Assessment of the Novel Selective Aldosterone Blocker Eplerenone Using Ambulatory and Clinical Blood Pressure in Patients With Systemic Hypertension William B. White, MD, Albert A. Carr, MD, Scott Krause, BSN, Rosanne Jordan, BS, Barbara Roniker, MD, and Wille Oigman, MD Eplerenone is a highly selective aldosterone blocking agent, which was recently approved for the treatment of hypertension and has also been shown to reduce mor- tality in post-myocardial infarction patients with heart failure. To assess its usefulness in patients with essential hypertension, we performed a 12-week, double-blind, placebo-controlled, parallel-arm, fixed-dose study over a range of doses using clinic and ambulatory blood pressure (BP). After single-blind placebo therapy for 3 to 4 weeks to obtain baseline measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg once daily). In addition, changes from baseline in serum potassium, active renin activity, and serum aldosterone were as- sessed. After 12 weeks of therapy, reductions in clinic BP showed a significant dose response in which 25 mg of eplerenone achieved statistical significance compared with placebo for systolic BP; maximum clinic BP reduc- tion was achieved with the 100 mg dose. Ambulatory BP monitoring showed that all doses of eplerenone (25 to 200 mg/day) lowered BP significantly greater than pla- cebo with a significant dose response. The 24-hour mean BP reductions ranged from 6.4/4.4 to 10.3/5.7 mm Hg on eplerenone compared with 1.3/0.8 mm Hg on placebo. One patient on placebo and 1 patient on 200 mg of eplerenone had episodes of elevated serum potassium levels (>5.5 mEq/L). Increases in serum al- dosterone were related to dose but not to reductions in 24-hour BP. Side effects and withdrawal rates attributed to eplerenone were similar to those of placebo. These data show that eplerenone is an effective antihyperten- sive agent at doses as low as 25 mg/day. The top effective dose in stage 1 to 3 hypertension based on clinic and ambulatory BP was 100 mg once daily. The incidence of elevated serum potassium levels was not increased across doses of eplerenone in this study. 2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:38 – 42) E plerenone is a novel selective aldosterone blocker that is a steroid nucleus-based antimineralocorti- coid that acts as a competitive and selective inhibitor of aldosterone at mineralocorticoid receptor sites in various tissues throughout the body. 1–3 Due to the presence of a 9,11-epoxide group in the structure of eplerenone, selectivity for the aldosterone receptor is enhanced and the drug has very low affinity for pro- gesterone and androgen receptors (e.g., 1% and 0.1%, respectively, of spironolactone’s receptor binding). The enhanced selectivity of eplerenone for the aldosterone receptor should allow for retained effects on lowering of blood pressure (BP) with im- proved tolerability. To assess the efficacy and safety of this new compound for the treatment of hyperten- sion, we performed a large, multicenter clinical trial using several doses of eplerenone in a placebo-con- trolled trial that utilized clinic and ambulatory BP measurement. METHODS Patient population: Adult men and women were included if they had untreated hypertension, their seated clinic systolic BPs were 180 mm Hg, the clinic diastolic BP was between 95 and 110 mm Hg, and the 24-hour mean diastolic BP was 85 mm Hg. Patients were excluded from the trial if they had recent myocardial infarction or unstable angina, congestive heart failure, clinically significant liver or renal dis- ease, known secondary hypertension, or uncontrolled diabetes mellitus (glycohemoglobin 10%). Men and women whose serum creatinine was 1.5 or 1.3 mmol/L, respectively, or whose serum potassium was 5.0 mmol/L at baseline were also excluded from the trial. Study design: The study was a multicenter, double- blind, randomized, placebo-controlled, parallel arm trial. After discontinuation of any current prestudy antihypertensive drug therapy, patients were given single-blind placebo tablets for 3 to 4 weeks to estab- lish baseline BPs and laboratory parameters. At ran- domization, patients received either placebo, or eplerenone (25, 50, 100, or 200 mg once daily). The treatment group received the drug for 12 weeks. If From the Section of Hypertension and Clinical Pharmacology, Univer- sity of Connecticut School of Medicine, Farmington, Connecticut; Southern Clinical Research and Management, Inc., Augusta, Geor- gia; Pharmacia Research and Development, Skokie, Illinois; and Hos- pital Universitario Pedro Ernesto, Rio de Janeiro, Brazil. Manuscript received January 15, 2003; revised manuscript received and ac- cepted March 20, 2003. Address for reprints: William B. White, MD, Section of Hyperten- sion and Clinical Pharmacology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06030- 3940. E-mail: wwhite@nso1.uchc.edu 38 ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matter The American Journal of Cardiology Vol. 92 July 1, 2003 doi:10.1016/S0002-9149(03)00461-2