Practice Update: Cardiology

VOL. 2 • NO. 2 • 2017

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4672

Significance of Subclinical Atrial Fibrillation in Older Patients

Conference European Society of Cardiology Congress 2017

JOURNAL SCAN Optical coherence tomography characterization of coronary lithoplasty for treatment of calcified lesions: first description

Antiplatelet regimen for patients with breakthrough strokes while on aspirin: a systematic review and meta-analysis

Ectopy on a single 12-lead ECG, incident cardiac myopathy, and death in the community

PracticeUpdate.com is a free online resource for medical information and expert insight.

Our Process Our top medical experts meet weekly to review and discuss all relevant literature (journal articles, news, and current topics) and select the most important content in each specialty. Take-Home Messages Take-home messages are added to articles to highlight key takeaways and ndings. Expert commentaries provide additional insights and guidance on important topics to help you identify critical information quickly and easily, freeing up more time for patient care. Our Boards Each PracticeUpdate specialty has its own diverse team of experts who hand select the articles on a weekly basis and give unique multi-specialty perspectives on a single topic. You bene t by receiving several viewpoints on one subject, enabling a more complete and multidimensional learning experience.

Benefits of PracticeUpdate.com • Our experts provide customized, curated research and clinical ndings. • Exclusive, free clinical information is scanned, selected, and prioritized. • Unbiased, impartial, independent medical information provided each week. • Stay current in your eld with distilled professional research, articles, and education.

PracticeUpdate.com

Join For Free Today at

CONTENTS 5

RESEARCH Editor’s picks 6 Significance of Subclinical Atrial Fibrillation in Older Patients 8 Optical Coherence Tomography Characterization of Coronary Lithoplasty for Treatment of Calcified Lesions 9 Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction 10 Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and Cancer-Related Mortality 11 Warfarin Use Is Associated With Progressive Coronary Arterial Calcification General cardiology 22 Bromocriptine Effective for the Treatment of Peripartum Cardiomyopathy 22 Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin Arrhythmias/heart rhythm disorders 23 3-Day Interruption of Direct Oral Anticoagulants Appropriate for Most Procedures 24 PAC or PVC on 12-Lead ECG May Predict Risk of Atrial Fibrillation, Heart Failure, or Death Cardiac procedures & surgery 26 Improved Outcomes With On- vs Off-Pump Coronary- Artery Bypass 27 Influence of Diabetes on Long-Term Coronary Artery Bypass Graft Patency Coronary heart disease 28 Coffee Consumption Associated With Reduced Mortality Risk

CONFERENCE 12 European Society of Cardiology Congress 2017 COVER 6 Significance of Subclinical Atrial Fibrillation in Older Patients

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 Associate Editors Joerg Herrmann MD , Benjamin Scirica MD Advisory Board Deepak Bhatt MDMPH FACC FAHA FSCAI FESC , Peter Libby MD , Paul Thompson MD , James Udelson MD , Ronald Victor MD , Gary Webb MD , Clyde Yancy MDMScMACCFAHAMACP Editorial Contributors Ashish Aggarwal MD , Samer Ajam MD , Jason Garlie MD , John Garner MD PracticeUpdate ® is a registered trademark of Elsevier Inc. 2017 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on the 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,andeducationalgrants. Individualaccess toPracticeUpdate. 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)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. CONTENT Abstracts are available when the publisher grants permission fromMEDLINE/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 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

12 ESC 2017: The Gender Gap in Death from Acute Myocardial Infarction Is Closing, Particularly in Women Younger Than Age 60 13 ESC 2017: Ablation of Atrial Fibrillation Improves Quality of Life More than Drugs – CAPTAF Trial 14 ESC 2017: Catheter Ablation Improves Outcomes in Patients With Heart Failure and Atrial Fibrillation – CASTLE-AF Trial 16 ESC 2017: The Interleukin-1 β Inhibitor Canakinumab Cuts Cardiovascular Disease and Lung Cancer Risk by Reducing Inflammation – CANTOS Trial 18 ESC 2017: Renal Denervation Lowers Blood Pressure in Hypertensive Patients Not Taking Antihypertensive Medication – SPYRAL HTN-OFF MED Trial 20 ESC 2017: Two Results of the PURE Study May Be Game Changers in Heart Disease Prevention 20 ESC 2017: Apixaban Lowers Stroke Risk in Patients Undergoing Cardioversion for Atrial Fibrillation – EMANATE Trial

FEATURES 29 My Approach to the Risk Stratification of Patients for Sudden Cardiac Death 30 My Approach to the Athlete With Wolff- Parkinson-White Syndrome (WPW)

PracticeUpdate Cardiology is published by Elsevier Australia ISSN 2206-4672 (Print) ISSN 2208-0228 (Online)

