Practice Update: Cardiology

VOL. 2 • NO. 1 • 2017

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4672

Sudden cardiac death: pharmacotherapy and proarrhythmic drugs

Opinion

A critical point is that one should NOT simply cut the leads in the pocket and remove the generator. Such an approach is highly unlikely to cure the infection and will make the task of removing the remainder of the leads more technically difficult. Dr Anne Curtis onmanaging patients with an infected ICD

Conference ACC 2017 ATS 2017

JOURNAL SCAN Incidence of AF sinks following normalization of testosterone levels after testosterone replacement therapy

Acute kidney injury after radial or femoral access for invasive acute coronary syndrome management

Update on the management of heart failure from the ACC/AHA/HFSA

2

Confidence from Evidence and Real World Experience * *Xarelto has evidence for its efficacy and safety profile for eligible patients from RCTs and real world studies in SPAF 1-3 and PE/DVT. 4,5 Xarelto is the world’s most prescribed NOAC, 6 with over 23 million patients treated across multiple indications. 7,8

RCT=randomised controlled trial; SPAF=stroke prevention in atrial fibrillation; PE=pulmonary embolism; DVT=deep vein thrombosis; NOAC=non-vitamin K antagonist oral anticoagulant. Calculation based on IMS Health MIDAS, Database: Monthly Sales June 2016.

Australia’s No.1 prescribed NOAC 7

PBS Information: Authority Required (STREAMLINED). Refer to PBS Schedule for full authority information.

PLEASE REVIEW THE FULL PRODUCT INFORMATION (PI ) BEFORE PRESCRIBING. APPROVED PI AVAILABLE AT WWW.BAYERRESOURCES.COM.AU/RESOURCES/UPLOADS/ PI/FILE9466.PDF OR UPON REQUEST FROM BAYER AUSTRALIA LTD. Minimum Product Information. XARELTO ® (rivaroxaban) INDICATIONS: Prevention of venous thromboembolism (VTE) in adult patients who have undergone major orthopaedic surgery of the lower limbs (elective total hip replacement, treatment for up to 5 weeks; elective total knee replacement, treatment for up to 2 weeks); 10 mg tablet once daily. Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke; 20 mg tablet once daily (15 mg for patients with CrCl 30-49 mL/min). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for the prevention of recurrent DVT and pulmonary embolism (PE); 15 mg tablet twice daily for 3 weeks, followed by 20 mg tablet once daily. Xarelto 15 mg and 20 mg tablets should be taken with food. Tablets may be crushed; these may be administered orally (mixed with water or applesauce), or given through gastric tubes. See full PI for details. CONTRAINDICATIONS: Hypersensitivity to rivaroxaban or to any of the excipients, clinically significant active bleeding, lesions at increased risk of clinically significant bleeding and patients with spontaneous impairment of haemostasis, significant hepatic disease which is associated with coagulopathy, dialysis or severe renal impairment with a creatinine clearance < 15 mL/min for Xarelto 10 mg or < 30 mL/min for Xarelto 15 mg and 20 mg, concomitant treatment with strong inhibitors of both CYP 3A4 and P-glycoprotein, Pregnancy, Lactation. PRECAUTIONS: Increased bleeding risk such as general haemorrhagic risk (see PI for list), bronchiectasis or history of pulmonary bleeding, renal impairment, hepatic impairment, surgery and interventions, spinal/epidural anaesthesia or puncture, patients with prosthetic valves (no clinical data), haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy, lactose intolerance. INTERACTIONS WITH OTHER MEDICINES: Care to be taken if concomitantly used with medicines affecting haemostasis; concomitant administration with NSAIDs, platelet aggregation inhibitors, other anticoagulants. ADVERSE EFFECTS: Please refer to PI for a complete list. Very common and common adverse reactions ( ≥ 1%) include post procedural haemorrhage, increased transaminases, gingival bleeding, constipation, diarrhoea, nausea, pyrexia, oedema peripheral, contusion, pain in extremity, headache, dizziness, haematuria, menorrhagia, epistaxis, haematoma, anaemia, rectal haemorrhage, fatigue and ecchymosis, haemoptysis, pruritus, conjunctival haemorrhage, abdominal pain, dyspepsia, gastrointestinal haemorrhage, syncope, hypotension, increased gamma-glutamyltransferase, tachycardia, abdominimal pain, vomiting, asthenia, wound haemorrhage, subcutaneous haematoma and rash. Less frequent but serious adverse reactions include: urticaria, hypersensitivity, hyperglycaemia, cerebral, cerebellar and intracranial haemorrhage, haemorrhagic transformation stroke, jaundice, eye haemorrhage, loss of consciousness, angioedema, allergic oedema, cholestasis, hepatitis and thrombocytopaenia. DOSAGE AND ADMINISTRATION: see INDICATIONS above. PI last updated on 23 December 2016. References: 1. Patel MR et al. N Engl J Med 2011;365:883–91. 2. Camm J et al. Eur Heart J 2015. 3. Tamayo S et al. Clin Cardiol 2015;38:63–8. 4. Prins MH e t al. Thrombosis J 2013;11(1):21. 5. Beyer-Westendorf J et al. Blood 2014;124:955–62. 6. IMS Health MIDAS, Database: Monthly Sales June 2015. 7. Calculation based on IMS Health MIDAS, Database: Monthly Sales June 2016. 8. Xarelto ® (rivaroxaban) Product Information, 23 December 2016. Bayer Australia Ltd. ABN 22 000 138 714, 875 Pacific Highway, Pymble NSW 2073. Xarelto ® is a registered trademark of Bayer Group, Germany. BAY4036/L.AU.MKT.GM.04.2016.0442. Prepared June 2017.

