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Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Pretreated With a Beta Blocker for Chronic Stable Angina Pectoris
Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Pretreated With a Beta Blocker for Chronic Stable Angina Pectoris Joseph S. Alpert, MD, Isaac Kobrin, MD, Vincent DeQuattro, MD, Richard Friedman, Alexander Shepherd, MD, PhD, Paul E. Fenster, MD, and Udho Thadani, MD
MD,
This study assessed the safety, tolerability, and efficacy of mibefradil when added to b-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive doubleblind treatment with either placebo (n Å 70), mibefradil 25 mg (n Å 67), or mibefradil 50 mg (n Å 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 { 51 seconds; p Å 0.036), time to onset of angina (48 { 65 seconds; p Å 0.002), and time to persistent 1mm ST-segment depression (47 { 77 seconds; p Å 0.004). Greater reductions in heart rate, blood pressure,
and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (02.1 { 4.0, p Å 0.020) compared with placebo. The addition of mibefradil to existing b-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable b-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated. Q1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:1025–1030)
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dose.6 For reasons of safety, and because it was thought that a lower dose of mibefradil might be effective when combined with a b blocker, this study used lower doses of mibefradil (25 and 50 mg). Also, the study was designed to characterize the concentration-effect relation between mibefradil plasma concentration and certain study parameters.
ibefradil (Ro 40-5967) is a novel calcium antagonist that belongs to a new structural class of benzimidazolyl-substituted tetraline derivatives.1 Mibefradil binds to a unique receptor site,2 and is the first calcium antagonist with the ability to selectively block T-type calcium channels. The pharmacokinetic features of mibefradil include a high bioavailability (approximately 90%) and long plasma half-life (17 to 25 hours),3,4 making it suitable for once-a-day dosing. Clinical studies have demonstrated that mibefradil is an effective antihypertensive,5 antianginal,6 and anti-ischemic7,8 agent, and its clinical effects have been shown to be associated with a slight decrease in heart rate.5–7 Moreover, both preclinical8–10 and clinical11,12 studies have shown that mibefradil lacks negative inotropic effects at doses in the therapeutic range. The objective of this study was to evaluate the efficacy and safety of mibefradil at once-daily doses of 25 and 50 mg compared with placebo in patients with chronic stable angina pectoris receiving concomitant b-blocker therapy. The results of a previous monotherapy dose-ranging trial in patients with stable angina pectoris indicated that 50 mg/day was the lowest effective dose and 100 mg/day was the highest effective and well-tolerated From the Department of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona. This study was supported by a grant from F. Hoffmann-La Roche Ltd, Nutley, New Jersey. Manuscript received September 27, 1996; revised manuscript received and accepted December 17, 1996. Address for reprints: Joseph S. Alpert, MD, Department of Medicine, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724-5035.
METHODS This multicenter, double-blind, placebo-controlled, parallel-group study was performed in 26 centers in the U.S. The protocol was approved by the local ethics committees at participating centers and conducted in accordance with the Helsinki Declaration, as amended in Tokyo, Venice, and Hong Kong. Patients: Male and female patients aged 18 to 70 years were eligible for inclusion in the study if they fulfilled the following criteria: (1) classic stress- or exercise-induced chronic stable angina pectoris for ¢2 months; (2) stable dose and regimen of b-blocker therapy for a minimum of 2 weeks before entry; and (3) resting heart rate ¢55 beats/min. Exclusion criteria were heart failure, cardiomyopathy, clinically relevant arrhythmias, uncontrolled hypertension, and any relevant clinical or laboratory abnormalities. Study protocol: Patients meeting the inclusion and exclusion criteria entered a 2-week washout and stabilization period, during which previous antianginal medications (with the exception of b blockers and tablet/spray nitroglycerin) were gradually stopped. A placebo run-in period of 1 week followed the washout period. To be eligible for randomization, patients were required to have 2 of 3 baseline exercise tol-