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMCN091701

VOL. 2 • NO. 2 • 2017

EDITOR’S PICKS 6

Significance of Subclinical Atrial Fibrillation in Older Patients Circulation Take-home message • This study followed 256 patients aged 74±6 years with implanted subcutaneous electrocardiographic monitors for 16.3±3.8 months to evaluate subclinical atrial fibrillation (SCAF). SCAF ≥5 minutes was detected in 90 patients. Older age, higher blood pressure, and larger left atrial dimension were baseline predictors of SCAF. There was no difference in SCAF occurrence between patients with or without a history of TIA, stroke, or systemic embolism. • These findings demonstrate the frequent detection of SCAF in older patients; however, the clinical significance is not clear at this time. Abstract BACKGROUND Long-term continuous electrocardiographic monitoring shows a substantial prevalence of asymptomatic, subclinical atrial fibril- lation (SCAF) in patients with pacemakers and patients with cryptogenic stroke. It is unknown if SCAF is also common in other patients without these conditions. METHODS We implanted sub-cutaneous electrocardiographic monitors (St. Jude CONFIRM-AF) in patients ≥ 65 years attending cardiovascular or neurology outpatient clinics if they had no history of atrial fibrillation (AF) but did have any of: CHA2DS2-VASc score of ≥ 2, sleep apnea, or body mass index > 30. Eligibility also required either left atrial enlargement (≥ 4.4 cm or volume ≥ 58 mL) or increased serum NT-ProBNP (≥290 pg/mL). Patients were monitored for SCAF lasting ≥ 5 minutes.

COMMENT By T. Jared Bunch MD A trial fibrillation (AF) continues to increase in incidence worldwide as populations age and people live longer with coexistent cardiovascular diseases. 1 Tominimize AF-related comorbidities, early recognition andmanagement of the arrhythmia is advocated. AF diagnosis has been in a constant state of evolu- tion as technologies have advanced to allow long-termmonitoring through multiple types of cardiac implantable electronic devices (CIED) andwearable devices. CIEDdetection of AF can significantly precede clinical symptoms and diagnosis of the arrhythmia. Such detection opportunities provide enthusiasm that very early treat- ment of the arrhythmia may alter risks of stroke, heart failure, and death, and perhaps alter that natural history of AF. AF management is based upon the identification of coexisting risk factors for adverse outcomes such as aging, diabetes, heart failure, stroke, vascular disease, etc. These same risk factors that predict AF outcomes also strongly predict its incidence. In a study of 100,000 patients without AF followed on average for 9 years, with each additional risk factor the odds of AF increased significantly from 3.05, 12.9, 22.8, 34.0, and 48.0, respectively. 2 In another study of patients with a cryptogenic stroke, AF was detected with a CIED in 12.4% at 1 year. 3 As AF risk factors are strongly associated with AF incidence, higher-risk patients may benefit from implantation of a implantable loop recorder (ILR) to prompt very early AF diagnosis. Healey and colleagues, on behalf of the ASSERT II trial inves- tigators, 4 in a study of 256 elderly patients (≥65 years) sought to determine the incidence of subclinical AF in higher-risk patients using ILRs. Higher risk was determined if the patient had a CHA2DS2-VASc score of ≥2 or left atrial enlargement with obstructive sleep apnea or a body mass index >30, or an elevated NT-ProBNP ≥290 pg/mL. In this study, 48% of the

RESULTS 256 patients were followed for 16.3±3.8 months. Baseline age was 74±6 years, mean CHA2DS2-VASc score was 4.1±1.4, left atrial diameter

averaged 4.7±0.8 cm, and 48% had a prior stroke, transient ischemic attack or systemic embolism. SCAF ≥ 5 minutes was detected in 90 patients (detection rate 34.4% per year; 95% confidence interval [CI], 27.7-42.3%). Baseline predictors of SCAF were increased age (HR per decade: 1.55; 1.11-2.15), left atrial dimension (HR per centimeter diameter: 1.43; 1.09-1.86), blood pressure (HR per 10 mmHg 0.87; 0.78-0.98), but not prior stroke. The rate of occurrence of SCAF in those with a history of prior stroke, systemic embolism or TIA was 39.4% per year versus 30.3% per year with- out (p=0.32). The cumulative SCAF detection rate was higher (51.9% per year) in those with left atrial volume above the median value of 73.5 mL. CONCLUSIONS SCAF is frequently detected by continuous electrocardiographic monitor- ing in older patients without prior history of AF who are attending outpatient cardiology and neurology clinics. Its clinical significance is unclear. Subclinical atrial fibrillation in older patients. Circulation 2017 Aug 04;[EPub Ahead of Print], JS Healey, M Alings, AC Ha, et al. www.practiceupdate.com/c/56679

PRACTICEUPDATE CARDIOLOGY

EDITOR’S PICKS 7

patients had a prior history of stroke or transient ischemic attack. The endpoint was device-detected AF for ≥5 minutes. AF was detected at a rate of 34.4% per year, with a mean time from ILR insertion to detection of 5.1±5.5 months. Subclinical or device-detected AF occurred before clin- ical diagnosis of the arrhythmia in 69% of the patients at a median of 82.5 days ear- lier. In patients with a history of a cerebral ischemic event, AF detection rates were higher at 39.4% per year. Among secondary endpoints, 4 patients had an ischemic stroke during follow-up, of whom none had detected AF. One hemor- rhagic stroke developed in a patient with detected AF who was started on anticoag- ulation. Of the 90 patients with AF, 60 were started on anticoagulation, in 45 of whom the decision was made from the device-de- tected arrhythmia. This study has several important clinical findings. First, the data continue to support the use of long-termmonitors for AF detec- tion in patients with a cryptogenic stroke. The average time required to detect (>5 months) highlights the utility of long-term implantable monitors compared with ambu- latory monitors. Current studies such as Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS) and Rivaroxaban Versus Aspirin in Second- ary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined

