Mibefradil, a T-Channel–Selective Calcium Antagonist

AJH

1998;11:88S–94S

Mibefradil, a T-Channel–Selective Calcium Antagonist Clinical Trials in Hypertension Suzanne Oparil

Mibefradil, a tetralol derivative, is the first representative of a new class of calcium antagonists. It selectively blocks entry of calcium into cells through T-type channels. The efficacy and tolerability of mibefradil in the treatment of mild-to-moderate essential hypertension were evaluated in four placebo-controlled, double-blind, dose-finding studies involving over 1000 patients. Two trials involved patients from the general population, one examined a subpopulation of elderly patients, and one evaluated patients receiving chronic hydrochlorothiazide (HCTZ) treatment. Based on these studies, the recommended doses of mibefradil are 50 mg and 100 mg. Doses >100 mg/day were associated with small gains in efficacy and an increased incidence of adverse effects. Response (sitting diastolic blood pressure normalization to <90 mm Hg or reduction by >10 mm Hg) rates to mibefradil ranged from 46.0% to 68.6% with 50 mg, and from 60.0% to 93.2% with 100 mg. Normalization rates paralleled the response rates, ranging from 34.0% to 62.9% with 50 mg, and from 42.5% to 81.8% with 100 mg.

T

he L- and T-type voltage-dependent, transmembrane calcium channels are important for normal functioning of the cardiovascular system. The biology of L-type channels has been

From the University of Alabama at Birmingham, Birmingham, Alabama. Address correspondence and reprint requests to Suzanne Oparil, MD, 1034 Zeigler Research Building, University of Alabama at Birmingham, UAB Station, Birmingham, AL 35294.

© 1998 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.

The effects on sitting systolic blood pressure were similar. Treatment was associated with a slight, potentially beneficial reduction in heart rate. Results were similar across all populations, indicating that no dose adjustment is required for elderly and for HCTZ-treated patients. The frequency of adverse events was similar to that reported for placebo groups, with headache being the most common complaint. In comparative trials, mibefradil was more effective than nifedipine SR and diltiazem CD, and at least as effective as amlodipine and nifedipine GITS. Overall, mibefradil was better tolerated than the comparison drugs. Mibefradil, at the recommended doses of 50 to 100 mg/day, is safe and effective for the treatment of mild-to-moderate hypertension. Am J Hypertens 1998;11:88S–94S © 1998 American Journal of Hypertension, Ltd.

KEY WORDS:

Mibefradil, diltiazem, nifedipine, hydrochlorothiazide, drug comparison, calcium antagonist.

studied extensively, and pharmaceutical modulation of L-type channels forms the basis of action of dihydropyridine-, phenylalkylamine-, and benzothiazepine-based calcium antagonists (CA). T-Type channels are found in vascular smooth muscle, stomach, small intestine, colon, and a number of secretory cells.1– 4 In the heart, T-type channels are confined to the sinoatrial node, atrioventricular (AV) node, and Purkinje cells.5– 8 L-Type channels have a major role in myocardial contraction, admitting the large amounts of calcium necessary for this process. 0895-7061/98/$19.00 PII S0895-7061(98)00005-3

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TABLE 1. PLACEBO-CONTROLLED STUDIES OF MIBEFRADIL IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION: STUDY DESIGNS Reference 6 7 8 9

n 202 300 308 306

Doses of Mibefradil Evaluated (mg) 25, 50, 100, 150 6.25, 12.5, 25, 50, 100, 150, 200 6.25, 12.5, 25, 50, 100 12.5, 25, 50, 100

Duration of Study (weeks)

Population Evaluated

4 4 4 8

General General Elderly HCTZ

HCTZ, hydrochlorothiazide treated.

