PracticeUpdate: Cardiology - Winter 2018

VOL. 3 • NO. 3 • WINTER 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4672

Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction

JOURNAL SCANS Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm

Current Smoking and Prognosis After Acute ST-Segment Elevation Myocardial Infarction: New Pathophysiological Insights

Effect of a Home-Based Wearable Continuous ECG Monitoring Patch on Detection of Undiagnosed Atrial Fibrillation: The mSToPS Randomized Clinical Trial

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

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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-Home Message 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. Althoughalladvertisingmaterial isexpected toconform toethical (medical)stand- ards, inclusion in thispublicationdoesnotconstituteaguaranteeorendorsement of the quality or value of such product or of the claims made of it by its manu- facturer. 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 contains content published in accordancewiththeeditorialpoliciesofElsevier’sPracticeUpdate.com.Allcontent printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from 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. • NLM assumes 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 Fleur Gill fleur.gill@elsevier.com 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: Myocardial infarction/gettyimages.com PracticeUpdate Cardiology is published by Elsevier Australia ISSN 2206-4672 (Print) ISSN 2208-0228 (Online)

Associate Editors

Joerg Herrmann MD Associate Professor of Medicine, Mayo Graduate School of Medicine, Rochester, Minnesota

Benjamin Scirica MD Cardiologist and Director, Innovation, Cardiovascular Division, Brigham and Women’s Hospital; Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts James Udelson MD Chief, Division of Cardiology; Director, Nuclear Cardiology Laboratory; Professor, Medicine and Radiology, Tufts University School of Medicine, Boston, Massachusetts Ronald Victor MD Director, Cedars-Sinai Center for Hypertension; Associate Director, Clinical Research; Burns and Allen Chair in Cardiology Research, Cedars-Sinai Heart Institute, Los Angeles, California Gary Webb MD Editor-in-Chief, ChiP Network and the ACHD Learning Center; Consultant, Cincinnati Adult Congenital Heart Program; Emeritus Professor, University of Cincinnati, Department of Pediatrics, 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

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 at Brigham and Women’s Hospital, Boston, Massachusetts Peter Libby MD

Mallinckrodt Professor of Medicine, Harvard Medical School, Boston, Massachusetts

Maurice E. Sarano MD, FACC Professor of Medicine, Mayo Medical School, Rochester, Minnesota

Paul Thompson MD Physician Co-Director, Hartford Healthcare Cardiovascular Institute, Hartford, Connecticut; Professor of Medicine, University of Connecticut, Storrs, Connecticut

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

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CONTENTS 5

EDITOR’S PICKS 7 Etripamil Nasal Spray for Rapid

COVER 6

11 Nitroglycerin Injection at the Radial Artery Puncture Site Reduces Occlusion After Transradial Coronary Catheterization 12 Current Smoking Impacts Prognosis After Acute ST-Segment Elevation Myocardial Infarction Comment by James E. Udelson MD 13 Epinephrine vs Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction Comment by Jason N. Katz MD, MHS 14 Home-Based Wearable Continuous ECG Monitoring Patch Improves the Detection of Undiagnosed Atrial Fibrillation Comment by Samuel J. Asirvatham MD, FACC, FHRS, Deepak Padmanabhan MD and Itzhak Z. Attia MS

Conversion of Supraventricular Tachycardia to Sinus Rhythm Comment by Ziad F. Issa MD, MMM 8 Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial Comment by Jonathan P. Piccini MD, MHS, FACC, FAHA, FHRS

Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction Comment by Ezra Amsterdam MD

9 Escitalopram vs Placebo Treatment for Depression Improves Long-Term Cardiac Outcomes in Patients With Acute Coronary Syndrome Comment by Viola Vaccarino MD, PhD 10 Regression of Diffuse Ventricular Fibrosis Following Catheter Ablation in Patients With Atrial Fibrillation and Systolic Dysfunction Comment by John M. Miller MD

16 Unmet Need for Adjunctive Dyslipidemia Therapy in Hypertriglyceridemia Management Comment by Peter Libby MD

EXPERT OPINION

17 Clinically Relevant Data on Pioglitazone and CV Risk Reduction Interview with Silvio E. Inzucchi MD

18 Cholesterol, Inflammation and Immunotherapy: Current Implications

20 Drs. Doug Zipes and Jared Bunch Discuss the CABANA Trial

and Future Directions Interview with Peter Libby MD by Jennifer N. Caudle DO

VOL. 3 • NO. 3 • 2018

EDITOR’S PICKS 6

Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction JACC: Journal of the American College of Cardiology

Take-home message • In this study, patients presenting to the emergency department with symptoms suggestive of NSTEMI were examined to validate the ESC 0/1-h algorithm. Among 4368 patients with available serial hs-cTnT measurements, the safety of rule-out, accuracy of rule-in, and overall efficacy were found to be high. Similar results were found among 3500 patients with serial hs-cTnI measurements. • These findings demonstrate the safety and efficacy of the ESC 0/1-h algorithm in patients with suspected NSTEMI.

