Practice Update: Cardiology

Best of 2016

DECEMBER 2016 ISSN 2206-4672

RESEARCH NEWS AND VIEWS FROM ELSEVIER

Top 2016 research ACC 2016 Partner 2 HOPE-3 DANAMI-3 DEFER Early BAMI STITCH ROC-ALPS

FIRE AND ICE INOVATE-HF ESC 2016 EMPA-REG OUTCOME FRISC11 ANNEXA-4

DANISH REM-HF

MORE CARE CE-MARC 2 CONSERVE NACIAM SAVE ENSURE-AF AHA 2016 FUTURE EUCLID ART PRECSION PIONEER AF-PCI GLAGOV AEGIS-1 ORION-1 MILANO-PILOT ATHENA HF

PracticeUpdate Cardiology Editor-in-Chief, Douglas Zipes MD, and Associate Editor, Joerg Herrmann MD, discuss their top stories in cardiology for 2016. Predictionmodel for SCA By Douglas Zipes MD 2016 Top stories in Cardiology

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com Account Manager Linnea Mitchell-Taverner l.mitchell-taverner@elsevier.com

C linical cardiac electrophysiology has come a long way since the early days of “His bundle studies.” With accurate mapping and catheter ablation, we’ve been able to eliminate morbidity and mortality associated with many arrhythmias. Maturation of pacemakers and implantable cardiac defibrillators (ICDs) has benefited countless patients. The arrhythmic challenges that remain include atrial fibrillation (AF) and sudden cardiac arrest (SCA). Ablation has helped many patients with AF, while ICDs have saved the lives of many thousands of patients resuscitated from SCA. Despite these advances, both arrhythmias continue to exert a major impact on the general population. An ejection fraction (EF) ≤ 35% helps identify those at risk for SCA. However, SCA remains a major clinical problem because a reduced EF is a better predictor of total mortality than of arrhythmic mortality. In fact, most SCAs occur in the general population among individuals with no past history of cardiac disease in whom the EF is not reduced. The SCA event is often the first manifestation of the presence of underlying heart disease. Therefore, predicting those at risk for SCA in the general population has been a major challenge. Yet, they represent the vast majority of the annual 350,000 sudden cardiac death (SCD) population in the US. That is why I have picked “Development and validation of a sudden cardiac death prediction model for the general population” by Deo et al ( Circulation 2016;134:806–816) as a top story for 2016. In this article, the authors analysed the records of 13,677 individuals in the Atherosclerosis Risk in Communities study (ARIC) and 4207 participants in the Cardiovascular Health Study (CHS) free of cardiovascular disease at baseline to derive a prediction model of SCD for the general population. There were 345 adjudicated SCD events in the analysis, which found 12 independent risk factors for SCD, including age, male sex, African American race, current smoking, systolic blood pressure, use of antihypertensive medication, diabetes, serum potassium, serum albumin, HDL, estimated GFR, and QTc interval. Strikingly, a reduced EF was found in only 1% of participants in an echocardiographic substudy and did not enhance risk prediction. This risk model outperformed the 2013 ACC/AHA CVD Pooled Cohort risk equations. These findings provide the first generalisable risk score to help identify people in the general population at risk for SCD. In the future, this risk score might be used to identify those in the highest- risk subgroups of the general population, who had a 5% risk of SCD over 10 years, so that therapy can be focused on this group to help prevent SCD. Clinicians need to follow future information from this study, which, hopefully, will translate into reducing SCD risk for their patients.

DISCLAIMER PracticeUpdate Cardiology provides highlights of key local and international conferences, timely and relevant news, expert opinions and journal article reviews for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia 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 verificationofdiagnosesanddrugdosagesshould 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. ISSN 2206-4672 PracticeUpdate provides professional research, expert insights, and education resources in a single online destination PracticeUpdate content is selected by medical experts in cardiology for its relevance, timeliness, and importance. It is guided by world-renowned editorial and advisory boards that represent community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights which matter, discover PracticeUpdate.com today. Conference news, expert opinions and journal article reviews are sourced from PracticeUpdate.com

Dr Zipes is Distinguished Professor, Professor Emeritus of Medicine, Pharmacology and Toxicology, and Emeritus Director of the Division of Cardiology and Krannert Institute of Cardiology at Indiana University School of Medicine.

PracticeUpdate® is a registered trademark of Elsevier Inc. © 2016 Elsevier Inc. All rights reserved.

PracticeUpdate Cardiology is published by Elsevier Australia ABN 70 001 002 357

Advertisers Novartis Entresto

475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 © 2016 Elsevier Inc. EMCN121601

