(Circulation. 1997;96:2557-2564.)
© 1997 American Heart Association, Inc.
Articles |
Efficacy of Mibefradil Compared With Amlodipine in Suppressing Exercise-Induced and Daily Silent Ischemia
Results of a Multicenter, Placebo-Controlled Trial
From the Shaare Zedek Medical Center (D.T.), Jerusalem, Israel; Oldchurch Hospital (H.K.), Romford, UK; Academisch Ziekenhuis (S.B.), The Netherlands; Univ. Klinik Rudolf Virchow (W.R.), Berlin, Germany; Instituto de Corado (J.A.R.), Sao Paulo, Brazil; and Hoffmann–La Roche (I.K.), Nutley, NJ.
Correspondence to Dan Tzivoni, MD, Professor of Medicine/Cardiology, Director, Department of Cardiology, Jesselson Heart Center, Shaare Zedek Medical Center, POB 3235, Jerusalem, 91031 Israel.
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Abstract |
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Background Mibefradil is a new benzimidazolyl-substituted tetraline-derivative calcium antagonist. Its vasodilatory activity combined with an ability to lower heart rate without negative inotropic effects as well as its long duration of action make it a promising anti-ischemic agent.
Methods and Results Three hundred nine patients with coronary artery disease, stable angina pectoris, and positive exercise tests were randomized to receive mibefradil (50, 100, or 150 mg), amlodipine (10 mg), or placebo. The anti-ischemic effects of mibefradil on exercise test and silent ischemia parameters were assessed. At doses of 100 and 150 mg, mibefradil increased exercise duration (by 55.5 and 51.0 seconds, respectively; P<.001 for both), increased time to onset of angina (by 98.3 and 82.7 seconds, respectively; P<.001), and increased time to 1-mm ST depression (by 81.7 and 94.3 seconds, respectively; P<.001). By comparison, a 10 mg/d dose of amlodipine significantly improved only time to onset of angina (treatment effect: 38.5 seconds, P=.036). Mibefradil 100 mg and 150 mg decreased the number of episodes of silent ischemia (treatment effects: -3.1 and -3.6, respectively; P<.001) and the duration of silent ischemia (treatment effects: -9.2 minutes, P=.048, and -14.6 minutes, P=.002, respectively). The decrease in the number of episodes of silent ischemia was also statistically significant in the group receiving 10 mg of amlodipine (-1.5; P=.036).
Conclusions Once-daily doses of 100 and 150 mg mibefradil were effective in improving exercise tolerance and reducing ischemic episodes during ambulatory monitoring in patients with coronary artery disease.
Key Words: mibefradil • coronary artery disease • ischemia • amlodipine • exercise • electrocardiography, ambulatory
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Introduction |
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Silent or symptomatic myocardial ischemia1 2 3 is associated with unfavorable cardiovascular outcomes.4 5 6 7 8 Some studies have found that the risk of adverse outcomes can be reduced by treating silent ischemia as well as angina pectoris.9 10 Calcium antagonists (CAs) are effective in reducing the frequency and duration of silent ischemia.11 12 CAs with negative chronotropic effects were shown to be more effective when given as monotherapy than were the dihydropyridines, which often require the addition of a ß-blocker.11
Mibefradil is the first compound in a new class of CAs, the benzimidazolyl-substituted tetraline derivatives.13 Mibefradil binds to a unique receptor site, resulting in competitive interference with the verapamil, diltiazem, and fantofarone sites without interfering with the dihydropyridine site.14 Unlike currently available CAs, which block only the L-type calcium channel, mibefradil selectively blocks the T-type channel.15 Mibefradil is a potent arterial vasodilator that acts on the vascular smooth muscles of peripheral and coronary arteries, and its administration is associated with negative chronotropic effects13 16 17 with no depressant effect on myocardial contractility.13 18 The antihypertensive, antianginal, and anti-ischemic effectiveness of mibefradil was confirmed by clinical studies in patients with hypertension,19 angina pectoris,20 ischemic heart disease,21 and impaired left ventricular function (ejection fraction <40%).22
In human pharmacokinetic studies, mibefradil was shown to have a high
bioavailability (
90%)16 and a long plasma half-life
(17 to 25 hours),23 making it suitable for once-daily
dosing. Steady-state plasma levels are reached after 3 to 4
days,16 and the compound is eliminated mainly by the
biliary system.