T-Type channels, however, do not play a role in myocardial contraction.8 They are thought to play a role in pacemaker function and in vascular smooth muscle contraction.9 The clinical implications of T-type channel blockade are under investigation. Mibefradil, a tetralol derivative, is the first representative of a new class of CA; it selectively blocks entry of calcium into cells through T-type channels.10 Mibefradil has a unique set of properties, including high bioavailability (approximately 90%),11 a long plasma half-life (17 to 25 h with chronic dosing),11,12 and the absence of negative inotropic effects and reflex neurohormonal stimulation.12–14 It reduces blood pressure by decreasing peripheral vascular resistance without inducing reflex tachycardia.15

The primary efficacy parameter in all studies was the change from baseline (the beginning of the treatment period) to the end of the active treatment period in trough sitting diastolic blood pressure (SDBP). Secondary efficacy parameters were the change from baseline in trough (24 h postdose) sitting systolic blood pressure (SSBP), peak blood pressure measurements, and response rates. Subjects were classified as responders if, at the end of the active treatment period, they exhibited a decrease from baseline in trough SDBP $ 10 mm Hg or were normalized to an SDBP , 90 mm Hg. The tolerability of trial medication was assessed at each visit by recording adverse events (AE). The characteristics of these patients are listed in Table 2.

PLACEBO-CONTROLLED STUDIES

Effects on Blood Pressure Each study demonstrated a linear dose trend in the reduction of SDBP and SSBP (P , .001). The lowest effective dose was 50 mg. At doses .100 mg, there was a small increase in efficacy, but the incidence of side effects also increased. The placebo-corrected treatment effects of the 50 mg and 100 mg mibefradil dose regimens are depicted in Figure 1, which shows consistent, clinically relevant, and significant decreases in SDBP and SSBP. No first-dose effect was observed, and the antihypertensive effect of mibefradil on SDBP was gradual, reaching near-maximal response within 1 to 2 weeks (Figure 2). Mean reductions in SDBP at trough ranged from 2.6 to 5.9 mm Hg in the placebo-treated group, 8.2 to 10.9 mm Hg with the 50-mg dose of mibefradil, and 11.7 to 17.0 mm Hg with the 100-mg dose of mibefradil. Response (SDBP normalization to #90 mm Hg or reduction by $10 mm Hg) rates ranged from 46.0% to 68.6% with 50 mg mibefradil and from 60.0% to 93.2% with 100 mg. Normalization rates paralleled the response rates, ranging from 34.0% to 62.9% with 50 mg, and from 42.5% to 81.8% with 100 mg. Trough: peak SDBP ratios for the 50 mg and 100 mg mibefradil doses in the three studies in which it was evaluated15–17 ranged from 77% to 86% at the 50 mg dose, and from 77% to 108% at the 100 mg dose. Mean decreases in SSBP at trough followed the same pattern as those observed with SDBP. Reduc-

The safety and efficacy of mibefradil have been evaluated in four placebo-controlled trials involving more than 1000 patients with mild-to-moderate hypertension. Two trials involved patients from the general population,15,16 one examined a subpopulation of elderly patients,17 and one evaluated patients receiving chronic hydrochlorothiazide (HCTZ) treatment.18 Based on data from these trials, the recommended safe and effective doses of mibefradil for the treatment of hypertension are 50 mg and 100 mg, once daily. The results of these trials are summarized below. These prospective, multicenter, randomized, double-blind studies involved 1116 male and female patients. In all of them, there was a 4-week placebo run-in period, after which eligible subjects were randomized to receive either placebo or mibefradil once daily for 4 or 8 weeks (Table 1). Patients were excluded from the trials if they had malignant or secondary hypertension, a major systemic disease (except for type II diabetes mellitus and appropriately treated hypothyroidism), or a history of drug or alcohol abuse. Those with cardiac conduction abnormalities greater than first-degree heart block or a sitting heart rate # 55 beats/min were also excluded. Concomitant use of medication affecting blood pressure (with the exception of HCTZ in one of the trials) or interfering with the effects of CA was not permitted.

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TABLE 2. PLACEBO-CONTROLLED STUDIES OF MIBEFRADIL IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION: DEMOGRAPHIC AND BASELINE CHARACTERISTICS Reference 6 7 8 9

n (ITT analysis)

Age (years, mean 6 SD)

Race (Nonblack:Black)

Sex (Male:Female)

Baseline SDBP (mm Hg, mean 6 SD)

202 300 308 306

55.7 6 8.8 51.3 6 8.9 71.7 6 5.4 55.2 6 9.3

201:1 222:78 290:18 284:22

122:80 168:132 117:191 145:161

104.6 6 4.3 101.1 6 4.3 99.0 6 5.6 99.3 6 5.8

ITT, intent-to-treat population; HCTZ, hydrochorothiazide; SDBP, sitting diastolic blood pressure.

tions in SSBP ranged from 4.9 to 6.9 mm Hg in the placebo-treated group, 9.7 to 16.6 mm Hg with the 50 mg dose of mibefradil, and 11.8 to 23.4 mm Hg with the 100 mg dose of mibefradil.

baseline heart rate, the greater the decrease in heart rate.