of these data in addition to other data from CIED trials that show lack of consistent tem- poral correlation between AF incidence and stroke, 5,6 we must question the tra- ditional hypothesis of the role of AF and stroke, and, as a consequence, how we will reduce stroke events in the future. References 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129(8):837-847. 2. Brunner KJ, Bunch TJ, Mullin CM, et al. Clinical predictors of risk for atrial fibrillation: implications for diagnosis and monitoring. Mayo Clin Proc 2014;89(11):1498-1505. 3. Sanna T, Diener HC, Passman RSet al. Cryptogenic stroke and underlying atrial fibrillation. N Eng J Med 2014;370(26):2478-2486. 4. Healey JS, Alings M, Ha AC, et al. Subclinical Atrial Fibrillation in Older Patients [published online August 4, 2017]. Circulation doi: 10.1161/ CIRCULATIONAHA.117.028845. [Epub ahead of print] 5. Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014;129(21):2094-2099. 6. Martin DT, Bersohn MM, Waldo AL, et al. Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients

Source (NAVIGATE ESUS) will evaluate if empiric anticoagulation, given the very high expected rates of subclinical AF in cryptogenic stroke patients, will lower sec- ondary stroke rates. Second, this study demonstrates the value of ILRs in higher-risk patients for AF with a yield of arrhythmia detection in approx- imately 1 in 3. What remains to be known is if this early detection can lead to tar- geted therapies that will significantly impact outcomes compared with conventional approaches based on clinical AF diagnosis. Third, this study highlights the lack of sen- sitivity in AF diagnosis based upon patient symptoms and routine clinical investigation. Finally, this study continues to prompt the question, is AF a marker of a systemic vas- cular disease state or a focal risk factor of the atrium? The answer to this question is critical as we consider pill-in-the-pocket anticoagulation, left atrial appendage closure devices, and rhythm control approaches to lower stroke risk. If AF is a focal disease of the left atrium, then these approaches should lower stroke risk. How- ever, if AF is a risk marker of severity of a systemic disease state, then anticoagula- tion strategies will be needed long-term and stroke risk reduction will be depend- ent on treatment and modification of the processes driving the systemic disease. In this study of patients at higher risk for AF with ILRs, the few strokes that did occur were independent of AF. In consideration

with implanted defibrillator and cardiac resynchronization devices. Eur Heart J 2015;36(26):1660-1668.

Dr Bunch is Medical Director of Electrophysiology for Intermountain Healthcare, Intermountain Heart Institute,

Intermountain Medical Center, Murray, Utah.

Take our survey to win

You may have noticed our new and improved look with more • expert opinions • research articles • conference coverage All content guided by PracticeUpdate’s internationally recognised Advisory & Editorial Board. We did it with you, the reader, in mind. Did we get it right or have we simply lost the plot?

Have your say . Simply go to www.surveymonkey.co.uk/r/PUOR or scan the QR code below to complete our 4-minute reader’s survey to stand a chance to WIN a FitBit Alta HR worth $249!*

*Recommended RRP. Terms and conditions apply.

Terms & conditions of entry: Entries are open to Australian residents (excluding the ACT) who are practising medical professionals. Only one entry per person will be accepted. Entrants must complete the survey by answering all questions and submitting the completed survey online via the link provided by 23.59 (AEST) 30th September 2017 to be eligible for the prize draw. There will be 1 (one) prize drawn on 30th September 2017 for a FitBit Alta HR worth $249 (recommended RRP). The winner will be notified by telephone and email on the same day. For full terms and conditions, go to www.elsevierhealth.com.au/terms-conditions . NSW Permit No. LTPM/17/01510. Important privacy notice: Elsevier Australia and its related bodies corporate recognise the importance of protecting your personal information in accordance with the Privacy Amendment (Private Sector) Act 2000. For our full privacy statement visit www.elsevier.com.au

VOL. 2 • NO. 2 • 2017

EDITOR’S PICKS 8

Optical Coherence Tomography Characterization of Coronary Lithoplasty for Treatment of Calcified Lesions JACC: Cardiovascular Imaging Take-home message

and laceration and dissections in others. Thus, the effect is more uniform and the device is safe; the only complications are related to dissections caused by the angi- oplasty component. All of this being said, the real effect and differential impact of this new technology cannot be judged until appropriate comparison studies are done. As the effect is largely an enhancement of balloon angioplasty effects, comparison with plain old balloon angioplasty would be the first step, then other plaque calcium-modifying strategies, such as the mentioned atherectomy options. Only then will we really know how useful of an adjunct this procedure is. The current data, however, are an important step in this direction. They provide the necessary feasibility and safety data to proceed. Coronary lithoplasty, here I come. Optical coherence tomography characteriza- tion of coronary lithoplasty for treatment of calcified lesions: first description. JACC Car- diovasc Imaging 2017 Aug 01;10(8)897-906, ZA Ali, TJ Brinton, JM Hill, et al. www.practiceupdate.com/c/56930 circumferential multiple fractures noted in >25%. The frequency of calcium fractures per lesion increased in the most severely calcified plaques (highest tertile vs. lowest tertile; p = 0.009), with a trend toward greater incidence of calcium frac- ture (77.8% vs. 22.2%; p = 0.057). Post-lithoplasty, mean acute area gain was 2.1 mm(2), which fur- ther increasedwith stent implantation, achieving a minimal stent area of 5.94 ± 1.98 mm(2) and mean stent expansion of 112.0 ± 37.2%. Deep dissec- tions, as part of the angioplasty effect, occurred in 13% of cases and were successfully treated with stent implantation without incidence of acute clo- sure, slow flow/no reflow, or perforation. CONCLUSIONS High-resolution imaging by OCT delineated calcium modification with fracture as a major mechanism of action of lithoplasty in vivo and demonstrated efficacy in the achievement of significant acute area gain and favorable stent expansion.