12–13

3

The year’s top research, all in one issue Welcome to our special issue, PracticeUpdate Cardiology: Best of 2016 – bringing you a collection of the best research of 2016 from the world’s top cardiology congresses. You’ll find the best in here plus key clinical commentary on why these studies are practice-changing. Our PracticeUpdate Cardiology advisory and editorial board members share their views on the best cardiology story of the year (see left) as well as commenting on the studies to make an impact from the American College of Cardiology, European Society of Cardiology and the American Heart Association. The Elsevier Australia editorial team has specially selected these highlights of 2016 including DAPT, PARTNER-2, EMPA-REG OUTCOME, DANISH, FUTURE, EUCLID and PRECISION. To discover more please visit practiceupdate.com On behalf of the Elsevier Australia PracticeUpdate Cardiology team, I thank you for your continued support and readership. We’ve had some big changes this year with a new name and improved content which we hope helps you in your clinical practice providing the best patient outcomes. I wish you well for 2017 – and to the breakthroughs next year will bring. Happy summer reading! Anne Neilson Managing editor, PracticeUpdate Cardiology (Australian Edition) While it is disappointing not to find a reduction in cardiovascular events with CPAP, our results showed that treatment of obstructive sleep apnoea in patients with cardiovascular disease is nevertheless worthwhile. They weremuch less sleepy and depressed, and their productivity and quality of life was enhanced. Doug McEvoy MD, Flinders University, on results of the SAVE study at ESC 2016. The study carries important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon. Steven Nissen MD, MACC, Cleveland Clinic, on the challenging clinical problem of muscle symptoms in statin-treated patients at ACC 2016. While ticagrelor was nomore effective in reducing risk than clopidogrel, we learned valuable information about this population, specifically, that patients with a history of lower extremity revascularisation are at higher risk of acute limb events and cardiovascular events. Schuyler Jones MD, Duke University School of Medicine, while presenting results of the EUCLID trial at AHA 2016.

Optimal duration of DAPT By Joerg Herrmann MD Mayo Graduate School of Medicine, Rochester, Minnesota. A pproximately 1 million percutaneous cor- onary interventions (PCIs) are performed annually in the United States. Accordingly, any recommendation that pertains to the care of these patients is of great magnitude and so is then the “2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Pa- tients With Coronary Artery Disease” ( J Am Coll Cardiol 2016;68:1082–1115). This update comes 5 years after the last ACC/AHA guidelines on myocardial revascularisation and 2 years after the corresponding ESC guidelines. Most importantly, the recommendations for the minimum duration of DAPT are now in sync across these major societies: a minimum of 1 month after bare-metal stenting and 6 months after newer-generation drug-eluting stenting in patients with stable coronary artery disease and 12 months after an acute coronary syndrome regardless of revascularisation strategy. Interestingly, to extend DAPT beyond the recom- mended minimum timeframe is given a class IIb rating in the ACC/AHA guideline. Accordingly, there is a universal mandate for DAPT early af- ter stenting, but long-term DAPT is an individual decision. Even though patient groups at increased ischemic/stent thrombosis risk on the one hand and at higher bleeding risk on the other hand can be listed, this does not provide much-needed concrete guidance for daily practice. This gap was addressed by the development of a pre- diction rule relative to which patient would derive a net benefit from prolonged DAPT based on the DAPT trial data and subsequent validation using the PROTECT trial data ( JAMA 2016;315:1735– 1749). Despite the fact that the “DAPT score” may not be applicable to all comers outside the DAPT trial criteria, and, in fact, performed only modestly in the validation cohort, it is still the best tool avail- able currently and a major advance. Thus, significant steps were taken in 2016 to pro- vide more concrete guidance on the optimal dura- tion of DAPT, which is one of the most common inquiries in daily practice. For this reason, these two articles should be remembered as top stories for the year 2016. Dr Herrmann is Associate Professor of Medicine at

DECEMBER 2016

AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS 4

Dr Joerg Herrmann discusses PARTNER 2, HOPE-3, DANAMI-3 DEFER, Early-BAMI and STITCH Extension studies

ACC 2016 2–4 APRIL 2016 • CHICAGO, USA

The American College of Cardiology’s 65th Annual Scientific Session & Expo saw the presentation of key studies such as the PARTNER 2, PROMISE, HOPE-3, INOVATE-HF and FIRE AND ICE trials. PracticeUpdate Cardiology Editorial Board members Dr Joerg Herrmann and Dr Doug Zipes discuss their top abstracts fromACC 2016.

Joerg Herrmann MD is Assistant Professor of Medicine, Mayo Graduate School of Medicine, and PracticeUpdate Cardiology Editorial Board member. He presents his top abstracts, and their take-home message, from ACC 2016.

Session 401: Opening showcase and the joint ACC/ JACC late-breaking clinical trials featuring the Simon Dack lecture Transcatheter aortic valve replacement compared with surgery in intermediate risk patients with aortic stenosis: final results from the randomised Placement of Aortic Transcatheter Valves 2 study. MB Leon, C Smith, M Mack, et al • In the PARTNER 2 trial, researchers randomised 2032 patients with aortic stenosis and an intermediate risk for surgery to undergo transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement. Assigned vascular access was mainly transfemoral (76.3%). The rate of death from any cause or disabling stroke was similar between the groups; however, when assessing the transfemoral access cohort only, the researchers found that TAVR was associated with a lower rate of death or disabling stroke than surgery (P = 0.05). Overall, surgery was associated with fewer major vascular complications and less paravalvular aortic regurgitation, and TAVR was associated with less kidney injury, severe bleeding, and new-onset atrial fibrillation. • Researchers concluded that TAVR is associated with similar rates of death and disabling stroke when compared with surgery among intermediate-risk patients. Blood pressure lowering in people at moderate risk. The HOPE-3 trial. EM Lonn • In the HOPE-3 trial, researchers randomised 12,705 patients with moderate cardiovascular risk to evaluate candesartan/ hydrochlorothiazide vs placebo for the primary prevention of cardiovascular events. In patients receiving candesartan/hydrochlorothiazide, there was a greater decrease in blood pressure (6.0/3.0 mmHg) than in the placebo group. At baseline, mean blood pressure was 138.1/18.9 mmHg. The rate of cardiovascular death and events was significantly lower among patients