Effect on Heart Rate The antihypertensive effects of mibefradil were associated with a slight, dose-dependent decrease in heart rate, which attained statistical significance in three15,17,18 of the four trials (Figure 3). In these three trials, heart rate fell by an average of 4.5 and 8.8 beats/min with the 50 mg and 100 mg doses of mibefradil, respectively. Baseline heart rate influenced the magnitude of heart rate reduction; the greater the

The efficacy of mibefradil in the treatment of hypertension has been compared to the other commonly prescribed CA, amlodipine, diltiazem CD, nifedipine SR, and nifedipine GITS.19 –22 These randomized, double-blind, active-controlled trials involved over 640 patients. Mibefradil was associated with a significantly greater reduction in trough SDBP and significantly higher response and normalization rates than were diltiazem CD and nifedipine SR.19,22 Mibefradil also reduced SSBP significantly more than did diltiazem CD. Moreover, mibefradil was at least as effective as amlodipine and nifedipine GITS in normalizing blood pressure (Figure 4). However, mibefradil was associated with a lower incidence of leg edema than was amlodipine and was better tolerated overall compared to nifedipine GITS.21,22

COMPARATIVE TRIALS

SAFETY AND TOLERABILITY

FIGURE 1. Change from baseline in trough SDBP and SSBP. SDBP, sitting diastolic blood pressure; SSBP, sitting systolic blood pressure; Mib, mibefradil. Reprinted with permission from Oparil et al, Am J Cardiol. 1997;80(4B):12C–19C.

In these trials, mibefradil was safe and well tolerated. At the 50 mg and 100 mg doses, the overall proportion of subjects who had at least one AE (30.9% and 40.5%, respectively) was only slightly different from that observed among subjects who received placebo (31.6%) (Figure 5). The most common AE included headache, leg edema, dizziness, and fatigue (Table 3). There was actually a greater incidence of some AE among subjects who received placebo than among those who received the 50 mg dose of mibefradil. These included headache (5.3% v 3.7%), leg edema (2.6% v 0.5%), lightheadedness (0.5% v 0.0%), upper respiratory infection (2.1% v 1.0%), and dyspnea (2.1% v 0.0%). Among patients who received the 100 mg dose of mibefradil, only headache (8.7% v 5.3%), leg edema (5.6% v 2.6%), and lightheadedness (2.6% v 0.5%) were more frequent than among those who received placebo. The incidence of premature withdrawal due to AE among subjects who received the 50 mg (3.1%) or the 100 mg (3.1%) dose of mibefradil was

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FIGURE 2. Mean trough SDBP over time in subjects treated with 50 mg and 100 mg of mibefradil (A: narrow-range, dose-finding study15; B: broad-range, dose-finding study16; C: dose-finding study in elderly subjects17; D: dose-finding study in subjects with background HCTZ18). SDBP, sitting diastolic blood pressure; HCTZ, hydrochlorothiazide; Mib, mibefradil.

not different from that among those who received placebo (3.2%). Dose-related sinus bradycardia (heart rate , 45 beats/min) and first-degree AV block were the only relevant treatment-emergent electrocardiograph (ECG) changes observed among subjects treated with 50 or 100 mg mibefradil. These changes were usually not associated with symptoms. The frequency of ST-T changes, supraventricular premature contractions, ventricular premature contractions, and prolonged QT interval observed among subjects treated with 50 or 100 mg mibefradil was similar to or less than that observed among patients who received placebo. In the broad range, dose-finding study,16 the incidence of first-degree AV block was 0% with 50 mg mibefradil, 13% with 100 mg mibefradil, and 6% with placebo. The incidence of sinus bradycardia was 3% with 50 mg

mibefradil, 8% with 100 mg mibefradil, and 0% with placebo. SUMMARY Mibefradil is the only known CA to selectively inhibit T-type channels.10 It also interacts with the L-type channel in a manner that is different from dihydropyridine-, phenylalkylamine-, and benzothiazepinebased CA.23 Mibefradil causes coronary and peripheral vasodilation through a direct effect on vascular smooth muscle.11 This effect is associated with a slight decrease in heart rate.14,23,24 In preclinical models, mibefradil was found to have no relevant depressant effect on myocardial contractility.13,25,26 The lack of negative inotropic effect has been confirmed in studies of patients with hypertension,12,15–18 angina pectoris,14 and impaired cardiac function secondary to chronic

