Adding the new calcium antagonist mibefradil to patients receiving long-term β-blocker therapy results in improved antianginal and antiischemic efficacy

Adding the new calcium antagonist mibefradil to patients receiving long-term β-blocker therapy results in improved antianginal and antiischemic efficacy Adam Schneeweiss, MD,a Isaac Kobrin, MD,b Vincent Charlon, PhD,b Abraham Caspi, MD,c Alon Marmor, MD,d Samuel Sclarovsky, MD,e Leonardo Reisin, MD,f and Zvi Schlesinger, MDg Tel Aviv, Rehovot, Zfat, Petach Tikva, Ashkelon, and Zeriffin, Israel, and Nutley, N.J.

Objective The objective of this study was to evaluate the efficacy, tolerability, and safety of mibefradil, a new selective T-type calcium channel blocker, in patients with chronic stable angina pectoris receiving concomitant β-blocker therapy.

Design This was a multicenter, double-blind, placebo-controlled study. Methods Ninety-five patients receiving a stable dose of β-blockers, which was not changed for the purpose of the study, were administered either 50 mg mibefradil once daily for 2 weeks, then 100 mg once daily for 2 weeks, or matching placebo. Efficacy was evaluated by treadmill exercise tolerance testing 24 hours after dose and by diary registration of anginal episodes and nitroglycerin consumption.

Results Two weeks of treatment with 50 mg mibefradil resulted in a significant increase in symptom-limited exercise duration and a significant delay in the onset of persistent 1 mm ST-segment depression (placebo-corrected treatment effect: 23.2 and 51.7 seconds, respectively). Treatment with the 100 mg dose for 2 additional weeks resulted in a larger improvement in treadmill exercise tolerance testing duration and onset of ischemia (placebo-corrected treatment effect: 52.7 and 75.8 seconds, respectively). In addition, a significant decrease in weekly anginal episodes was observed with the 100 mg dose of mibefradil compared with the effect in the placebo group (–53% vs –12%, p = 0.037).

Conclusions The combined treatment of mibefradil and β-blockers was well tolerated, and the overall incidence of adverse events was no different from that with β-blockers alone. The results indicate that adding mibefradil to chronic βblocker treatment is associated with significant improvement in efficacy, which is not achieved at the expense of tolerability. (Am Heart J 1998;135:272-80.)

Calcium antagonists (CAs) are often used in combination with β-blockers (BBs) to manage chronic stable angina pectoris when patients remain symptomatic while they are taking a single agent.1 The assumption underlying combination therapy is that BBs and CAs have complementary actions on myocardial oxygen supply and demand and that BBs inhibit the reflex increase in heart rate caused by some CAs. From aCardiovascular Research Foundation, Tel Aviv; bHoffmann-LaRoche, Nutley; cKaplan Hospital, Rehovot; dRivka Ziv Hospital, Zfat; eBeilinson Medical Center, Petach Tikva; fBarzilai Medical Center, Ashkelon; and gAssaf Harofeh Medical Center, Zeriffin. Submitted Feb. 10, 1997; accepted July 24, 1997. Reprint requests: Adam Schneeweiss, MD, Cardiovascular Research Foundation, 9 Kahilat Sofia St., 69018 Tel Aviv, Israel. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/87145

Despite the clear rationale for the combination of BB and CA as antianginal therapy, improvement in efficacy parameters has not been consistently observed in trials assessing the combination, nor has clinical benefit from combination therapy been well defined.1,2 Furthermore it is still not clear whether and to what extent the BB dose should be adjusted before a CA is added. Recently the safety of several CAs (mainly short-acting dihydropyridines) has become an issue of concern, and some investigators postulate that the increased morbidity and mortality observed with these compounds might be mediated by reflex tachycardia, negative inotropic effects, and proischemic and proarrhythmic effects.3-5 In addition, the safety of the other two classes of CAs in the presence of βblockade has the potential for adverse effects on cardiac conduction and left ventricular function.6,7

