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Issue 106 - 2017Making Education Easy

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Welcome to the latest issue of Cardiology Research Review.This month we report disappointing results for preoperative levosimendan in patients at risk for low cardiac output syndrome after cardiac surgery; for a multifactorial intervention (wireless pill bottles, lottery-based incentives, and social support) to improve medication adherence and outcomes for AMI patients; and for resveratrol in patients with peripheral artery disease. On a more positive note, a meta-analysis that evaluated the optimal timing of invasive strategies in patients with NSTE-ACS supports common clinical practice in Australia, and an analysis of real-world data confirms that treatment strategies in ACS should be based on clinical characteristics, not gender.

We hope you find these and the other selected studies interesting, and look forward to receiving any feedback you may have.

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Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardiopulmonary bypassAuthors: Cholley B et al.

Summary: The LICORN trial assessed the use of preoperative levosimendan to prevent postoperative low cardiac output syndrome after cardiac surgery. 336 patients with left ventricular ejection fraction ≤40% who were scheduled for isolated or combined CABG surgery with cardiopulmonary bypass were randomised to a 24-h infusion of levosimendan 0.1 µg/kg/min or placebo, initiated after anaesthetic induction. The composite end-point (need for a catecholamine infusion 48h after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96h after study drug initiation, or need for postoperative renal replacement therapy) occurred in 52% and 61% of patients in the levosimendan and placebo groups, respectively (p=NS).

Comment: Levosimendan is an inotropic agent that increases myocardial contractility without increasing oxygen demands. It is therefore theoretically appealing for use in acute decompensated heart failure, but several randomised trials have not been able to demonstrate any benefit with it in this context. Similarly, in this study looking at its use in patients with reduced ejection fraction undergoing cardiac surgery, it was no better than placebo in reducing need for support post-operatively. This being the case, there would seem to be little place for using levosimendan in clinical practice.

Reference: JAMA 2017;318(6):548-56Abstract

Effect of electronic reminders, financial incentives, and social support on outcomes after myocardial infarctionAuthors: Volpp K et al.

Summary: The HeartStrong trial investigated the impact of electronic reminders, financial incentives and social support on medication adherence and vascular outcomes after AMI. 1509 patients who were prescribed at least 2 of 4 study medications (statin, aspirin, beta-blocker, antiplatelet agent), and were hospital inpatients for 1–180 days and discharged home with a principal diagnosis of AMI were included. Patients were randomised 2:1 to an intervention group (electronic pill bottles combined with lottery incentives and social support for medication adherence) or to usual care. There were no significant between-group differences in time to first rehospitalisation for a vascular event or death, time to first all-cause rehospitalisation, or total number of repeat hospitalisations. Mean medication adherence and mean medical costs in the year after enrolment did not differ significantly between groups.

Comment: Adherence to medication and achievement of target levels are often less than ideal after MI, and promoting lifestyle changes is even harder. The multifactorial intervention described above did not improve compliance or reduce hospitalisation in this US study, but this is in contrast with the Australian COACH programme and SMART-REHAB trial, where these outcomes were improved with nurse and smart phone interventions, respectively. Perhaps Australians are more receptive to this post-MI contact than in the US, but more study needs to be done, and perhaps a more individualised approach undertaken.

Reference: JAMA Intern Med 2017;177(8):1093-1101Abstract

ACS = acute coronary syndrome; AMI = acute MI;CABG = coronary artery bypass graft; CAD = coronary artery disease;CVD = cardiovascular disease; LDL = low-density lipoprotein; MI = myocardial infarction; NSTE-ACS = non–ST-elevation ACS;PCI = percutaneous coronary intervention;SAVR = surgical aortic valve replacement;TAVR = transcatheter aortic valve replacement.

Abbreviations used in this issue:

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In this issue: > Preoperative levosimendan does not prevent low cardiac output syndrome

> Multifactorial lifestyle intervention fails to improve outcomes after AMI

> Resveratrol does not improve symptoms of peripheral artery disease

> What is the best timing for an invasive strategy in NSTE-ACS?