CONTENTS 3

RESEARCH Editor’s picks 4 Sudden cardiac death: pharmacotherapy and proarrhythmic drugs 5 GI safety of celecoxib vs naproxen in patients with cardiothrombotic diseases and arthritis after upper GI bleeding 6 Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in “real-world” clinical practice 7 Elderly patients cared for by younger physicians have lower mortality rates 7 Lower risk of heart failure Hypertension 13 Maternal antihypertensive use and congenital heart defects Arrhythmias/heart rhythm disorders 14 Systemic inflammation as a novel QT-prolonging risk factor in patients with Torsades de Pointes 15 Incidence of AF sinks following normalization of testosterone levels after testosterone replacement therapy Cardiac imaging 16 Acute kidney injury after radial or femoral access for invasive acute coronary syndrome management 17 Effect of metformin and lifestyle on coronary artery calcium in the Diabetes Prevention Program Heart failure 18 Update on the management of heart failure from the ACC/ AHA/HFSA 19 Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients Interventional cardiology 20 Long-term outcomes improve when patients are switched to clopidogrel after ACS and death in patients initiated on SGLT-2 inhibitors vs other glucose-lowering drugs

Cover 4 Sudden cardiac death:

PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. 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 FHFSA Editor-in-Chief PracticeUpdate® is a registered trademark of Elsevier Inc. © 2017 Elsevier Inc. All rights reserved. ABOUT 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 www. practiceupdate.com PracticeUpdate and PracticeUpdate Cardiology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Cardiology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Editorial Manager Anne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Editorial Contributors Ashish Aggarwal MD, Samer Ajam MD, Jason Garlie MD

pharmacotherapy and proarrhythmic drugs

Conference coverage

8 ACC 2017 8 ACC expert roundups

10 ATS 2017 10 COPD exacerbations in those with CVD may raise MI/stroke risk 12 Sleep apnea may increase risk of atrial fibrillation

Features 21

My approach to the patient with an infected implantable cardioverter defibrillator (ICD) 22 My approach to the patient with left main disease

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

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VOL. 2 • NO. 1 • 2017

EDITOR’S PICKS 4

Sudden cardiac death: pharmacotherapy and proarrhythmic drugs JACC: Clinical Electrophysiology Take-home message • The authors of this retrospective study examined death certificates and autopsy information for 1363 individuals in Denmark who experienced sudden cardiac death (SCD). The study objective was to determine if exposure to specific drug therapy increased risk for SCD. The cohort’s median age at death was 38 years, and 786 (58%) had been exposed to one or more drugs in the 90 days before death. Analgesic, antihypertensive, and antibiotic drugs were the most commonly used in the cohort. Importantly, a higher risk for sudden arrhythmic death syndrome (SADS) was identified with exposure to drugs classed as “brugadogenic” or drugs with QT-prolonging properties than with explained SCD (OR, 2.16 for brugadogenic and 2.91 for QT-prolonging). • The results of this study indicate that “brugadogenic” and QT-prolonging drugs are associated with an increased risk for SADS. The authors recommend better identification of individuals at risk for arrhythmias as a strategy for lowering rates of SCD.

Abstract OBJECTIVES This study sought to describe the use of pharmacotherapy in a nationwide cohort of young patients with sudden cardiac death (SCD). BACKGROUND Several drugs have been associ- ated with an increased risk of SCD and sudden arrhythmic death syndrome (SADS). It remains unclear how pharmacotherapy may contrib- ute to the overall burden of SCD in the general population. METHODS This was a nationwide study that included all deaths that occurred between 2000 and 2009 and between 2007 and 2009 in people age 1 to 35 years and 36 to 49 years, respectively. Two physicians identified all SCDs through review of death certificates. Autopsy reports were collected. Pharmacotherapy prescribed within 90 days before SCD was identified in the Danish Registry of Medicinal Product Statistics. RESULTS We identified 1,363 SCDs; median age was 38 years (interquartile range: 29 to 45 years), and 72% (n = 975) were men. Autopsy was per- formed in 55%. Overall, 58% of SCD cases (n = 786) received at least 1 drug within 90 days before death. The most common drugs were analgesic drugs (n = 239; 18%), antihypertensive drugs (n = 234; 17%), and antibiotic drugs (n = 218; 16%). After multivariable adjustment, prescription of “brugadogenic” drugs or >1 QT-prolonging drug was associated with an increased risk of SADS compared with explained SCD (odds ratio: 2.16 [95% confidence interval: 1.12 to 4.17] and 2.91 [95% confidence interval: 1.46 to 5.81], respectively). CONCLUSIONS Pharmacotherapy was identified in 58% of the SCD cases. After multivariable adjustment, there was a 2- and 3-fold increased risk of SADS compared with explained SCD in patients receiving brugadogenic drugs or >1 QT-prolonging drug, respectively. Identification of high-risk patients is warranted to lower the burden of SCD. Sudden cardiac death: pharmacotherapy and proarrhythmic drugs: a nationwide cohort study in Denmark. JACC Clin Electrophysiol 2017 May 05;[EPub Ahead of Print], B Risgaard, BGWinkel, R Jabbari, et al.