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Mibefradil (Ro 40-5967) is a novel CA that belongs to a new structural class of benzimidazolyl-substituted tetraline derivatives.8 Mibefradil binds to a unique receptor site.9 Unlike established CAs, mibefradil selectively blocks T-type calcium channels.10 The pharmacokinetic features of mibefradil include a high bioavailability (approximately 90%) and a long plasma half-life (17 to 25 hours),11,12 both of which make it suitable for once-a-day dosing. Clinical studies have shown that mibefradil is effective and well tolerated in the treatment of hypertension13 and angina14,15 when administered once daily at doses of 50 and 100 mg. Mibefradil therapy is associated with a modest decrease in heart rate,13,14 an absence of reflex tachycardia, no increase in neurohormones, and a lack of negative inotropic effects demonstrated in preclinical and clinical studies.16-19 Because of safety concerns and the inconsistent additive therapeutic effect observed when a CA is combined with a BB, this study was designed to evaluate the efficacy, safety, and tolerability of mibefradil in patients with chronic stable angina pectoris receiving concomitant β-blocker therapy.

Methods This multicenter, double-blind, placebo-controlled parallel group study was performed in six centers in Israel. The protocol was approved by the local ethics committees in the participating centers and was conducted in accordance with the Helsinki Declaration as amended in Tokyo, Venice, and Hong Kong.

Patients Male and female patients 18 to 70 years old were eligible for inclusion if they fulfilled the following criteria: (1) classical exercise-induced chronic stable angina pectoris for 2 months or more, (2) stable dose and regimen of BB therapy for a minimum of 2 weeks before entry, and (3) heart rate ≥55 beats/min. Exclusion criteria were heart failure, cardiomyopathy, clinically relevant arrhythmias, uncontrolled hypertension, and any relevant clinical or laboratory abnormalities. All patients provided written informed consent.

Study protocol After a 2-week washout and stabilization period during which previous antianginal medications (with the exception of BBs and tablet/spray nitroglycerin) were gradually stopped, a qualifying exercise tolerance test (ETT) was performed. At that time a single-blind placebo run-in period of 1 week was started, at the end of which a second qualifying ETT was performed. To be eligible for randomization, patients were required to have two out of three baseline ETTs meet the following criteria. (1) The duration of the first

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Table I. Demographics and baseline characteristics Placebo (n = 47) Age (yr) Sex (M:F) Weight (kg) Previous MI (%) Previous CABG (%) Previous PTCA (%)

64.3 ± 7.6 36:11 77.0 ± 12.2 19 (40.4%) 7 (14.9%) 7 (14.9%)

Mibefradil 50/100 mg/day (n = 48) 63.1 ± 10.1 41:7 78.0 ± 11.7 22 (45.8%) 4 (8.3%) 4 (8.3%)

Values for age and weight are mean ± SD. MI, Myocardial infarction; CABG, coronary artery bypass grafting; PTCA, percutaneous transluminal coronary angioplasty.

ETT had to be 3 to 8 minutes. (2) The duration of the second ETT had to be 2.5 to 9.2 minutes and within ±15% of the previous one. If the second ETT was not within ±15% of the first ETT, a third ETT could be performed within 1 to 3 days. In such a case the duration of the third ETT had to be 2.5 to 9.2 minutes and ±15% of the second ETT. (3) The onset of moderate angina had to be the reason for exercise termination for all baseline ETTs. Qualified patients were randomly assigned to either 50 mg mibefradil for 2 weeks followed by 100 mg for 2 weeks or matching placebo for 4 weeks. Throughout the placebo run-in and double-blind treatment periods, patients continued to receive stable daily BB therapy. ETTs were repeated at the end of 2 and 4 weeks of double-blind treatment or when patients withdrew from the study. All ETTs were performed according to the Bruce protocol 22 to 26 hours after drug administration. Heart rate and blood pressure were measured before the ETT was started, every 3 minutes during the ETT, at the time of appearance of at least 1 mm ST-segment depression, at the onset of angina, at exercise termination, and every 2 minutes for 10 minutes during recovery. During active treatment ETTs could be stopped because of moderate angina or other symptoms (e.g., dyspnea or weakness) or for safety concerns (e.g., arrhythmia or hypotension), whichever came first (defined as symptom-limited ETT). Safety was evaluated by continuous monitoring of adverse events (including intercurrent illnesses) by physical examinations and by electrocardiographic and laboratory assessments.