with a systolic blood pressure >143.5 mmHg receiving active treatment. Overall, the rate of cardiovascular death and events were similar between groups. • In patients with an intermediate risk for cardiovascular disease, researchers concluded that lowering blood pressure with candesartan/ hydrochlorothiazide was not associated with fewer major cardiovascular events than placebo. Effects of rosuvastatin on cardiovascular disease in moderate risk primary prevention in diverse ethnic groups. J Bosch • In the HOPE-3 trial, researchers randomised 12,705 patients with moderate risk for cardiovascular disease to evaluate rosuvastatin vs placebo for the primary prevention of cardiovascular events. In patients receiving rosuvastatin, there was a greater decrease in LDL (26.5%) than in patients receiving placebo. Rosuvastatin was also associated with fewer cardiovascular deaths and events than placebo (P = 0.002 and P < 0.001, respectively). Muscle symptoms were more common in the rosuvastatin group. • In patients with an intermediate risk for cardiovascular disease, researchers concluded that rosuvastatin was associated with fewer major cardiovascular events than placebo. Effects of combined lipid and BP-lowering on cardiovascular disease in a moderate risk global primary prevention population. S Yusuf • In the HOPE-3 trial, researchers randomised 12,705 patients with moderate risk for cardiovascular disease to receive candesartan/ hydrochlorothiazide, rosuvastatin, or placebo in combination or alone. In patients receiving combined blood pressure and lipid-lowering therapy, there was a greater decrease in LDL (33.7 mg/dL) and a greater decrease in systolic blood pressure (6.2 mmHg) than in patients receiving dual placebo. The combined-therapy group also had significantly lower rates of

PRACTICEUPDATE CARDIOLOGY

ACC 2016 5

Session 406: Featured clinical research I: interventional cardiology and surgery Ten-Year outcome of coronary artery bypass graft surgery versus medical therapy in patients with ischemic cardiomyopathy: Results of the Surgical Treatment for Ischemic Heart Failure Extension study. EJ Velazquez, KL Lee, RH Jones, et al • In the STICH Extension study, researchers evaluated the 10-year survival of coronary artery bypass grafting (CABG) with medical therapy versus medical therapy alone in patients with ischaemic cardiomyopathy. A total of 1212 patients were randomised. The rate of death from any cause was significantly higher inmedical therapy group than in the CABG group (66.1% vs 58.9%, respectively; P = 0.02). Cardiovascular mortality was also higher in the medical therapy group than in the CABG group (49.3% vs 40.5%, respectively; P = 0.006). • After 10-year follow-up, results showed that CABG plus medical therapy was associated with lower rates of death and cardiovascular events than medical therapy alone among patients with ischaemic cardiomyopathy.

or deferred stent implantation. They did not find differences in death, heart failure, myocardial infarction, or repeat revascularisation. • Researchers concluded that deferred stent implantation resulted in similar outcomes to standard PCI procedure. Effect of early administration of intravenous beta blockers in patients with ST-elevation myocardial infarction before primary percuta- neous coronary intervention. The Early-BAMI trial. V Roolvink, B Ibanez, JP Ottervanger, et al • The use of beta blockers before primary PCI is not well studied; therefore, in the Early-BAMI trial, researchers randomised 683 patients with ST-segment elevation myocardial infarction (STEMI) to receive intravenous metoprolol or placebo before PCI. The mean age was 62 years, and majority of patients were male (75%). Researchers did not find a significant difference in infarct size between the groups or in the rate of adverse events. The metoprolol group had a lower incidence of malignant arrhythmias than the placebo group (3.6% vs 6.9%, respectively; P = 0.05). • Metoprolol administered before primary PCI did not reduce infarct size when compared with placebo among patients with STEMI.

cardiovascular death and events (P = 0.005 and P = 0.003, respectively). Adverse events associated with combined therapy included muscle weakness and dizziness. • In patients with an intermediate risk for cardiovascular disease, researchers concluded that combined blood pressure and lipid-lowering therapy is associated with fewer cardiovascular events than placebo. Session 405: Joint American College of Cardiology/TCT late-breaking clinical trials The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: DEFERred stent implantation in connection with primary PCI. H Kelbæk, L Kober, S Helqvist, et al The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: iPOST conditioning during primary PCI. T Engstrøm, H Kelbæk, S Helqvist, et al • Stent implantation can result in thrombotic embolisation; therefore, in the DANAMI-3 DEFER trial, researchers randomised 1215 patients with ST-segment elevation myocardial infarction to undergo standard primary percutaneous coronary intervention (PCI) with stent implantation

© 2016 Lagniappe Studio

DECEMBER 2016

AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS 6

Dr Doug Zipes discusses ROC-ALPS, FIRE AND ICE and INOVATE-HF trials

Douglas P Zipes MD is Editor-in-Chief of PracticeUpdate Cardiology. Here are his top abstracts, and their take-home message, from ACC 2016.