> Early invasive vs initial conservative strategy in women with NSTE-ACS

> Lifetime risk of CVD is associated with educational achievement

> TAVR vs SAVR in patients with severe aortic stenosis

> Mortality risk in patients with CAD and renal failure

> PCI vs CABG in unprotected left main CAD

> Efficacy of anacetrapib when added to ongoing lipid-modifying therapy

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Effect of resveratrol on walking performance in older people with peripheral artery diseaseAuthors: McDermott M et al.Summary: The RESTORE trial investigated the effects of resveratrol on walking performance in patients with peripheral artery disease (PAD). 66 patients aged ≥65 years with PAD were randomised to receive a capsule of resveratrol (125mg or 500mg) or placebo daily for 6 months. The primary outcome measure was the change in 6-minute walk distance at study end. Six-month mean changes in 6-minute walk distance were 4.6m in the resveratrol 125 mg/day group, −12.8m in the resveratrol 500mg group, and −12.3m in the placebo group. Mean changes in maximal treadmill walking time were 0.5 min, −0.6 min and 0.4 min, respectively.

Comment: It has been postulated that resveratrol is the active antioxidant in red wine that confers its cardioprotective effects, but there are no clinical trial data to support this. This study looked at resveratrol in patients with PAD and found no benefit over 6 months. The advocates for resveratrol will argue about the patient population, the dose, the duration of therapy and the outcomes measured, but at present the postulated benefits of resveratrol are more hype than substance.

Reference: JAMA Cardiol 2017;2(8):902-07Abstract

Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndromeAuthors: Jobs A et al.Summary: This meta-analysis evaluated the optimal timing of a routine invasive strategy in patients with NSTE-ACS. A search of Medline, Cochrane Central Register of Controlled Trials, and Embase identified 8 randomised controlled trials (n=5324) that compared an early versus delayed invasive strategy in patients presenting with NSTE-ACS. Meta-analysis of the data found no significant mortality reduction in the early invasive group compared with the delayed invasive group. A pre-specified analysis of high-risk patients found that an early invasive strategy reduced mortality in patients with elevated cardiac biomarkers at baseline (hazard ratio, 0.761), diabetes (0.67), a Global Registry of Acute Coronary Events (GRACE) risk score >140 (0.70), and age ≥75 years (0.65).

Comment: This meta-analysis is supportive of common clinical practice in Australia, where high risk patients, such as those with positive biomarkers or dynamic ST changes and ongoing pain, have an early invasive strategy after ACS, and lower risk patients are sometimes deferred. This approach targets the highest risk patients and it appears to confer a mortality advantage, whereas delay in the lower risk group seems to have no disadvantage.

Reference: Lancet 2017;390(10096):737-46Abstract

Early invasive versus initial conservative strategies for women with non–ST-elevation acute coronary syndromesAuthors: Elgendy I et al.

Summary: This study analysed real-world data to determine whether an early invasive strategy is associated with better outcomes in women with NSTE-ACS. Women admitted with a primary diagnosis of NSTE-ACS were identified from National Inpatient Sample years 2012 and 2013. The incidence of in-hospital mortality in women undergoing an early invasive strategy was compared with that in women who were initially treated with a conservative strategy. Among 372,080 women with NSTE-ACS, 41.3% were managed with an early invasive strategy and 58.7% with an initial conservative strategy. After propensity score matching (19,965 women treated with an early invasive strategy and 20,009 treated with an initial conservative strategy), the risk of in-hospital mortality was lower with an early invasive strategy (2.1% vs 3.8%; odds ratio [OR], 0.55). The benefit was seen in women presenting with non–ST-segment elevation MI but not unstable angina.

Comment: Because coronary artery disease is more prevalent in men, there is a preponderance of male gender in studies of intervention in ACS. There is no physiological reason why women should do worse than men in ACS with high risk features, but there has been some suggestion that outcomes could be worse. This is probably a reflection of low numbers rather than a true effect, as is demonstrated in this analysis. This being the case, treatment strategy in ACS should be based on clinical characteristics, not gender.