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Patients were asked to complete a diary throughout the trial to assess the total weekly nitroglycerin consumption and number of weekly anginal episodes. Safety was evaluated by continuous monitoring of adverse events (including intercurrent illnesses) by physical examination, and electrocardiographic and laboratory assessments. The study design and schedule of visits is depicted in Figure 1. Predose blood samples were also collected at the final visit, provided an ETT had been performed, for determination of plasma concentrations of mibefradil. Statistical analysis: The analysis of the intent-to-treat population was regarded as the main analysis of the study. The intentto-treat population included all randomized patients who received at least 1 dose of study medication, and had at least 1 baseline ETT and 1 postrandomization ETT. The primary efficacy variable was the change from baseline in symptom-limited ETT duration at week 2. Secondary efficacy variables included the changes from baseline to week 2 in: (1) time to persisFIGURE 1. Study design: BB Å b blocker; ETT Å exercise tolerance test; Mib Å tent 1-mm ST depression; (2) time to onmibefradil. set of angina; (3) blood pressure, heart rate, and heart rate–blood pressure proderance tests (ETTs) meet the following specific cri- uct during ETT; (4) number of weekly anginal atteria: (1) The duration of the first ETT had to be 3 tacks; and (5) weekly nitroglycerin consumption. to 8 minutes. (2) The duration of the second ETT The therapeutic response rate at week 2, defined as had to be 2.5 to 9.2 minutes and within { 15% of an increase in ETT duration of ¢60 seconds or an the previous one. If the second ETT was not within increase in ETT time without developing anginal { 15% of the first ETT, a third ETT could be per- symptoms, was also calculated. Baseline ETT was formed within 1 to 3 days. In such a case, the du- defined as the last ETT before randomization. Evaluation of the changes from baseline in preration of the third ETT had to be 2.5 to 9.2 minutes and { 15% of the second ETT. (3) The reason for dose ETT parameters was performed by analysis of stopping exercising of all baseline ETTs had to be covariance using a model containing treatment, centhe onset of moderate angina. Qualified patients were ter, and treatment-by-center as fixed factors, and randomized to receive once-daily treatment with 25 baseline ETT duration as a covariant. To compare mg of mibefradil, 50 mg of mibefradil, or matching the active treatments with placebo, estimated treatplacebo for 2 weeks. Throughout the placebo run-in ment effects were defined as the paired difference and double-blind treatment periods, patients contin- between both groups in the center-adjusted mean ued to receive daily stable b-blocker therapy. An change from baseline (calculated from the analysis ETT was performed at the end of the 2-week double- of covariance model). Because of the abnormal disblind treatment period or when patients withdrew tribution of the data, anginal diary variables were from the study. All ETTs were performed according analyzed using nonparametric methods (Mannto the Bruce protocol 22 to 24 hours after drug ad- Whitney U test with Hodges-Lehmann estimate). With use of a high-performance liquid chromaministration. Heart rate and blood pressure were measured before starting the ETT, every 3 minutes tography technique, plasma samples obtained before during the ETT, at the time of appearance of at least dosing at the final visit were analyzed for concentra1-mm ST-segment depression, at onset of angina, at tions of mibefradil. The