dependent mechanisms of AF. Data-Driven Discovery and Validation of Cir- culating Blood-Based Biomarkers Associated With Prevalent Atrial Fibrillation. Eur Heart J 2019 Jan 07;[EPub Ahead of Print], W Chua,

Dr. Daoud is Professor of Internal Medicine and Section Director of Electrophysiology at Ohio State University Medical Center in Columbus, Ohio.

Y Purmah, VR Cardoso, et al. www.practiceupdate.com/c/78558

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Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study JACC: Journal of the American College of Cardiology Take-home message • Patients with suspected coronary artery disease underwent coronary CTA to evaluate the prognostic implications of adverse coronary plaque characteristics. At least one adverse plaque feature was seen in 34% of patients. Patients with adverse plaque had a threefold risk of coronary heart disease death or nonfatal myocardial infarction compared with those without adverse plaque. The risk of coronary heart disease death or nonfatal myocardial infarction was doubled in those with obstructive disease. The combination of obstructive disease and adverse plaque was associated with a 10-fold increase in coronary heart disease death or nonfatal myocardial infarction compared with normal coronary arteries. • Adverse coronary plaque characteristics increase the risk of coronary heart disease death or nonfatal myocardial infarction.

COMMENT By Stephan Achenbach Prof. Dr. med. T he SCOT-HEART trial is a 5-year follow-up trial that ran- domized 4146 patients with suspected coronary artery disease to receive initial management by exercise testing only (usually exercise ECG) or exercise testing and coronary CTA. It showed that the 5-year rate of myocardial infarction was slightly but significantly lower in the CT group than in the “stand- ard care” group (2.3% vs 3.9%). 1 Williams et al now publish a secondary analysis of this trial. In 1769 participants, coronary CTA datasets were examined for the presence of plaque with “adverse plaque features” (suggesting plaque vulnerability). These features included positive remode- ling and plaque with low CT attenuation (<30 HU). In the 5-year follow-up, it was indeed shown that patients with these plaque features had a higher risk of events (coronary heart disease death or myocardial infarction) than patients without: the rates were 4.1% versus 1.4%, corresponding to a hazard ratio of 3.01 (95% CI, 1.61–5.63; P=.001). At first sight, there is an impressively elevated risk (“factor of 3“) and a result that creates the impression that patients with adverse plaque features may be at high event risk. However, one has to be aware that plaques with adverse plaque features were found in 34% of these symptomatic patients and that, even with such plaque, the 5-year event rate was only 4.1%, meaning that 96% of patients with such plaque had no event. Hence, the positive predictive value is

extremely low; so, it is difficult to draw any conclusions regarding potential management if such plaque were found. It is interesting to see that very similar results were found by Ferencik et al, who analyzed the PROMISE population. 2 In these 4415 patients with suspected CAD who were followed for 3 years, the presence of adverse plaque was associated with a 6.4% risk of coronary events (as opposed to 2.4% in individuals without adverse plaque features). The usual limitations apply to both trials – rather low-risk patients with atypical symptoms and patients were treated knowing the CT results. Overall, interesting results, but another important confirmation that in stable, symptomatic patients, event rates are very low – as these trials demonstrate, low event rates are present even if high-risk plaque is detected. A single plaque with potential high- risk features is therefore usually no cause for undue alarm. References 1. SCOT-HEART Investigators, Newby DE, Adamson PD, Berry C, et al. Coronary CT angiography and 5-year risk of myocardial infarction. N Engl J Med 2018;379(10):924-933. 2. FerencikM, Mayrhofer T, Bittner DO, et al. Use of high-risk coronary atherosclerotic plaquedetection for risk stratification of patientswith stable chest pain: a secondary analysis of the PROMISE randomized clinical trial. JAMACardiol 2018;3(2):144-152.

Dr. Achenbach is Chairman of the Department of Cardiology at Friedrich-Alexander-Universität Erlangen-Nurnberg in Germany.

Abstract BACKGROUND Unlike most noninvasive imaging modalities, coronary computed tomography angiography can characterize subtypes of ath- erosclerotic plaque. OBJECTIVES The purpose of this study was to investigate the prognostic implications of adverse coronary plaque characteristics in patients with suspected coronary artery disease. METHODS In this SCOT-HEART (ScottishCOmputed Tomography of the HEART Trial) post hoc anal- ysis, the presence of adverse plaque (positive remodeling or low attenuation plaque), obstruc- tive disease, and coronary artery calcification within 15 coronary segments was assessed on coronary computed tomography angiography of 1,769 patients who were followed-up for 5 years.

RESULTS Among study participants (mean age 58 ± 10 years; 56% male), 608 (34%) patients had 1 or more adverse plaque features. Coro- nary heart disease death or nonfatal myocardial infarction was 3 times more frequent in patients with adverse plaque (n = 25 of 608 [4.1%] vs. n = 16 of 1,161 [1.4%]; p < 0.001; hazard ratio [HR]: 3.01; 95% confidence interval (CI): 1.61 to 5.63; p = 0.001) and was twice as frequent in those with obstructive disease (n = 22 of 452 [4.9%] vs. n = 16 of 671 [2.4%]; p = 0.024; HR: 1.99; 95% CI: 1.05 to 3.79; p = 0.036). Patients with both obstructive disease and adverse plaque had the highest event rate, with a 10-fold increase in coronary heart disease death or nonfatal myo- cardial infarction compared with patients with

normal coronary arteries (HR: 11.50; 95% CI: 3.39 to 39.04; p < 0.001). However, these associa- tions were not independent of coronary artery calcium score, a surrogate measure of coronary plaque burden. CONCLUSIONS Adverse coronary plaque char- acteristics and overall calcified plaque burden confer an increased risk of coronary heart dis- ease death or nonfatal myocardial infarction. Coronary Artery Plaque Characteristics Associated With Adverse Outcomes in the SCOT-HEART Study. J Am Coll Cardiol 2019 Jan 29;73(3)291-301, MC Williams, AJ Moss, M Dweck, et al. www.practiceupdate.com/c/79080

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