Making Education Easy November 7-11 2015, Orlando, Florida

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Welcome to this review of the American Heart Association (AHA) Scientific Sessions 2015, held in Orlando, Florida on November 7-11. This huge meeting is the leading cardiovascular meeting in the US and was attended by almost 18,000 delegates to hear the latest in basic, clinical, translational and population cardiology research.

This review has been created to allow those unable to attend, but with a keen professional interest, to access a summary of some of the presentations. Selection and review of the research has been carried out independently by Prof John French of Liverpool Hospital, Sydney who attended the meeting.

We hope you enjoy these selections, and as always, look forward to hearing your comments and feedback.

Kind Regards,

Dr Janette Tenne

Medical Research Advisor

janette.tenne@researchreview.com.au

Impact of a comprehensive lifestyle peer-group-based intervention on cardiovascular risk factors: a randomized controlled trialSpeaker: Fuster V.

Summary: These investigators tested the hypothesis that a peer-group strategy could modify lifestyle behaviours in patients with CV risk factors. Adult subjects aged 25-50 years with ≥ 1 cardiovascular risk factor were randomised to 12 months of a monthly meeting where role-play, brainstorming and other activities were employed to target diet, exercise and emotional behaviours (peer intervention, n = 277) or to self-management (control, n = 266). Change in the composite Blood pressure, Exercise, Weight, Alimentation and Tobacco (Fuster-BEWAT) score from baseline to 12 months was the primary outcome measure. Mean Fuster-BEWAT scores were significantly higher in the intervention group vs controls at 12 months: 8.84 vs 8.17, p = 0.02. Similarly the intervention group had significantly greater improvement in Fuster-BEWAT score: difference 0.75 (0.32, 1.18), p = 0.02. The individual component of tobacco (smoking cessation) was also significantly improved for intervention subjects vs controls.

Comment: This trial, which recruited mainly women, randomised them to either usual care, or a peer-group support regimen for lifestyle modification. In contrast to many cardiovascular trials which mainly consist of men, this showed a benefit among women, especially those who were highly adherent to the program, and smoking was reduced. This method of risk factor modification showed improvement though it is suspected this could be gender specific.

Presented November 9, 2015, 11:04 - 11:13 AMLate Breaking Clinical Trial

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AHA 2015

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In this issue:In this review:Can a peer-group intervention lower CV risk?

QOL impact of post-PCI ranolazine

Individualising post-PCI treatment duration for DAPT

In-hospital initiation of varenicline for ACS patients

Can knowing genetic risk alter LDL cholesterol levels?

Suspected ACS with no flow-limiting coronary artery lesions

Fibrinolytic therapy in STEMI

Multi-vessel intervention in STEMI

Meta-analysis: multi-vessel PCI in STEMI

Multi-vessel vs single vessel PCI during index hospitalisation

Stenosis of non-culprit lesions during primary PCI

ACS = acute coronary syndrome; CV = cardiovascular; DAPT = dual antiplatelet therapy; PCI = percutaneous coronary intervention; STEMI = ST-elevation myocardial infarction.

Abbreviations used in this review:

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Independent commentary by Professor John French, Director of Coronary Care and Cardiovascular Research at Liverpool Hospital, Sydney, and conjoint Professor at the University of New South Wales. After basic physician training he undertook a PhD at the University of Adelaide, further cardiology training at Greenlane Hospital, Auckland, New Zealand, and a Wellcome Trust Postdoctoral Fellowship at University College London, UK. Prior to his current position Professor French was appointed to Greenlane Hospital and the University of Auckland from 1992-2003. Professor French has been an investigator and co-investigator in numerous randomised controlled trials, and was on the steering committees of the SHOCK, OAT, HERO-2 and CRISP-AMI trials. Professor French has served on the clinical endpoints committees of several major trials. Professor French’s current major research interests include the acute coronary syndromes especially ST elevation MI, and cardiac biomarkers especially high sensitivity troponins.

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Angina and quality of life following PCI with incomplete revascularization: results from the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) trialSpeaker: Alexander KP.