" I recommend that the 0/1-h algorithm for patients

Abstract BACKGROUND The safety of the European Soci- ety of Cardiology (ESC) 0/1-h algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin (hs-cTn) has been questioned. OBJECTIVES This study aimed to validate the diagnostic performance of the 0/1-h algorithm in a large multicenter study. METHODS The authors prospectively enrolled unselected patients in 6 countries presenting to the emergency department with symptoms sug- gestive of NSTEMI. Final diagnosis was centrally adjudicated by 2 independent cardiologists. Hs-cTnT and hs-cTnI blood concentrations were measured at presentation and after 1 h. Safety of rule-out was quantified by the negative predic- tive value (NPV) for NSTEMI, accuracy of rule-in by the positive predictive value (PPV), and over- all efficacy by the proportion of patients triaged towards rule-out or rule-in within 1 h. RESULTS Prevalence of NSTEMI was 17%. Among 4,368 patients with serial hs-cTnT measurements available, safety of rule-out (NPV 99.8%, 2,488 of 2,493), accuracy of rule-in (PPV 74.5%, 572 of 768), and overall efficacy were high by assign- ing three-fourths of patients either to rule-out (57%, 2,493 to 4,368) or rule-in (18%, 768 to 4,368). Similarly, among 3,500 patients with serial hs-cTnI measurements, safety of rule-out (NPV 99.7%, 1,528 of 1,533), accuracy of rule-in (PPV 62.3%, 498 of 800), and overall efficacy were high by assigning more than two-thirds of patients either to rule-out (44%, 1,533 of 3,500) or rule-in (23%, 800 of 3,500). Excellent safety was confirmed in multiple subgroup analyses including patients presenting early (≤3 h) after chest pain onset. CONCLUSIONS The ESC 0/1-h algorithm using hs-cTnT and hs-cTnI is very safe and effective in triaging patients with suspected NSTEMI. Prospective Validation of the 0/1-h Algorithm for Early Diagnosis of Myocardial Infarction. J Am Coll Cardiol 2018 Aug 07;72(6)620-632, R Twer- enbold, JT Neumann, NA Sörensen, et al. www.practiceupdate.com/c/71698 with low-risk chest pain be considered for use by institutions with laboratories well-practiced and expert with hs-cTn assays. "

COMMENT By Ezra Amsterdam MD T he utility of very early measurement of high-sensitivity cardiac troponin (hs-cTn) to reliably exclude (ACS) has been supported by multiple studies in thousands of patients. However, the safety of this approach, which comprises measurement of cTn at patient presenta- tion and 1 hour later (0/1-h), has been questioned. The aim of this prospective, multicenter validation investigation was assessment of the accuracy and safety of the 0/1-h algorithm for ruling out ACS in patients presenting with chest pain. The study cohort comprised >8100 patients, approximately half of whom were evalu- ated by high-sensitivity cardiac troponin T (hs-cTnT) and half by high-sensitivity car- diac troponin I (hs-cTnI). The safety of the 0/1-h rule-out algorithm was confirmed by a negative predictive value of 99.7% (1528 of 1533 patients), similar to the estimates observed in previous studies. It is notable that 30% of patients presented very early (≤3 hours after symptom onset); they comprise the largest cohort of early presenters ever tested for performance of the 0/1-h algorithm, and their outcomes matched those of the later presenters.

Results consistent with the overall cohort findings were demonstrated in multiple subgroup analyses, including sex, age, his- tory of CAD, and renal dysfunction. Patients who ruled out had very low all-cause mor- tality at 30 days and 1 year (0.1% and 0.8% for hs-cTnT, respectively; 0.1% and 1.0% for hs-cTnI, respectively). The 30-day mortality was ~ 24 to 29 times higher in patients tri- aged toward rule-in comparedwith patients triaged toward rule-out by the hs-cTn. Based on these results, I recommend that the 0/1-h algorithm for patients with low- risk chest pain be considered for use by institutions with laboratories well-prac- ticed and expert with hs-cTn assays. For the present in this country, I feel it is pru- dent to use a 0/3-h algorithm for low-risk patients presenting with chest pain.

Dr. Amsterdam is Distinguished Professor of Internal Medicine, and Associate Chief for Academic Affairs in the Division of Cardiovascular Medicine at University of California (Davis) Medical

Center in Sacramento, California.

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EDITOR’S PICKS 7

Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm JACC: Journal of the American College of Cardiology

with etripamil was <3 min. Adverse events were mostly related to the intranasal route of admin- istration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose. CONCLUSIONS Etripamil nasal spray rapidly termi- nated induced SVT with a high conversion rate. The safety and efficacy results of this study pro- vide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm. J Am Coll Cardiol 2018 Jul 31;72(5)489-497, BS Stambler, P Dorian, PT Sager, et al. www.practiceupdate.com/c/71370 still need to be verified in phase III controlled studies conducted outside of the electrophysiology laboratory in non-sedated patients. " " …its safety and efficacy

Take-home message • In this phase II study, 104 patients with paroxysmal supraventricular tachycardia were given etripamil to determine its safety and efficacy. Patients who received etripamil nasal spray exhibited between 65% and 95% conversion from supraventricular tachycardia to sinus rhythm, compared with 35% in the placebo group. Median time to conversion was less than 3 minutes with etripamil. Frequently reported adverse events included local irritation or reduced blood pressure with the highest dose. • These results support further study investigating self-administration of etripamil in a real-world setting. Abstract

BACKGROUND There is no nonparenteral medi- cation for the rapid termination of paroxysmal supraventricular tachycardia. OBJECTIVES The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraven- tricular tachycardia (SVT). METHODS This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a cathe- ter ablation. Patients in sustained SVT for 5 min

received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events. RESULTS One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active com- pound dose groups versus placebo. In patients who converted, the median time to conversion