• Optical coherence tomography (OCT) findings were evaluated in 31 patients with severely calcified stenotic coronary lesions treated with lithoplasty prior to stent implantation. Intraplaque calcium fracture following lithoplasty was seen in 43% of lesions, and circumferential multiple fractures were seen in >25% of lesions. The most severely calcified plaques showed the highest frequency of calcium fractures per lesion. The mean acute gain in area after lithoplasty was 2.1 mm 2 and stent implantation increased this further to a maximal stent area of 5.94 mm 2 . Mean stent expansion was 112.0%. Deep dissection was seen in 13% of cases, and all were successfully treated with stent implantation. • The main mechanism of action of lithoplasty is to cause intraplaque calcium frac- tures and hence gain increased area, which facilitates stent expansion. Abstract

angle were not very prominent, even with 94 pulses on average. However, the goal is more the fragmenta- tion into pieces, or, better stated, fractures into the planes of coronary artery calcifi- cation. Calcium fractures were noted in nearly 50% of cases and circumferential multiple fractures in 25%. These numbers were not significantly increased by stent implantation. These observations may thus argue in favor of a lithotripsy effect and sufficient improvement of lesion com- pliance. Importantly, these effects were more pronounced with increasing calcifi- cation severity, and an effect was noted irrespective of depth within the vessel. This being said, OCT is not as sound as IVUS to visualize coronary calcifications, especially those of deeper location. Nevertheless, these are important dis- tinguishing features from the effects of rotational and orbital atherectomy, which cannot modify deep-seated calcium. In further distinction, lithotripsy does not pul- verize or abrade the plaque, with distal microembolization risk, or entail a guide- wire bias that leads to asymmetry and eccentricity of the effect in some lesions, California) delivers localized, lithotripsy-enhanced disruption of calcium within the target lesion (i.e., lithoplasty) for vessel preparation before stent implantation. METHODS We analyzed OCT findings in 31 patients in whom lithoplasty was used to treat severely calcified stenotic coronary lesions. RESULTS After lithoplasty, intraplaque calcium fracture was identified in 43% of lesions, with

COMMENT By Joerg Herrmann MD T his study is an important contribution even though only 31 patients were included. This is half the cohort of patients currently in the DISRUPT CAD program on a novel mode of percutane- ous intervention: coronary lithoplasty. The terminology is noteworthy. This is not litho- tripsy, which is pure shockwave therapy. It is lithoplasty; that is, with an element of angi- oplasty. Indeed, the coronary lithoplasty catheter is a balloon angioplasty cath- eter that contains a series of unfocused electrohydraulic lithotripsy emitters. The balloon is advanced to the lesion, inflated to 4 atm (to unfold), and 10 pulses are deliv- ered (ie, lithotripsy). This is then followed by further dilation to nominal pressures and reference vessel size (ie, angioplasty). The procedure is repeated for a mini- mum of 20 pulses. Of further note, OCT was performed before lithotripsy, requir- ing predilation in 20% of the cases. Given these elements of angioplasty involved, the acute gain in luminal dimensions can- not be attributed to lithotripsy effects alone. One may even argue that the modification effects on calcium thickness and calcium BACKGROUND The ShockwaveCoronary Rx Lithop- lasty System (Shockwave Medical, Fremont, OBJECTIVES This study sought to determine the mechanistic effects of a novel balloon-based lithoplasty system on heavily calcified coronary lesions and subsequent stent placement using optical coherence tomography (OCT).

Dr Herrmann is Associate Professor of Medicine, Mayo Graduate School of Medicine, Rochester, Minnesota.

PRACTICEUPDATE CARDIOLOGY

EDITOR’S PICKS 9

Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction JAMA: The Journal of the American Medical Association

Take-home message • This study evaluated single-nucleotide polymorphisms associated with serum calcium levels to determine risk for CAD and MI related to these genetic markers. The results revealed that an increase in serum calcium levels due to genetic variations over a lifetime were associated with an increased risk of CAD and MI. • While a genetic predisposition to elevated serum calcium levels poses an increased CAD risk, the study was unable to make an association between calcium supple- mentation and increased CAD or MI risk. Abstract

obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide associa- tion meta-analysis of serum calcium levels (N=up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium’s 1000 genomes-based genome-wide associa- tion meta-analysis (N=up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with base- line data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum cal- cium, and estimates were combined using an inverse-variance weighted meta-analysis. EXPOSURES Genetic risk score based on genetic variants related to elevated serum calcium levels. MAIN OUTCOMES AND MEASURES Co-primary out- comes were the odds of CAD and myocardial infarction. RESULTS Among the mendelian randomized ana- lytic sample of 184 305 individuals (60 801 CAD cases [approximately 70%with myocardial infarc- tion] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weightedmeta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08- 1.45; P=.003) for CAD and 1.24 (95% CI, 1.05-1.46; P=.009) for myocardial infarction. CONCLUSIONS AND RELEVANCE A genetic predis- position to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medi- um-term calcium supplementation is unknown. Association of genetic variants related to serum calcium levels with coronary artery dis- ease and myocardial infarction. JAMA 2017 Jul 25;318(4)371-380, SC Larsson, S Burgess, K Michaëlsson. www.practiceupdate.com/c/56387

OBJECTIVE To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. DESIGN, SETTING, AND PARTICIPANTS The analy- ses were performed using summary statistics

IMPORTANCE Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.