The purpose of the present trial was to assess the effects of mibefradil on exercise-induced and silent daily ischemia in patients with stable exertional angina pectoris, as well as to determine the therapeutic doses of this agent. Another objective of the study was to compare its efficacy with that of amlodipine.
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Methods |
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This was a prospective, randomized, double-blind, placebo-controlled, parallel-design trial involving 23 centers in seven countries. The principal investigators and sites are described in the "Appendix." The protocol was approved by each institution's ethics committee.
Patients
This study included male and female outpatients older than
20 years of age with chronic, stable, exercise-induced angina pectoris
and proven coronary artery disease documented either by the
presence of significant coronary occlusion on angiography,
previous myocardial infarction, or the presence of typical angina with
evidence of ischemia during stress tests.
Patients were excluded if they had any of the following: (1) myocardial infarction or cardiac surgery within 3 months or coronary angioplasty within 6 months of the screening visit; (2) clinical signs of congestive heart failure (New York Heart Association class II, III, or IV); (3) sinus bradycardia <55 bpm, AV block, or any clinically significant arrhythmia; (4) blood pressure >180/105 or <100/60 mm Hg; (5) major systemic disease; or (6) childbearing potential.
Study Protocol
All patients entered a 1- to 2-week washout period, during
which all antianginal treatments were gradually discontinued (except
immediate-release nitroglycerin). Thereafter, all
patients entered a 1-week placebo run-in period during which they
underwent two to three exercise tolerance tests (ETTs) and 48-hour
ambulatory ECG monitoring (AEM). To be eligible for randomization,
patients were required to have at least two positive exercise tests
(Bruce protocol) with exercise duration within ±15% of the previous
one. The reason for stopping the ETT had to be the onset of moderate
angina.
At the end of the placebo period, patients were randomized to one of five treatment groups (placebo; 25, 50, or 100 mg of mibefradil; or amlodipine 5 mg). After 1 week, mibefradil doses were increased to 50, 100, or 150 mg, and the amlodipine dose was increased to 10 mg. At the end of the 2-week high-dose treatment period, all patients had a repeat ETT and 48-hour AEM. All ETTs were performed 22 to 24 hours after drug administration. All patients provided weekly diaries documenting the number of anginal attacks, sublingual nitroglycerin consumption, and daily activities.
Ambulatory ECG Monitoring
AEM was performed with the use of Marquette AM three-channel
recorders. The electrodes were placed in V3-,
V5-, and aVF-like positions. All cassettes were
analyzed with the use of Marquette software at the core
laboratory of CardioClin at Shaare Zedek Medical Center, Jerusalem. An
ischemic episode was defined as a period of ST-segment
depression (horizontal or downsloping) of 
1 mm lasting 1
minute and returning to baseline. Two episodes had to be separated by
an interval of 2 minutes.
Statistical Analysis
The main analysis of the study parameters
was performed on the intent-to-treat population. This population
included all randomized patients who received at least one dose
of study medication and who had at least one baseline and one
postrandomization ETT.
The primary efficacy parameter of the study was the change from baseline in total ETT duration at week 3. Secondary efficacy parameters included the changes from baseline to week 3 in (1) time to 1-mm ST-segment depression, (2) time to onset of angina, (3) number of episodes of silent ischemia per 48 hours, (4) duration of silent ischemic episodes, and (5) weekly anginal episodes and nitroglycerin consumption.
We evaluated the dose relationship by use of a trend test and by
applying the appropriate linear hypotheses in the ANCOVA. Baseline ETT
duration was used as a covariate, and treatment, center, and
treatment-by-center interactions were used as model effects. Paired
comparisons of each dose group with placebo were performed using the
appropriate contrast in the linear model, and a closed-test procedure
was followed to adjust the probability values for multiple comparisons
between treatment groups. Because no differences in statistical
significance after adjustment were observed, only the unadjusted
probability values are presented in the present report. All
statistical tests were two-sided and were performed using an 
level
of .05.
The diary parameters (change from baseline in anginal attacks per week and weekly nitroglycerin consumption) and the AEM parameters (change from baseline in number and total duration of silent ischemic episodes) were evaluated by use of nonparametric methods because of the underlying nonnormal distributions. These included the Jonckheere-Terpstra test for assessing dose-response relationships, the Mann-Whitney-Wilcoxon rank test for comparing the mibefradil groups with either placebo or active control, and the Hodges-Lehmann (adapted to ties) estimates.