0.001 for noninferiority). Researchers did not find a difference in safety between the groups. • Results showed that cryoballoon ablation was noninferior to radiofrequency ablation for the treatment of drug-refractory paroxysmal AF. A randomised trial of rate control versus rhythm control for atrial fibrillation after cardiac surgery. AM Gillinov, E Bagiella, A Moskowitz, et al • In order to compare the efficacy of rate and rhythm control for postoperative atrial fibrillation, researchers randomised 523 patients to receive rate control or rhythm control treatment. The majority of patients had undergone either coronary artery bypass surgery or isolated valve surgery. Researchers did not find a difference in the total number of hospital days, rates of death, or serious adverse events. At 60 days, significantly more patients in the rhythm- control group had a stable heart rhythm without AF in the previous 30 days than patients in the rate-control group (97.9% vs 93.8%; P = 0.02), but there was no significant difference in the rate of patients free from AF from discharge to 60 days. • Researchers concluded that rate and rhythm control for postoperative AF are associated with similar treatment outcomes. Session 412: Late-breaking clinical trials The effect of vagal nerve stimulation in heart failure: primary results of the INcrease Of VAgal TonE in chronic Heart Failure (INOVATE- HF) Trial. MR Gold, BJ Berman, M Borggrefe, et al • In order to evaluate the safety and efficacy of vagal stimulation, researchers of the INOVATE-HF trial randomised more than 700 patients with heart failure to undergo implantation of a vagal stimulation device or to continue medical management. Researchers did not find a difference in the rates of hospitalisation for heart failure or death between the groups. There were no major safety concerns. • The trial was ended early for clinical futility, and researchers concluded that vagal stimulation in patients with heart failure did not offer additional benefits compared with medical management.

Session 410 : Joint American College of Cardiology/ New England Journal of Medicine late-breaking clinical trials Antiarrhythmic drugs for shock-refractory out- of-hospital cardiac arrest: the Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study. PJ Kudenchuk • In patients with out-of-hospital cardiac arrest (OHCA), antiarrhythmic drugs are often used for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, even though there is no proven survival benefit. Researchers randomised 3027 patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia OHCA to receive standard care along with amiodarone, lidocaine, or placebo. They did not find differences in survival or neurologic outcome between the groups.

• Researchers concluded that survival and neurologic outcomes were not improved with amiodarone or lidocaine when compared with placebo for OHCA due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Largest randomised trial demonstrates an effective ablation of atrial fibrillation: the FIRE AND ICE Trial (NCT01490814). K Heinz Kuck • In order to compare the efficacy of the two most common methods for ablation, the researchers of the FIRE AND ICE trial randomised 762 patients with drug- refractory paroxysmal atrial fibrillation (AF) to undergo cryoballoon ablation or radiofrequency ablation. After 90 days, 138 patients in the cryoballoon group and 143 patients in the radiofrequency group experienced clinical failure (HR 0.96; P <

© 2016 Lagniappe Studio

PRACTICEUPDATE CARDIOLOGY

PracticeUpdate.com

In a vast sea of information

We uncover the most relevant clinical updates in your specialty

Look deeper with PracticeUpdate.com The online resource with in-depth insights and inside commentary that matters most to specialists • No matter what other resources you now use, this is one research and review tool you’ll find essential to stay updated. • Designed for specialists, with an all-MD/specialist editorial board to ensure clinical relevance and meaningful analysis

• Cardiology • Dermatology • Diabetes • Eye Care • Gastroenterology • Neurology • Oncology • Primary Care • Urology Join now for FREE, automatic updates on topics in:

AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS 8

Evolocumab proven superior to ezetimibe in lowering cholesterol

S teven Nissen, MD, MACC, of the Cleveland Clinic, explained, “Statin intolerance has been one of the most vexing problems faced by cardiologists. Patients with high levels of LDL cholesterol and high risk of cardiovascular events are often reluctant or unwilling to take statins. This situation is extremely frustrating for both patients and physicians because there have not been good alternatives for treatment.” The prevalence of muscle-related statin intolerance is debated: large randomised trials have reported low rates of muscle symptoms, while observational studies have suggested that 5 to 20% of patients experience muscle symptoms. The phase 3, randomised, double-blind Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin-intolerant Subjects (GAUSS) 3 trial enrolled 511 patients at 53 centres. Their LDL cholesterol averaged >210 mg/dL (5.44 mmol/L). Eighty two percent had tried and failed to tolerate three or more statins. A total of 42.6% of 491 patients who had previously reported muscle pain with at least two different statins had a recurrence of symptoms during blinded administration of atorvastatin, but not while taking placebo. More than a quarter, 26.5%, reported muscle pain while taking placebo but not while taking atorvastatin, suggesting that though statin intolerance can be confirmed in a substantial proportion of patients with self- reported intolerance, a significant proportion experience muscle pain that cannot be attributed to statins. After the initial phase, 218 patients with confirmed statin intolerance were enrolled in the second segment, with 145 randomised to evolocumab and 73 to ezetimibe. Participants in the second phase had an average baseline LDL cholesterol of 220 mg/dL (5.7 mmol/L). After 24 weeks of treatment with either evolucumab or ezetimibe, patients with confirmed statin intolerance who were given evolocumab showed an average 52.8% reduction in LDL cholesterol, a coprimary

The first major clinical trial to include a blinded, placebo- controlled “statin rechallenge” in patients with a history of muscle-related side effects has shed new light on statin- associated muscle symptoms. The trial also demonstrated that monthly self-injection of the nonstatin cholesterol- lowering agent evolocumab reduced levels of low density lipoprotein (LDL) cholesterol more than ezetimibe, a drug used in statin-intolerant patients. These findings were reported at the ACC 2016.