COMMENT By Paul D Thompson MD Is there a bone to pick with calcium supplementation?

Twenty percent of American adults take calcium (Ca) supplements, but is this good for the heart? Ca supplementation in cross-sectional studies has been asso- ciated with an increased risk of coronary artery disease (CAD), especially myocar- dial infarction (MI). Randomized clinical trials are the best strategy to determine the risk and benefits of a potentially ther- apeutic intervention. A meta-analysis of nine randomized controlled trials of Ca supplementation with or without vita- min D suggested a 24% increase in CAD risk with Ca, but these results have been questioned, and meta-analyses have their own limitations. So, in the absence of a widely accepted clinical trial–based con- clusion, perhaps the next best approach is a “mendelian randomization” study. Mendelian randomization studies eval- uate the effect of an intervention, in this case increases in blood Ca, by examining what happens to individual with genetic variants that increase Ca levels. Larsson and colleagues used this approach to examine the association of CAD with six genes regulating serum Ca. They found that having genes associated

with a predicted 0.5% increase in blood Ca was associated with a 25% increase in CAD risk (95% CI, 8%–45%) and a 24% increase in MI risk (CI, 5%–46%). Several possible mediating mechanisms exist. Ca could increase coronary calcium, alter the coagulation cascade where Ca has prominent roles, or alter the arterial wall calcium-sensing receptor thereby alter- ing downstream gene expression. These results are provocative and add to the concern raised by the cross-sectional and prospective studies of Ca supple- mentation. Patients and clinicians need to balance these concerns with other con- cerns such as the risk of osteoporosis. Right now, there is only smoke around the Ca supplementation concerns, but, where there is smoke, there is usually fire.

Dr Thompson is Physician Co-Director of the Hartford Healthcare Cardiovascular Institute, Hartford, and Professor of Medicine, University of Connecticut, Storrs, Connecticut.

VOL. 2 • NO. 2 • 2017

EDITOR’S PICKS 10

Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and Cancer- Related Mortality JACC: Journal of the American College of Cardiology Take-home message • Data from the National Health Interview Survey and the National Death Index records were analyzed to evaluate the association between alcohol consumption and the risk of all-cause, cancer-, and cardiovascular disease (CVD)-associated mortality. Light or moderate alcohol intake was significantly associated with a reduced risk for all-cause mortality and CVD-specific mortality compared with lifetime abstinence. Conversely, heavy alcohol consumption was significantly asso- ciated with an increased risk for all-cause mortality and cancer-related mortality. The risk of all-cause mortality and cancer-related mortality was also significantly increased in the setting of binge drinking ≥1 day/week. • While light and moderate alcohol consumption may have a protective effect on the risk of all-cause and CVD-specific mortality, heavy drinking and binge drinking are associated with an increased all-cause and cancer-specific mortality risk. Abstract

COMMENT By Paul D Thompson MD Picking Your Poison H ow should we advise patients regarding the risks and benefits of alcohol consumption? Many prior studies have suggested a J-shaped relationship between alcohol and health, meaning that risk is high both in those who abstain from alcohol and those who drink heavily, compared to low and mod- erate drinkers. But many prior studies did not correct for the “abstainer” effect. This refers to the possibility that some abstain- ers quit drinking but were former, perhaps heavy, drinkers. Xi and colleagues ( J Am Coll Cardiol 2017;70:913–22) used reported alcohol intake provided by 333,247 subjects in the 1997-2009 National Health Interview Surveys to examine the relationship between alco- hol consumption and all, cancer and cardiovascular (CV) deaths in the United States. Subjects were divided into lifetime abstainers (<12 drinks ever), infrequent drinkers (<12 drinks in any year), for- mer drinkers (≥12 drinks in a previous year), light (<3), moderate (>3 <15 drinks/ week for men and >3 <8 drinks/week for women; and heavy current drinkers. Binge drinking was defined as ≥5 drinks in a day during the past year. The median follow-up was 8.2 years. Compared to abstainers, light and mod- erate alcohol consumers had a 21 and 22% reduction in all-cause mortality and a 26 and 29% reduction in cardiovas- cular death. In contrast, heavy drinkers had an 11% increase in total mortality and a 27% increase in cancer mortality. Binge drinking ≥1 per week was associ- ated with a 13% increase in total and a 22% increase in cancer mortality. These results support the J-shaped rela- tionship between alcohol and health. Light tomoderate alcohol intake appears beneficial to total andCVhealthbut heavy and binge drinking increase all cause and cancer specific mortality. Patients who wish should be permitted to imbibe but discouraged from >2 daily drinks for men and >1 daily drink for women.