The correlation between changes in exercise and AEM ischemic parameters was initially performed by use of a linear model with the different treatment arms as covariates. Because this method yielded poor correlation, a nonlinear approach that measured the probabilistic predictive power between two variables was used, modeled on similar investigations.24 In this approach, the number of patients who exhibited improvement in exercise and in AEM ischemic parameters (mutual improvement) was compared with the number of patients who did not show improvement in both variables. The ratio of such frequencies is called ODDS, and it can be put to a significance test. Two exercise test parameters were chosen as variables: time to 1-mm ST-segment depression and exercise test duration. Of the AEM parameters, two variables were chosen: number of silent ischemic episodes and duration of such episodes. For each variable, the frequency of subjects exhibiting a positive change or a nonpositive (<0) change was recorded. A 2x2 frequency table was used for each exercise and AEM variable to calculate the odds of favorable response to unfavorable response.
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Results |
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Patient Characteristics
A total of 453 patients entered the run-in period. Of these, 144 patients failed to meet the inclusion criteria or were unable to proceed for administrative or other reasons. As a result, a total of 309 patients entered the randomization period. Of the 309 randomized patients, 62 received placebo, 64 received amlodipine, and 183 received mibefradil in one of the three doses. Six patients were excluded from the intent-to-treat analysis of efficacy (1 from the 50-mg mibefradil group and 5 from the amlodipine group) because they did not have an ETT performed after randomization. The baseline characteristics of the patient population are summarized in Table 1
. The groups were well matched in regard
to age, sex, weight, and previous history of myocardial infarction,
coronary angioplasty, or coronary bypass surgery. The
groups were also well matched with regard to baseline ETT
parameters (Table 2).
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Exercise Test Parameters
The effects of each treatment on ETT parameters
are summarized in Table 2
. Compared with placebo, 3 weeks of treatment
with mibefradil was associated with statistically significant increases
in total ETT duration at doses of 100 mg (P<.001) and 150
mg (P<.001) but not at the 50-mg dose. Compared with
baseline values, the increases in ETT duration were 22%, 32%, and
29% for the 50-, 100-, and 150-mg doses, respectively. In the group
receiving 10 mg of amlodipine, ETT duration was increased by 19% from
baseline (P>.05).
Compared with placebo, increases in time to onset of angina were statistically significant for the 100- (P<.001) and 150-mg (P<.001) doses of mibefradil but not for the 50-mg dose. Compared with baseline values, the percent increases in time to onset of angina were 24%, 51%, and 45% for the 50-, 100-, and 150-mg doses of mibefradil, respectively. The 28% increase in time to onset of angina for the 10-mg dose of amlodipine was also statistically significant (P=.036) compared with placebo.
The increases in time to onset of ischemia of 32%, 45%, and 47% were statistically significant (P<.001) for all three mibefradil dose groups. In the group receiving 10 mg of amlodipine, time to onset of ischemia improved by 20% from baseline (P>.05). The increases in exercise duration, time to onset of angina, and time to onset of ischemia after 3 weeks of treatment produced a highly significant (P<.001) linear dose trend across all of the mibefradil treatment groups in each ETT parameter.
When the mibefradil groups were compared with the amlodipine
group, a significantly (P<.020 for each ETT
parameter) greater improvement was observed with the 100-
and 150-mg dose groups for each of the three ETT parameters
(Figure).
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Hemodynamic Effects
Table 3 summarizes the changes
in blood pressure, heart rate, and double product at rest and at
termination of exercise after 3 weeks of treatment. Compared with
placebo, there was an insignificant drop in systolic blood
pressure for all treatment groups. The mibefradil groups demonstrated
dose-dependent and statistically significant reductions in
diastolic blood pressure (up to -7 mm Hg at rest and
-10 mm Hg at exercise termination). Amlodipine therapy was
associated with a statistically significant (P<.006) drop
in diastolic blood pressure at rest but not at exercise
termination. The main difference between the treatment groups was the
change in heart rate, which decreased in a dose-dependent and
statistically significant manner in the mibefradil groups (by 5.7 to
13.2 bpm) and increased slightly in the amlodipine group at rest and at
exercise termination.
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Silent Ischemia
Silent ischemia was observed in 171 patients on AEM
at baseline. The effects of each treatment on the number and duration
of silent ischemic episodes in these patients are summarized in
Table 4. Compared with placebo after 3
weeks, treatment with mibefradil resulted in a statistically
significant reduction of the number of ischemic episodes at
doses of 100 and 150 mg (P<.001 for both doses) but not at
the 50-mg dose. Compared with baseline values, the decreases in the
number of ischemic episodes were 50%, 88%, and 88% for the
50-, 100-, and 150-mg doses of mibefradil, respectively. In the 10-mg
amlodipine group, the number of ischemic episodes decreased by
38% from baseline.