relationships between miexercise termination, and every 2 minutes for 10 befradil-plasma concentration and the changes in (1) minutes during recovery. During treatment, ETTs time to onset of angina during ETT, (2) time to onset could be stopped because of moderate angina or of persistent 1-mm ST-segment depression during other symptoms (e.g., dyspnea or weakness) or for ETT, (3) total exercise time, (4) heart rate, and (5) safety concerns (e.g., arrhythmia or hypotension), PR interval were evaluated using the nonlinear whichever came first (defined as symptom-limited mixed-effect model. Noneffect, linear, and EMAX ETT). were the models tested. 1026
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or were unable to proceed for administrative or other reasons. The Placebo Mibefradil 25 mg Mibefradil 50 mg remaining 205 patients with reproVariable (n Å 70) (n Å 67) (n Å 68) ducible exercise-induced moderate angina were randomized to receive Men:women 52:18 55:12 51:17 Age (yr) 62.1 { 9.8 62.6 { 8.9 64.5 { 8.0 either placebo (n Å 70), mibefradil Weight (kg) 84.4 { 15.1 85.9 { 14.5 84.3 { 15.8 25 mg (n Å 67), or mibefradil 50 White:black:other 55:6:9 53:7:7 55:9:4 mg (n Å 68). The 3 groups were Myocardial infarction 25 (36) 27 (40) 20 (29) well matched in terms of demoCoronary angioplasty 19 (27) 18 (27) 12 (18) graphic and baseline characteristics Coronary bypass 13 (19) 12 (18) 16 (24) (Tables I and II). Three patients in *Does not include data from 2 patients excluded from intention-to-treat efficacy analyses. the mibefradil group withdrew preValues for age, weight and exercise tolerance test duration are mean { SD. maturely from the study: 1 for an adverse event (25 mg), 1 because of asymptomatic bradycardia (50 mg), TABLE II Change from Baseline in Exercise Tolerance Test Variables After Two and 1 for administrative reasons Weeks of Treatment (50 mg). Placebo Mibefradil 25 mg Mibefradil 50 mg Exercise performance: Four paVariable (n Å 70) (n Å 65) (n Å 66) tients (2 each in the 25- and 50-mg Exercise duration mibefradil groups), including 3 who Baseline (sec) 351 { 99 355 { 87 356 { 87 failed to complete the study, were Change from baseline 16 { 58 30 { 51 36 { 51* not included in the intent-to-treat ef(sec) ficacy analyses because of missing Change 4.5% 8.6% 10.2% Onset of angina postrandomization ETT measureBaseline (sec) 263 { 99 270 { 96 281 { 98 ments. † Change from baseline 16 { 83 40 { 83 48 { 65 The effects of each treatment on (sec) ETT variables are summarized in Change 6.1% 14.8% 17.2% Time to persistent ST-segment Table II. Compared with placebo, depression the addition of once-daily treatment Baseline (sec) 289 { 110 276 { 100 284 { 106 with mibefradil 50 mg to existing bChange from baseline 19 { 69 38 { 68 47 { 77‡ blocker therapy for 2 weeks resulted (sec) in statistically significant increases Change 6.6% 13.8% 16.7% in exercise duration (p Å 0.036), *p Å 0.036; p Å 0.002; p Å 0.004, all versus placebo as treatment effect (mibefradil-placebo). time to onset of angina (p Å 0.002), Values are expressed as mean { SD. and time to persistent 1-mm STsegment depression (p Å 0.004). Whereas treatment with mibefradil TABLE III Changes from Baseline at Week Two in Hemodynamic Variables During 25 mg was also associated with Exercise Tolerance Test at Rest and Upon Termination of Exercise improvements in all 3 ETT paramVariable Placebo Mibefradil 25 mg Mibefradil 50 mg eters, the values compared with plaRest cebo were not statistically signifiDiastolic blood pressure (mm Hg) 00.4 { 10.1* 01.6 { 8.8† 04.2 { 8.9† cantly better. More patients in the Systolic blood pressure (mm Hg) 02.1 { 17.2* 01.5 { 15.3† 09.6 { 16.9† mibefradil dose groups were able to ‡ † § Heart rate (beats/min) 02.0 { 8.8 03.8 { 10.9 06.0 { 10.3 increase their exercise tolerance Double product (mm Hg 0435 { 1,984‡ 0619 { 1,919† 01,450 { 1,883† time without developing angina 1 beats/min) Termination of exercise than those in the placebo group. Diastolic blood pressure (mm Hg) 00.5 { 10.8x 01.2 { 9.5§ 03.0 { 11.2‡ Hemodynamic effects: Treatment x § ‡ Systolic blood pressure (mm Hg) 01.7 { 