included. Self-reported alcohol consumption patterns were categorized into 6 groups: lifetime abstainers; lifetime infrequent drinkers; former drinkers; and current light, moderate, or heavy drinkers. Secondary exposure included partici- pants’ binge-drinking status. The main outcome was all-cause, cancer, or CVD mortality. RESULTS After a median follow-up of 8.2 years (2.7 million person-years), 34,754 participants died of all causes (including 8,947 CVD deaths and 8,427 cancer deaths). Compared with lifetime abstainers, those who were light or mod- erate alcohol consumers were at a reduced risk of mortality for all causes (light-hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.76 to 0.82; moderate-HR: 0.78; 95% CI: 0.74 to 0.82) and CVD (light-HR: 0.74; 95% CI: 0.69 to 0.80; mod- erate-HR: 0.71; 95% CI: 0.64 to 0.78), respectively. In contrast, there was a significantly increased risk of mortality for all causes (HR: 1.11; 95% CI: 1.04 to 1.19) and cancer (HR: 1.27; 95% CI: 1.13 to 1.42) in adults with heavy alcohol consumption. Binge drinking ≥1 d/week was also associated with an increased risk of mortality for all causes (HR: 1.13; 95% CI: 1.04 to 1.23) and cancer (HR: 1.22; 95% CI: 1.05 to 1.41). CONCLUSIONS Light and moderate alcohol intake might have a protective effect on all-cause and CVD-specific mortality in U.S. adults. Heavy or binge drinking was associated with increased risk of all-cause and cancer-specific mortality. Relationship of alcohol consumption to all- cause, cardiovascular, and cancer-related mortality in US adults . J Am Coll Cardiol 2017 Aug 22;70(8)913-922, B Xi, SP Veeranki, M Zhao, et al. www.practiceupdate.com/c/57186

BACKGROUND Previous studies have revealed inconsistent findings regarding the associa- tion of light to moderate alcohol consumption with cardiovascular disease (CVD) and cancer mortality. OBJECTIVES The aim of this study was to examine the association between alcohol consumption and risk of mortality from all causes, cancer, and CVD in U.S. adults. METHODS Data were obtained by linking 13 waves of the National Health Interview Surveys (1997 to 2009) to the National Death Index records through December 31, 2011. A total of 333,247 participants ≥18 years of age were

Dr Thompson is Physician Co-Director of the Hartford Healthcare Cardiovascular Institute, Hartford, and Professor of Medicine, University of Connecticut, Storrs, Connecticut.

PRACTICEUPDATE CARDIOLOGY

EDITOR’S PICKS 11

Warfarin Use Is Associated With Progressive Coronary Arterial Calcification JACC: Cardiovascular Imaging

Following propensity-weighted adjustment for clinical trial and a range of clinical, ultrasonic, and laboratory parameters, there was no signifi- cant difference in the annualized change in PAV in the presence and absence of warfarin treat- ment (0.33 ± 0.05% vs. 0.25 ± 0.05%; p = 0.17). A significantly greater annualized increase in CaI was observed in warfarin-treated compared with non-warfarin-treated patients (median 0.03; IQR: 0.0 to 0.08 vs. median 0.02; IQR: 0.0 to 0.06; p < 0.001). In a sensitivity analysis evaluating a 1:1 matched cohort (n = 164 per group), signifi- cantly greater annualized changes in CaI were also observed in warfarin-treated compared with non-warfarin-treated patients. In a multivariate model, warfarin was independently associated with an increasing CaI (odds ratio: 1.16; 95% con- fidence interval: 1.05 to 1.28; p = 0.003). CONCLUSIONS Warfarin therapy is associated with progressive coronary atheroma calcification independent of changes in atheroma volume. The impact of these changes on plaque stabil- ity and cardiovascular outcomes requires further investigation. Warfarin use is associated with progressive coronary arterial calcification: insights from serial intravascular ultrasound. JACC Cardio- vasc Imaging 2017 Jul 13;[EPub Ahead of Print], J Andrews, PJ Psaltis, O Bayturan, et al. www.practiceupdate.com/c/56095

Take-home message • The authors of this post hoc analysis sought to determine the effect of warfarin use on coronary percent atheroma volume (PAV) and calcium index (CaI). Using data from 8 prospective studies, 171 patients treated with warfarin were compared with 4129 not treated with warfarin. Researchers found no difference in PAV between individuals treated with warfarin compared with individuals not treated with warfarin. However, individuals treated with warfarin had a significantly higher annualized CaI increase than counterparts not receiving warfarin. • The researchers concludes that warfarin use is associated with a significantly greater annualized increase in the coronary calcium index. The clinical significance of this finding is unknown, and further investigation is required to assess whether this finding influences cardiovascular outcomes. Abstract

this study compared changes in PAV and CaI in matched arterial segments in patients with cor- onary artery disease who were treated with (n = 171) and without (n = 4,129) warfarin during an 18- to 24-month period. RESULTS Patients (mean age 57.9 ± 9.2 years; male 73%; prior and concomitant 3-hydroxy-3-methyl- glutaryl coenzyme A reductase inhibitors (statin) use, 73% and 97%, respectively) demonstrated overall increases in PAV of 0.41 ± 0.07% (p = 0.001 compared with baseline) and in CaI (median) of 0.04 (interquartile range [IQR]: 0.00 to 0.11; p < 0.001 compared with baseline).

