Long-term safety and efficacy of the selective aldosterone blocker eplerenone in patients with essential hypertension.

BACKGROUND: Even within the normal range, aldosterone levels are linked to end-organ toxicity and mortality in patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers does not sufficiently reduce plasma aldosterone levels. OBJECTIVE: This study was conducted to assess the long-term safety profile and efficacy of the selective aldosterone blocker eplerenone. METHODS: This was a multicenter, open-label, uncontrolled trial in patients with mild to moderate essential hypertension. After a 1-week washout of previous antihypertensive medications, eplerenone was initiated at 50 mg once daily; the dose was titrated to a maximum of 200 mg/d to achieve a diastolic blood pressure <90 mm Hg and a systolic blood pressure <140 mm Hg. Thereafter, another antihypertensive agent could be added and titrated once, or another agent could be substituted for eplerenone. Eplerenone treatment was continued for up to 14 months in a subset of patients. RESULTS: Five hundred eighty-six patients were enrolled in the study. Their adjusted mean blood pressure (BP) at baseline was 150/96 mm Hg. The majority (80.4%) were white; 51.5% were male and 48.5% were female; 62.3% were between the ages of 45 and 64 years and 21.7% were aged >64 years. Three hundred eighty-five patients (65.7%) completed the study; 98 (16.7%) were withdrawn due to treatment failure (only 4.8% of them after month 4), and 40 (6.8%) were withdrawn due to treatment-emergent adverse events. Four hundred thirty-three of 582 (74.4%) patients in the intent-to-treat population achieved BP control during eplerenone treatment: 261 (44.8%) received eplerenone monotherapy and 172 (30.0%) received eplerenone plus another antihypertensive agent. CONCLUSIONS: Eplerenone therapy was effective in the treatment of mild to moderate hypertension over a 14-month period, either as monotherapy or in combination with another antihypertensive agent. Use of eplerenone was well tolerated in the population studied.

Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study.

BACKGROUND: Elevated renin-angiotensin-aldosterone system activity correlates with left ventricular hypertrophy (LVH) and cardiovascular risk, but the relative contributions of angiotensin II and aldosterone remain unclear. This study compared LVH regression during treatment with the selective aldosterone blocker eplerenone, enalapril, and their combination in patients with hypertension. METHODS AND RESULTS: A 9-month, double-blind, randomized study was performed in 202 patients with LVH and hypertension who received eplerenone 200 mg daily, enalapril 40 mg daily, or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5 to 25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was >90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, renin-angiotensin-aldosterone system hormones, albuminuria, and safety were also assessed. Eplerenone significantly reduced LV mass from baseline (-14.5+/-3.36 g; n=50) similarly to enalapril (-19.7+/-3.20 g; n=54; P=0.258), but eplerenone/enalapril (-27.2+/-3.39 g; n=49) was more effective than eplerenone alone (P=0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, -23.8 and -11.9 mm Hg; enalapril, -24.7 and -13.4 mm Hg; and eplerenone/enalapril, -28.7 and -14.4 mm Hg, P=0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone (P=0.033), and elevated potassium was more common with eplerenone. CONCLUSIONS: Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone.

Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.

BACKGROUND: Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. METHODS: Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia. RESULTS: During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001). CONCLUSIONS: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and tolerability of monotherapy with the selective aldosterone blocker eplerenone in both black and white patients with hypertension. BACKGROUND: Essential hypertension and cardiovascular-renal-target organ damage is more prevalent in black than white adults in the U.S. METHODS: Black (n = 348) and white (n = 203) patients with mild-to-moderate hypertension were randomized to double-blind treatment with eplerenone 50 mg, the angiotensin II receptor antagonist losartan 50 mg, or placebo once daily. Doses were increased if blood pressure remained uncontrolled. The primary end point was change in mean diastolic blood pressure (DBP) after 16 weeks of therapy. RESULTS: Adjusted mean changes from baseline in DBP were -5.3 +/- 0.7, -10.3 +/- 0.7, and -6.9 +/- 0.6 mm Hg in the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan). In black patients, DBP decreased by -4.8 +/- 1.0, -10.2 +/- 0.9, and -6.0 +/- 0.9 mm Hg for the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan), whereas in white patients, DBP decreased by -6.4 +/- 1.0, -11.1 +/- 1.1, and -8.4 +/- 1.0 mm Hg, respectively (p = 0.001 eplerenone vs. placebo, p = 0.068 for eplerenone vs. losartan). For reduction of systolic blood pressure (SBP), eplerenone was superior to placebo and losartan in all patients combined and in black patients, and was superior to placebo in white patients. Eplerenone was as effective as losartan in reducing SBP and DBP in the high renin patient, but more effective than losartan in the low renin patient. Similarly, eplerenone was at least as effective as losartan in patients with differing baseline levels of aldosterone. Both eplerenone and losartan were well tolerated. CONCLUSIONS: The antihypertensive effect of eplerenone was equal in black and white patients and was superior to losartan in black patients.

Drug development and the heart hospital.

Conducting clinical trials to support the development of new pharmaceutical entities or devices offers specialized heart hospitals unique opportunities. The populations they serve with cardiovascular diagnoses provide a predictable reservoir for recruitment of patients into trials of cardiovascular drugs or devices. The later stages in new chemical entity development require hundreds to thousands of patients to achieve statistical power. This need provides opportunities for rapid screening and identification of patients who would potentially benefit from and be appropriate for study. Clinically sophisticated support personnel to facilitate the conduct of research trials are likely to be available in the staff structure of a heart hospital. Meticulous attention to patient safety and privacy, good clinical practice, and high-quality data collection are imperative.