List of Authors:
Pitt Bertram, McMurray John, Krum Henry, van Veldhuisen Dirk J, Swedberg Karl, Shi Harry, Vincent John, Pocock Stuart, Zannad Faiez
Abstract:
Purpose : In chronic moderate-to-severe HF and post MI CHF with LVSD, aldosterone antagonists have been shown to improve survival. More recently the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF) demonstrated a reduction of the primary endpoint which was a composite of death from cardiovascular causes and hospitalization for heart failure (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001) in patients with chronic systolic HF in NYHA class II. It is not known however whether eplerenone can improve outcomes in mildly symptomatic patients, especially in the high risk groups defined as age ≥ 75 years, LVEF<30%, eGFR<60 ml/min/1.73 m2, diabetes and patients with low BP (<median).
Methods : We randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy and analyzed prespecified subgroups of patients with high risk. After the premature stopping of enrollment into the trial due to efficacy (mean FU 21 months) patients had an additional follow-up of up to 7 months.
Results and Conclusions: In the subgroup of patients ≥ 75 years the HR for the primary endpoint was 0.66 (95%CI 0.49-0.88; p=0.0044). In patients with a LVEF<30% the HR was 0.65 (95%CI0.53-0.78; p<0.0001); in those with type-2 diabetes the HR was 0.54 (95%CI 0.42-0.70; p<0.0001), in patients with a eGFR <60 ml/min/1.73 m2 the HR was 0.62 (95%CI 0.49-0.79; p<0.0001) and in patients with a systolic BP < the median of 123 mmHg the HR was 0.62 (95%CI 0.51-0.79; p<0.0001).
Additionally, in these five sub-groups, the secondary endpoints of all-cause hospitalization and HF hospitalization achieved statistically significant relative risk reductions for the eplerenone group compared to the placebo group (p<0.01). In each of the high risk sub-groups evaluated, patients receiving eplerenone had a significant increase in the incidence of hyperkalaemia (K+ > 5.5 mmol/l). However, there was no significant increase in serious hyperkalemia (K+ > 6.0 mmol/l), hyperkalaemia leading to drug discontinuation, hospitalization for hyperkalemia, or hospitalization for worsening renal function. The beneficial effect of eplerenone on the primary endpoint of the EMPHASIS trial (death from cardiovascular causes and hospitalization for heart failure) remained significant over an additional follow-up of up to 7 months (HR 0.66; 95%CI 0.57-0.77; p<0.0001).
Conclusions: The consistency of the efficacy and safety of eplerenone in addition to standard therapy on pre-specified high-risk subgroups and the persistence of a significant beneficial effect on the primary endpoint (cardiovascular mortality or hospitalization for heart failure) over an additional up-to 7 months of follow-up on double-blind therapy in conjunction with prior beneficial results from EPHESUS presents compelling evidence for the use of eplerenone in patients with systolic heart failure and mild symptoms.