endpoint, vs a 16.7% reduction in those taking ezetimibe. For the study’s other coprimary endpoint, average change in LDL cholesterol for weeks 22 and 24, patients taking evolocumab showed a reduction of 54.5%, and those taking ezetimibe, a 16.7% reduction. After 24 weeks, those given evolocumab exhibited an average LDL cholesterol level of 104 mg/dL (2.69 mmol/L); 64.1% of patients taking evolocumab finished the trial with LDL cholesterol below 100 mg/dL (2.69 mmol/L), and 29.9% finished below 70 mg/ dL (2.69 mmol/L). One patient receiving evolocumab and five given ezetimibe discontinued due to muscle- related adverse events. Dr Nissen said, “The findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients. Evolocumab lowered LDL cholesterol substantially with few patients experiencing muscle symptoms.” He added, “The study carries important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.” The study was limited by modest size and short duration, but Dr Nissen stated it was adequately powered to address its primary endpoint.

The study carries important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.

PRACTICEUPDATE CARDIOLOGY

ACC 2016 9

Death and stroke rates are equivalent for surgery and TAVR at 2 years Intermediate-risk patients with

T his outcome of the randomissed, controlled Placement of AoRtic TraNscathetER Valves (PARTNER) 2A noninferiority trial – the first to evaluate TAVR in patients considered at intermediate risk – suggests that TAVR is at least as safe and effective as surgery in these patients. Results were presented at the ACC 2016. Patients receiving TAVR also experienced shorter hospital stays and a lower incidence of some major complications than those undergoing surgery. Martin B. Leon, MD, of New York Presbyterian Medical Center and coprincipal investigator of the PARTNER trials, explained that roughly one in five patients undergoing surgical aortic valve replacement in the US are at intermediate risk; so intermediate- and high-risk patients comprise the top quartile of patients needing an aortic valve replacement.

Of those in the TAVR group, 76% underwent transfemoral placement, and the rest, transthoracic placement in which the new valve was threaded through a cut in the chest wall. Results in meeting the primary endpoint of all-cause death and disabling strokes were comparable at 2 years: 19.3% for TAVR and 21.1% for surgery. Among TAVR patients with transfemoral placement of the valve, the combined rate of death and disabling stroke was lower, 16.8% for TAVR vs 20.4% for surgery (P = 0.05). Dr Leon said, “When we compared transthoracic TAVR patients to those having surgery, they were about the same. The transfemoral group clearly experienced lower rates of death and strokes.” The researchers also found significant differences in the secondary clinical endpoints of hospital stay, valve function, and major complications. Some favoured TAVR, some surgery. For example, TAVR patients spent less time in the hospital. Average time in the intensive care unit was 2 days with TAVR versus 4 days with surgery, and average hospitalisation for TAVR was 6 days versus 9 days with surgery. TAVR also appeared to improve aortic valve areas more than surgery, meaning that the valve performed better as measured by echocardiography through 2 years. TAVR also yielded significantly lower rates of acute kidney injury, severe bleeding events, and new-onset atrial fibrillation than surgery. The surgery group, on the other hand, experienced fewer major vascular complications and paravalvular regurgitation. Dr Leon said, “Two-year follow-up allowed enough time to accurately assess the relative performance of these two valve replacement therapies,” adding that he suspects the findings will potentially affect future clinical TAVR guidelines. “We know surgery is good, but it is a major procedure and for many patients, a less invasive approach may be preferable. As we continue to evolve the procedure and technology, it’s important to know whether TAVR is an effective alternative in these lower-risk patients.”

severe aortic stenosis who receive minimally invasive transcatheter aortic valve replacement (TAVR) experience similar rates of death and disabling strokes after 2 years as those undergoing standard open heart surgical replacement.

We know surgery is good, but it is amajor procedure and for many patients, a less invasive approachmay be preferable. As we continue to evolve the procedure and technology, it’s important to knowwhether TAVR is an effective alternative in these lower-risk patients.

He said, “For the past 5 years, TAVR has been growing in use and acceptance largely based on clinical evidence from multiple randomised controlled trials. These have been limited to patients at the highest risk for surgery, however. We have demonstrated that death and stroke are equivalent in these patients and may be fewer in the transfemoral group.” Outcomes using the Sapien XT valve were compared with open heart surgery valve replacement among 2032 intermediate-risk patients treated between 2011 and 2013 at 57 sites, all but two in the US. Patients were randomly assigned to TAVR (n=1011) or surgery (n=1021).