20.8 04.4 { 21.7 07.2 { 21.2 with mibefradil was associated with Heart rate (beats/min) 00.9 { 11.8x 05.8 { 13.4§ 09.5 { 15.9‡ a dose-dependent decrease in heart Double product (mm Hg 0417 { 3,433x 01,439 { 3,848§ 02,297 { 4,276‡ 1 beats/min) rate and blood pressure at rest and at termination of ETT at week 2 *n Å 68; n Å 64; n Å 66; n Å 65; n Å 69. (Table III), leading to a larger reValues are expressed as mean { SD. duction in double product in both mibefradil groups than in the plaAll tests were 2-sided and performed using an cebo group. Similar results were apparent for hemoalpha level of 0.05. Data are expressed as the mean dynamic measurements obtained at the onset of angina and onset of ischemia. { SD unless otherwise stated. TABLE I Demographic and Baseline Characteristics
†
†
‡
‡
§
x
Anginal symptoms and nitroglycerin consumption:
RESULTS Patients: A total of 230 patients entered the placebo run-in period. Of these, 25 failed to meet the final selection criteria with respect to ETT variables,
The changes from baseline in diary parameters are summarized in Table IV. The number of anginal episodes per week was reduced in a dose-dependent manner; the decrease in the number of anginal epi-
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from the 25- to the 50-mg dose group was higher than a dose-proMibefradil 50 mg portional increase. A linear corre(n Å 67) lation was observed for mibefradil plasma concentration and the 3.3 { 5.8 change from baseline in time to on02.1 { 4.0* set of ischemia. 064% Tolerability and safety: All 205 patients randomized to receive pla1.6 { 3.4 cebo or mibefradil treatment were 00.9 { 2.9 056% included in the safety analyses. The combination of mibefradil and b blockers was well tolerated. The incidence of adverse events, including those assessed by the investigators as unrelated to treatment, was slightly higher in the mibefradil groups compared with the placebo group. Table V lists the incidence of treatment-related adverse events in each treatment group for those events reported by ¢2 patients in any group. Dizziness and lightheadedness were the only treatment-related adverse events not reported in the placebo group that were reported by ¢2 mibefradil-treated patients. The other 2 common treatment-related adverse events— hypotension and headache—were reported with a higher frequency in the placebo group than in the mibefradil treatment groups. Approximately two thirds of all treatment-related adverse events were judged to be mild in severity by the investigators, and only 1 adverse event was considered serious. An escape junctional rhythm at a rate of 52 beat/min was noted on an electrocardiogram recorded 2 hours after the last visit (26 hours after the final dose of mibefradil 50 mg) in a 71-year-old man; the nodal rhythm resolved upon cessation of all medication. One patient, a 65-year-old woman, died of an acute myocardial infarction that developed subsequent to coronary angioplasty performed 7 days after study completion; the death was considered unrelated to study treatment (mibefradil 50 mg). One patient was withdrawn from the study because of postural hypotension accompanied by dizziness, chest pain, and dyspnea that developed after the first dose of 25 mg. A second patient was prematurely withdrawn after 7 days of treatment with mibefradil 50 mg because of symptomatic bradycardia (36 beats/ min) noted on electrocardiogram. Mibefradil treatment was associated with a mean dose-related decrease in heart rate (Table III) and a slight, dose-related increase in the PR interval (Table VI). No consistent pattern of laboratory changes or individual abnormalities was observed during this trial.
TABLE IV Changes from Baseline at Week Two in Diary Parameters Variable Anginal episodes (no./wk) Baseline Change from baseline Change Nitroglycerin consumption Baseline Change from baseline Change
Placebo (n Å 70)
Mibefradil 25 mg (n Å 64)
2.9 { 3.3 00.4 { 1.8 014%
2.3 { 3.4 00.8 { 1.8 035%
1.9 { 3.0 00.4 { 2.1 021%
1.3 { 2.7 00.4 { 1.6 031%
*p Å 0.020 versus placebo as treatment effect (mibefradil-placebo). Values are expressed as mean { SD.