COMMENT By Raymond L. Woosley MD, PhD T he study by Risgaard, et al pro- vides reinforcing evidence for a strong connection between sudden cardiac death (SCD) in the general pop- ulation and the use of medicines known for their potential to induce arrhythmias. The fact that over 135 medications (www. CredibleMeds.org) in use today result in QT prolongation, a proven independent predictor of sudden cardiac death, has long suggested that such an association might exist. This study has demonstrated that use of these QT-prolonging drugs in a general population is associated with a threefold higher risk for SCD. Likewise, the more than 20 drugs known to induce arrhythmias in patients with Brugada syn- drome (www.brugadadrugs.org) were associated with a twofold higher risk for

SCD. It is remarkable that this risk, long associated with the elderly, is promi- nent in a relatively young population under age 50. The international trend of increasing use of prescription medicines comes with a need for greater aware- ness of their potential harm and the use of modern technology, such as risk factor surveillance and clinical decision-support systems, to reduce that harm.

Dr Woosley is founding President and Chairman of the Board for CredibleMeds Worldwide, a non-profit organization dedicated to safe use of

medications. He is Emeritus Professor of Medicine and Pharmacology at the University of Arizona College of Medicine.

PRACTICEUPDATE CARDIOLOGY

EDITOR’S PICKS 5

GI safety of celecoxib vs naproxen in patients with cardiothrombotic diseases and arthritis after upper GI bleeding The Lancet Take-home message

in the naproxen group (p=0.008; crude hazard ratio 0.44, 95% CI 0.23–0.82; p=0.010). Exclud- ing patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. INTERPRETATION In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recur- rent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardi- ovascular safety. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic dis- eases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independ- ent, double-blind, double-dummy, randomised trial. Lancet 2017 Apr 11;[EPub Ahead of Print], FKL Chan, JYL Ching, YK Tse, et al.

• In this double-blind trial, 514 patients with arthritis and cardiothrombotic diseases who presented with upper gastrointestinal bleeding were randomized (1:1) to treat- ment with a proton-pump inhibitor plus naproxen or celecoxib. In the celecoxib group, recurrent upper gastrointestinal bleeding occurred in 14 patients compared with 31 patients in the naproxen group. At 18 months of follow-up, the cumulative incidence of recurrent bleeding was significantly lower in the celecoxib group compared with the naproxen group (5.5% vs 12.3%; P =0.008). Discontinuation of treatment led to adverse events in 8% of patients in the celecoxib group and 7% in the naproxen group. There were no treatment-related deaths during the study. • The results suggest that, to reduce the risk of recurrent upper gastrointestinal bleeding, patients at high risk of both cardiovascular and gastrointestinal events should be treated with celecoxib plus a proton-pump inhibitor; naproxen should be avoided.

ulcer and duodenal ulcer, and two bleeding ero- sions). The cumulative incidence of recurrent bleeding in 18 months was 5.6% (95% CI 3.3– 9.2) in the celecoxib group and 12.3% (8.8–17.1)

Abstract BACKGROUND Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesised that a cyclooxy- genase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. METHODS For this industry-independent, dou- ble-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrom- botic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer heal- ing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral admin- istrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esome- prazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. FINDINGS Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat popula- tion. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gas- tric ulcers, three duodenal ulcers, one gastric

COMMENT By Jay L. Goldstein MD

T he hypothetical question of whether the use of aspirin negates the clinical benefit of a coxib is tested in a population of patients at high risk for recurrent upper GI bleeding who are H. pylori negative, have had upper gastrointestinal bleeding, and who have the ongoing need for non-steroidal therapy for arthritis as well as the need for low-dose aspirin for cardiovascular prophylaxis. This randomized prospec- tive trial compared rates of recurrent bleeding in patients who were being treated with 20 mg of esomeprazole and 80 mg of aspirin who additionally received either 200 mg daily of celecoxib or 1 g of naproxen per day. The results of the trial demon- strate that a COX-2-selective NSAID is still associated with a finite but significantly reduced risk of recurrent upper GI bleeding over the duration of the study (18 months). What does this mean to clinicians? In patients who are at high risk and require non-steroidals and aspirin therapy, the ques- tion goes beyond the simple need of a PPI for acid reduction and risk reduction. This study extends the question to the appropriateness of a coxib vs a non-selective NSAID. As this study demonstrates, use of a coxib has a clear benefit with a ≥50% reduction in the rate in recurrent upper GI bleeding; use of aspirin does not necessarily negate the benefit of a coxib in this population. However, the reduced risk does not equate to no risk. The bleeding rate in the coxib arm was approximately 1 in 20; this rate of approxi- mately 5% reminds the clinician that, despite the advantages of using a coxib with acid reduction, the risk of recurrent bleeding is still significant. Given the age/risk of the pop- ulation and associated morbidity and mortality associated with upper GI bleeding, one should always avoid use of any anti-inflammatory unless there is a stronger anticipation of a significantly greater benefit than risk. The conclusion of this study takes us one step closer to greater safety, but still reminds us that nothing is absolute.

Dr Goldstein is Vice Chairman of the Department of Medicine, and Head, Division of Gastroenterology at Northshore University HealthSystem, Illinois.

