Eplerenone in patients with myocardial infarction and “mid‐range” ejection fraction: An analysis from the EPHESUS trial

Abstract Background Trials using mineralocorticoid receptor antagonists (MRAs) in myocardial infraction (MI) without heart failure (HF) or systolic impairment have been underpowered to assess morbidity‐mortality benefit. In EPHESUS 6632 patients were included, of whom 11% had an ejection fraction (EF) of 40% and HF or diabetes. We aim to assess the potential benefit of MRAs in MI with EF of 40%. Methods Cox models with interaction term for EF. The primary outcome was a composite of cardiovascular death or hospitalization for cardiovascular reasons. Hypothesis Patients with an EF of 40% benefit similarly from MRA therapy to those with an EF <40%. Results In EPHESUS, 753 patients had an EF = 40% and 5864 an EF < 40%. Patients with an EF = 40% were younger (63 vs 64 years), had lower heart rate (73 vs 75 bpm), less atrial fibrillation (10% vs 14%), previous MI (21% vs 28%), HF hospitalization (5% vs 8%), and had more often reperfusion therapy and/or revascularization (55% vs 44%). The mean EF was 40.0 ± 0.3% in those with EF = 40% vs 32.2 ± 5.9% in those with EF < 40%. The primary outcome occurred in 13.3% (10 events per 100 py) of the patients with EF = 40% vs 22.9% (19 events per 100 py) in those with EF < 40%; adjusted HR for EF = 40% vs <40% = 0.65 (0.53‐0.81). Eplerenone reduced the event‐rate homogenously regardless of EF (interactionp EF = 40% vs EF < 40% = 0.21). Similar findings were observed for cardiovascular and all‐cause death. Conclusion Eplerenone reduces hospitalizations and mortality in patients with MI and EF = 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the “mid‐range zone” may also benefit from MRA therapy which might help clinicians in their treatment decisions.


| INTRODUCTION
Mineralocorticoid receptor antagonists (MRAs) have clear "IA" guideline indication for patients with a myocardial infraction (MI) and a left ventricular ejection fraction (EF) inferior to 40% if accompanied by signs and symptoms of heart failure (HF) or diabetes. 1,2 Despite the guideline recommendations, MRAs are prescribed in a small proportion of these patients. 3,4 In patients with an EF of 40% or greater, the potential benefit of MRAs is unknown. A large proportion of patients with a recent MI have a EF of 40% or greater regardless of having (or not) signs and symptoms of HF. In the HF field, patients with an EF situated between 40% and 50% have been called "mid-range" EF patients, 1 and there is some evidence suggesting that they might benefit from MRA therapy. 5,6 However, in MI this specific population has not been studied in dedicated trials using MRAs, and trials including patients without HF at presentation have been underpowered to ascertain morbidity-mortality benefit. 7,8 In the Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction (EPHESUS) trial, 9 eplerenone reduced the relative rate of all-cause death by 15% and the composite of death from cardiovascular causes or hospitalization for cardiovascular events by 13%. In EPHESUS, patients could be enrolled within 3 to 14 days after a MI, if they had an EF ≤ 40% and HF or diabetes. In this large trial, it is thus possible that many of these patients had an EF of 40% or greater due to a "digit preference" for EF values in multiples of 5%, as it has been described in previous reports that patients with EF between 35% and 45% are attributed to have an EF of 40%. 10,11 We performed an analysis of the EPHESUS trial to assess the characteristics, event-rates and the effect of eplerenone in patients with EF = 40%, compared with those with EF < 40%.

| Study outcomes
In the present analysis, the primary outcome is a composite of cardiovascular death or cardiovascular hospitalization. Cardiovascular death alone, all-cause death, and HF hospitalization were also assessed.
Hyperkalemia (defined as a potassium concentration above 5.5 mmol/l at any time throughout the follow-up) and worsening renal function (WRF, defined as a decline superior to 30% in the estimated glomerular filtration rate at any time throughout the follow-up) were assessed as major safety outcomes.
The outcomes were centrally adjudicated by endpoint committees and defined by the conventional criteria. 9

