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Published on: March 26, 2016
Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial
João Pedro Ferreira1,2, Paula Abreu3, John J V McMurray4
1National Institute of Health and Medical Research (INSERM), Center for Clinical Multidisciplinary Research 1433, INSERM U1116, University of Lorraine, Regional University Hospital of Nancy, French Clinical Research Infrastructure Network (F-CRIN) Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists (INI-CRCT), Nancy, France.
Insights
Eplerenone effectively treats heart failure across different kidney function levels, but lower doses in patients with reduced kidney function led to more adverse events, suggesting dose adjustment is needed.
Area of Science:
- Cardiology
- Pharmacology
- Nephrology
Background:
- Current heart failure guidelines suggest a target eplerenone dose of 50 mg/day.
- The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) investigated eplerenone's effects based on renal function.
- Estimated glomerular filtration rate (eGFR) was used to stratify patients into different eplerenone dose groups.
Purpose of the Study:
- To evaluate the efficacy and safety of different eplerenone doses stratified by renal function in heart failure patients.
- To determine if eplerenone's treatment effect varies across different levels of kidney function.
- To assess the occurrence of adverse events, such as hyperkalemia and renal failure, in relation to eplerenone dosage and renal function.
Main Methods:
- The EMPHASIS-HF trial randomized patients to receive eplerenone or placebo.
- Dosing was stratified by eGFR: 50 mg/day for eGFR ≥ 50 mL/min/1.73 m² and 25 mg/day for eGFR 30-49 mL/min/1.73 m².
- The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality.
Main Results:
- Eplerenone demonstrated superiority over placebo in both eGFR strata (≥ 50 and 30-49 mL/min/1.73 m²).
- Hazard ratios for the primary outcome were 0.58 (95% CI 0.45-0.74) for eGFR ≥ 50 and 0.62 (95% CI 0.49-0.78) for eGFR 30-49.
- Patients with impaired renal function (eGFR 30-49) experienced more hyperkalemia, renal failure events, and drug discontinuations despite lower eplerenone doses.
Conclusions:
- Eplerenone's treatment effect in heart failure is consistent across different renal function levels.
- Lower eplerenone doses (25 mg/day) in patients with eGFR 30-49 mL/min/1.73 m² were as effective as higher doses (50 mg/day) in patients with eGFR ≥ 50 mL/min/1.73 m².
- Current guidelines may need revision to recommend tailoring eplerenone dosage based on renal function due to increased adverse events in patients with impaired kidney function.
Background:
Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
Methods And Results:
In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR ≥ 50 mL/min/1.73 m2 and ≤ 25 mg/day if eGFR 30-49 mL/min/1.73 m2 . Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR ≥ 50 mL/min/1.73 m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49 mL/min/1.73 m2 stratum: HR 0.62, 95% CI 0.49-0.78; Pinteraction = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49 mL/min/1.73 m2 stratum more often had hyperkalaemia, renal failure events, and drug discontinuation.
Conclusion:
In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49 mL/min/1.73 m2 was as effective as 50 mg/day in patients with eGFR > =50 mL/min/1.73 m2 . However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should.
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