Congestive Heart Failure Post-Myocardial Infarction
The eplerenone post-acute myocardial infarction heart failure efficacy and survival study
(EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study
in patients clinically stable 3–14 days after an acute myocardial infarction (MI) with left
ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%) and
either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion
by exam or chest x-ray or S3). Patients with CHF of valvular or congenital etiology, patients
with unstable post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum
creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI
drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft
surgery.
Patients randomized to INSPRA were given an initial dose of 25 mg once daily and titrated to
the target dose of 50 mg once daily after 4 weeks if serum potassium was
< 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium
levels were ≥ 5.5 mEq/L. [See DOSAGE AND ADMINISTRATION.]
EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries.
The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other)
and male (71%). The mean age was 64 years (range, 22–94 years).
The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II
(64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI.
Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%),
dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%).
The mean dose of INSPRA was 43 mg/day. Patients also received standard care including aspirin
(92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or
HMG-CoA reductase inhibitors (60%).
Patients were followed for an average of 16 months (range, 0–33 months).
The ascertainment rate for vital status was 99.7%.
The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2)
the time to first occurrence of either cardiovascular (CV) mortality
[defined as sudden cardiac death or death due to progression of congestive heart failure (CHF),
stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of
CHF, ventricular arrhythmias, acute myocardial infarction, or stroke).
For the co-primary endpoint for death from any cause, there were 478 deaths in the INSPRA group
(14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with INSPRA was reduced
by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank
test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components
of mortality are provided in Table 9.
Figure 1. Kaplan-Meier Estimates of All-Cause Mortality
Table 9. Components of All-Cause Mortality in EPHESUS
Most CV deaths were attributed to sudden death, acute MI, and CHF.
The time to first event for the co-primary endpoint of CV death or hospitalization, as defined
above, was longer in the INSPRA group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95,
p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV
hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke,
ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92
(95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined
all-cause hospitalization and mortality were driven primarily by CV mortality. The combined
endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented
in Table 10.
Table 10. Rates of Death or Hospitalization in EPHESUS
Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios
appeared favorable for INSPRA for both genders and for all races or ethnic groups, although the
numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence
of CHF and patients greater than 75 years did not appear to benefit from the use of INSPRA.
Such subgroup analyses must be interpreted cautiously.
Figure 2. Hazard Ratios of All-Cause Mortality by Subgroups
Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which
mortality was reduced.
Hypertension
The safety and efficacy of INSPRA have been evaluated alone and in combination with other
antihypertensive agents in clinical studies of 3091 hypertensive patients.
The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65).
The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated
baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females).
Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline
diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect
of INSPRA. In these two studies, 611 patients were randomized to INSPRA and 140 patients to
placebo. Patients received INSPRA in doses of 25 to 400 mg daily as either a single daily dose or
divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure
achieved by INSPRA in these studies at doses up to 200 mg are shown in Figures 3 and 4.
Figure 3. INSPRA Dose Response - Trough Cuff SBP Placebo-Subtracted Adjusted Mean Change from
Baseline in Hypertension Studies
Figure 4. INSPRA Dose Response - Trough Cuff DBP Placebo-Subtracted Adjusted Mean Change from
Baseline in Hypertension Studies
Patients treated with INSPRA 50 to 200 mg daily experienced significant decreases in sitting
systolic and diastolic blood pressure at trough with differences from placebo of 6–13 mm Hg
(systolic) and 3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour
ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data
demonstrated that INSPRA, administered once or twice daily, maintained antihypertensive efficacy
over the entire dosing interval. However, at a total daily dose of 100 mg, INSPRA administered
as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood
pressure reductions than 100 mg given once daily.
Blood pressure lowering was apparent within 2 weeks from the start of therapy with INSPRA, with
maximal antihypertensive effects achieved within 4 weeks. Stopping INSPRA following treatment for
8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal
of INSPRA greater than following placebo or active control withdrawal. Blood pressures in patients
not taking other antihypertensives rose 1 week after withdrawal of INSPRA by about 6/3 mm Hg,
suggesting that the antihypertensive effect of INSPRA was maintained through 8 to 24 weeks.
Blood pressure reductions with INSPRA in the two fixed-dose monotherapy studies and other studies
using titrated doses, as well as concomitant treatments, were not significantly different when
analyzed by age, gender, or race with one exception. In a study in patients with low renin
hypertension, blood pressure reductions in Blacks were smaller than those in whites during the
initial titration period with INSPRA.
INSPRA has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor
antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered
concomitantly with one of these drugs INSPRA usually produced its expected antihypertensive effects.
There was no significant change in average heart rate among patients treated with INSPRA in the
combined clinical studies. No consistent effects of INSPRA on heart rate, QRS duration, or PR or
QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during
pharmacokinetic studies.