COMMENT By Ziad F. Issa MD, MMM C atheter ablation is the treatment of choice in patients with paroxysmal supraventricular tachycardia (SVT) who desire to avoid or are unresponsive or intolerant to drug therapy. For patients requiring therapy who are reluctant to undergo cath- eter ablation, drug therapy remains a viable alternative, although with significantly lower efficacy rates. For patients with frequent episodes of SVT, chronic prophylactic therapy is recommended. Selected patients with very infrequent, well tolerated episodes of paroxysmal SVT may be treated only for acute episodes. For acute conversion of SVT, vagal maneuvers (including Val- salva and carotid sinus massage) are the first-line intervention, though their success rate remains limited (<30%). When vagal maneuvers fail, outpatients may use a single oral dose to acutely terminate an episode of SVT. This so-called “pill in the pocket” approach necessitates the use of a drug that has a short onset of action (ie, immediate-release preparations), and currently, no such drugs are available for nonparenteral self-administration. Although oral verapamil, diltiazem, beta-blockers, and flecainide have been utilized in these situations, their onset of action is relatively slow and their efficacy is modest. Therefore, in many patients with sustained SVT, acute termination of the arrhythmia often requires intravenous drug therapy in a controlled medical environment.

The study by Stambler et al examined the efficacy of different doses of intranasal etripamil (a rapid-onset, short-acting, pheny- lalkylamine class L-type calcium-channel blocker) in terminating sustained (>5 minutes) SVT induced in the electrophysiology laboratory. The drug demonstrated high efficacy for rapid termi- nation (within 15 min) of SVT compared with placebo. The median time to conversion from SVT to sinus rhythm was <3 min. Atrio- ventricular nodal reentry was the mechanism of the SVT in the vast majority of study patients. Although a self-administered etripamil nasal spray can poten- tially become an important approach for the acute management of SVT, its safety and efficacy still need to be verified in phase III controlled studies conducted outside of the electrophysiology laboratory in non-sedated patients. Additionally, whether study findings can be extended to patients with longer durations of sustained SVT and those with other SVT mechanisms is yet to be evaluated.

Dr. Issa is Executive Director of Cardiac Electrophysiology at Prairie Heart Institute of Illinois, and Medical Director of Cardiac Electrophysiology Laboratory at HSHS St. John’s Hospital in Springfield, Illinois.

VOL. 3 • NO. 3 • 2018

EDITOR’S PICKS 8

Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial JACC: Heart Failure Take-home message • In this study, researchers looked at the association between atrial fibrillation (AF) and outcomes of patients enrolled in the TOPCAT trial. The goal was to determine if AF modified the response to spironolactone and if spironolactone was associated with the incidence of AF in those patients without baseline AF. In the 760 patients with HFpEF studied, spironolactone treatment was not associated with the primary composite outcome of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Also, spironolactone treatment did not increase the risk of AF in HFpEF patients without baseline AF. • The results indicate that AF increases overall cardiovascular risk in patients with HFpEF, and that spironolactone treatment does not increase or reduce this risk.

COMMENT By Jonathan P. Piccini MD, MHS, FACC, FAHA, FHRS T his analysis from the TOPCAT investigators emphasizes how common atrial fibrillation (AF) is in patients with heart failure and preserved ejection fraction (HFpEF). Overall, 43% of the patients with HFpEF in TOPCAT had AF at the begin- ning of the trial and an additional 6% developed new-onset AF after the beginning of the study. Thus, about half of the HFpEF patients had AF. Patients with AF had higher adjusted rates of the composite outcome of cardiovascular mortality, aborted cardiac arrest, or heart failure. Unfortunately, the occurrence of new-onset AF was not reduced by spironolactone treatment, but the presence of AF did not impact the beneficial treatment effect of spironolactone on reducing the composite outcome of cardiovascular mortality, aborted cardiac arrest, or heart failure. Thus, this important study from TOPCAT highlights that AF is very common and is associated with worse outcomes in HFpEF. Although hyperaldosteronism is associated with an increased risk of AF, 1 the evidence for prevention of AF with mineralocorti- coid receptor antagonists has been mixed and these data from TOPCAT continue that trend. 2,3 More work will be required to figure out if spironolactone can effectively prevent primary and recurrent AF in patients with and without heart failure. References 1. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Incidence of atrial fibrillation and mineralocorticoid receptor activity in patients with medically and surgically treated primary aldosteronism. JAMA Cardiol 2018 Jul 18. doi: 10.1001/jamacardio.2018.2003. [Epub ahead of print] 2. Dabrowski R, Borowiec A, Smolis-Bak E, et al. Effect of combined spironolactone-beta-blocker +/- enalapril treatment on occurrence of symptomatic atrial fibrillation episodes in patients with a history of paroxysmal atrial fibrillation (SPIR-AF study). Am J Cardiol 2010;106(11):1609-1614. 3. Pretorius M, Murray KT, Yu C, et al. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit Care Med 2012;40(10):2805-2812.

