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, Congestive Heart
Failure Post-Myocardial Infarction.)
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 HF (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 1.
Figure 1. Kaplan-Meier Estimates of All-Cause Mortality
Table 1. 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
2.
Table 2. 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 391 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.