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The decreases in the duration of silent ischemic episodes were statistically significant for the 100- (P<.048) and 150-mg (P <.002) doses of mibefradil but not for the 50-mg dose. The decrease in duration of ischemic episodes was 42%, 69%, and 90% for the 50-, 100-, and 150-mg doses of mibefradil, respectively. The 39% decrease from baseline in duration of silent ischemic episodes for the 10-mg amlodipine dose was not significantly different from placebo. The number and duration of silent ischemic episodes decreased significantly in a dose-dependent manner across the mibefradil treatment groups (P<.001).
A larger reduction in silent ischemia episodes and in the duration of silent ischemia was observed for both the 100- and 150-mg doses of mibefradil compared with the 10-mg dose of amlodipine. However, the difference reached statistical significance (P<.030) only for the number of episodes.
Correlation Between Changes in Exercise and AEM Ischemic
Variables
The linear correlations between exercise duration and number
of silent ischemic episodes and time to 1-mm ST depression and
number of silent ischemic episodes are shown in Table 5. These predictive linear correlations
were very poor and did not achieve statistical significance. The
probabilistic approach is represented in Table 6. According to the latter
analysis, the improvement in exercise ischemic
parameters was associated with a high probability of
improvement in AEM ischemic parameters. For
example, in the group of patients treated with mibefradil 100 mg once a
day, it was 5.8 times more probable than improbable that patients with
improvement in exercise time would exhibit a reduction in the duration
of silent ischemia episodes. This association gained higher
probability as the dosage of mibefradil increased.
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Anginal Symptoms and Nitroglycerin Consumption
A decrease in the number of anginal episodes and weekly
nitroglycerin consumption was observed in all of the
mibefradil treatment groups. The difference in the
nitroglycerin consumption of patients who received 100
or 150 mg/d mibefradil reached statistical significance (Table 7). However, the decrease in the number
of anginal episodes in these groups did not reach statistical
significance. No change in the frequency of anginal episodes and
nitroglycerin consumption was observed in the
amlodipine-treated patients.
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Tolerability and Safety
The most frequently occurring side effects reported in the
present study (including those judged by the investigator to be
unrelated to treatment) are summarized in Table 8. Whereas pedal edema (12.5%) was the
most frequent side effect reported in the amlodipine group, dizziness
(11.3%) was the most frequent side effect in the group receiving 150
mg of mibefradil. Only small differences were observed among the
various treatment groups with regard to the other side effects.
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First-degree AV block was noted in one, four, and six cases in the groups receiving 50, 100, and 150 mg of mibefradil, respectively, and in none of the patients in the placebo or amlodipine groups. Similarly, no placebo- or amlodipine-treated patients developed asymptomatic bradycardia, but two and eight cases were seen in the groups receiving 100 and 150 mg of mibefradil, respectively. Premature withdrawals owing to adverse events occurred in three (4.8%), six (3.2%), and four (6.2%) patients treated with placebo, mibefradil, and amlodipine, respectively. Wenckebach second-degree AV block was observed on AEM in two patients treated with 50 and 100 mg of mibefradil, and one case of third-degree AV block was observed on AEM in a patient treated with the 150-mg dose of mibefradil.
The PQ interval increased slightly in the mibefradil-treated patients, reaching a maximum of 11.5±21.2 ms in the 100-mg dose group; heart rate decreased in a dose-dependent manner by as much as 13.2 bpm in the 150-mg group; and corrected QT interval decreased slightly in all treatment groups, reaching a maximum of -7.2 ms in the group receiving 50 mg of mibefradil. There was no change in the frequency of atrial and ventricular arrhythmias in any treatment group. No consistent pattern of laboratory changes or individual abnormalities was observed during the trial.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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In the present study, once-daily 100- and 150-mg doses of mibefradil were found to be effective in improving exercise-induced ischemia and in suppressing silent ischemic episodes. The 50-mg dose of mibefradil showed only borderline effectiveness. The efficacy of the 100- and 150-mg doses was similar in improving ETT parameters; the 150-mg dose was slightly better than the 100-mg dose in suppressing silent ischemia, but there were fewer side effects observed with the 100-mg dose than with the 150-mg dose. Thus, the once-daily 100-mg dose may be regarded as the best tolerated and most effective dose of mibefradil. This observation is in agreement with the findings of previous dose-ranging studies in patients with stable angina pectoris20 and in patients with silent ischemia.21
Amlodipine, a dihydropyridine CA, was chosen for comparison with mibefradil because it is considered effective and safe and is widely used as an anti-anginal and antihypertensive drug.25 The study demonstrated that both the improvement in all three ETT parameters and the reduction in the number of silent ischemic episodes were significantly greater with once-daily 100- and 150-mg doses of mibefradil than with the daily 10-mg dose of amlodipine. The superior ability of mibefradil to improve all ETT parameters could be explained by the heart rate–lowering effect of mibefradil and the consequent decrease in double product. This effect, combined with its potent coronary vasodilatory properties, makes mibefradil an effective anti-ischemic drug.