| Statistical analysis
Baseline clinical characteristics of patients were summarized by EF groups (<40% vs 40%) using means and SD for continuous variables, frequencies and percentages for categorical variables, and hazard ratios (HRs), incidence rates, and incidence-rate differences with their 95% confidence interval (95%CI) for treatment effect estimates.
Time-to-first-event curves were obtained using the Kaplan-Meier method and compared using the log-rank test. Univariate Cox proportional hazards' modeling was used to explore the association between EF and/or the intervention and the study outcomes, and a Cox model with interaction term on EF was performed to assess the potential heterogeneity of the treatment effect by EF. We also performed adjusted models for reducing the potential confounding of the associations between EF and outcomes. The covariates for this multivariate model were chosen according to their clinical relevance or historical association with the outcome in the previous studies 12-14 and included age, sex, body mass index, heart rate, estimated glomerular filtration rate, sodium, potassium, previous MI, peripheral vascular disease, previous HF hospitalization, atrial fibrillation, diabetes, hypertension, chronic obstructive pulmonary disease, angiotensin-converting-enzyme-inhibitors/angiotensin-receptor blockers, beta-blockers, Q-wave MI, Killip class, reperfusion therapy, and study drug (eplerenone or placebo). Proportional hazards assumptions were tested based on Schoenfeld residuals with time interaction.
All the statistical analyses were performed using the STATA/SE software, version 15.1 (Stata Corp, College Station, Texas).

| Events by left ventricular EF categories
Patients with an EF = 40% had lower event rates compared to patients with an EF < 40%. The primary outcome occurred in 13.3% of the patients with an EF = 40% vs 22.9% in those with an EF < 40%, with corresponding event rates per 100 person-years of 10

| Treatment effect
Eplerenone (compared with placebo) reduced the event rates with similar magnitude regardless of the EF, with relative reductions of the primary outcome ranging from 2% to 56% in patients with EF = 40% and 5% to 23% in patients with EF < 40%; p for interaction = 0.21. The effect of treatment was more imprecise in patients with EF = 40% due to a smaller sample size/loss of statistical power. All the studied outcomes pointed toward a benefit of eplerenone regardless of the EF (Table 3 and Figure 1).
The effect of treatment was of higher absolute magnitude in the early follow-up period (first 6 months), regardless of EF (Figure 2 and

| DISCUSSION
In EPHESUS, treatment with eplerenone (vs placebo) significantly reduced the composite of time-to-first cardiovascular death or cardiovascular hospitalization, cardiovascular and all-cause death, and HF hospitalization, regardless of the EF (40% vs <40%). These findings support the use of eplerenone also in MI patients with EF of 40%.
In HF, patients enrolled in the Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT) trial, who had a "midrange" EF, might have benefited more from spironolactone therapy. 5 In our study, and as previously documented, 9 there was an increased incidence of hyperkalemia and WRF among patients receiving eplerenone (additionally, our study suggests that these side effects might have been experienced mainly by patients with an EF < 40%).
This finding underscores the need to measure serum potassium and creatinine levels serially and to adjust the dose of eplerenone accordingly. In EPHESUS, the protocol mandated "if at any time during the study the serum potassium is >5.5 mEq/l but <6.0 mEq/l, the dose of study drug will be reduced to the next lower dose level or temporarily withheld if the patient is receiving 25 mg of eplerenone every other day. 9 In a renal function stratified analysis from the EMPHASIS-HF trial, we found that a dose of 25 mg/day of eplerenone in patients with eGFR <50 ml/min is as effective as 50 mg/day in patients with eGFR ≥ 50 ml/min; these are the doses that should be used in clinical practice (ie, personalized approach) because, by adapting the dose according to the renal function, one may avoid side-effects and drugdiscontinuation. 17

| LIMITATIONS
This is a post hoc nonprespecified analysis of the EPHESUS trial. In consequence, these results are prone to bias inherent to secondary studies and should be regarded as exploratory and hypothesis generating. Moreover, EPHESUS was not designed with sufficient power to draw statistical conclusions about subgroups (baseline characteristics were well balanced between MRA and placebo groups, but they were not between EF < 40 and EF = 40%). We have addressed this issue by adjusting for potential confounders. Generally, the absence of significant "interactions" in all the studied outcomes, points toward a consistent eplerenone effect regardless of the EF subgroup.

| CONCLUSIONS
Eplerenone reduces hospitalizations and mortality in patients with EF of 40% similarly to patients with EF < 40%. These findings suggest that MI patients with EF in the "mid-range zone" may also benefit from MRA therapy which might help clinicians in their treatment decisions.