Statistics The intent-to-treat population was analyzed for all the efficacy parameters. The intent-to-treat population included all randomized patients who received at least one dose of study medication and had at least one baseline ETT and one postrandomization ETT. The primary efficacy parameters were the changes from baseline in symptom-limited ETT duration at week 2 and week 4. Secondary efficacy parameters included the changes

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Table II. Change from baseline in ETT parameters after 2 weeks of treatment

Exercise duration Baseline (BL) (sec) Change from BL (sec) Change (%) Time to onset of angina BL (sec) Change from BL (sec) Change (%) Time to onset of persistent ST-segment depression BL (sec) Change from BL (sec) Change (%)

Placebo (n = 46)

Mibefradil 50 mg (n = 48)

Placebocorrected treatment effect (sec)

350.7 ± 104.0 15.8 ± 60.6 4.5

343.1 ± 90.9 40.2 ± 45.6* 11.7

23.2

272.6 ± 106.6 37.2 ± 83.0 13.6

262.1 ± 95.4 62.9 ± 58.2 24

21.7

287.5 ± 118.1 11.9 ± 92.1 4.1

281.5 ± 113.9 63.4 ± 76.0† 22.5

51.7

Placebo (n = 46)

Mibefradil 100 mg (n = 48)

Placebocorrected treatment effect (sec)

350.7 ± 104.0 –5.1 ± 64.4 –1.5

343.1 ± 90.9 48.1 ± 64.9* 14.0

52.7

272.6 ± 106.6 8.6 ± 95.6 3.2

262.1 ± 95.4 71.6 ± 93.3† 27.3

52.6

287.5 ± 118.1 –11.6 ± 76.0 –4.0

281.5 ± 113.9 68.0 ± 94.6* 24.2

75.8

Values are mean ± SD. *p = 0.043. †p = 0.003.

Table III. Change from baseline in ETT parameters after 4 weeks of treatment

Exercise duration Baseline (BL) (sec) Change from BL (sec) Change (%) Time to onset of angina BL (sec) Change from BL (sec) Change (%) Time to onset of persistent ST-segment depression BL (sec) Change from BL (sec) Change (%) Values are mean ± SD. *p = ≤ 0.001. †p = 0.009.

from baseline to week 2 and week 4 in (1) time to persistent 1 mm ST-segment depression, (2) time to onset of angina, (3) blood pressure, heart rate, and rate-pressure product (heart rate multiplied by the systolic blood pressure) during ETT, (4) number of weekly anginal attacks, and (5) weekly nitroglycerin use. The therapeutic success rates at week 2 and week 4, defined as an increase in ETT duration of ≥60 seconds or an increase in ETT duration without the development of angina or an increase in ETT duration without the development of ischemia, were also calculated. Baseline was defined as the last ETT before randomization. The evaluation of the changes from baseline in ETT para-

meters at trough was performed with an analysis of covariance (ANCOVA) with a model containing treatment, center, and treatment-by-center as fixed factors and the related baseline ETT parameter as a covariant. To compare the active treatment with placebo, estimated treatment effects were defined as the paired difference between both groups in the center-adjusted mean change from baseline (calculated from the ANCOVA model). For the evaluation of the changes from baseline in anginal diary variables (weekly anginal attacks and nitroglycerine consumption), analysis of variance (ANOVA) was performed. All tests were two-sided and were performed at an α-

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level of 0.05. Data are expressed as the mean ± SD unless otherwise stated.