VOL. 2 • NO. 1 • 2017

EDITOR’S PICKS 6

Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in “real-world” clinical practice JACC: Journal of the American College of Cardiology Take-home message

in analyses restricted to 6-month survivors. Sim- ilar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implan- tation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001). CONCLUSIONS As in clinical trials, use of ambula- tory hemodynamic monitoring in clinical practice is associated with lower HFH and comprehen- sive HF costs. These benefits are sustained to 1 year and support the “real-world” effectiveness of this approach to HF management. Ambulatory hemodynamic monitoring reduces heart failure hospitalizations in “real-world” clinical practice. J Am Coll Cardiol 2017 May 16;69(19)2357-2365, AS Desai, A Bhimaraj, R Bharmi, et al. Associate Chief–Clinical Affairs, Cardiovascular Division of Medicine, as well as Medical Director of the Heart and Vascular Center at Penn Medicine in Philadelphia. COMMENT By Mariell L Jessup MD, FACC, FAHA, FESC T he CHAMPION trial, published in 2011, reported a 37% reduction in heart failure-related hospitaliza- tions in NYHA class III patients implanted with a pulmonary artery pressure mon- itor compared with a control group. There were many skeptics; the FDA delayed approval for several years. Thus, the current study examining a retrospective cohort of 1114 Medicare patients receiving the same hemo- dynamic monitor is now reported as representative of a real-world practice. The investigators noted a 45% lower rate of cumulative heart failure–related hospitalizations compared with a similar period before implantation, with a corre- sponding heart failure cost reduction of US$7433 per patient. Nonetheless, the accompanying editorial by Krumholz and Dhruva suggests residual skep- ticism about the magnitude of effect attributed to the device alone. Clearly, more real-world evidence is needed. Dr Jessup is Professor of Medicine at the Perelman School of Medicine, University of Pennsylvania, and

• In this retrospective study, data from 1114 patients undergoing pulmonary artery pressure sensor implantation were evaluated to examine the effectiveness of ambulatory hemodynamic monitoring in reducing heart failure hospitalization. Of these patients, 1020 heart failure hospitalizations occurred before device implan- tation compared with 381 hospitalizations, 139 deaths, and 17 device implantations and/or transplants in the 6 months following implantation. This decreased rate of heart failure hospitalizations was associated with a 6-month cost reduction of US$7433 per patient. • These data support the real-world effectiveness of the use of ambulatory hemodynamic monitoring in clinical practice.

Abstract BACKGROUND In the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Associ- ation [NYHA] Functional Class III Heart Failure Patients) trial, heart failure hospitalization (HFH) rates were lower in patients managed with guid- ance from an implantable pulmonary artery pressure sensor compared with usual care. OBJECTIVES This study examined the effective- ness of ambulatory hemodynamic monitoring in reducing HFH outside of the clinical trial setting. METHODS We conducted a retrospective cohort study using U.S. Medicare claims data from patients undergoing pulmonary artery pressure sensor implantation between June 1, 2014, and December 31, 2015. Rates of HFH during pre- defined periods before and after implantation

were compared using the Andersen-Gill extension to the Cox proportional hazards model while accounting for the competing risk of death, ventricular assist device implantation, or cardiac transplantation. Comprehensive heart failure (HF)-related costs were compared over the same periods. RESULTS Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence inter- val [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month com- prehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust

PRACTICEUPDATE CARDIOLOGY

EDITOR’S PICKS 7

Elderly patients cared for by younger physicians have lower mortality rates BMJ: British Medical Journal Take-home message • The purpose of this observational study was to investigate whether physician age influences outcomes in hospitalized patients. The investigators examined data from 736,537 admissions between 2011 and 2014 for Medicare beneficiaries ≥65 years; patient care was managed by 18,854 hospitalist physicians. Adjusted 30-day mortality rates were lower in patients cared for by physicians under 40 years of age (10.8%), and increased step-wise as physician age increased: 11.1%mortality ratewhen the physician was 40 to 49 years, 11.3%when the physician was 50 to 59 years, and 12.1% when the physician was ≥60 years. Importantly, there was no association between age of a physician and 30-day mortality when a physician cared for a high volume of patients. Cost of medical care was slightly higher with older physicians, but readmission rates were not associated with physician age. • The authors conclude that elderly patients cared for by younger physicians have a lower mortality rate than patients cared for by older physicians, but this mortality difference is not present if the physician cares for a high volume of patients. Abstract OBJECTIVES To investigate whether outcomes of patients who were admitted to hospital differ between those treated by younger and older physicians. DESIGN Observational study. SETTING US acute care hospitals. PARTICIPANTS 20% random sample of Medicare fee-for-service beneficiaries aged ≥65 admitted to hospital with a medical condition in 2011-14 and treated by hospitalist physicians to whom they were assigned based on scheduled work shifts. To assess the generalizability of findings, analyses also included patients treated by general internists including both hospitalists and non-hospitalists. MAIN OUTCOME MEASURES 30 day mortality and readmissions and costs of care. RESULTS 736537 admissions managed by 18854 hospitalist physicians (median age 41) were included. Patients’ characteristics were similar across physician ages. After adjustment for characteristics of patients and physicians and hospital fixed effects (effectively comparing physicians within the same hospital), patients’ adjusted 30 day mortality rates were 10.8% for physicians aged <40 (95% con- fidence interval 10.7% to 10.9%), 11.1% for physicians aged 40–49 (11.0% to 11.3%), 11.3% for physicians aged 50–59 (11.1% to 11.5%), and 12.1% for physicians aged ≥60 (11.6% to 12.5%). Among physicians with a high volume of patients, however, there was no association between physician age and patient mortality. Readmissions did not vary with physician age, while costs of care were slightly higher among older physicians. Similar patterns were observed among general internists and in several sensitivity analyses. CONCLUSIONS Within the same hospital, patients treated by older physicians had higher mortality than patients cared for by younger physicians, except those phy- sicians treating high volumes of patients. Physician age and outcomes in elderly patients in hospital in the US: obser- vational study. BMJ 2017 May 16;357(xx)j1797, Y Tsugawa, JP Newhouse, AM Zaslavsky, et al. This mortality difference is not present if the physician cares for a high volume of patients.

