The results from a new post-hoc sub-group analysis of the EMPHASIS-HF trial have showed statistically significant reductions in the primary composite endpoint of cardiovascular death and heart failure hospitalization for five pre-defined high risk patient sub-groups with chronic heart failure ( CHF ) New York Heart Association ( NYHA ) class II and mild symptoms treated with Eplerenone ( Inspra ) in addition to standard therapy versus those treated with placebo plus standard therapy.

The results were presented during a Hot Line Session of The European Society of Cardiology Congress ( ESC ) in Paris.

Significant reductions in the risk of the primary endpoint of cardiovascular mortality and heart failure hospitalization were observed in the following five pre-specified high risk sub-groups: a) patients aged 75 years or older: 78 events ( 23.6% ) among 330 patients on eplerenone and 107 events ( 32.7% ) among 327 patients on placebo ( HR=0.66, p=0.004 ); b) patients with a left ventricular ejection fraction ( LVEF ) less than 30%: 180 events ( 19.3% ) among 934 patients on Eplerenone and 267 events ( 27.3% ) among 978 patients on placebo ( HR=0.65, p less than 0.0001 ); c) patients with type 2 diabetes: 99 events ( 21.6% ) among 459 patients on Eplerenone and 141 events ( 35.2% ) among 400 patients on placebo ( HR=0.54, p less than 0.0001 ); d) patients with estimated glomerular filtration rate ( eGFR ) less than 60 ml/min/1.73m2 : 107 events ( 24.4% ) among 439 patients on Eplerenone and 163 events ( 34.5% ) among 473 patients on placebo ( HR=0.62, p=0.0001 ); e) patients with systolic blood pressure ( SBP ) less than median, 123 mmHg: 138 events ( 20.6% ) among 669 patients on Eplerenone and 201 events ( 29.4% ) among 683 patients on placebo ( HR=0.62, p less than 0.0001 ).

Additionally, in these five sub-groups, the secondary endpoints of all-cause hospitalization and heart failure hospitalization achieved statistically significant ( p less than 0.01 ) relative risk reductions for the Eplerenone group compared to the placebo group.

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 less than 0.001 in favor of Eplerenone ) in the primary endpoint was evident. The main results of the EMPHASIS-HF study were published in New England Journal of Medicine ( NEJM ) in November 2010.

After halting of recruitment, additional primary endpoints were observed while patients remained on double-blind therapy for a mean seven months of follow-up. Analysis of the data covering the full double-blinded period indicates that the effect of Eplerenone on the primary endpoint remained significant over the additional follow-up period ( HR=0.66, p less than 0.0001 ).

No new safety information emerged from these additional analyses. In each of the high risk sub-groups evaluated, patients receiving Eplerenone had a significant increase in the incidence of hyperkalaemia ( K+ greater than 5.5 mmol/l ). However, there was no significant increase in serious hyperkalemia ( K+ greater than 6.0 mmol/l ), hyperkalaemia leading to drug discontinuation, hospitalization for hyperkalemia, or hospitalization for worsening renal function.

EMPHASIS HF 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 ).

The primary objective of this trial is to evaluate the efficacy and safety of Eplerenone plus standard heart failure therapy - including an angiotensin converting enzyme ( ACE ) inhibitor and/or an angiotensin receptor blockers ( ARB ), plus a beta-blocker - versus placebo plus standard heart failure therapy on the cumulative incidence of cardiovascular mortality and heart failure 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 25 mg 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.

The EMPHASIS-HF trial demonstrated a statistically significant 37% relative risk reduction for patients with chronic systolic heart failure and mild symptoms treated with Eplerenone ( p less than 0.0001 ) plus standard therapy compared to placebo plus standard therapy in the primary composite endpoint of death from cardiovascular causes or heart failure hospitalization. There were also statistically significant reductions in the other major secondary endpoints of all-cause mortality, cardiovascular mortality, all-cause hospitalization and heart failure hospitalization.

Source: Pfizer, 2011

XagenaMedicine2011