Reference: Am J Med 2017;130(9):1059-67Abstract

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Association of educational attainment with lifetime risk of cardiovascular diseaseAuthors: Kubota Y et al.Summary: This analysis of data from the Atherosclerosis Risk in Communities Study estimated lifetime risks of CVD according to categories of educational achievement. 13,948 individuals aged 45–64 years who were free of CVD at baseline were followed from 1987 through 2013. Educational attainment was found to have an inverse dose-response relationship with cumulative risk of CVD, which became evident in middle age. In males, lifetime risks of CVD were 59.0% for grade school, 52.5% for high school education without graduation, 50.9% for high school graduation, 47.2% for vocational school, 46.4% for college with or without graduation, and 42.2% for graduate/professional school. Corresponding lifetime CVD risks in women were 50.8%, 49.3%, 36.3%, 32.2%, 32.8%, and 28.0%, respectively. The association of educational attainment with CVD was independent of family income, income change, occupation, or parental educational level.

Comment: In both the USA and Australia, there is a clustering of CVD in lower socioeconomic groups who are often poorly educated and make unhealthy lifestyle choices. Intervention to reduce cardiovascular risk and disease in this population is challenging, as medical contact is often limited, even when available, until an acute event occurs. The benefits of a healthy lifestyle with respect to food choices, exercise, smoking and alcohol consumption need to be taught early in the school life of students, so that even if they do not complete secondary school, they will have had at least some exposure to the benefits of healthier living.

Reference: JAMA Intern Med 2017;177(8):1165-72Abstract

Health status benefits of transcatheter vs surgical aortic valve replacement in patients with severe aortic stenosis at intermediate surgical riskAuthors: Baron S et al., for the PARTNER 2 InvestigatorsSummary: This analysis of the PARTNER 2 trial compared the effects of TAVR and SAVR on health-related quality of life. 2032 patients with severe aortic stenosis at intermediate surgical risk were randomised to TAVR with the Sapien XT valve or SAVR and were followed up for 2 years. Health status was assessed using the Kansas City Cardiomyopathy Questionnaire, the Medical Outcomes Study Short Form-36, and the EuroQOL-5D. Over 2 years, both TAVR and SAVR were associated with significant improvements in disease specific and generic health status. At 1 month, TAVR was associated with better health status than SAVR, but this difference was restricted to patients treated via transfemoral access and was not seen in patients treated via transthoracic access. There were no significant differences between TAVR and SAVR in any health status measures at 1 or 2 years.

Comment: There is a trend to do TAVR rather than surgery in lower risk patients as time goes on. In this analysis of the PARTNER study, the early health status of intermediate risk patients who had AVR was better with TAVR via a transfemoral approach than those who had surgery. This difference is likely to diminish with time, and it will be important to document this, as there is still some concern as to the durability of the TAVR valves compared with surgically implanted bioprosthetic valves.

Reference: JAMA Cardiol 2017;2(8):837-45Abstract

Two-year outcome and risk factors for mortality in patients with coronary artery disease and renal failureAuthors: Engelbertz C et al.Summary: The observational CAD-REF Registry study examined 2-year outcomes and risk factors for mortality in patients with CAD and chronic kidney disease (CKD). 3352 patients with angiographically documented CAD were classified into 5 groups according to baseline estimated glomerular filtration rate (eGFR) and were followed-up for 2 years. With decreasing renal function, patients were more likely to have diabetes, hypertension, peripheral artery disease, and previous cardiovascular events and interventions. The number of diseased vessels increased with worsening renal function. Two-year mortality was 6.5% for the whole cohort. Kaplan-Meier-curves showed that patients with CKD stages 4 and 5 had the highest mortality (22.4%). Multivariate Cox regression analyses found that significant risk factors for 2-year all-cause mortality were lower eGFR, current smoking, left ventricular ejection fraction, diabetes treated with oral medication or insulin, age, and peripheral artery disease. A 10-ml/min/1.73m2 decrease in eGFR increased the risk of mortality by 19% irrespective of other risk factors.

Comment: Chronic renal failure is often an underappreciated risk factor for coronary events, and CAD is the most common cause of death in these patients. This study nicely shows that the worse the renal function, the worse the CAD and outcome, and reinforces the importance of recognising and treating renal disease in patients with CAD and vice versa.