Summary: The aim of this randomised, placebo controlled clinical trial was to investigate the efficacy of ranolazine (an inhibitor of the late sodium current with anti-ischaemic properties) in reducing angina and improving quality of life in patients with incomplete revascularisation post-PCI. Subjects, 2,651 patients with a history of angina and incomplete revascularisation post-PCI, received ranolazine or placebo during a follow-up of ≥ 1 year. Both groups had improvements in symptoms of angina following PCI, but no difference was observed between groups at 1 month: Seattle Angina Questionnaire (SAQ) frequency score 86.6 (± 18.1) vs 85.8 (± 18.5), p = 0.27; or 12 months, 88.4 (± 17.8) vs 88.5 (± 17.8), p = 0.94 for ranolazine and placebo respectively. Similar results were observed in the adjusted analysis. Ranolazine was associated with a significant improvement in SAQ frequency score at 6 months in patients with diabetes (mean difference 3.3; 95% CI 0.6, 6.1; p = 0.02), and those with baseline SAQ angina frequency ≤ 60 (mean difference 3.4; 0.6, 6.2; p = 0.02) but was not different to placebo at 12 months on either measure. Significantly more patients discontinued ranolazine than placebo at 12 months: 27.2 vs 21.3% respectively, p < 0.001.

Comment: Ranolazine was proposed as a metabolic sparing drug to improve tolerability of angina. This trial aimed to determine whether people with incomplete revascularisation had less angina with ranolazine compared to placebo. There were no significant differences in quality of life parameters. Perhaps the one exception was a suggestion that there may be a minor benefit in patients with diabetes compared to those without. Though overall, based on these data there is no indication to use ranolazine to improve quality of life.

Presented: November 10, 2015, 11:45 - 11:54 AMLate Breaking Clinical Trial

Reference: Alexander KP et al. Circulation. 2015 Nov 10. [Epub ahead of print]Abstract

Individualizing treatment duration of dual antiplatelet therapy after percutaneous coronary intervention: an analysis of the DAPT studySpeaker: Yeh RW.

Summary: The aim of this work was to develop a decision tool to enable calculation of the risks and benefits of continuing dual antiplatelet therapy (thienopyridine plus aspirin) for ≥ 12 months after PCI for an individual patient. The tool was based on a composite of individual characteristics from patients’ who had participated in the DAPT study (n = 11,648) and was designed to consider the risk of both ischaemia and bleeding with longer-term therapy. Multivariable models were constructed to predict risk of events (including fatal events) occurring 12-30 months post-PCI; stent thrombosis or myocardial infarction (ischaemic model) and GUSTO moderate to severe bleeding events (bleeding model). The ‘benefit-risk difference’ was calculated for each patient by calculating the difference between absolute reductions in ischaemia risk and absolute increase in bleeding risk. Continued dual antiplatelet therapy was associated with benefit-risk differences between -3.7% and 19.3% dependent on factors including age, smoking status, diabetes, presentation with MI, prior PCI, stent type and diameter, and heart failure/ejection fraction.

Comment: This follow up report from the DAPT study was an analysis of the efficacy and bleeding risks of continuing dual anti-platelet therapy among those who had tolerated DAPT for one year. It places a numeric risk on the individual factors which contribute either to an ischaemic or bleeding risk. With respect to the latter, this study only identified age as a significant factor and this is a limitation of the score. Nonetheless, it was apparent that those with a lower score (higher bleeding risk and lower ischaemic risk) didn’t benefit from continuation of dual anti-platelet therapy and indeed some with the lowest quartile of DAPT score were actually at risk of harm whereas those in the third and fourth quartiles (higher ischaemic risk and lower bleeding risk) had a reduction and adverse events, though there was no difference in mortality. The cut point of this was a DAPT score of 2. Whether the DAPT score translates to other patient subsets remains to be determined. Also the score is only applicable to patients continuing on clopidogrel rather than other anti-platelet agents.