Lower risk of heart failure and death in patients initiated on

SGLT-2 inhibitors vs other glucose-lowering drugs

Circulation

Take-home message • This study compared SGLT-2 inhibitors with other glucose-lowering drugs with respect to cardio- vascular risk reduction. The results revealed that patients receiving SGLT-2 inhibitors, regardless of the specific agent, had lower rates of cardiovas- cular death and heart failure compared with those receiving other glucose-lowering drugs. • The authors concluded that SGLT-2 inhibitors may offer the class effect of cardiovascular risk reduc- tion in patients with type 2 diabetes. Abstract BACKGROUND Reduction in cardiovascular death and hospital- ization for heart failure (HHF) was recently reported with the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) empagliflozin in type 2 diabetes patients with atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose lowering drugs (oGLDs) in six countries to determine if these benefits are seen in real- world practice, and across SGLT-2i class. METHODS Data were collected via medical claims, primary care/ hospital records and national registries from the US, Norway, Denmark, Sweden, Germany and the UK. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios (HRs) for HHF, death and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. RESULTS After propensity matching, there were 309,056 patients newly initiated on either SGLT-2i or oGLD (154,528 patients in each treatment group). Canagliflozin, dapagliflozin, and empag- liflozin accounted for 53%, 42% and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteris- tics were balanced between the two groups. There were 961 HHF cases during 190,164 person-years follow up (incidence rate [IR] 0.51/100 person-years). Of 215,622 patients in the US, Norway, Denmark, Sweden, and UK, death occurred in 1334 (IR 0.87/100 person-years), and HHF or death in 1983 (IR 1.38/100 person-years). Use of SGLT-2i, versus oGLDs, was associated with lower rates of HHF (HR 0.61; 95% CI 0.51-0.73; p<0.001); death (HR 0.49; 95% CI 0.41-0.57; p<0.001); and HHF or death (HR 0.54; 95% CI 0.48-0.60, p<0.001) with no significant heter- ogeneity by country. CONCLUSIONS In this large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice (NCT02993614). Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study. Circulation 2017 May 18;[EPub Ahead of Print], M Kosiborod, MA Cavender, AZ Fu, et al.

VOL. 2 • NO. 1 • 2017

CONFERENCE COVERAGE 8

ACC 2017: Round-up of key trials by Dr Joerg Herrmann

Dr Herrmann, Associate Professor of Medicine at Mayo Graduate School of Medicine in Minnesota, shares his take-home messages from some of the key trials presented at the American College of Cardiology’s 66th Scientific Session & Expo, 17-19 March, Washington DC, USA.

iFR-SWEDEHEART and DEFINE-FLAIR Two studies, one result: iFR (instant wave-free ratio)- guided percutaneous coronary intervention (PCI), at a threshold of 0.89, is noninferior to FFR (fractional flow reserve)-guided PCI, at a threshold of 0.8, in terms of key clinical endpoints (ie, major adverse cardiac events) and is better tolerated from a patient perspective. 1–2 Both studies also showed that FFR identified more lesions deemed to be hemodynamically significant and led to more interventions. The overall agreement of the two studies is remarkable as the iFR-SWEDEHEART study was a randomized clinical trial based on a comprehen- sive registry 1 whereas DEFINE-FLAIR was a traditional prospectively enrolling randomized clinical trial. 2 Most certainly, these two studies will promote the use of iFR in clinical practice, a procedure that is much easier, faster, and less costly to perform. An aspect challenged by the current data is the definition of cutoffs. The best match of iFR to an FFR value of 0.8 with a 96% sensitiv- ity and 91% specificity is in the range of 0.85 to 0.94. A hybrid approach has thus been advocated – that is, to defer PCI if the iFR is greater than 0.93, to perform PCI if the iFR is less than 0.86, and to perform FFR if the iFR is between 0.86 and 0.93. These two studies simplified this approach to an iFR cutoff of 0.89. Statistically, an iFR of 0.89 matches an FFR cutoff of 0.8 only with a 73% sensitivity and an 88% specificity, but clinically it seems closer to 100%. References 1. Götberg M, Christiansen EH, Gudmundsdottir IJ, et al., on behalf of the iFR-SWEDEHEART Investigators. N Engl J Med DOI: 10.1056/NEJMoa1616540. 2. Davies JE, Sen S, Dehbi HM, et al. N Engl J Med DOI: 10.1056/ NEJMoa1700445.