Reference: Int J Cardiol 2017;243:65-72Abstract

Clinical outcomes with percutaneous coronary revascularization vs coronary artery bypass grafting surgery in patients with unprotected left main coronary artery diseaseAuthors: Palmerini T et al.Summary: This meta-analysis of randomised controlled trials compared the risk of all-cause mortality after PCI vs CABG in patients with unprotected left main coronary artery disease (ULMCAD). A search of Medline, Embase, Cochrane databases, and proceedings of international meetings identified 6 trials (n=4,686) that compared PCI with CABG for the treatment of ULMCAD. After a median follow-up of 39 months, there were no significant differences between PCI and CABG groups for all-cause mortality or cardiac mortality. However, the relative risk for mortality tended to be lower with PCI than CABG in patients in the lower SYNTAX score tertile, similar in the intermediate tertile, and higher in the upper SYNTAX score tertile. PCI and CABG had a similar long-term composite risk of death, MI or stroke, with fewer events within 30 days after PCI offset by fewer events after 30 days with CABG.

Comment: The debate continues to rage regarding optimal revascularisation strategy in patients with left main disease. This meta-analysis suggests that lower risk patients do better with PCI but high-risk patients do better with surgery, and that long term outcomes are similar, although there was more repeat revascularisation with PCI, as would be expected. These issues need to be discussed with the patient before a decision is made, but if PCI is to be undertaken it should be by a high-volume proceduralist.

Reference: Am Heart J 2017;190:54-63Abstract

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Research Reviews are prepared with an independent commentary from relevant specialists. To become a reviewer please email geoff@researchreview.com.au.Research Review Australia Pty Ltd is an independent Australian publisher. Research Review receives funding from a variety of sources including Government depts., health product companies, insurers and other organisations with an interest in health. Journal content is created independently of sponsor companies with assistance from leading local specialists. Privacy Policy: Research Review will record your email details on a secure database and will not release them to anyone without your prior approval. Research Review and you have the right to inspect, update or delete your details at any time. Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits. Research Review publications are intended for Australian health professionals.

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A multiregional, randomized evaluation of the lipid-modifyingefficacy and tolerability of anacetrapib added to ongoing statintherapy in patients with hypercholesterolemia or low high-density lipoprotein cholesterolAuthors: Ballantyne C et al.

Summary: This study assessed the efficacy and safety of anacetrapib when added to ongoing lipid-modifying therapy in patients with hypercholesterolaemia or low high-density lipoprotein (HDL) cholesterol levels. 583 patients who were taking an optimal dose of statin ± other lipid-modifying therapies for at least 6 weeks but were still not at their LDL cholesterol goal (according to coronary heart disease risk category) or who still had low HDL cholesterol levels were included. Patients were randomised 1:1 to receive anacetrapib 100 mg/day or placebo for 24 weeks in addition to current therapy. Anacetrapib reduced LDL cholesterol by 37% and increased HDL cholesterol by 118% relative to placebo (both p<0.001). Anacetrapib also reduced non-HDL cholesterol, apolipoprotein B, and lipoprotein a compared with placebo, and increased apolipoprotein AI (all p<0.001). There were no significant between-group differences in the number of discontinuations to an adverse event, or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or cardiovascular events.

Comment: The role of cholesteryl ester transfer protein (CETP) inhibition in lipid lowering is questionable. Torcetrapib raised HDL and lowered LDL, but had such significant off target effects there was an increase in MI and stroke, so its clinical development was stopped. The outcome studies with dalcetrapib and evacetrapib showed significant effects on lipids but no improvement in outcomes, so that the studies were stopped for futility. Anacetrapib showed some significant but underwhelming benefits in the recently reported REVEAL study, but there was confusing data about the magnitude of LDL lowering with it. Given this, I doubt whether these agents will ever be used in routine practice as, although the numbers will look better, there is little evidence that this translates into a clinically significant benefit.

Reference: Am J Cardiol 2017;120(4):569-76Abstract

Independent commentary by Associate Professor John Amerena, FRACP, FACC, FCSANZ, Dept. of Clinical and Biomedical Science, University of Melbourne (Geelong).

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