OBJECTIVES This study compared serial changes in coronary percent atheroma volume (PAV) and calcium index (CaI) in patients with coro- nary artery disease who were treated with and without warfarin. BACKGROUND Warfarin blocks the synthesis and activity of matrix Gla protein, a vitamin K-de- pendent inhibitor of arterial calcification. The longitudinal impact of warfarin on serial coronary artery calcification in vivo in humans is unknown. METHODS In a post hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound examinations,

COMMENT By James E Tisdale PharmD, BCPS, FCCP, FAPhA, FAHA W arfarin has been used for decades as an oral anticoagu- lant agent, exerting its effects via inhibition of synthesis of vitamin K-dependent clotting factors. Warfarin also inhibits synthesis and activity of matrix G1a protein (MGP), a vitamin K-dependent protein synthesized by vascular smooth muscle. MGP inhibits metabolism of coronary artery calcium, and absence of MGP promotes medial calcification in experimental models and correlates with arterial calcification in humans. In this paper, Andrews et al hypothesized that changes in cor- onary calcium are greater in patients taking warfarin than in patients not treated with this anticoagulant. The investigators analyzed eight prospective randomized trials that used serial coronary intravascular ultrasound, and compared changes in coronary percent atheroma volume (PAV) and calcium index (CaI) in patients with coronary disease who were receiving war- farin (n = 171) vs those who were not (n = 4129). After performing propensity-weighted adjustment for clinical trial and clinical, ultra- sound, and laboratory parameters, the investigators report the novel finding that, although there was no significant influence of warfarin on annualized change in PAV, significantly greater annu- alized changes in CaI were found in warfarin-treated patients, and warfarin was independently associated with increasing CaI. Therefore, there was no warfarin-associated progression

in atheroma volume despite significantly greater warfarin-asso- ciated coronary calcification. The clinical impact of these findings remains uncertain. Although increasing coronary artery calcification has been associated with cardiovascular events, plaque calcification may also repre- sent a more stable atheroma type that may be less susceptible to plaque rupture and less likely to progress. Therefore, the impact of warfarin-associated increased coronary calcification with no change in atheroma volume on clinical coronary events and overall patient outcomes requires further study. In addition, the influence of genetic polymorphisms of vitamin K epoxide reductase complex 1 (VKORC1, the primary target of warfarin) and cytochrome P450 2C9 (the primary enzyme responsible for war- farin metabolism) on the degree of warfarin-induced coronary artery calcification and associated clinical outcome remains to be studied. Overall, the findings of this paper are novel and set the stage for a series of further investigations.

Dr Tisdale is Professor, College of Pharmacy, Purdue University; Adjunct Professor, School of Medicine, Indiana University, Indianapolis, Indiana.

VOL. 2 • NO. 2 • 2017

CONFERENCE COVERAGE 12

European Society of Cardiology Congress 2017 26–30 AUGUST 2017 • BARCELONA, SPAIN

ESC 2017: The Gender Gap in Death fromAcuteMyocardial Infarction Is Closing, Particularly inWomen Younger Than Age 60 The gender gap in death from acute myocardial infarction has been closing over the past two decades, particularly in women younger than 60 years of age. The retrospective analysis included over 50,000 patients and found that overall in-hospital mortality for patients with acute myocardial infarction halved over the 20-year period. It was presented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30. D ragana Radovanovic, MD, of the AMIS Plus Data Centre, University of Zurich, Switzerland, explained that research Mean age did not change for either gender during the observation period. confidence interval 0.80–0.94, P < .001) but was not significant in men (odds ratio 0.98, 95% confidence interval 0.94–1.03). The interaction between gender and admission year was significant at P = .006.

The researchers found a decrease in crude in-hospital mortality from 1997 to 2016. In STEMI patients, in-hospital mortality dropped significantly, from 9.8% to 5.5% in men and from 18.3% to 6.9% in women (P < .001 for both). In NSTEMI patients, it fell from 7.1% to 2.1% in men and 11.0% to 3.6% in women (P < .001 for both). Dr. Radovanovic said that in-hospital mor- tality of patients with acute myocardial infarction fell by at least half over the 20-year period. Differences in death rates between men and women also dropped. Previous research showed that younger women with acute myocardial infarction experienced higher mortality than men of similar age; therefore, Dr. Radovanovic and coinvestiga- tors analyzedmortality separately in patients younger than 60 years of age. In women, they found 6% and 13% decreases in mortality with each sub- sequent admission year for STEMI and NSTEMI, respectively. No significant decreases were observed in men younger than 60 years of age. Mortality per year decreased dramatically in NSTEMI women (odds ratio 0.87, 95%

in the 1990s “showed that younger women with acute myocardial infarction had a higher mortality than men of similar age. Little is known about whether this gender difference has persisted over the years.” Dr. Radovanovic and colleagues set out to assess changes in in-hospital mortality of men and women with acute myocar- dial infarction over a 20-year period. The adjusted in-hospital mortality rate was cal- culated logistic regression analysis. Data were collected from 1997 through 2016 in the nationwide AcuteMyocardial Infarction in Switzerland registry (AMIS Plus). The study included 51,725 patients with acute myocar- dial infarction from83 Swiss hospitals. Among them, 30,398 (59%) presented with ST-seg- ment elevation myocardial infarction (STEMI) and 21,327 (41%) with non-ST-segment eleva- tion myocardial infarction (NSTEMI). The study population was 73% male (mean age 63.9 ± 12.8 years) and 27% female (mean age 71.7 ± 12.5 years). Womenwereolder than men in both the STEMI (71.3 ± 12.7 vs 62.8 ± 12.8 years, P < .001) and the NSTEMI group (72.2 ± 12.2 vs 65.6 ± 12.6 years, P < .001).