Presented: November 10, 2015, 11:30 - 11:39 AMLate Breaking Clinical Trial

®

* In patients with ACS, BRILINTA reduces the risk of CV death, MI or stroke vs clopidogrel at 12 months (primary composite endpoint: ARR 1.9%, RRR 16%; p<0.001).1,2

improved outcomesstart here*

Please click here to review full product information before prescribing. Further information available on request from AstraZenecaACS=acute coronary syndromes; CV=cardiovascular; MI=myocardial infarction; ARR=absolute risk reduction; RRR=relative risk reduction. References: 1. Wallentin L et al. N Engl J Med 2009;361:1045–57. 2. BRILlNTA® Approved Product Information. BRILINTA® is a registered trademark of the AstraZeneca group of companies. Registered user AstraZeneca Pty Ltd. ABN 54 009 682 311. 5 Alma Road, North Ryde NSW 2113. Medical Information: 1800 805 342. www.astrazeneca.com.au, 407584.022, WL287191, July 2015

PBS Information: Authority Required (STREAMLINED). Treatment of acute coronary syndrome (myocardial infarction or unstable

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The efficacy and safety of varenicline, a selective alpha4beta2 nicotinic receptor partial agonist, for smoking cessation in patients hospitalized with acute coronary syndrome: a randomized controlled trialPresenter: Eisenberg MJ.

Summary: The authors of this multicentre, double-blind randomised, placebo-controlled trial investigated the efficacy of in-hospital initiation of varenicline for smoking cessation in patients admitted to hospital with ACS (n = 302). At baseline subjects were smoking a mean of 21.4 (± 10.6) cigarettes per day and had a smoking history of 35.9 (± 11.6) years; 80.4% had Fagerström Test of Nicotine Dependence scores ≥ 4 (moderate to severe nicotine dependence). On the primary outcome measure, point prevalence of smoking abstinence at 24 weeks (7-day recall and biochemical validation using expired carbon monoxide), subjects randomised to varenicline had significantly higher rates of abstinence than those who received placebo: 47.3 vs 32.5% (NNT 6.8). Similarly continuous abstinence was reported in 35.8 vs 25.8% respectively (NNT 10.0), and the proportion of patients with a ≥ 50% reduction in the number of cigarettes smoked daily was 67.4 vs 55.6% respectively (NNT 8.5). Adverse event rates and major cardiovascular event rates were similar between groups.

Comment: Varenicline reduced smoking rates compared to placebo after an acute coronary syndrome though still abstinent from smoking rates at 6 months overall was only ~30% with a 10% absolute difference in rates associated with treatment. As the absolute difference in rates at 4 weeks was >20% the key indices of success of varenicline will be treatment-associated differences in rates of cessation at 12 and 24 months. Persistent quitters at 24 months tend to continue and gain the prognostic benefits associated with smoking cessation. The main side effects of nausea, insomnia and abnormal dreams were more frequent with treatment which may have contributed to a time-dependent reduction in the relative increase in smoking cessation with varenicline

Presented: November 9, 2015, 10:55 - 11:04 AMLate Breaking Clinical Trial

The effect of disclosing genomic risk of coronary heart disease on LDL cholesterol levels: The Myocardial Genes (MI-GENES) StudyPresenter: Kullo I.

Summary: The aim of this randomised, controlled trial was to determine whether patients’ knowledge of their genetic risk status for CHD would result in lower LDL-cholesterol levels. Participants aged 45-65 years who had a 10-year CHD risk of 5-20% and were not taking statins were randomised to receive a conventional 10-year CHD risk assessment (controls, n = 103) or conventional CHD risk assessment plus a genetic risk score (GRS) derived from genetic variables (n = 28) unrelated to blood pressure and lipids. On the primary outcome measure of LDL-cholesterol at 6 months, subjects who received GRS had significantly greater reductions; p = 0.03 vs conventional risk assessment in a mixed effects model, with more pronounced improvements in those with the greatest genetic risk. GRS was also associated with an increased likelihood of patients starting a statin but had no impact on dietary fat intake, exercise or anxiety levels.

Comment: This trial randomised patients to genetic, compared to conventional (physician-based) risk screening, and examined effects on LDL-cholesterol levels at 6 months. Perhaps not surprisingly those at highest genetic risk tended to have the best improvement, among Olmsted County (Mayo Clinic, Rochester) residents who were aged 45-65 who were not on a statin and had an estimated 10-year CHD event risk of 5-20%.

Presented: November 9, 2015Late Breaking Clinical Trial (no abstract available)

SESSION: Patients with suspected acute coronary syndromes, who have no flow-limiting coronary artery lesionsPresenters: Beltrami AP., Reynolds H., Prasad A.

