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PRIORITY PRESS - Canadian Cardiovascular Congress 2010

Montreal, Quebec / October 23-27, 2010

Based on a series of expert projections, the coming results of EMPHASIS-HF (The Effect Of Eplerenone Versus Placebo on Cardiovascular Mortality and Heart Failure Hospitalization in Subjects with NYHA Class II Chronic Systolic Heart Failure) may change clinical practice. Although the final results will not be revealed until the upcoming American Heart Association (AHA) 2010 meeting, enrolment into the study was stopped by the Data and Safety Monitoring Committee earlier this year when the reduction in the primary end point of cardiovascular (CV) death or heart failure (HF) was sufficiently lower on eplerenone that further recruitment was considered unethical.

Revisiting Aldosterone Antagonism

“The EMPHASIS trial appears as if it will complete the continuum in HF,” stated Dr. Peter Liu, Scientific Director, Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto, Ontario. Referring to the previous evidence that aldosterone antagonists are effective in advanced HF and in the treatment of left ventricular dysfunction (LVD) after myocardial infarction (MI), Dr. Liu predicted that the improvement in outcomes from use of eplerenone in mild-to-moderate HF may reduce the need for implantable devices to reduce risk of arrhythmias.

In the phase III EMPHASIS HF study, patients with New York Heart Association (NYHA) class II HF were randomized to receive a single 25-mg eplerenone tablet once daily or matching placebo. After 4 weeks, participating investigators were permitted to raise the dose to 2 tablets daily (eplerenone 50 mg or matching placebo). All patients otherwise received current standards of HF therapy. The study was conducted at 270 centres in 30 countries, including Canada. The planned enrolment was 3100 patients with completion anticipated in October 2011. Study enrolment was halted in May 2010.

By blocking the renin-angiotensin-aldosterone system (RAAS), aldosterone antagonists decrease reabsorption of sodium and water. However, in addition to their diuretic effect, their ability to participate in RAAS inhibition also appears to have profound effects on the pathophysiological processes that lead to cardiac enlargement and loss of pump function. The first large study demonstrating benefit with aldosterone antagonists was conducted with the non-selective inhibitor spironolactone in patients with NYHA III and IV HF. In this placebo-controlled study called RALES (Randomized Aldactone Evaluation Study), the aldosterone antagonist was associated with a 30% (P<0.001) drop in all-cause mortality (Pitt et al. N Engl J Med 1999;341:709-17). It also reduced hospitalizations due to HF. A subsequent study with eplerenone, which is more selective for the aldosterone receptor and has therefore been associated with reduced risk of side effects, was conducted in patients with LV ejection fraction <40% after MI. Called EPHESUS (Eplerenone Post Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the study again associated eplerenone with a significant all-cause mortality benefit (HR 0.85, P<0.008). The 13% reduction in the primary composite end point of death from CV causes, hospitalization for HF, recurrent MI, stroke or ventricular arrhythmia was also highly significant (P=0.002) (Pitt et al. N Engl J Med 2003;348:1309-21).

EMPHASIS on Mild to Moderate HF

EMPHASIS-HF addresses the population in between early-stage and end-stage HF. In mild-to-moderate HF, the more favourable side effect profile of eplerenone—particularly the much lower risk of adverse effects related to the androgen-related blockade caused by spironolactone, such as gynecomastia—is expected to make this a viable treatment for improving outcome in the context of the anticipated positive results. Although both of the available aldosterone antagonists are associated with hyperkalemia, this side effect is typically manageable.

Several investigators, including Dr. Jean Rouleau, Dean, Faculty of Medicine, Université de Montréal, Quebec, emphasized that the benefits of aldosterone antagonists in the trials so far have been demonstrated on top of other RAAS inhibitors, particularly ACE inhibitors or angiotensin receptor blockers, which are already being administered. Although Dr. Rouleau was cautious about interpreting the results of EMPHASIS-HF in advance of the data, he indicated that positive results would be anticipated based on the agent’s mechanism of action and past studies in early and late stages of LVD.

Aldosterone Antagonism Throughout the HF Continuum

“If you remember only one thing from what I said today, it should be that aldosterone receptor blockers have never lost in a randomized trial. I think we underuse them,” Dr. Rouleau told delegates. He noted that another trial with this class of agent called TOPCAT (Treatment of Preserved Cardiac Function in Heart Failure with an Aldosterone Antagonist) is underway and also has the potential to alter routine patient care. In this study, 4500 adults with HF and LV ejection fraction of =45% are being randomized to spironolactone or placebo. Relatively few studies have been previously conducted in patients with preserved systolic function. There are more than 200 clinical centres participating in 6 countries including Canada. Enrolment began in 2006. With a planned follow-up of 54 months, results are still some distance away.

Commenting on the same set of studies in HF, Dr. Marc Pfeffer, Dzau Professor, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, predicted that aldosterone antagonists would be a staple through the HF continuum. Although he, too, cautioned that he does not know the results of EMPHASIS, he said, “I am pretty excited about where this seems to be heading.” Dr. Pfeffer was senior author of the landmark SAVE (Survival And Ventricular Evaluation) study that originally confirmed the hypothesis that an inhibitor of RAAS can prevent adverse cardiac remodelling after MI. Nevertheless, Dr. Pfeffer has been impressed that the initial benefit achieved with the ACE inhibitor captopril in SAVE has been extended when other RAAS inhibitors have been used “on top of, on top of and on top of” as improved suppression of this hormonal complex is achieved.

Better earlier intervention in HF has major implications for outcome. In Canada, HF is a leading cause of hospitalization in older patients. In an analysis of a Canadian database with input from all provinces except Quebec in the years 2005 to 2006, the in-hospital mortality rate from HF correlated closely with increasing age. While a substantial proportion of deaths were due to diagnoses other than HF, such as chronic obstructive pulmonary disease or pneumonia, impaired heart function was likely to be a contributing factor, according to Dr. Sulan Dai, Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada, Ottawa, Ontario. With age, the length of hospital stay increased and the likelihood of being discharged home, rather than to an extended-care facility, diminished.

Providing the rationale for better prevention strategies, “HF has a high in-hospital mortality, particularly among elderly Canadians, and it is associated with many other cardiac and non-cardiac conditions,” Dr. Dai reported here at the CCC. She noted that her agency is developing new approaches to tracking HF in Canada. It is hoped that better data will increase attention to this problem.

Summary

Aldosterone antagonists have already demonstrated benefit in late-stage HF and in patients with LVD after MI, but new data are expected to greatly expand the role of these agents in routine patient care. A major study of eplerenone in NYHA class II HF was stopped prematurely because of efficacy. Results of that study, to be presented at the 2010 AHA meeting, are expected to redefine optimal management in this patient population. Another major multinational study with spironolactone is underway in patients with preserved systolic function. Although the results of that study are further away, the focus on this form of RAAS inhibition is based on the potential for fundamental suppression of the neurohormonal pathophysiologic processes that drive progressive disease.