TABLE V Overview of Adverse Events Excluding Those Unrelated to Treatment Mibefradil (mg/day)
Patients with adverse events [no. (%)] Patients with treatment-related adverse events [no. (%)] Leg edema Headache Dizziness Hypotension Lightheadednes
Placebo (n Å 70)
25 mg (n Å 67)
50 mg (n Å 68)
16 (22.9)
17 (25.4)
21 (30.9)
9 (12.9)
10 (14.9)
12 (17.6)
1 (1.4) 3 (4.3) — 2 (2.9) —
1 2 1 4
— (1.5) (3.0) (1.5) (6.0)
2 1 3 1
(2.9) (1.5) (4.4) (1.5) —
TABLE VI Overview of Most Common Treatment-Emergent Electrocardiographic Changes by Dose Group
Sinus bradycardia [no. (%)]* ST-T changes First-degree atrioventricular block† Ventricular premature contractions Left-axis deviation Left ventricular hypertrophy Total patients with ¢1 electrocardiogram change
Placebo (n Å 70)
Mibefradil 25 mg (n Å 67)
Mibefradil 50 mg (n Å 68)
17 (24) 11 (16) 2 (3)
16 (24) 6 (9) 10 (15)
22 (32) 6 (9) 9 (13)
4 (6)
1 (1)
6 (9)
2 (3) 0 29 (41)
5 (7) 2 (3) 32 (48)
1 (1) 0 37 (54)
*Sinus bradycardia: heart rate õ55 beats/min with ú10 beats/min decrease from baseline, or heart rate õ45 beats/min. † First-degree atrioventricular block: PR interval ú200 ms.
sodes per week from baseline to the end of therapy in the 50-mg mibefradil group versus that in the placebo group was statistically significant (p Å 0.020). There was no significant difference in the mean change from baseline in weekly nitroglycerin usage between the placebo and the 25- or 50-mg mibefradil dosage groups. Concentration-effect relations: After 2 weeks of treatment, the mean trough plasma concentrations of mibefradil were 83.9 { 49.7 ng/ml in the 25-mg dosage group and 297.1 { 139.2 ng/ml in the 50-mg group. The increase in trough plasma concentration 1028
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DISCUSSION The results of the present study clearly indicate that the addition of mibefradil 50 mg to chronic bblocker monotherapy is associated with significant improvement in multiple ETT variables including exercise duration, time to onset of angina, and APRIL 15, 1997
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number of anginal episodes. Treatment with the 25-mg dose of mibefradil was also associated with antianginal and anti-ischemic effects, but these did not reach statistical significance. This observation is in accord with the results shown by Bakx et al6 in patients with chronic stable angina pectoris who were not receiving chronic background therapy, thus confirming that the 50-mg dose of mibefradil is the lowest proven effective dose in patients with chronic stable angina pectoris. The increased efficacy observed with the addition of mibefradil to b-blocker therapy was not achieved at the expense of safety or tolerability; the combination was as well tolerated as b-blockers alone. Clinical experience with other calcium antagonists suggests caution in the concomitant use of calcium antagonists and b-blockers because of the possibility of symptomatic bradycardia, conduction defects, hypotension, and impaired cardiac contractility.6,13 – 18 However, clinical benefits, including improved exercise capacity and reduced frequency of anginal episodes, have been observed when patients with symptomatic ischemic heart disease receive combined b-blocker and calcium antagonist therapy.19 – 22 The magnitude of the benefits observed with the combination of mibefrdil and b blockers was similar to that reported from earlier calcium antagonist/b-blocker combination therapeutic trials.19 – 22 Although the combination of mibefradil and a b blocker was associated with a dose-related decrease in heart rate (reaching a mean of 06.0 beats/ min with 50 mg of mibefradil at week 2), the incidence of bradycardia was only slightly higher in the mibefradil groups than in the placebo group, and the percentage of patients whose heart rate was õ45 or 40 beats/min was similar in mibefradil- and placebo-treated patients. The additive effect of mibefradil and b blockers