© 2016 Lagniappe Studio

DECEMBER 2016

AMERICAN COLLEGE OF CARDIOLOGY SCIENTIFIC SESSIONS 10

Women andmen with suspected heart disease report similar symptoms

K shipra Hemal, MD, of the Duke Clinical Research Institute, Durham, North Carolina, explained that PROMISE included one of the largest cohorts of women ever enrolled in a heart disease study. It also found that women had a greater number of cardiac risk factors than men, yet were more likely to be characterised as lower risk by their healthcare providers and objective scores that measure and predict heart disease risk. Dr Hemal said, “The most important take-home message for women from this study is that their risk factors for heart disease differ from men’s, but their symptoms of coronary artery blockages are the same.” Dr Hemal asserted the finding that women exhibit more risk factors for heart disease than men means measures to reduce this risk need to be a priority for women as well as men. Previous studies have suggested that women experiencing myocardial infarction are less likely to suffer classic symptoms such as angina and more likely to experience atypical symptoms such as back pain, abdominal pain, and fatigue that may be less readily recognised as symptoms of myocardial infarction. Dr Hemal and colleagues sought to shed light on a different group of patients – those without a prior heart disease diagnosis who were being evaluated for symptoms suggestive of heart disease. Only a few studies, most several decades old, have examined sex differences in this group of patients. PROMISE, conducted at 193 centres in the US and Canada, enrolled 10,003 patients, more than 5200 who were women. Half of patients were randomly selected to receive a cardiac CT scan to assess the degree of narrowing. The rest received a functional or stress test – exercise electrocardiogram, stress echocardiography, or nuclear stress test. The team examined patient data to assess differences between women and men in age, race or ethnicity, risk factors, symptoms, and evaluation and test results. Compared with men, women were older (average age 62 vs 59 years for men), more often nonwhite, less likely to smoke or be overweight, and more likely to have high blood pressure, high cholesterol, history of stroke, sedentary lifestyle, family history of early-onset heart disease, and history of depression. Chest pain was the primary symptom for 73.2% of women and 72.3% of men. The two sexes, however, described their pain differently. Women were more likely to describe

Angina and shortness of breath are the most common symptoms

it as “crushing,” “pressure,” “squeezing,” or “tightness. ” Men were more likely to describe it as “aching,” “dull,” “burning,” or “pins and needles.” Equal proportions of women and men (15%) reported shortness of breath as a symptom. Women were more likely than men to have back pain, neck or jaw pain, or palpitations as their primary symptom, the percentage of patients of both sexes reporting these symptoms was very small (1% of women vs 0.6% of men for back pain, 1.4% of women vs 0.7%of men for neck or jawpain, 2.7% of women vs 2% of men for palpitations). Women scored lower than men on heart disease risk assessment scores, suggesting a lower risk of heart disease. Before diagnostic tests were conducted, healthcare providers were more likely to doubt that women had heart disease. Nontraditional risk factors such as depression, sedentary lifestyle, and family history of early- onset heart disease – risk factors that in this study were more commonly found in women than in men – are excluded from most risk assessment questionnaires. Dr Hemal said, “For healthcare providers, the study showed the importance of considering differences between women and men throughout the diagnostic process for suspected heart disease. Providers also need to know that, in the vast majority of cases, women and men with suspected heart disease have the same symptoms.” Women were more likely than men to be referred for a stress echocardiography or nuclear stress test and less likely than men (9.7% vs 15.1%) to test positive. Factors predicting a positive test differed for women compared with men. In women, body mass index and score on one of five risk assessment questionnaires (Framingham risk score) predicted a positive test, whereas in men scores on two risk assessment questionnaires (Framingham and modified Diamond-Forrester risk scores) predicted a positive test. Dr Hemal said, “The fact that this was one of the largest cohorts of women ever evaluated in a heart disease study lends validity to our findings. A limitation of the study was that it looked only at the diagnostic process and not at whether there were differences between women and men in numbers or outcomes of myocardial infarction.” She added, “The next step in this research will be to examine whether and how the differences we identified between women and men influence outcomes.”

reported by both women and men

with suspected heart disease, in contrast to prior data, according to the Randomized PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) study.

PRACTICEUPDATE CARDIOLOGY

ACC 2016 11

Statins should be usedmore broadly in intermediate-risk populations Lowering cholesterol with statins significantly reduced adverse cardiovascular events in people with average cholesterol and blood pressure levels who were considered to be at intermediate risk for heart disease, reports the large Heart Outcomes Prevention Evaluation (HOPE) 3 trial.

S alim Yusuf, MBBS, DPhil, of McMaster University, Hamilton, Ontario, Canada, explained that studies have focused on the impacts of cholesterol- and blood pressure- lowering drugs on established cardiovascular or renal disease, diabetes, other high-risk conditions, or in patients with markedly elevated cholesterol or blood pressure levels. Guidelines recommend these drugs mainly in patients at high risk of cardiovascular disease. HOPE-3 is the first trial to assess outcomes of preventive treatment with cholesterol- and blood pressure-lowering drugs in a large, globally diverse population at intermediate risk of cardiovascular disease. Statins – alone or in combination with antihy- pertensive drugs – were found to be superior to placebo in achieving both the study’s first copri- mary endpoint (a composite of cardiovascular death, heart attack, and stroke) and its second coprimary endpoint (a composite of those events plus heart failure, resuscitated cardiac arrest, and revascularisation procedures such as bypass sur- gery or angioplasty). For these endpoints, antihypertensive drugs were found to improve outcomes over placebo only in patients with elevated blood pressure. These drugs were associated with no improvements in patients without elevated blood pressure, and there was a trend toward worse outcomes in those with relatively low blood pressure. Dr Yusuf said, “The implications for practice are huge. We certainly should consider using statins much more widely than we have used them thus far. In particular, for patients with hypertension, our study suggests you can double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously.” The trial included 12,705 people in 21 countries on six continents. All participants had at least one known cardiovascular risk factor, such as smoking, an elevated waist-to-hip ratio, or family history of heart disease. None, however, had been diagnosed with cardiovascular disease. The trial was designed to focus on preventing cardiovascular disease before it starts. Participants were randomly assigned to receive either a statin – 10 mg of rosuvastatin – or