Dr. Radovanovic noted that women still experience higher in-hospital mortality from acute myocardial infarction than men, prob- ably because they are on average 8 years older when they suffer a heart attack, and they harbor more cardiovascular risk fac- tors and comorbidities. According to Dr. Radovanovic, although in-hospital mortality continues to be higher in women than men, overall age-adjusted mortality has decreased more prominently in women than men, particularly those younger than 60 years of age. The nar- rowing of the gender gap in mortality over the past 20 years may be due to increasing use of percutaneous coronary intervention (PCI) in women. The use of reperfusion to open blocked arteries, especially PCI, increased in all patients admitted for acute myocardial infarction. In STEMI patients, use of PCI increased from 60% to 93% in men and 45% to 90% in women.

PracticeUpdate Editorial Team

PRACTICEUPDATE CARDIOLOGY

ESC 2017 13

ESC 2017: Ablation of Atrial Fibrillation Improves Quality of Life More than Drugs – CAPTAF Trial Ablation of atrial fibrillation has been shown to improve quality of life more than drugs, even though the reduction in atrial fibrillation burden did not differ significantly between treatments. T his conclusion, based on results of the multicenter, prospective, rand- omized Catheter Ablation compared heart failure, left atrial and ventricular func- tion and diameters, exercise capacity, health care economics, rhythm, atrial fibrillation bur- den, successful vs failed treatment, safety, and “cross-overs” over time.

CAPTAF included 155 patients with symp- tomatic atrial fibrillation who had failed one drug for either rate or rhythm control. Patients suffered at least one episode of atrial fibrillation documented on electro- cardiography in the previous 12 months. At least one symptomatic paroxysmal episode had occurred in the previous 2 months, or at least two symptomatic episodes of persistent atrial fibrillation necessitating cardioversion in the previous 12 months. Patients received an implantable cardiac monitor for a 2-month run-in period, then were randomized to ablation with pulmo- nary vein isolation or antiarrhythmic drug therapy with adequate dosages according to guidelines. The primary endpoint was the change in general health, as measured by the Short Form 36-item health survey, from base- line to 12 months. Secondary endpoints included quality of life (by Short Form 36 and EuroQol 5 Dimensions), symptoms, European Heart Rhythm Association Symptom Classification, burden of atrial fibrillation, and safety. “We measured the burden of atrial fibril- lation before randomization so we got a good idea of burden at baseline,” Dr. Blom- ström-Lundqvist said. The main secondary endpoints were mor- bidity and mortality as composite outcome, cardiovascular hospitalization, symptoms,

with optimized Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial, was pre- sented at the 2017 European Society of Cardiology (ESC) Congress, from August 26–30. Carina Blomström-Lundqvist, MD, PhD, of the University of Uppsala, Sweden, explained that previous randomized trials have reported that pulmonary vein isola- tion is more effective in preventing atrial fibrillation than antiarrhythmic drugs. None of these trials, however, employed contin- uous cardiac rhythm monitoring, so effects on the burden of atrial fibrillation could not be assessed reliably. Until now, no trial of ablation of atrial fibril- lation has employed quality of life as the primary endpoint even though the main indication for ablation of atrial fibrillation is symptom relief. “Instead,” Dr. Blom- ström-Lundqvist said, “30-s recurrences of atrial fibrillation have been used as the primary endpoint, hardly a relevant meas- ure of successful therapy.” The main purpose of the CAPTAF trial was to compare the treatment effects of abla- tion of atrial fibrillation and antiarrhythmic drugs using quality of life as the primary endpoint and an implantable cardiac moni- tor to assess the burden of atrial fibrillation.

“We tried to record silent atrial fibrillation via a patient log book. We got a record for the first year but in the second year, patients were reluctant to record these episodes. We haven’t analyzed these data yet.” After 12 months of follow-up, the primary endpoint of general health score had improved significantly more in the ablation group (mean change 11.0; 95% confidence interval 6.7–15.2) than in the drug group (mean change 3.1; 95% confidence interval –0.9–7.1), P = .0084. Furthermore, all qual- ity-of-life Short Form 36 subscales except for bodily pain and social functioning had improved significantly more in the ablation group than in the drug group. European Heart Rhythm Association symp- tom score improved significantly more from baseline to 12 months in the ablation group (from mean 3.0±0.7 to 1.6±0.8) than in the drug group (from mean 2.9±0.7 to 2.1±1.1; P = .0079). Reduction of burden in atrial fibrillation (that is, the proportion of time in atrial fibrilla- tion), obtained from the implantable cardiac monitor, was numerically larger in the abla- tion than in the drug group, but change from baseline did not reach statistical significance between treatment groups. The complication rate was comparable between treatment groups. Dr. Blomström-Lundqvist concluded, “Qual- ity of life should be the primary endpoint in future trials since the main indication for rhythm control is improvement.” She continued, “The lack of a statistically significant difference between treatment groups in the reduction in burden of atrial fibrillation suggests that other mechanisms may explain the better improvement of quality of life and symptoms achieved with pulmonary vein isolation compared to anti- arrhythmic drugs.” She added, “We confirmed that quality of life improved greatly with ablation vs anti- arrhythmic drugs. We think it’s because of side effects of antiarrhythmic drugs, but we have not determined this definitively.”

PracticeUpdate Editorial Team

© ESC Congress 2017 – European Society of Cardiology

VOL. 2 • NO. 2 • 2017