on lowering heart rate in this study was similar in magnitude to that observed with similar doses in studies where there was no concomitant b-blocker treatment.5 – 7 Whereas no safety concern regarding heart rate was identified in the trial, the number of patients was small, and patients with heart rates õ55 beats/ min at baseline were excluded. Further studies that include patients with low heart rates at baseline are needed to elucidate the effect of this combination therapy on heart rate. Combining mibefradil with a b blocker had an additive lowering effect on resting diastolic blood pressure. However, the decrease was small. The lack of hypotension and postural hypotension with the mibefradil– b-blocker combination may be due to mibefradil’s gradual onset of action and consistent 24-hour antihypertensive effect.5,23 The addition of mibefradil to b-blocker treatment was associated with a slight dose-related increase in the PR interval that was similar in magnitude to that observed with mibefradil alone.5 – 7 This effect resulted in an increased incidence of first-degree atrioventricular block with the combination. No cases
of second- or third-degree atrioventricular block were observed. No patient developed heart failure during the trial. Interpretation of the plasma concentration and drug effect data demonstrated an absence of a relationship for plasma concentrations and total exercise time and time to onset of angina. However, a linear relation was found for plasma concentrations of mibefradil and time to onset of ischemia. An explanation for these findings could be that ST-segment depression is an objective measure, while exercise duration and time to onset of angina are both highly subjective variables. Acknowledgment: We thank F. Hoffmann-La Roche Ltd: Robert Pordy, MD, Maurizio Rainisio, and Catherine Ward, on behalf of the Ro 40-5967 International Study Group, Basel, Switzerland.
APPENDIX Contributing Investigators: Stephen Archer, MD; Steven G. Chrysant, MD; Clinton Corder, MD; Robert Detrano, MD; William H. Frishman, MD; W. Thomas Garland, MD; Stephen Glasser, MD; General Hillard, MD; Lawrence D. Horowitz, MD; Michael Koren, MD; Benjamin Levy, MD; Thomas Martin, MD; Felix Mestas, MD; John R. Morse, MD; Paul Ogden, MD; Jeffrey Osborn, MD; John Setaro, MD; William Smith, MD; Henry Stratmann, MD; William Strauss, MD; George J. Taylor, MD; Robert Weiss, MD; John Wertheimer, MD; Charles Wilmer, MD; Laurence Yellen, MD; Kamen Zakov, MD.
1. Osterrieder W, Holck M. In vitro pharmacologic profile of Ro 40-5967, a novel Ca2/ channel blocker with potent vasodilator but weak inotropic action. J Cardiovasc Pharmacol 1989;13:754–759. 2. Rutledge A, Triggle D. The binding interaction of Ro 40-5967 at the L-type C channel in cardiac tissue. Eur J Pharmacol 1995;290:155–158. 3. Clozel J-P, Osterrieder W, Kleinbloesem C, Welker HA, Schla¨ppi B, Tudor R, Hefti F, Schmitt R, Eggers H. Ro 40-5967: a new nondihydropyridine calcium antagonist. Cardiovasc Drug Rev 1991;9:4–17. 4. Welker H, Eggers H, Kleinbloesem C. Ro 40-5967, pharmacokinetics of a new calcium antagonist (abstr). Eur J Clin Pharmacol 1989;36:A304. 5. Bernink PJLM, Prager G, Schelling A, Kobrin I. Antihypertensive properties of the novel calcium antagonist mibefradil (Ro 40-5967). Hypertension 1996;27:426–432. 6. Bakx AL, van der Wall EE, Braun S, Emanuelsson H, Bruschke AV, Kobrin I. Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: a multicenter, placebocontrolled study. Ro 40-5967 International Study Group. Am Heart J 1995;130:748–757. 7. Braun S, van der Wall EE, Emanuelsson H, Kobrin I. Effects of a new calcium antagonist, mibefradil (Ro 40-5967), on silent ischemia in patients with stable chronic angina pectoris: a multicenter placebo-controlled study. J Am Coll Cardiol 1996;27:317–333. 8. Clozel J-P, Ve´niant M, Osterrieder W. The structurally novel Ca2/ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drugs Ther 1990;4:731–736. 