OBJECTIVE: The EPHESUS trial showed that the use of eplerenone in the setting of heart failure after acute myocardial infarction is highly cost-effective. This analysis considers the cost-effectiveness of eplerenone in patient population who were taking both ACE inhibitors/ARBs and β-blockers at baseline from EPHESUS. METHODS: A total of 6632 patients were randomized to eplerenone 25-50 mg/day (n=3319) or placebo (n=3313) used concurrently with standard therapy and followed for up to 2.5 years. Of these, 4359 (66%) patients (eplerenone: 2162; placebo: 2197) were taking both ACE inhibitors/ARBs and β-blockers at baseline. Trial wide efficacy and resource utilization were used in the analysis. Resources included hospitalizations, outpatient services, and medications. Eplerenone was priced at $3.6/day. The incremental cost-effectiveness of eplerenone in cost per life-year gained (LYG) and cost per quality-adjusted life year (QALYs) gained was estimated using data from the Framingham, Saskatchewan and Worcester studies to project long-term survival. Both costs and effectiveness were discounted at 3%. RESULTS: As in the overall study population, the costs tended to be similarly higher in the eplerenone arm for patients who were taking both ACE inhibitors and β-blockers (cost difference=$1697). The number of LYG with eplerenone was 0.1637 based on Framingham, 0.0970 with Saskatchewan, and 0.2121 with Worcester data. The incremental cost-effectiveness ratio (ICERs) was $10,372 per LYG with Framingham (99% under $50,000 per LYG), $17,493 with Saskatchewan, and $8,003 with Worcester. The ICERs are systematically higher when calculated in cost per QALY gained ($15,021, $25,283, and $11,499 per QALY gained, respectively), as the utilities were below 1 with no difference between the treatment arms. CONCLUSIONS: As was for the entire EPHESUS population, aldosterone blockade with eplerenone is effective in reducing mortality and, is cost-effective in increasing years of life for EPHESUS subgroup patients who were taking both ACE inhibitors and β-blockers.