Abstract OBJECTIVES This study assessed the relationship between atrial fibrilla- tion (AF) and outcomes in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, to evalu- ate whether AF modified the treatment response to spironolactone and whether spironolactone influenced post-randomization AF. BACKGROUND AF is common in heart failure with preserved ejection frac- tion (HFpEF) and likely contributes to increased risk of adverse outcomes. METHODS A total 1,765 patients enrolled in TOPCAT trial in North and South America were divided into 3 groups: no known AF, history of AF without AF at enrollment, and AF found on the electrocardiogram (ECG) at enroll- ment. We assessed outcomes and treatment response to spironolactone in all groups, and the association between post-randomization AF and outcomes in patients free of AF at baseline. The primary outcome of the TOPCAT trial was a composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization. RESULTS Seven hundred sixty patients (43%) had a history of AF (18%) or AF on ECG at enrollment (25%). The highest adjusted risk was associated with AF at enrollment (primary outcome, hazard ratio: 1.34; 95% confidence interval: 1.09 to 1.65; p = 0.006; and an increased early risk of secondary outcomes). Neither history of AF nor AF at enrollment modified the ben- eficial treatment effect of spironolactone. Post-randomization AF, which occurred in 6.3% of patients, was not influenced by spironolactone treat- ment, but was associated with an increased early risk of the primary outcome (hazard ratio: 2.32; 95% confidence interval: 1.59 to 3.40; p < 0.0001) and secondary outcomes. CONCLUSIONS AF at enrollment was associated with increased cardiovas- cular risk in HFpEF patients in the TOPCAT study. Post-randomization AF, which was associated with an increased risk of morbidity and mortality, was not influenced by spironolactone. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial. JACC Heart Fail 2018 Jul 06;[EPub Ahead of Print], M Cikes, B Claggett, AM Shah, et al. www.practiceupdate.com/c/70960

Dr. Paccini is a Clinical Cardiac Electrophysiologist and Associate Professor of Medicine at Duke University Medical Center and the Duke Clinical Research Institute in Durham, North Carolina.

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EDITOR’S PICKS 9

Escitalopram vs Placebo Treatment for Depression Improves Long-Term Cardiac Outcomes in Patients With Acute Coronary Syndrome JAMA: The Journal of the American Medical Association

Take-home message • Patients with depression following recent acute coronary syndrome (ACS) were randomized to receive escitalopram (n=149) or placebo (n=151) for 24 weeks to evaluate the effect on long-term major adverse cardiac events (MACE). After a median of 8.1 years of follow-up, MACE occurred in 40.9% of the escitalopram group vs 53.6% of the placebo group (P = .03). • Treatment of post-ACS depression with escitalopram is associated with a lower risk of MACE vs treatment with placebo. Further studies are needed to confirm these findings. " …these new data support the general recommendation that treating depression in cardiac patients is important. " Abstract IMPORTANCE Depression has been associated with poorer medical outcomes in acute coro- nary syndrome (ACS), but there are few data on the effects of antidepressant treatment on long-term prognosis. OBJECTIVE To investigate the effect on long-term major adverse cardiac events (MACE) of escit- alopram treatment of depression in patients with recent ACS. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted among 300 patients with recent ACS and depression enrolled from May 2007 to March 2013, with follow-up completed in June 2017, at ChonnamNational University Hospital, Gwangju, South Korea. INTERVENTIONS Patients were randomly assigned to receive either escitalopram in flexible dos- ages of 5, 10, 15, or 20 mg/d (n= 149) or matched placebo (n= 151) for 24 weeks. MAIN OUTCOMES AND MEASURES The primary out- come was MACE, a composite of all-cause mortality, myocardial infarction (MI), and

percutaneous coronary intervention (PCI). Four secondary outcomes were the individual MACE components of all-cause mortality, cardiac death, MI, and PCI. Cox proportional hazards models were used to compare the escitalopram and placebo groups by time to first MACE. RESULTS Among 300 randomized patients (mean age, 60 years; 119 women [39.3%]), 100% com- pleted a median of 8.1 (interquartile range, 7.5-9.0) years of follow-up. MACE occurred in 61 patients (40.9%) receiving escitalopram and in 81 (53.6%) receiving placebo (hazard ratio [HR], 0.69; 95% CI, 0.49-0.96; P= .03). Compar- ing individual MACE outcomes between the escitalopram and placebo groups, respectively, incidences for all-cause mortality were 20.8% vs 24.5% (HR, 0.82; 95% CI, 0.51-1.33; P= .43), for cardiac death, 10.7% vs 13.2% (HR, 0.79; 95% CI, In this recent clinical trial among patients with ACS, a 24-month treatment with the antidepressant escitalopram was associ- ated with a 31% reduction in the primary endpoint of major adverse cardiovascular events (a composite of all-cause mortal- ity, cardiac death, MI, and PCI) after a COMMENT By Viola Vaccarino MD, PhD D epression is a common comorbid- ity in patients with coronary heart disease, and a known adverse prognostic indicator. It has been 15 years since the publication of the landmark NIH- funded Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial, which failed to demonstrate that treating depression in patients with acute coro- nary syndromes (ACS) would improve their clinical outcomes. These results were met with shocking disbelief from the behavioral cardiology research and practice community. Since then, several small and medium-sized clinical trials have continued to demonstrate that phar- macological and behavioral approaches to depression treatment are moder- ately effective in reducing the burden of depression and improving the quality of life of cardiac patients. However, whether treatment of depression also improves their cardiovascular morbidity and mor- tality has not been demonstrated.

median follow-up of 8.1 years. Although these results support the notion that treat- ing depression in ACS patients favorably influences their clinical outcomes, they need further confirmation. This study was based on a relatively small sample from a single center in Korea, where patient characteristics and treatment modalities may differ from other settings. In the US, previous studies of depression treatment on long-term clinical cardiovascular end- points in ACS patients have been negative thus far, although they were also limited in sample size. Thus, althoughmore research is needed, these new data support the general recommendation that treating depression in cardiac patients is important, as it can improve patients’ psychologi- cal well-being, quality of life, medication adherence, healthy lifestyle, and possibly, long-term clinical outcomes.