SURTAVI In August, the FDA approved the use of the bal- loon-expandable SAPIEN 3 and SAPIEN XT valves for transcatheter aortic valve replacement (TAVR) in inter- mediate-risk patients. Here now comes the answer for the self-expandable valves such as the CoreValve and Evolute R valve in patients with severe aortic stenosis at intermediate surgical risk (that is, those with an estimated risk of 30-day surgical death of 3% to 15%, according to the criteria of the Society of Thoracic Surgeons Pre- dicted Risk of Mortality [STS-PROM]) – the SURTAVI trial. 1 The key finding is that of no difference in death from any cause or disabling stroke at 24 months between TAVR and surgical aortic valve replacement (SAVR); that is, the study met its noninferiority primary endpoint. Surgery was associated with higher rates of acute kidney injury (4.4% vs 1.7%), atrial fibrillation (43.4% vs 12.9%), and transfusion requirements (40% vs 12.5%), whereas TAVR patients had a higher need for pacemaker implantation (25.9% vs 6.6%) and higher rates of residual aortic regurgitation (75% vs 33%); however, nearly none severe, 5% moderate aortic regurgitation – thus almost all patients were split only between trace or mild aortic regurgitation). Paravalvular leak was noted in 60% to 70% of TAVR patients; again, nearly none severe, 5%moderate aortic regurgitation, and thus almost all either only a trace or mild degree. TAVR resulted in better aortic valve hemodynamics (greater aortic valve area and lower aortic valve gradient) than surgery, and neither TAVR nor surgery showed evidence of structural valve deterioration at 24 months. Aortic valve re-intervention rates remained low, but were 1%, 2%, and 3% at 1, 12, and 24 months in the TAVR group vs 0.2%, 0.5%, and 0.7% with SAVR. Overall, SURTAVI results do not come as a surprise; self-expandable TAVR is on par with SAVR with regard

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primary endpoint of symptomatic recur- rent fatal or nonfatal VTE was reduced by approximately 70% in both rivaroxaban groups (1.2% VTE occurrence with 10 mg and 1.5% with 20 mg vs aspirin at 4.4% VTE occurrence; HR = 0.26 for 10 mg rivarox- aban vs aspirin and HR = 0.34 for 20 mg vs aspirin; P < 0.001 for both comparisons). 1 There was no difference among prespeci- fied subgroups, including type of prior VTE event (provoked vs unprovoked) and dura- tion of prior anticoagulation therapy. There was a trend toward a higher rate of major or clinically relevant non-major bleeding in the rivaroxaban 20 mg per day group compared with the aspirin group (3.3% vs 2.0%; HR, 1.59; P = 0.08); however, the rates in individual safety endpoints did not dif- fer, and the incidence of adverse events was similar among the groups. While not reaching statistical significance, there was a signal for the elderly (>75 years of age) and fragile in particular to do better with rivaroxaban 10 mg per day than aspirin in terms of bleeding. Thus, in summary, the EINSTEIN-CHOICE trial showed that patients with VTE ben- efit from extended anticoagulation, and rivaroxaban 10 mg per day seems to strike the best balance in terms of efficacy and safety compared with aspirin. These results are also in line with the AMPLIFY-EXT trial published 4 years ago, which showed that extended (12-month) anticoagulation with apixaban 2.5 mg per day or 5 mg per day is safe and efficacious compared with placebo for the prevention of recurrent VTE. 2 Obvi- ously, an open question now is in regard to the timing of stopping the therapy. Both, EINSTEIN-CHOICE and AMPLIFY-EXT do not show a solid plateau in the comparator groups, suggesting that anticoagulationmay need to continue beyond the time frame specified in these trials. References 1. Weitz JI, Lensing AWA, Prins MH, et al. N Eng J Med DOI:10.1056/NEJMoa1700518. 2. Agnelli G, Buller HR, Cohen A, et al. N Engl J Med 2013;368(8):699-708. Both, EINSTEIN-CHOICE and AMPLIFY-EXT do not show a solid plateau in the comparator groups, suggesting that anticoagulation may need to continue beyond the time frame specified in these trials.

was again 75%. Similar to what was found in PRAMI and any other study that had been done in between, the main reduction is by a lower number of future revascularizations, which is intuitive. However, one may want to consider the trend of a 50% lower MI rate with the complete versus the culprit-only approach. The effect size on this endpoint was much stronger in PRAMI. Overall, COMPARE-ACUTE is building momentum for a complete revascularization approach in STEMI patients, confirming the PRAMI trial data. In an era of cost- confinement, this seems most certainly a very cost-effective approach. The risks of multivessel intervention should still not be forgotten; in this trial, more than two-thirds of patients had just one more vessel to be taken care of at the time of STEMI. References 1. Wald DS, Morris JK, Wald NJ, et al. N Engl J Med 2013; 369 (12):1115-1123. 2. Smits PC, Abdel-Wahab M, Neumann F-J, et al. N Engl J Med DOI: 10.1056/NEJMoa1701067. EINSTEIN-CHOICE The EINSTEIN-CHOICE trial compared two doses of rivaroxaban, 10 mg per day and rivaroxaban 20 mg per day, and aspirin 100 mg per day for the duration of 12 months in patients with a venous thromboembolic event (VTE; 50% isolated deep-vein thrombosis, 40% unprovoked) who had completed recommended 6 to 12 months of treatment and were in equipoise in regard to extended anticoagulation. The

to the aortic valve. One has to point out, though, that the average age in this trial was nearly 80 years and that the long-term use over decades in younger patients is not as defined. Also, the complication profile var- ies by type of valve and is to be outlined and considered by patients when deciding which type of procedure to undergo. Reference 1. Reardon MJ, Van Mieghem NM, Popma JJ, et al. N Engl J Med DOI:10.1056/NEJMoa1700456. COMPARE-ACUTE Some 3.5 years ago, the PRAMI trial re-rev- olutionized our views of non-culprit lesion intervention in the setting of a STEMI. 1 The mantra had been “culprit only,” but the PRAMI trial indicated a 75% reduction in major adverse cardiovascular events (MACE) with “preventive” stenting of any lesion greater than 50% in addition to the culprit lesion. Several other trials revis- ited this question, but here is another that stands out: the COMPARE-ACUTE trial. 2 Unique about the trial is that all patients underwent FFR of any lesion with at least a 50% diameter stenosis, and about half of these were significant in both groups; that is, those who would be allowed to have additional PCI based on the informa- tion provided and those who would have culprit-only intervention despite the infor- mation provided. Strikingly, even though no longer based on angiography findings alone, the MACE reduction with this strategy