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Figure 1

Results Patient characteristics A total of 122 patients entered the placebo run-in period, 27 of whom failed to meet the final selection criteria with regard to exercise tolerance test parameters or were unable to proceed for administrative or other reasons. The remaining 95 patients were randomized to receive either placebo (n = 47) or mibefradil (n = 48). One patient from the placebo group was excluded from the ITT analysis because a postrandomization ETT was not performed. Seven patients (three in the placebo group and four in the mibefradil group) withdrew from the study before completion. Two patients in each group were withdrawn for administrative reasons, and one and two patients, respectively, were withdrawn as a result of adverse events. The baseline characteristics of the patient population randomized are summarized in Table I. The two treatment groups were well balanced, and no significant differences were found between the them with regard to age, sex, weight, and history of myocardial infarction, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting.

Exercise performance The addition of once-daily treatment with 50 mg mibefradil to existing BB therapy for 2 weeks resulted in a statistically significant increase from baseline in exercise duration compared with placebo (40.2 vs 15.8 seconds, p = 0.043) (Table II and Fig. 1). Likewise, there was a statistically significant delay in the onset of persistent 1 mm ST-segment depression with mibefradil during ETT compared with placebo (63.4 vs 11.9 seconds, p = 0.003). The change from baseline to time of onset of angina favored the mibefradil group but did not achieve statistical significance (62.9 vs 37.2 seconds, p = 0.162). Two weeks later (week 4), after dose escalation from 50 to 100 mg in the mibefradil group (Table III), the changes from baseline in all three ETT parameters were significantly better for mibefradil compared with placebo in ETT duration (treatment effect in seconds: 48.1 vs –5.1, p < 0.001), time to persistent 1 mm ST-segment depression (68.0 vs –11.6 seconds, p = 0.001), and time to onset of angina (71.6 vs 8.6 seconds, p = 0.009). The improvement in ETT parameters occurred in a greater proportion of mibefradil-treated than placebo-

Overall summary of effects of mibefradil expressed as treatment effect (mibefradil minus placebo) and 95% confidence intervals on exercise tolerance test (ETT) parameters after 2 and 4 weeks.

treated patients. Compared with the placebo group (BB monotherapy), more mibefradil-treated patients were able to increase total exercise duration by at least 60 seconds (35.4% vs 21.7%, NS at week 2, and 41.7% vs 17.4%, p = 0.01 at week 4) or were able to increase ETT duration without stopping as a result of angina (20.8% vs 17.4%, NS at week 2, and 37.3% vs 17.4%, p = 0.08 at week 4). Moreover, a greater proportion of mibefradil–treated patients at week 2 were able to increase exercise duration without having STsegment depression compared with the placebo-treated patients (27% vs 6.5%, p = 0.008). Similarly, at week 4 only 4.3% of the placebo-treated patients were able to increase exercise duration without having ST-segment depression, whereas 43.8% (p < 0.001) of the mibefradil-treated patients could do so.

Hemodynamic effects Treatment with mibefradil was associated with decreases in heart rate and blood pressure at rest and at ETT termination (Table IV), leading to a larger reduction in double product in the mibefradil group compared with the placebo group (BB monotherapy).

Anginal symptoms and nitroglycerin consumption Compared with placebo (BB monotherapy), treatment with the 50 and 100 mg doses of mibefradil was associated with larger reductions in the number of

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Table IV. Changes from baseline in hemodynamic parameters during ETT Week 2 ETT stage variable Rest DBP SBP HR Rate-pressure product* Exercise termination DBP SBP HR Rate-pressure product*

Week 4

Placebo (n = 46)

Mibefradil 50 mg (n = 48)

Placebo (n = 46)

Mibefradil 100 mg (n = 48)