Dr. Vaccarino is the Wilton Looney Chair of Cardiovascular Research, and Professor and Chair of the Department of Epidemiology at the Rollins School of Public Health, Emory University in Atlanta,

Georgia. She holds a joint appointment at the Emory School of Medicine, Department of Medicine, Division of Cardiology.

0.41-1.52; P= .48); for MI, 8.7% vs 15.2% (HR, 0.54; 95% CI, 0.27-0.96; P= .04), and for PCI, 12.8% vs 19.9% (HR, 0.58; 95% CI, 0.33-1.04; P= .07). CONCLUSIONS AND RELEVANCE Among patients with depression following recent acute coronary syndrome, 24-week treatment with escitalopram compared with placebo resulted in a lower risk of major adverse cardiac events after a median of 8.1 years. Further research is needed to assess the generalizability of these findings. Effect of Escitalopram vs Placebo Treatment for Depression on Long-Term Cardiac Outcomes in Patients With Acute Coronary Syndrome: A Randomized Clinical Trial. JAMA 2018 Jul 24;320(4)350-358, JM Kim, R Stewart, YS Lee, et al. www.practiceupdate.com/c/71435

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EDITOR’S PICKS 10

Regression of Diffuse Ventricular Fibrosis Following Catheter Ablation in Patients With Atrial Fibrillation and Systolic Dysfunction JACC: Clinical Electrophysiology Take-home message • This study compared outcomes in 36 patients with persistent atrial fibrillation and an idiopathic cardiomyopathy who were randomly assigned to treatment using catheter ablation (CA) or medical rate control (MRC) to compare the effects of these treatments on ventricular remodeling. An additional 16 individuals served as normal controls. At baseline, myocardial T1 time was higher in both groups of patients compared with controls. At 6 months, myocardial T1 remained higher in both groups of patients than in normal controls. However, myocardial T1 was significantly decreased in the CA group compared with the MRC group. Additionally, the left ventricular ejection fraction was significantly improved in the CA group compared with the MRC group at 6 months. • These findings suggest that diffuse ventricular fibrosis regresses when CA is used to treat atrial fibrillation-mediated cardiomyopathy. The authors suggest that this indicates that it may be important to treat these arrhythmias quickly to help prevent ventricular remodeling. COMMENT By John M. Miller MD Lower T1 Times After AF Ablation in Heart Failure Patients –What’s the Big Deal? P rabhu et al, in a sub-study of the CAMERA-MRI trial (Cathe- ter Ablation versus Medical Rate Control in Atrial Fibrillation [AF] and Systolic Dysfunction – a Magnetic Resonance Imaging [MRI]-Guided Multi-centre Randomised Controlled Trial), provide results of MRI and left ventricular (LV) systolic function changes in patients with heart failure and persistent AF who either underwent catheter ablation (CA) to restore and maintain sinus rhythm, or standard rate control during ongoing AF. Only 18 patients were in each group, with another 16 patients without AF serving as controls. The authors report mildly (but statistically significantly) decreased T1 times in CA patients compared with rate control patients, and, although T1 times were better, they were still worse than control patients’ values – in small groups of patients, over a short follow-up.

Abstract OBJECTIVES This study sought to determine if diffuse ventricular fibrosis improves in patients with atrial fibrillation (AF)-mediated cardiomyo- pathy following the restoration of sinus rhythm. BACKGROUND AF coexists in 30% of heart failure (HF) patients and may be an underrecognized reversible cause of left ventricular systolic dys- function. Myocardial fibrosis is the hallmark of adverse cardiac remodeling in HF, yet its revers- ibility is unclear. METHODS Patients with persistent AF and an idiopathic cardiomyopathy (left ventricular ejec- tion fraction [LVEF] ≤45%) were randomized to catheter ablation (CA) or ongoing medical rate control as a pre-specified substudy of the CAM- ERA-MRI (Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunc- tion—an MRI-Guided Multi-centre Randomised

follow-up, finding such marked decreases in fibrosis over a rela- tively short time span is dramatic. Patients with the most fibrosis showed the biggest improvements with CA. The mechanism(s) by which fibrosis regresses is unclear; we used to think that “scar is forever”; however, a growing body of evidence suggests that reverse remodeling – actual regression of fibrosis, with associated improved function – is achievable. This study provides hope that even individuals with advanced LV fibrosis in the setting of AF may be able to reverse this process and enjoy improved function with successful CA, and the results may extend to other forms of arrhythmia-related LV dysfunction such as that associated with frequent premature ventricular com- plexes. Regression of fibrosis and recovery of function – now, THAT is a big deal!

