Pfizer Inc. announced results from the EMPHASIS-HF trial showing a statistically significant reduction in risk of cardiovascular (CV) death or heart failure (HF) hospitalization for patients with chronic heart failure with mild symptoms treated with Inspra (eplerenone) versus those given placebo in addition to standard HF therapy.  The results were presented to physicians attending the American Heart Association Scientific Sessions in Chicago and were simultaneously published online in the New England Journal of Medicine.

The EMPHASIS-HF trial demonstrated a statistically significant 37% relative risk reduction for the eplerenone group (p<0.0001) compared to placebo in the primary composite endpoint of death from CV causes or HF hospitalization.  There were also statistically significant reductions in other secondary endpoints of all-cause mortality (24%; p=0.008), CV mortality (24%; p=0.012), all-cause hospitalization (23%, p<0.0001) and HF hospitalization (42%; p<0.0001).  

Heart failure can lead to a reduction in the quality of life, frequent admissions to hospital and a greatly shortened life expectancy, despite the availability of several effective treatments.  Dr Faiez Zannad, Professor of Therapeutics and cardiologist at the CHU (University Hospital) of the Henri Poincare University of Nancy, France and co-chair of the EMPHASIS-HF Steering Committee said: "It is encouraging to see a clinical trial deliver results that are sufficiently strong to meet strict pre-defined stopping criteria.  Patients such as those enrolled in EMPHASIS-HF typically have a poor prognosis and today's results should therefore provide real encouragement for doctors and patients alike."

The primary objective of the EMPHASIS-HF trial was to evaluate the efficacy and safety of eplerenone plus standard HF therapy versus placebo plus standard HF therapy on the cumulative incidence of the composite endpoint of CV death or HF hospitalization.  Patients enrolled in the study had New York Heart Association (NYHA) Class II chronic systolic heart failure with mild symptoms.  

No new safety information emerged as a result of this study.  As anticipated, there was a higher incidence of hyperkalemia (elevated potassium, defined as serum potassium level >5.5mmol/L.) among patients assigned to eplerenone compared to placebo (11.8% vs 7.2%, respectively; p<0.001).  In contrast, the incidence of hypokalemia (low potassium, defined as serum potassium level <3.5mmol/L.) was lower in the eplerenone group compared to placebo (7.5% vs 11.0%, respectively; p=0.002).  

In May 2010, recruitment to the EMPHASIS-HF trial was halted early after the second pre-specified interim analysis showed that the study's pre-defined stopping rules had been met and a significant difference (two-sided P<0.001 in favor of eplerenone) in the primary endpoint was evident.

Eplerenone is not authorised for use in the patient population studied in the EMPHASIS-HF trial in any individual market.

EMPHASIS HF (A6141079) is a phase 3B, multinational (2,737 patients from 272 centres in 29 countries), randomized, double-blind placebo-controlled, parallel-group trial.  It is conducted in a NYHA II chronic systolic heart failure population, which is a distinct population from the EPHESUS study population (patients with left ventricular dysfunction (LVEF less than or equal to 40 %) and clinical evidence of heart failure after recent myocardial infarction).  In Europe, the current approved indication for eplerenone is based on the EPHESUS study population.

The primary objective of this trial is to evaluate the efficacy and safety of eplerenone plus standard heart failure (HF) therapy - including an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blockers (ARB), plus a beta–blocker – versus placebo plus standard HF therapy on the cumulative incidence of cardiovascular (CV) mortality and HF hospitalization (a composite primary endpoint).  The mean follow-up time was 21.1 months.

Patients were to be randomized (1:1) to receive eplerenone 25 mg once daily (OD) or matching placebo.  At four weeks, the dose of study drug could be increased to 50 mg OD (two 25mg tablets of eplerenone or two matching placebo tablets once daily) based on serum potassium level.  The trial was designed to enroll 3100 patients and to continue until a total of 813 adjudicated primary endpoint events were reported.

In May 2010, Pfizer announced that it planned to halt recruitment to the EMPHASIS-HF trial early on the recommendations of the trial's independent Executive Steering Committee (ESC).  The recommendations follow a second interim analysis by the independent Data Safety Monitoring Committee (DSMC) of the EMPHASIS-HF trial confirming the study has reached its primary efficacy endpoint early according to the protocol pre-defined stopping rules.

The study was funded by Pfizer.

INSPRA (eplerenone) is a steroid nucleus-based mineralcorticoid receptor (MR) antagonist with a higher degree of selectivity than spironolactone.  Eplerenone is thought to be a more selective blocker at the mineralcorticoid receptor since there is evidence that some of the effects result from a blockade of cortisol stimulation of the MR-receptor.