–0.7 ± 7.1 –2.8 ± 12.9 –0.2 ± 8.8 –176 ± 1215

–3.8 ± 5.7 –5.2 ± 13.5 –7.4 ± 9.6 –1325 ± 1734

–1.1 ± 9.0 –3.5 ± 15.9 0.9 ± 7.9 –98 ± 1353

5.0 ± 8.3 –7.5 ± 15.9 –10.1 ± 10.9 –1787 ± 1910

–1.9 ± 8.9 –1.6 ± 14.0 1.5 ± 16.7 –18 ± 3299

–4.5 ± 9.2 –8.5 ± 19.3 –9.1 ± 14.3 –2452 ± 3270

–1.5 ± 10.0 –1.0 ± 19.9 0.5 ± 11.8 –42 ± 2940

–6.6 ± 12.7 –5.8 ± 19.7 –14.7 ± 16.6 –2984 ± 3936

DBP, diastolic blood pressure; SBP, systolic blood pressure; HR, heart rate; BL, baseline. *Heart rate × systolic blood pressure.

weekly anginal attacks and weekly use of nitroglycerin. The differences reached statistical significance (p = 0.037) only for the number of anginal attacks with 100 mg mibefradil (Table V).

Safety results The combination of mibefradil and β-blockers was well tolerated, having a similar overall incidence of patients with at least one treatment-related adverse event compared with the placebo group (10.4% vs 10.6%, respectively). Table VI lists the incidence of treatment-related adverse events for each treatment group. With regard to the incidence of specific adverse events, only small differences were noted between patients treated with mibefradil and those treated with placebo. Three patients were prematurely discontinued from the study because of adverse events: one placebotreated patient because of dizziness, one mibefradiltreated patient because of dizziness and fatigue, and another mibefradil-treated patient because of vomiting and weakness. One patient previously treated with mibefradil died of cardiac arrest 6 days after uneventful completion of the study. The death was considered by the investigators to be unrelated to treatment. Sinus bradycardia (heart rate <55 beats/min and a decrease from baseline of >10 beats/min or a heart rate <45 with a decrease of >0), which was the most frequent treatment-emergent electrocardiographic change in both treatment groups, was reported more frequently in the mibefradil group (45.8%) than in the placebo group (31.9%). In contrast, no increase occurred in the frequency of first-degree atrioventricular block in patients treated with the combination of mibefradil and BBs compared with those treated with BBs alone (8.3%

vs 8.5%, respectively) (Table VII). At the end of 4 weeks of therapy the combination of mibefradil with BBs compared with placebo (BB monotherapy) was associated with a larger mean dose-related decrease in heart rate (–9.5 beats/min vs –2.8 beats/min) and corrected QT (QTc) interval (–11.6 msec vs –9.5 msec) and a slightly larger PQ interval (13.4 msec vs 2.6 msec). No consistent pattern of laboratory changes or individual laboratory abnormalities was observed during the trial.

Discussion The results of the study clearly indicate that adding mibefradil to BB treatment produced a significant doserelated improvement in ETT parameters. Additive antianginal and antiischemic effects were evident both at week 2 (50 mg dose) and week 4 (100 mg dose) as reflected by the placebo-corrected treatment effects in exercise duration (23.2 and 52.7 seconds, respectively), delay in onset of angina (21.7 and 52.6 seconds, respectively), and delay in the onset of ischemia (51.7 and 75.8 seconds, respectively). This improvement was also demonstrated by the larger proportion of mibefradiltreated patients who could increase exercise duration without having angina or ischemia. Treatment with both the 50 and 100 mg doses of mibefradil was associated with larger reductions in weekly anginal attacks and nitroglycerin use when compared with placebo, reaching statistical significance for the decrease in anginal episodes with the 100 mg dose (–53% vs –12%, respectively). The absence of statistical significance in the diary parameters may be explained by the fact that anginal attacks were not a prerequisite for study entry, and as a result 30% of