So, what’s the big deal? T1 times strongly correlate with diffuse fibrosis, and shorter times with less fibrosis. Actual decrease in fibrosis on late gadolinium enhancement was seen in the CA group, more than the rate control group, accompanied by sig- nificant (14 percentage point) improvement in ejection fraction (EF) – with one-third of CA patients improving to a normal EF. Although there were relatively few patients and only 6 months of

Dr. Miller is Professor of Medicine at Indiana University School of Medicine as well as Director of Clinical Cardiac Electrophysiology and the Cardiac Electrophysiology Training Program at Indiana University in Indianapolis, Indiana.

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Nitroglycerin Injection at the Radial Artery Puncture Site Reduces Occlusion After Transradial Coronary

Catheterization Circulation: Cardiovascular Interventions

Take-home message • In this randomized study of patients undergoing transradial coronary catheter- ization (n=188), the authors evaluated the efficacy of a subcutaneous injection of 0.5 mL 0.1% nitroglycerin at the radial artery puncture site for reducing risk of radial artery occlusion. In the nitroglycerin-treated group, the incidence of radial artery occlusion was significantly lower compared with the placebo group (5.4% vs 14.4%, respectively). • Dilating the radial artery with a subcutaneous nitroglycerin injection reduced the risk of post-catheterization artery occlusion. Abstract

Controlled Trial) trial. All patients had cardiac magnetic resonance imaging scans (including myocardial T1 time), serum B-type natriuretic peptide, 6-min walk tests, and Short Form- 36 questionnaires performed at baseline and 6 months. Sixteen patients with no history of AF or left ventricular systolic dysfunction were enrolled as normal controls for T1 time. RESULTS Thirty-six patients (18 in each treatment arm) were included in this substudy. Demograph- ics, comorbidities, and myocardial T1 times were well matched at baseline. At 6 months, patients in the CA group had a significant reduction in myocardial T1 time from baseline compared with the medical rate control group (−124 ms; 95% confidence interval [CI]: −23 to −225 ms; p = 0.0176), although it remained higher than that of normal controls at 6 months (p = 0.0017). Improvements in myocardial T1 time with CA were associated with significant improvements in absolute LVEF (+12.5%; 95% CI: 5.9% to 19.0%; p = 0.0004), left ventricular end-systolic volume (p = 0.0019), and serum B-type natriuretic pep- tide (−216 ng/l; 95% CI: −23 to −225 ng/l; p = 0.0125). CONCLUSIONS The improvement in LVEF and reverse ventricular remodeling following suc- cessful CA of AF-mediated cardiomyopathy is accompanied by a regression of diffuse fibrosis. This suggests timely treatment of arrhythmia-mediated cardiomyopathy may mini- mize irreversible ventricular remodeling. Regression of Diffuse Ventricular Fibrosis Following Restoration of Sinus Rhythm With Catheter Ablation in Patients With Atrial Fibril- lation and Systolic Dysfunction: A Substudy of the CAMERA MRI Trial. JACC Clin Electrophys- iol 2018 Jun 27;[EPub Ahead of Print], S Prabhu, may be able to reverse this process and enjoy improved function with successful CA… " " This study provides hope that even individuals with advanced LV fibrosis in the setting of AF

BACKGROUND Transradial coronary cathe- terization is widely used as a diagnostic or interventional procedure for coronary disease. However, it can lead to adverse complications, such as radial artery occlusion. We sought to determine whether preprocedural injection of nitroglycerin at the radial artery puncture site reduces radial artery occlusion.

" In the nitroglycerin-treated group, the incidence of

METHODS AND RESULTS A total of 188 patients undergoing transradial coronary catheteriza- tion were randomized in a single-blind fashion to receive subcutaneous injection of 0.5 mL 0.1% nitroglycerin or a placebo at the radial artery puncture site. The participants under- went ultrasound examinations of the radial artery before and at 24 hours after the pro- cedure. Of the 188 patients enrolled, 182 completed the study, as the procedure failed in 2 participants in the nitroglycerin-treated group and 4 in the placebo group. Baseline demo- graphic and clinical characteristics were similar between 2 groups. Comparing the radial artery diameters before and after the operation, there was a statistically significant increase in the nitroglycerin-treated group (2.48±0.45 ver- sus 2.45±0.46 mm; P=0.003) but a decrease in the placebo control group (2.41±0.50 ver- sus 2.46±0.49 mm; P<0.001). Importantly, the radial artery occlusion was significantly lower compared with the placebo group (5.4% vs 14.4%, respectively). "

incidence of radial arterial occlusion was sub- stantially lower in the nitroglycerin-treated group than in the placebo control group (5.4% versus 14.4%; P=0.04). There was not signifi- cant difference in other complications (forearm hematoma and radial artery pseudoaneurysm, respectively), and there was no incidence of cause hypotension or an intolerable headache. CONCLUSIONS Subcutaneous injection of nitroglycerin at the radial artery puncture site dilates the radial artery and reduces the incidence of early radial artery occlusion post-catheterization. Subcutaneous Injection of Nitroglycerin at the Radial Artery Puncture Site Reduces the Risk of Early Radial Artery Occlusion After Transra- dial Coronary Catheterization: A Randomized, Placebo-Controlled Clinical Trial. Circ Cardi- ovasc Interv 2018 Jul 01;11(7)e006571, Y Chen, Z Ke, J Xiao, et al. www.practiceupdate.com/c/70868

BT Costello, AJ Taylor, et al. www.practiceupdate.com/c/70274

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Current Smoking Impacts Prognosis After Acute ST-Segment Elevation Myocardial

Infarction JACC: Cardiovascular Imaging

Take-home message • Patients who underwent emergency PCI following acute STEMI were followed to evaluate the pathophysiology and outcomes among current smokers. Smokers had higher levels of C-reactive protein and neutrophils than nonsmokers on day 1. At 2 days post MI, smoking was a significant independent predictor of infarct zone hemorrhage on imaging. Over a median follow-up of 4 years, smoking was a significant independent predictor of all-cause death, heart failure events, and major adverse cardiovascular events. • Continued smoking following STEMI is associated with increased inflammation and an increased infarct-zone hemorrhage, which results in adverse long-term outcomes.