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American Thoracic Society 2017 International Conference 19–24 MAY • WASHINGTON DC, USA

COPD exacerbations in those with CVDmay raiseMI/stroke risk After an acute exacerbation of chronic obstructive pulmonary disease (COPD), patients with a history of cardiovascular disease or those at risk for cardiovascular disease appear more likely to suffer a myocardial infarction or stroke. W ithin 30 days after an acute exac- erbation, the risk of myocardial infarction and stroke rose four- lung function, such as occurs with COPD, is a risk factor for cardiovascular disease. One theory for why this happens is that COPD triggers inflammation and that inflammation, in turn, leads to cardiovas- cular disease.

Each year the American Thoracic Society International Conference highlights research in lung disease, critical illness, and sleep disorders. The PracticeUpdate Editorial Team reports on two key clinical trials presented at this year’s meeting.

fold. Within 31 days to 1 year after the exacerbation, the odds nearly doubled. A year after the exacerbation, the risk did not differ significantly. This conclusion was based on results of a secondary analysis of adjudicated Study to Understand Mortality and MorbidiTY (SUMMIT) trial data. Ken M. Kunisaki, MD, MS, of the University of Minnesota and Minneapolis Veterans Administration Health Care System, said, “Previous studies have shown that lower

“Since COPD exacerbations lead to par- ticularly high levels of inflammation, we wondered whether these exacerbations would be linked to higher rates of cardio- vascular disease events.” Dr Kunisaki and colleagues analyzed data from SUMMIT. SUMMIT enrolled cur- rent and former smokers between the ages of 40 and 80 years who suffered

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Providers should be particularly aware of the risk of a cardiovascular disease event in patients seeking acute medical care following an exacerbation of COPD.

COPD was increased significantly, par- ticularly during the first 30 days following an acute exacerbation of COPD (hazard ratio 3.8; 95% confidence interval 2.7, 5.5), though it remained increased between 30 days to 1 year (hazard ratio 1.8; 95% confi- dence interval 1.5, 2.3); and was no longer significant beyond 1 year following an acute exacerbation of COPD (hazard ratio 1.1; 95% confidence interval 0.8, 1.6). When analyses were restricted to the individual treatment arms in SUMMIT, the same general pattern was observed in each, with an increased risk for cardiovas- cular disease events early after an acute exacerbation of COPD and no significant increase >1 year after the acute exacerba- tion of COPD. Their findings led Dr Kunisaki and his team to consider evaluating interventions follow- ing an exacerbation of COPD in patients with cardiovascular disease. Dr Kunisaki said, “One approach might be to study currently used cardiac medica- tions, such as antiplatelet agents, statins and/or beta-blockers immediately following exacerbations of COPD. Another might be to use experimental drugs that specifically reduce inflammation.” “Until effective interventions are identified,” he added, “patients who have experienced a recent COPD exacerbation should pay attention to and seek immediate care for symptoms of myocardial infarction.” He added, “Providers should be particu- larly aware of the risk of a cardiovascular disease event in patients seeking acute medical care following an exacerbation of COPD.” Study limitations included the fact that all participants had a history of cardiovascular disease or multiple risk factors for cardio- vascular disease. Whether exacerbations of COPD pose the same risk of cardiovascular disease in patients with no or lower cardiovascular disease risk is not known. Another study of COPD reported at ATS assessed the incidence of in-hospital COPD mortality from 2005–2014. The number of hospitalizations for COPD in

the US fluctuated within a narrow range between 2005 and 2014. In-hospital deaths decreased substantially during that same time. Khushboo Goel, MD, of the University of Arizona, Tucson, and colleagues, set out to examine trends in COPD hospitaliza- tions and in-hospital mortality in a nationally representative sample and to evaluate potential differences by sex and race. She and her team analyzed data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, which cap- tures 95% of all hospital discharges in the US. They reported 8,575,820 hospitaliza- tions for COPD-related health problems between 2005–2014. During that time, those who died in the hospital declined from 24,226 to 9090, a 62% decrease. Dr Goel said, “This was certainly an encour- aging trend. We expected to see a decline because of improvements in caring for con- ditions such as pneumonia, sepsis, septic shock, and thromboembolic diseases asso- ciated with COPD exacerbations, but the magnitude of the decline in mortality was surprising.” She noted that the decreasing mortality trend applied to white, black, and Hispanic patients. Most striking was that each year, women accounted for most of the hospitalizations and in-hospital deaths. Women made up 57–58% of hospitalizations and 51–55% of in-hospital deaths. Dr Goel said, “Possible explanations for the higher COPD burden in US women include the growing number of women who smoke, the increased severity of symp- toms they may experience, and longer life expectancy.” The study also found that from 2005 to 2014, the average age of those hospital- ized remained nearly constant at 67 years. The number of COPD patients treated at teaching hospitals increased from 212,346 to 371,215 and the average length of a hos- pital stay decreased from 5.2 to 4.2 days.