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Table V. Mean change from baseline in diary parameters after 2 and 4 weeks of treatment After 2 weeks of treatment Placebo (n = 47) Anginal attacks per week BL Change from BL Change (%) NTG consumption per week BL Change from BL Change (%)

Mibefradil 50 mg (n = 46)

4.1 ± 0.7 –0.1 ± 0.6 –2%

4.5 ± 0.8 1.7 ± 0.7 –38%

2.8 ± 0.7 –0.3 ± 0.5 –11%

2.2 ± 0.6 –1.2 ± 0.5 –60% After 4 weeks of treatment

Placebo (n = 47) Anginal attacks per week BL Change from BL Change (%) NTG consumption per week BL Change from BL Change (%)

Mibefradil 100 mg (n = 46)

4.1 ± 0.7 –0.5 ± 0.7 –12%

4.5 ± 0.8 –2.4 ± 0.7 –53%*

2.8 ± 0.7 –0.3 ± 0.6 –11%

2.2 ± 0.5 –1.6 ± 0.5 –73%

Values are mean SEM. BL, Baseline; NTG, nitroglycerin. *p = 0.037.

patients at baseline did not have anginal episodes. Although the study was not powered to evaluate changes from baseline when so many patients were without symptoms, there were nevertheless clear trends favoring mibefradil at 50 and 100 mg in terms of decreasing the number of anginal attacks and nitroglycerine consumption per week. The achievement of symptomatic relief (longer exercise duration and fewer anginal episodes) and delay in the onset of ischemia on top of BB treatment has considerable clinical relevance. Combining mibefradil with a BB allowed improvement in antianginal and antiischemic effect without increasing BB dosage and possibly risking substantial increases in the incidence of adverse events. Thus patients can have an improvement in clinical status with tolerated doses of BBs, which are generally below those needed for full β-blockade. The antianginal and antiischemic effects of mibefradil were associated with a reduced rate-pressure product at both rest and exercise termination. Attenuating increases in systolic blood pressure or heart rate that normally accompany and serve to limit exercise are clinically ben-

eficial and may play a role in the antianginal activity of a CA such as mibefradil, which lowers both arterial blood pressure and heart rate.20 These effects have been demonstrated in previous studies of mibefradil monotherapy in angina pectoris.14 Contrary to the observations of this trial, in which mibefradil provided dose-related additional antianginal and antiischemic efficacy when added to β-blocker treatment, some studies evaluating the combination of BBs and other CAs suggest that the actions of the two classes of drugs do not always result in additive antianginal effects.21-24 Furthermore there are safety concerns about the use of CAs as monotherapy and in combination with BBs in patients with ischemic heart disease. Recent retrospective studies have raised concern about the long-term safety of several CAs. Most of these observations were made with short-acting CAs. However, CAs are a heterogeneous group, and recent data support the safety of verapamil (DAVIT,25 APSIS26) and the newer long-acting dihydropyridines, amlodipine (PRAISE27), felodipine (VHeFt III28), and nisoldipine (DEFIANT II29) in patients with myocardial infarction

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Table VI. Overview of adverse events (as judged by the investigator as remotely, possibly, or probably treatment-related)

Patients with AEs (no. [%]) Dizziness Fatigue Weakness Angina pectoris Constipation Diarrhea Tinnitus Somnolence Vomiting

Placebo (n = 47)

Mibefradil 50/100 mg/day (n = 48)

5 (10.6) 4 (8.5) — 1 (2.1) 1 (2.1) 1 (2.1) — — — —

5 (10.4) 2 (4.2) 2 (4.2) 1 (2.1) — — 1 (2.1) 1 (2.1) 1 (2.1) 1 (2.1)

Table VII. Summary of treatment-emergente.ectrocardiographic changes seen in ≥2% of patients

Sinus bradycardia (no. [%]) First-degree atrioventricular block Ventricular premature contractions Supraventricular premature contractions Total patients with ≥1 electrocardiographic change

Placebo (n = 47)

Mibefradil 50/100 mg/day (n = 48)

15 (32)

22 (46)

4 (9)

4 (8)

3 (6)

2 (4)

2 (4)

1 (2)

19 (40)

26 (54)

AE, Adverse event.

