This report summarizes the results of 4 double-blind, placebo-controlled studies designed to determine the efficacy, tolerability, and dose-response characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of mild-to-moderate essential hypertension. Two of these studies were conducted in the general population of essential hypertensives, 1 in elderly patients, and 1 in patients on chronic hydrochlorothiazide treatment. A total of 1,116 patients were randomized to receive 1 of 7 doses of mibefradil (6.25-200 mg; n = 927), or placebo (n = 189). Each study demonstrated a significant linear dose response in the reduction of sitting diastolic (SDBP) and sitting systolic (SSBP) blood pressure. In all 4 trials, SDBP was significantly reduced with the recommended doses of 50 and 100 mg mibefradil (placebo-corrected treatment effects of -4.1 to -6.8 mm Hg and -8.8 to -11.1 mm Hg, respectively, for the 50- and 100-mg doses). A similar reduction in SSBP occurred in 3 of 4 studies at the 50-mg dose (-7.5 to -10.7 mm Hg) and in 4 of 4 studies at the 100-mg dose (-6.8 to -16.7 mm Hg). Lower doses did not reduce blood pressure significantly; doses > 100 mg had little additional effect and an increased incidence of adverse events. Overall, response and normalization rates were dose related and averaged 61% and 51%, respectively, for the 50-mg dose and 78% and 65%, respectively, for the 100-mg dose. The onset of the antihypertensive effect was gradual, with no first-dose effect; near maximal response was reached within 1-2 weeks. Trough/peak ratios ranged from 77-86% with the 50-mg dose and from 77-108% with the 100-mg dose, indicating a sustained effect over a 24-hour period. A slight decrease in heart rate was observed, ranging from -2.2 to -5.5 beats/min at the 50-mg dose and from -4.0 to -8.8 beats/min at the 100-mg dose. The efficacy and safety results were similar across all populations studied, including the elderly and hydrochlorothiazide-treated patients, indicating that no dose adjustment is needed for these populations. Thus, the results of these 4 placebo-controlled trials confirm that when taken at the recommended doses of 50 and 100 mg once daily, mibefradil is an effective, safe, and well-tolerated therapy for the treatment of mild-to-moderate hypertension.