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FIGURE 3. Change from baseline in trough sitting heart rate.

ischemic heart disease.24 Mibefradil seems to be more selective in its hemodynamic effects than are nifedipine, verapamil, or diltiazem. In all four placebo-controlled studies, significant reductions in SDBP and SSBP occurred with the 50 mg and 100 mg doses of mibefradil. Similar efficacy was observed in all patient populations. A significant linear dose trend was observed across all four trials, indicating that increasing doses of mibefradil are associated with greater decreases in blood pressure. Doses .100 mg, however, were associated with small gains in efficacy, but were accompanied by an increased incidence of AE, making 100 mg the highest recommended safe and effective dose. Therapeutic response and normalization rates for mibefradil treatment were also dose-related in all four studies, with overall values of 78% and 65%, respectively, with the 100 mg dose. The high response rates and the magnitude of the decreases in blood pressure were comparable or superior to those produced by other CA, including diltiazem,19 nifedipine,21 and amlodipine.20

FIGURE 5. Incidence (%) of adverse events.

FIGURE 4. Summary of the changes from baseline (mean 6 SEM) in trough sitting diastolic blood pressure (SDBP) in four active-controlled studies.

The onset of the antihypertensive effect produced by the recommended doses of mibefradil was gradual. The maximum therapeutic effect was reached after 1 to 2 weeks of therapy. Exaggerated responses to 50 or 100 mg mibefradil were not observed in any of the patient populations studied, including elderly patients and patients being treated with diuretics, indicating that no dose adjustment is necessary for these groups. There was no evidence of a first-dose effect in any study, even in the study of elderly hypertensive patients.18 This is an especially desirable characteristic, since the abrupt onset of the antihypertensive effect observed with conventional short-acting CA may be associated with increased morbidity and mortality.27 The blood-pressure reduction achieved with 50 or

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TABLE 3. PLACEBO-CONTROLLED STUDIES OF MIBEFRADIL IN PATIENTS WITH MILD-TO-MODERATE HYPERTENSION: INCIDENCE (%) OF THE MOST FREQUENT ADVERSE EVENTS Adverse Event Headache Leg edema Dizziness Fatigue Flushing Lightheadedness Upper respiratory tract infection Rhinitis Bronchitis Dyspnea Total patients with $1 adverse event

Placebo (n 5 190)

Mibefradil 50 mg (n 5 191)

Mibefradil 100 mg (n 5 195)

5.3 2.6 2.1 1.6 1.6 0.5 2.1 0.5 2.1 2.1 31.6

3.7 0.5 2.1 2.1 2.1 — 1.0 2.6 0.5 — 30.9

8.7 5.6 2.1 2.1 1.5 2.6 1.5 2.6 — 0.5 40.5

100 mg mibefradil is maintained consistently over the 24-h period. Trough:peak ratios indicate that after 4 weeks of therapy most of the antihypertensive effect observed at peak was still present at trough. Decreases in blood pressure were sustained throughout the 24-h period; there were no blood-pressure fluctuations that could be associated with adverse clinical events. In all studies, mibefradil was associated with a slight, dosedependent decrease in heart rate. This is a desirable effect, since several epidemiological studies have found that lower heart rates are associated with decreased cardiovascular morbidity and mortality, especially in patients with ischemic heart disease.28 –30 The incidence of treatment-related AE among patients receiving 50 or 100 mg mibefradil was only slightly different from that among patients who received placebo. A slightly greater incidence of headache, leg edema, and lightheadedness was noted in the 100 mg dose group than in the 50 mg dose group. In comparison studies with other CA, mibefradil had greater overall efficacy than did diltiazem CD and nifedipine SR. Moreover, mibefradil was at least as effective as amlodipine and nifedipine GITS in lowering blood pressure and was as well or better tolerated than the other CA. The results of all the trials indicate that mibefradil, at the recommended doses of 50 to 100 mg/day, is an effective, safe, and well-tolerated once-daily treatment for mild-to-moderate essential hypertension.

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