Sinus bradycardia: heart rate <55 with a drop from baseline >10 beats/min or heart rate <45 with drop >0.

and congestive heart failure (CHF). Consistent with these findings are the observations from a meta-analysis of CAs in myocardial infarction, which included a difference in mortality between patients taking CAs that increased the heart rate (dihydropyridines) and those that decreased the heart rate (diltiazem and verapamil), with a relative risk of 1.16 versus 0.95, respectively.30 Mibefrail has a promising profile for patients with CHF because it lacks negative inotropic effects and does not induce reflex tachycardia or neurohormonal activation. Its effects on symptoms and hard end points such as morbidity and mortality are currently under investigation in a large multicenter trial, MACH 1.31 Safety problems associated with the combination of BBs and CAs differ according to the specific agent used. With verapamil and diltiazem, the safety problems might result from the additive negative inotropic, dromotropic, and chronotropic effects.6,7 With dihydropyridines, abolition of reflex tachycardia by a BB may be detrimental because acceleration of heart rate may be necessary to compensate for vasodilation in the presence of impaired left ventricular function.32,33 No downward adjustment of the stable BB dosage was done before mibefradil therapy was initiated, and the combined treatment was very well tolerated. There was no worsening of the safety profile of the combination regimen, because the overall incidence of adverse events and frequency of specific adverse events observed was similar to that in the placebo (BB monotherapy) group. The safety of the combination of mibefradil and a β-blocker demonstrated in this study is noteworthy. Indeed, clinical experience with other CAs suggests caution when combining a CA and a BB because of the possibility of additional adverse events

such as symptomatic bradycardia, hypotension, conduction defects, and high-degree atrioventricular block.34-39 Although combining mibefradil with a BB was associated with a dose-related decrease in heart rate (reaching a mean of –9.5 beats/min at week 4), the incidence of bradycardia was only modestly higher in the mibefradil group than in the placebo (BB monotherapy) group (46% vs 32%), and none of the patients was prematurely discontinued from the study because of bradycardia. Although no safety concern regarding heart rate was identified in the trial, the number of patients was not large, and patients with heart rate <55 beats/min at baseline were excluded. Therefore further studies to evaluate the safety of the combination are required in patients with low baseline heart rates (i.e., <55 beats/min). Both mibefradil and BBs prolong the PQ interval. Despite the negative chronotropic effect of each drug, the combination did not result in an increased incidence of high-degree atrioventricular block as reflected by the absence of second- and third-degree atrioventricular block among patients in the study. Patients with symptomatic CHF were excluded from the trial. Therefore the results should not be extrapolated to patients with angina and CHF. However, there were no cases of unmasking of latent CHF as might occur when diltiazem and verapamil are combined with BBs.38 Although the experience is limited, and cardiac function was not studied in patients treated with the combination of mibefradil and BBs, preclinical and initial clinical findings demonstrated that mibefradil had no clinically relevant negative inotropic effect at therapeutic concentrations and was not associated with reflex increase in neurohormones and sympathetic activity.16-19,40

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These properties are especially important because many patients with ischemic heart disease have or may have left ventricular systolic dysfunction. An antianginal drug that would not further compromise a failing heart would be beneficial in such patients. In conclusion, adding 50 and 100 mg mibefradil to patients with stable angina pectoris receiving chronic BB treatment is associated with significant improvements in antianginal and antiischemic efficacy. The additive effects were not achieved at the expense of safety or tolerability, because the combination of mibefradil and a BB was as well tolerated as BB monotherapy. No preadjustment of BB dose is necessary for the combination, thus simplifying its clinical use. Because the experience with the combination of BBs and mibefradil is not large, further studies are required to establish the safety of the combination.

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