Summary/Comment: This important session reviewed the various scenarios that can occur in patients presenting with suspected acute coronary syndrome who end up not having flow limiting coronary artery disease or an unstable coronary lesion. Several syndromes were described including syndrome X, coronary artery spasm, myopericarditis, Takotsubo cardiomyopathy, though due to a security scare the final presentation on coronary artery dissection which may have also discussed fibromuscular dysplasia did not occur. Professor Beltrami from Adelaide presented a dramatic case of a patient with coronary spasm developing ventricular fibrillation who had normal coronaries and the treatment was high doses of calcium blockers such as diltiazem. Whether provocative laboratory testing for spasm should be routinely applied in patients in whom it is suspected is not informed by trial based evidence largely due to the relatively small number of patients affected, so it is not clear whether the potential morbidity associated with provocative testing is more than compensated for by a more definitive rather than presumptive diagnosis. Dr Harmony Reynolds from New York gave an excellent talk on differentiating myocarditis in patients with elevation in biomarkers not thought to be due to an acute coronary syndrome. This problem is relatively common in younger patients and the pivotal diagnostic importance of performing a cardiac MRI was highlighted. This has many associated socio-economic implications for the patients who are young and potentially avoid a diagnostic label of acute myocardial infarction, with its attendant insurance related consequences etc. Professor Prasad from St George’s hospital in London gave a very eloquent talk on stress or Takotsubo cardiomyopathy including reverse Takotsubo cardiomyopathy with its definite female gender preponderance. One issue which remains uncertain and contentious is when the vasodilating beta-blocker and/or ACE inhibitor therapy should be discontinued, or if it should be discontinued, in patients who have returned for some time (months or a few years) to strictly normal left ventricular systolic function. There is no evidence to guide management in this circumstance.

Presented: November 10, 2015, 9.00 – 10.30 AMInvited Speaker Session (no abstract available)

SESSION: Fibrinolytic therapy in STEMI: still the most common reperfusion strategy in the worldSpeakers: Armstrong PW., Huber K., El Deeb M., Zeymer U., Van de Werf F., Danchin N., Alexander T.

Summary/Comment: This series of presentations started with Professor Paul Armstrong from Edmonton, Canada on the pharmaco-invasive approach to STEMI. The other presenters in this session were, Professor Van der Werf, Prof Huber, Prof Zeymer, Prof Danchin, Drs El Deeb and Alexander. Armstrong focused particularly on the CAPTIM-WEST and STREAM I data suggesting that especially for an early presenter who did not have immediate access to primary angioplasty an approach of fibrinolysis followed by immediate transfer including rescue angioplasty in the approximately one third of patients in whom this is indicated achieves a similar outcome to primary PCI. Indeed though these trials are underpowered for mortality, because of the attributable risk of cardiogenic shock to late mortality outcomes the reduction in cardiogenic shock translated to appropriately powered trials may translate into a mortality advantage for the pharmaco-invasive approach. It is unlikely given that such a study would require over 10,000 patients. El Deeb reminded the audience that fibrinolytic therapy remained the most widely used therapy and indeed the most common agent was streptokinase.

Presented: November 8, 2015 8.00 – 11.00Conference webcast

SESSION: Complete vs. incomplete revascularization in STEMIA quantitative appraisal of recommendations regarding multi-vessel intervention in ST-elevation myocardial infarction: insights from the US nationwide inpatient sample and an updated comprehensive meta-analysis of observational dataAuthors: Chatterjee S.

Summary: These authors used data from the US Nationwide Inpatient Sample (NIS) to determine whether multi-vessel PCI for STEMI is associated with excess in-hospital mortality compared to single-vessel PCI. In-hospital mortality rates for multi- and single-vessel PCI were 1.91 vs 8.9 % respectively (from respective total procedure numbers of 11,454 and 157,011): OR (unadjusted analysis) 0.20 (95% CI 0.17, 0.23). Similar results were derived under multivariate analysis (OR 0.28; 0.24, 0.33) and in a 1:3 propensity-matched model; 1.91 vs 5.32%, OR 0.28 (0.24, 0.32). No difference in early mortality rates between the two procedures was observed in a comprehensive meta-analysis of 19 observational studies (n = 76,399); 5.3 vs 5.06% for multi- and single-vessel PCI respectively; OR 0.87 (0.65, 1.17), p = 0.37.