placebo daily and either an antihypertensive – a combination of 16 mg of candesartan and 12.5 mg of hydrochlorothiazide – or placebo daily. Patients were randomised to one of four groups: statin + antihypertensive, statin only, antihypertensive only, or placebo. Outcomes were tracked for a median of 5.6 years. Cardiovascular death, myocardial infarction, or stroke occurred in 3.5% of patients receiving a statin + an antihypertensive and in 5% of those receiving placebo. Relative risk reduction in those taking a statin + an antihypertensive was 30%, 40% in those with elevated blood pressure, and 20% in those without elevated blood pressure. Results for the study’s second coprimary endpoint were identical. Dr Yusuf concluded that the findings point to the value of a more simplified approach, which places more emphasis on statins in the general population and adds low doses of combination antihypertensive medications in patients with mild hypertension. In the study, combination therapy reduced risk among people with elevated blood pressure by 40% safely, without dose titration or the need for frequent blood testing. He added, “Most hypertension guidelines focus on what agents to use and what blood pressure to aim for. There has been very little emphasis on the importance of statins in treating patients with hypertension. Our approach, which used a combination of moderate doses of two antihypertensive drugs plus a statin, appeared to produce the biggest ‘bang,’ in terms of reducing events, with few side effects.” A limitation of the study was that, while it tracked patients for more than 5 years – longer than most clinical trials – it can take many more years or even decades to show full improvement in outcomes of primary disease prevention interventions. Extending the study even longer might have revealed larger benefits. Participants will be tracked for an additional 3 to 5 years. Dr Yusuf and colleagues will continue to examine effects on cognitive decline, erectile dysfunction, and vision, along with potential differences among ethnic groups and geographic regions.

The implications for practice are huge. We certainly should consider using statins much more widely than we have used them thus far. In particular, for patients with hypertension, our study suggests you can double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously.

DECEMBER 2016

EUROPEAN SOCIETY OF CARDIOLOGY CONGRESS 14

Dr Deepak Bhatt picks ASCOT, EMPA-REG OUTCOME, FRISC II and ANNEXA-4 as some of his ESC 2016 top abstracts

ESC 2016 27–31 AUGUST 2016 • ROME, ITALY

This year’s European Society of Cardiology (ESC) Congress saw the presentation of key studies such as the DANISH, PRAGUE-16, CE MARC 2, SAVE and NACIAM trials. PracticeUpdate Cardiology Advisory Board member Dr Deepak Bhatt lists his top abstracts from ESC 2016, while Professor TomMarwick and Professor Garry Jennings share their insights from the meeting.

Deepak Bhatt MD, MPH, FACC, FAHA, FSCAI, FESC is Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital Heart & Vascular Center and Professor of Medicine at Harvard Medical School.

Clinical trial update: prevention The influence of blinding and un-blinding on statin related adverse events: new evidence from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Presented by A Gupta Clinical trial update: heart failure and pacing Effects of empagliflozin on cardiovascular mortality by prevalent or incident heart failure in EMPA-REG OUTCOME. Presented by D Fitchett Effects of empagliflozin on overall heart failure burden in EMPA-REG OUTCOME. Presented by D Fitchett

Clinical trial update: coronary artery disease A life-time perspective on the effects of an early invasive compared with a non-invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome – the FRISC II 15 years follow-up. Presented by L Wallentin Hot line: prevention and lipids A naturally randomised trial comparing the effect of long-term exposure to lower LDL-C, lower SBP, or both on the risk of cardiovascular disease. Presented by BA Ference Hot line: coronary artery disease and imaging

AMERICA – Systematic detection and management of multivascular involvement of atherothrombosis in coronary patients in comparison with treatment of coronary disease only. Presented by J-P Collet Clinical trial update: platelet therapy Prevention of first stroke with ticagrelor in patients with prior myocardial infarction: insights from PEGASUS- TIMI 54. Presented by M Bonaca Hot line: preventive strategies 2 ANNEXA-4 –Andexanet alfa for reversal of Factor Xa inhibitors in patients with acute major bleeding. Presented by SJ Connolly Registries: miscellaneous Optimal blood pressure in CAD patients: is there a J-curve phenomenon? Insights from 22,695 hypertensive CAD patients in the CLARIFY registry. Presented by PG Steg

© ESC Congress 2016 – International Center for Documentary Arts (ICDA) PRACTICEUPDATE CARDIOLOGY

ESC 2016 15

Professor TomMarwick discusses the DANISH, REM-HF, MORECARE, CE-MARC 2, CONSERVE andNACIAMtrials

Tom Marwick, MBBS, PhD, MPH, Director and Chief Executive of BakerIDI Heart and Diabetes Institute.

1. DANISH: ICDs in nonischaemic heart failure For me, this was the top trial presented at this year’s meet- ing. The DANISH study looked at primary prevention with ICDs for patients with nonischaemic heart failure. Most cardiologists have, at some stage, had some disquiet about the impact of primary prevention ICDs, especially in the elderly. Many ICDs are implanted and never discharge. This Danish group, in a pragmatic clinical trial, looked at whether there was a benefit of implanting an ICD in nonischaemic HF with an impaired ejection fraction. The investigators reported no difference in all-cause mor- tality with ICD versus medical care in nonischaemic HF. This is despite the fact that ICDs reduce sudden cardiac death. The results point to the role of multi-morbidity – HF patients are very likely to have multiple diseases. The message from this study is that ICDs do not benefit older patients – the study did a subgroup analysis of patients older than 68 years – whereas it might benefit younger patients. This is contrary to current guidelines and an incredibly important observation. 2. REM-HF and MORE CARE: remote telemonitoring in heart failure The REM-HF and MORE CARE were two studies of remote telemonitoring in HF presented at the ESC. The conclusions were pretty much the same: telemonitoring did not change HF outcomes. We know that telemonitoring is inexpensive, and some private insurers in the US are considering it as a means of controlling costs. Clearly, the long-term care of patients with HF requires more than monitoring – we can get huge amounts of data but there needs to be some kind of interventional strategy that arises from the interpretation of the data. These results are a reality check on what telemonitoring has to offer – I don’t think they signal the end of telemonitoring but it needs to be thought through more carefully. 3. CE-MARC 2 and CONSERVE: diagnostic