cardiovascular disease or multiple risk fac- tors for cardiovascular disease and whose forced expiratory volume in 1 s (FEV1) was 50–70% of predicted and whose FEV1/ forced vital capacity (total volume of exha- lation) was ≤70%. A Cox model was used with a time- dependent covariate for acute exacerbation of COPD events (defined as symptomatic deterioration requiring treatment with antibiotics or systemic corticosteroids). The team controlled for other risk factors and analyzed the hazard of cardiovascular disease events at 1–30 days, 31 days–1 year, and >1 year following acute exacerbation of COPD events. The primary analysis included data from all four SUMMIT arms (placebo, fluticasone furoate, vilanterol, fluticasone furoate + vilanterol), but additional sensitivity analy- ses restricted the model to individual study arms. The hazard of cardiovascular disease events following acute exacerbations of

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Sleep apneamay increase risk of atrial fibrillation Obstructive sleep apnea may raise the risk of developing atrial fibrillation, reports a retrospective clinical cohort study. T etyana Kendzerska, MD, PhD, of the University of Ottawa Canada, explained that obstructive sleep

apnea is characterized by repetitive epi- sodes of shallow or paused breathing during sleep that lead to a drop in blood oxygen level and disrupted sleep. “There is strong biologic plausibility that obstructive sleep apnea may increase the risk of developing atrial fibrillation through a number of mechanisms,” she said. “Evidence is emerging from ani- mals and smaller studies in humans that obstructive sleep apnea may increase the risk of developing atrial fibrillation through oxidative stress, increased sympathetic activity, metabolic abnormalities, endothe- lial dysfunction, and cardiac stretch from intrathoracic pressure swings.”

needed to confirm this finding and under- stand the potential mechanisms.” Drs Kendzerska and Leung did not include hypertension in their primary analysis. “Hypertension may be the causal path- way between obstructive sleep apnea and atrial fibrillation, so including it might have diminished the association between obstructive sleep apnea and atrial fibrilla- tion,” Dr Kendzerska said. She added, “In our secondary analysis, however, we did control for hypertension, and the association between oxygen desaturation and atrial fibrillation remained significant, suggesting that obstructive sleep apnea can cause atrial fibrillation directly without the intermediate step of developing hypertension.” Limitations of the study included not hav- ing data on adherence to continuous positive air pressure for obstructive sleep and whether or not a participant’s hyper- tension was being treated. Drs Leung and Kendzerska are analyzing data connect- ing obstructive sleep apnea to emergency department visits for atrial fibrillation. Dr Kendzerska concluded that this large clinical cohort with suspected obstructive sleep apnea free of arrhythmias at baseline, sleep time spent with oxygen desaturation <90% was a significant independent pre- dictor of incident hospitalization for atrial fibrillation over the next 10 years. The findings support a causal relationship between obstructive sleep apnea, chronic nocturnal hypoxemia, and new-onset atrial fibrillation.

Other studies have shown that women with sleep apnea are at higher risk of cardiovascular consequences, including mortality. Greater endothelial dysfunction, higher propensity to develop pulmonary and systemic hypertension, and impaired heart rate responses to autonomic challenges in women with obstructive sleep apnea may explain these findings...

Participants hospitalized for atrial fibrillation in follow-up were more likely to be older, male, current or ex-smokers, and suffered a higher level of comorbidities, and more severe obstructive sleep apnea as meas- ured by apnea-hypopnea index or degree of nocturnal oxygen desaturation. In univariate analyses, apnea-hypopnea index >30 vs ≤30 events per hour and ≥10 vs <10 minutes of sleep time spent with oxygen desaturation <90% were significant predic- tors of hospitalization for atrial fibrillation: HR 1.92, 95% CI 1.41–2.62 and HR 2.81, 95% CI2.07–3.81, respectively. After controlling for known risk factors, sleep time spent with oxygen hazard ratio 1.64, 95% confidence interval 1.18–2.28. This associationwas signifi- cantly stronger inwomen thanmen (P = 0.02). Dr Leung said, “Other studies have shown that women with sleep apnea are at higher risk of cardiovascular consequences, includ- ingmortality. Greater endothelial dysfunction, higher propensity to develop pulmonary and systemic hypertension, and impaired heart rate responses to autonomic challenges in women with obstructive sleep apnea may explain these findings, but further studies are

Dr Kendzerska and Richard S. Leung, MD, PhD, of the University of Toronto, reviewed the records of 8256 adults (aver- age age 47 years) referred with suspected obstructive sleep apnea, but free of phy- sician-diagnosed heart rate abnormalities, including atrial fibrillation at baseline. Par- ticipants were followed for up to 13 years. During that time, 173 developed atrial fibril- lation that resulted in hospitalization. They controlled for known risk factors such as age, sex, smoking status, alcohol dependency/intoxication, prior congestive heart failure, chronic obstructive pulmonary disease, and pulmonary embolism/infarc- tion. Cox regression analysis was used to investigate the longitudinal association between obstructive sleep apnea and hos- pitalization for atrial fibrillation. A total of 8256 subjects were analyzed. Median age was 47 years, 62% were men, the median apnea-hypopnea index was 15 events per hour, and 28% were apnea-hypopnea index >30. Over a median follow-up duration of 10 (interquartile range 7–13 years), 173 participants (2.1%) were hospitalized for atrial fibrillation.

PracticeUpdate Editorial Team

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