INSPRA Rx

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 to 14 days after an acute MI with LV dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%) and either diabetes or clinical evidence of HF.

EPHESUS involved 6,632 patients in 27 countries. Patients who were randomly assigned 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. Patients were followed for an average of 16 months (range, 0 to 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 mortality (defined as sudden cardiac death or death due to progression of HF, stroke, or other CV causes) or CV hospitalization (defined as hospitalization for progression of HF, ventricular arrhythmias, acute MI, or stroke).

For the co-primary endpoint for death from any cause, results showed 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 [HR], 0.85; 95% CI, 0.75-0.96; P =0.008). The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the Inspra arm (HR 0.87; 95% CI, 0.79-0.95, 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 HF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% CI, 0.86-0.99; P =0.028).

For more clinical trial data, see full labeling.

Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95–114 mm Hg were conducted to assess the antihypertensive effect of Inspra. In these 2 studies, patients (n=611) were randomly assigned to Inspra and to placebo (n=140). Patients received Inspra in doses of 25–400 mg daily as either a single daily dose or divided into two daily doses. 

Results showed that patients treated with Inspra 50–200 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, given 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 daily 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 initiation of Inspra therapy, with maximal antihypertensive effects achieved within 4 weeks, and the effect was maintained through 8 to 24 weeks. 

Inspra has been studied concomitantly with treatment with ACE inhibitors, ARB, calcium channel blockers, beta-blockers, and hydrochlorothiazide. When co-administered with one of these drugs, Inspra usually produced its expected antihypertensive effects.

For more clinical trial data, see full labeling.