Several recent clinical trials evaluated the anti-ischemic effects of various CAs either alone or in combination with ß-blockers.26 27 28 29 30 31 32 33 The studies demonstrated that ß-blockers reduced the extent of ischemia during AEM.27 31 32 33 Results for the dihydropyridine CAs were less consistent.26 27 28 29 30 In the present study, mibefradil 100 mg/d as monotherapy decreased the number and duration of silent ischemia episodes by 88% and 69%, respectively. These results are better than any previously reported for CAs and are comparable to the best reported results for ß-blockers.
The poor linear correlation between improvement in exercise ischemic parameters and ambulatory ischemia has already been reported by several investigators.34 35 36 Stone et al37 studied 910 patients in the ACIP trial and found a weak yet significant correlation between time to 1-mm ST depression and number of silent ischemic episodes during 48 hours (r=.37, P<.001) and between heart rate at onset of ischemia during exercise and number of silent ischemic episodes (r=.29, P<.001). In their opinion, these observations suggest that the mechanisms responsible for ischemia identified by exercise test parameters and silent ischemia parameters may be different. Methodologically, the linear correlations between variables that measure ischemic changes from baseline may be inadequate. Although subjects exposed to an underlying drug may exhibit a statistically significant improvement with regard to a particular end point, the extent of the response may vary considerably among and within such subjects in a nonlinear manner. We therefore took the probability predictive approach, which defines improvement or no improvement. According to this approach, a high predictive power was found in the mibefradil group (dose dependent) between improvement in exercise and AEM ischemic parameters. These results indicate that the likelihood of a patient showing improvement by one test is very high if improvement was demonstrated in the other test. The assessment of the clinical benefits of anti-ischemic therapy is therefore greatly enhanced by adding the probabilistic prediction approach to the linear correlation approach. The latter approach alone fails to predict the extent of mutual improvement in the underlying ischemia variables.
The increased efficacy achieved by mibefradil compared with amlodipine did not compromise safety or tolerability. In fact, a higher incidence of pedal edema (12.5%) was reported in the amlodipine group, whereas no pedal edema was reported in the group receiving mibefradil 100 mg/d.
Conclusions
This large, multicenter study demonstrated that mibefradil
at doses of 100 and 150 mg once daily was highly effective in improving
ischemic parameters on exercise and reducing the
extent of silent ischemic episodes. The excellent efficacy and
safety of mibefradil in a once-a-day regimen and the absence of reflex
tachycardia and pedal edema make it a promising new
compound for the treatment of patients with angina and silent
ischemia.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Ole Amtorp, MD; Shimon Braun, MD; Abraham Caspi, MD; Kevin Channer, MD; Anthony Gershlick, MD; Antonio de Padua Mansur, MD; Alon Marmor, MD; Jean McEwan, MD; Tiziano Moccetti, MD; José Carlos Monteiro de Melo, MD; Jobst Nitsch, MD; Edward Perrins, MD; Leonardo H. Reisin, MD; Paul Rylance, MD; Adrianus Schelling, MD; Zvi Schlesinger, MD; Aristarco Siqueira, MD; Ernst E. van der Wall, MD; Andrew Watt, MD.
F. Hoffmann–LaRoche Ltd: Gabriele Bieksha; Norbert Neumann, PhD; Maurizio Rainisio.
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Acknowledgments |
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This study was supported by a grant from F. Hoffmann–La Roche Ltd, Basel, Switzerland. Special thanks to Zvi Gilula, PhD, Department of Statistics, Hebrew University Jerusalem, Israel.
Received February 24, 1997; revision received May 5, 1997; accepted May 15, 1997.
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