Abstract OBJECTIVES The aimof this study was tomechanis- tically investigate associations among cigarette smoking, microvascular pathology, and longer term health outcomes in patients with acute ST-segment elevation myocardial infarction (MI). BACKGROUND The pathophysiology of myocar- dial reperfusion injury and prognosis in smokers with acute ST-segment elevation MI is incom- pletely understood. METHODS Patients were prospectively enrolled during emergency percutaneous coronary inter- vention. Microvascular function in the culprit artery was measured invasively. Contrast-en- hanced magnetic resonance imaging (1.5-T) was performed 2 days and 6 months post-MI. Infarct size and microvascular obstruction were assessed using late gadolinium enhancement imaging. Myocardial hemorrhage was assessed with T2* mapping. Pre-specified endpoints included: 1) all-cause death or first heart failure hospitalization; and 2) cardiac death, nonfatal MI, or urgent coronary revascularization (major adverse cardiovascular events). Binary logistic regression (odds ratio [OR] with 95% confidence interval [CI]) with smoking status was used. RESULTS In total, 324 patients with ST-seg- ment elevation MI were enrolled (mean age 59 years, 73% men, 60% current smokers). Cur- rent smokers were younger (55 ± 11 years vs. 65 ± 10 years, p < 0.001), with fewer patients with hypertension (52 ± 27% vs. 53 ± 41%, p = 0.007). Smokers had better TIMI (Thrombolysis In Myocardial Infarction) flow grade (≥2 vs. ≤1, p = 0.024) and ST-segment resolution (none vs. partial vs. complete, p = 0.010) post-percutane- ous coronary intervention. On day 1, smokers had higher circulating C-reactive protein, neu- trophil, and monocyte levels. Two days post-MI, smoking independently predicted infarct zone hemorrhage (OR: 2.76; 95% CI: 1.42 to 5.37; p = 0.003). After a median follow-up period of 4 years, smoking independently predicted all- cause death or heart failure events (OR: 2.20; 95% CI: 1.07 to 4.54) and major adverse cardio- vascular events (OR: 2.79; 95% CI: 2.30 to 5.99). CONCLUSIONS Smoking is associated with enhanced inflammation acutely, infarct-zone hemorrhage subsequently, and longer term adverse cardiac outcomes. Inflammation and irreversible myocardial hemorrhage post-MI rep- resent mechanistic drivers for adverse long-term prognosis in smokers. Current Smoking and Prognosis After Acute ST-Segment Elevation Myocardial Infarction: New Pathophysiological Insights. JACC Cardi- ovasc Imaging 2018 Jul 13;[EPub Ahead of Print], C Haig, D Carrick, J Carberry, et al. www.practiceupdate.com/c/71165

COMMENT By James E. Udelson MD A s far back as 1985, many groups have reported on the “smoker’s paradox” following acute cor- onary syndromes. Patients with ACS who are current smokers in clinical trials and observational databases are often reported to have slightly better outcomes (usually out to 1 year) after ACS, in con- trast to what one might expect. In virtually all of these reports, smokers are much younger than nonsmokers, have less hypertension and diabetes, and have less underlying multivessel CAD. In some of the reports, the apparently better out- come disappears after adjustment for baseline differences, suggesting that a better anatomic and comorbidity profile in smokers may offset the unfavorable effects of smoking per se. Few studies have explored the likely complex mechanisms underlying these observations in depth. Haig and col- leagues, in the current paper, perform highly comprehensive biomarker and cardiac MRI studies (in a highly experi- enced imaging center) in a large group of patients with ST-elevation MI (STEMI) undergoing primary PCI. They followed the patients for outcomes over a median of 4 years, much longer than prior studies. The smoker vs non-smoker demograph- ics were similar to those in other trials. They found slightly better post-PCI TIMI flow status (consistent with prior reports), lower microvascular resistance (of bor- derline significance), better early

" …the much longer follow-up in this study compared with prior studies allowed a clearer picture of how the balance of these

observations associated with true outcomes, and very clearly, the bad outweighs the good.

"

ST-segment resolution, and lower levels of NT-proBNP in smokers, all of which would seem favorable. However, smok- ers had a more unfavorable inflammatory biomarker profile early post-MI, and the early (day 2) cardiac MRI findings showed that smoking status was associated with a higher likelihood of myocardial hemor- rhage, whereas infarct size was similar. Over the long-term follow-up, smoking at the time of the STEMI was associated with death or heart failure events as well as with major adverse cardiac events. This highly comprehensive study goes a long way in advancing our understand- ing of the mechanisms involved in the many observations over the years about post-ACS outcomes in smokers versus nonsmokers. Although very early signals were mixed, the much longer follow-up in this study compared with prior studies allowed a clearer picture of how the bal- ance of these observations associated with true outcomes, and very clearly, the bad outweighs the good.