at MRI or SPECT imaging for perfusion versus the current NICE guidelines (which use a probability-based approach for test selection). They found that the use of a functional test reduced the need for angiography and reduced inter- ventions. In fact, in the group that had the functional test, 8% of the subsequent angiography was unnecessary com- pared with 28% in the group that was guided by the NICE guidelines. So that one was a win for doing stress testing. The CONSERVE trial was a comparison between coronary CT angiography versus invasive angiography in symptomatic patients to reduce the number of negative angiograms. The study showed that if CT angiogram was performed before catheterisation, there was an 85% reduction of invasive angiography, with similar outcomes. That one was a win for CT angiography. I think it’s an interesting juxtaposition that one study says “do a non-invasive CT test before an angiogram so that you can avoid doing angiography” while the other says “do a non-invasive stress test instead of using current guidelines” because, again, you can save a bunch of angiograms. It also demonstrates how we’re still really uncertain about how to use non-invasive testing in people with chest pain. There is still a lot of work to be done in this area and I think the emphasis here is that MRI perfusion imaging is an interesting strategy that we should probably think more about in Australia. 4. NACIAM: N-acetylcysteine with glyceryl trinitrate on infarct size This is an important Australian trial investigating the free radical scavenger N-acetylcysteine. The hypothesis was that, in people having myocardial infarction, some of the damage from the infarct is related to free radicals. And so if you could scavenge the free radicals, either that would be of direct benefit or it would enable nitrates to be effective. The investigators found a 38% reduction in infarct size with the use of the N-acetylcysteine with glyceryl trinitrate versus glyceryl trinitrate alone. What we’ve been doing with MI has really been focused on early revascularisation for a long time, but not so much on other things we can do to try to salvage tissue. This is a nice example of such a strategy. Second, this group in Adelaide has been really imaginative about selecting agents for that purpose. It’s nice to see one of these come in with a really impactful result.

trials on imaging technologies for recognition of coronary disease

Both of these were diagnostic trials on the use of new im- aging technologies for the recognition of coronary disease, comparing combinations of functional testing with CT and invasive angiography. In CE-MARC-2, the authors looked

DECEMBER 2016

EUROPEAN SOCIETY OF CARDIOLOGY CONGRESS 16

Professor Garry Jennings discusses the SAVE, NORSTENT, ENSURE-AF and DANISH trials Garry Jennings, AM, MBBS, MD, FRCP, FRACP, Chief Medical Adviser of the Heart Foundation of Australia. Clinical trial updates:

their inhibitors, and SGLT2 inhibitors for diabetes. The meeting also saw the release of important new ESC guidelines that will no doubt influence Australian experts as our own guidelines are revised: revised atrial fibrillation guidelines recommended NOACs over warfarin; heart failure guidelines were updated; dyslipidaemia guidelines took a different line to the US in recommending statins, lifestyle for everyone with dyslipidaemia but not providing targets based on risk level; and the CVD prevention guidelines put great emphasis on the Mediterranean diet, amongst other lifestyle measures.

• ENSURE-AF found that edoxaban was equivalent to warfarin in the prevention of stroke around the time of electrical cardioversion. • A study was presented showing that the CHADS-DS2-Vasc score for defining risk in people with atrial fibrillation overestimates the number of people with low risk. GARFIELD-AF, a new score was proposed. There was also much interest in some new drug classes including PCSK9 inhibitors, powerful LDL- cholesterol lowering agents, dual angiotension receptor blocker/ neprilysin inhibitors for heart failure, new oral anticoagulants (NOACs) and

• The SAVE study was presented by Doug McEvoy from Flinders University in Adelaide and coordinated from the George Institute in Sydney. This international study, with over 2000 people with moderately severe sleep apnoea, examined whether CPAP reduced cardiovascular endpoints shown to be associated with sleep apnoea in observational studies. The result was that CPAP reduced snoring and improved quality of life but had no effect on the combined cardiovascular endpoints or on mortality. Blood pressure was also similar in CPAP and control subjects. Published simultaneously in the New England Journal of Medicine with a supplementary editorial, the study showed that CPAP improves symptoms of sleep apnoea but not outcomes.

The release of important new ESC guidelines will no doubt influence Australian experts as our own guidelines are revised.

• The DANISH trial casts doubts on previously accepted guidelines for the use of ICDs in people with nonischaemic heart failure. • NORSTENT showed no difference in outcomes in a comparison of drug-eluting and bare metal stents. However, revascularisation rates over the next 2 years were less with the former. PRAGUE-18 did not detect a difference between prasugrel and ticagrelor but, like a number of studies where no differences were seen, recruitment failed to meet targets and the study was underpowered.

PRACTICEUPDATE CARDIOLOGY