Presented: November 8, 2015, 3:45 - 4:00 PMAbstract

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Complete revascularization for multivessel disease ST elevation myocardial infarction: insights from an updated meta-analysisAuthors: Kundu A.

Summary: This meta-analysis encompassing 7 RCTs (n = 2,006) assessed differences in outcomes for STEMI patients undergoing complete revascularisation (single setting or staged) vs culprit vessel only PCI. The primary outcome measure of major adverse cardiovascular events (MACE) was significantly reduced with complete revascularisation vs culprit only PCI; OR 0.52 (95% CI 0.32, 0.85), p = 0.009, however recurrent MI (OR 0.74; 0.4, 1.37) and all-cause mortality (OR 0.75; 0.51, 1.12) were similar between groups.

Presented: November 8, 2015, 4:00 - 4:15 PMAbstract

Multivessel coronary artery revascularization during index hospitalization has favorable outcomes compared to infarct related artery only revascularization in STEMI patients- meta-analysis of randomized control trialsAuthors: Gaddam S.

Summary: These authors undertook a meta-analysis to test their hypothesis that complete revascularisation at the time of primary PCI or index hospitalisation would be associated with superior outcomes compared to culprit vessel PCI. RCTs identified for inclusion encompassed 1,819 patients (919 multi-vessel PCI, 900 single vessel PCI) with a mean follow-up of 28 months. Repeat vascularisation was significantly reduced with multi- vs single- vessel PCI in the pooled analysis (OR 0.39; p < 0.0001).

Presented: November 8, 2015, 4:15 - 4:30 PMAbstract

The severity of nonculprit lesion is exaggerated in the primary percutaneous coronary intervention settingAuthors: Othman FS.

Summary: These authors investigated the severity of non-culprit coronary artery stenosis in 777 patients undergoing primary PCI at the Qatar Cardiovascular Centre between October 2013 and October 2014. Significant differences in the degree of stenosis of non-culprit vessels were observed during acute MI vs non-AMI angiogram (71.6% vs 64.5%, p ≤ 0.001).

Presented: November 8, 2015, 4:30 - 4:45 PMAbstract

Comment: This session included four presentations on complete compared to incomplete revascularisation amongst patients with STEMI who had multi-vessel disease. The first presentation from Chatterjee reported a study based on administrative data. There was some adjustment for risk and those at lower risk seemed to have improved outcomes with multi-vessel PCI. There were then two studies analyzing the 6-8 trials totaling ~2000 patients. These reports were the same except for exclusion of two of the small trials in the second presentation. The conclusion of both studies showed that there was no difference in death or MI among patients with multi-vessel disease having complete revascularisation versus those in whom the culprit artery only was dealt with at the index procedure. The 4th presentation by Othman showed data from the Gulf. The percentage of STEMI patients with multi-vessel disease was very high at 80%, approximately double the rate reported from most series elsewhere. At present there is no clear evidence from a trial of sufficient size to guide patient management.

®

* In patients with ACS, BRILINTA reduces the risk of CV death, MI or stroke vs clopidogrel at 12 months (primary composite endpoint: ARR 1.9%, RRR 16%; p<0.001).1,2

* BRILINTA is initiated with a single 180mg dose and then continued at 90mg twice daily in combination with aspirin.2

improved outcomesstart here*

Please click here to review full product information before prescribing. Further information available on request from AstraZenecaACS=acute coronary syndromes; CV=cardiovascular; MI=myocardial infarction; ARR=absolute risk reduction; RRR=relative risk reduction. References: 1. Wallentin L et al. N Engl J Med 2009;361:1045–57. 2. BRILlNTA® Approved Product Information. BRILINTA® is a registered trademark of the AstraZeneca group of companies. Registered user AstraZeneca Pty Ltd. ABN 54 009 682 311. 5 Alma Road, North Ryde NSW 2113. Medical Information: 1800 805 342. www.astrazeneca.com.au, 407584.022, WL287191, July 2015

PBS Information: Authority Required (STREAMLINED). Treatment of acute coronary syndrome (myocardial infarction or unstable

angina) in combination with aspirin.

STREAMLINED AUTHORITY CODE 3879