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Epinephrine vs Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction JACC: Journal of the American College of Cardiology

RESULTS Fifty-seven patients were randomized into 2 study arms, epinephrine and norepineph- rine. For the primary efficacy endpoint, cardiac index evolution was similar between the 2 groups (p = 0.43) from baseline (H0) to H72. For the main safety endpoint, the observed higher incidence of refractory shock in the epineph- rine group (10 of 27 [37%] vs. norepinephrine 2 of 30 [7%]; p = 0.008) led to early termination of the study. Heart rate increased significantly with epinephrine from H2 to H24 while remain- ing unchanged with norepinephrine (p < 0.0001). Several metabolic changes were unfavorable to epinephrine compared with norepinephrine, including an increase in cardiac double prod- uct (p = 0.0002) and lactic acidosis from H2 to H24 (p < 0.0001). CONCLUSIONS In patients with CS secondary to acute myocardial infarction, the use of epi- nephrine compared with norepinephrine was associated with similar effects on arterial pres- sure and cardiac index and a higher incidence of refractory shock. Epinephrine Versus Norepinephrine for Cardio- genic Shock After Acute Myocardial Infarction. J Am Coll Cardiol 2018 Jul 10;72(2)173-182, B Levy, R Clere-Jehl, A Legras, et al. www.practiceupdate.com/c/70550 optimal management strategies for this phenotypically and hemodynamically diverse and deadly condition. At this time, if faced with a choice for your patient with CS, it would seem that norep- inephrine may be a more preferred initial vasoactive medication. More importantly, however, is that the treating physician understands the unique pathophysiology of his/her patient and the unique phar- macology of each drug, and then closely and systematically monitors the clinical response of the patient to therapy.

Take-home message • This is a prospective, multicenter, double-blind study comparing 57 patients randomized to receive epinephrine or norepinephrine for cardiogenic shock following an acute myocardial infarction (AMI). Based on a comparison of cardiac index evolution using an intention-to-treat analysis, efficacywas not statistically different between the two groups frombaseline (H0) to H72. Because a higher incidence of refractory shock occurred in the epinephrine group (37%of patients comparedwith 7%of the norepinephrine group), the study was terminated prematurely. There was a significant increase in heart rate fromH2 toH24 in the epinephrine group only. Additionally, increases in cardiac double product and in lactic acidosis fromH2 to H24 occurred only in the epinephrine group. • Although this study included a relatively small number of patients, it suggests that there is a higher risk of refractory shock in patients treated with epinephrine compared with norepinephrine. However, the authors note that different patterns may be present in cardiogenic shock with etiologies other than AMI. Abstract

BACKGROUND Vasopressor agents could have certain specific effects in patients with cardio- genic shock (CS) after myocardial infarction, which may influence outcome. Although nor- epinephrine and epinephrine are currently the most commonly used agents, no randomized trial has compared their effects, and interven- tion data are lacking. OBJECTIVES The goal of this paper was to com- pare in a prospective, double-blind, multicenter, COMMENT By Jason N. Katz MD, MHS C ardiogenic shock (CS) is complicated. It is difficult to define, diverse in its etiology and presentation, and chal- lenging tomanage. Despite the fact that we have found ways – mechanical and phar- macologic – to rapidly re-perfuse coronary arteries and favorably alter the natural his- tory of myocardial infarction (MI), mortality in CS remains unacceptably high. No soci- ety-endorsed guidelines currently exist for the management of CS, and recommenda- tions crafted by key opinion leaders rest precariously upon a very tenuous evidence base. The paper by Levy and colleagues is another in a series of small, but important, steps in helping to optimize care for these complex patients. In this prospective, mul- ticenter, double-blinded study, individuals with persistent CS (despite percutaneous coronary intervention) were randomized either to epinephrine or norepinephrine for vasoactive support. There were no differences in the majority of collected hemodynamic endpoints (including cardiac

randomized study, the efficacy and safety of epi- nephrine and norepinephrine in patients with CS after acute myocardial infarction. METHODS The primary efficacy outcome was cardiac index evolution, and the primary safety outcome was the occurrence of refractory CS. Refractory CS was defined as CS with sustained hypotension, end-organ hypoperfusion and hyper- lactatemia, and high inotrope and vasopressor doses.

index, stroke volume index, andmean arte- rial pressure) and no differences in death, the use of additional inotropic therapies, or the employment of mechanical circulatory support. There was, however, a greater increase in heart rate and serum lactate with the use of epinephrine, along with a greater incidence of refractory CS. This was clearly a difficult trial to con- duct. Despite a targeted sample size of 80 patients, only 57 were enrolled over a 4-year period at 9 participating centers. The trial was stopped early due to higher rates of refractory CS in the epinephrine-treated group – a safety endpoint (it is important to emphasize) that was not prespecified. Although not necessarily practice-changing, there is certainly a lot to glean from this study. The findings provide important mecha- nistic insights into the use of vasoactive medications for CS. It also should compel the cardiovascular community to intensify collaborative efforts focused on defining

Dr. Katz is Associate Professor of Medicine, Medical Director for the Cardiac Intensive Care Unit, Cardiothoracic Surgical Intensive Care Unit, and Mechanical Heart Program, and Director of Cardiovascular Clinical Trials at University of North Carolina School of Medicine in Chapel Hill, North Carolina.

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