9. Ve´niant M, Clozel J-P, Hess P, Wolfgang R. Ro 40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction. J Cardiovasc Pharmacol 1991;17:277–284. 10. Ve´niant M, Clozel J-P, Hess P, Wolfgang R. Hemodynamic profile of Ro 40-5967 in conscious rats: comparison with diltiazem, verapamil, and amlodipine. J Cardiovasc Pharmacol 1991;18(suppl 10):S55–S58. 11. Rousseau MF, Hayashida W, van Eyll C, Hess OM, Benedict CR, Ahn S, Chapelle F, Kobrin I, Pouleur H. Hemodynamic and cardiac effects of the selective T-type and L-type calcium channel blocker, mibefradil, in patients with varying degrees of left ventricular systolic dysfunction. J Am Coll Cardiol; 1996;28:972–979. 12. Portegies MC, Schmitt R, Kraaij CJ, Braat SH, Gassner A, Hagemeijer F, Pozenel H, Prager G, Viersma JW, van der Wall EE. Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris. J Cardiovasc Pharmacol 1991;18:746–751. 13. Anastassiades C. Nifedipine and b-blocker drugs. Br Med J 80;281:1251– 1252.
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14. Opie L, White D. Adverse interaction between nifedipine and b-blockade. Br Med J 1980;281:1462. 15. Ishikawa T, Imamura T, Koiwaya Y, Tanaka K. Atrioventricular dissociation and sinus arrest induced by oral diltiazem. N Engl J Med 1983;309:1124– 1125. 16. Hossack K. Conduction abnormalities due to diltiazem. N Engl J Med 1982;307:953–954. 17. McGourty J, Silas J. b-blockers and verapamil: a cautionary tale. Br Med J 1984;289:1624. 18. Misra M, Thakur R, Bhandari K. Sinus arrest caused by atenolol–verapamil combination. Clin Cardiol 1987;10:365–367. 19. Strauss WE, Parisi AF. Combined use of calcium-channel and b adrenergic blockers for the treatment of chronic stable angina. Ann Intern Med 1988;109:571–581.
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20. Packer M. Combined b-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med 1989;320:709–718. 21. Packer M, Meller J, Medina N, Yushak M, Smith H, Holt J, Guererro J, Todd GD, McAllister RG Jr, Gorlin R. Hemodynamic consequences of combined b-adrenergic and slow calcium-channel blockade in man. Circulation 1982;65:660–668. 22. Johnston D, Lesoway R, Humen D, Kostuk W. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine, and diltiazem in exertional angina pectoris: a placebo-controlled, double-blind randomized, crossover study. Am J Cardiol 1985;55:680–687. 23. Schmitt R, Kleinbloesem C, Belz GG, Schroeter V, Feifel U, Pozenel H, Kirch W, Halabi A, Woittiez A-J, Welker HA, van Brummelen P. Hemodynamic and humoral effect of the novel calcium antagonist Ro-5967 in patients with hypertension. Clin Pharmacol Ther 1992;52:314–323.
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MD,
This study assessed the safety, tolerability, and efficacy of mibefradil when added to b-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive doubleblind treatment with either placebo (n Å 70), mibefradil 25 mg (n Å 67), or mibefradil 50 mg (n Å 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 { 51 seconds; p Å 0.036), time to onset of angina (48 { 65 seconds; p Å 0.002), and time to persistent 1mm ST-segment depression (47 { 77 seconds; p Å 0.004). Greater reductions in heart rate, blood pressure,
and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (02.1 { 4.0, p Å 0.020) compared with placebo. The addition of mibefradil to existing b-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable b-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated. Q1997 by Excerpta Medica, Inc. (Am J Cardiol 1997;79:1025–1030)
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dose.6 For reasons of safety, and because it was thought that a lower dose of mibefradil might be effective when combined with a b blocker, this study used lower doses of mibefradil (25 and 50 mg). Also, the study was designed to characterize the concentration-effect relation between mibefradil plasma concentration and certain study parameters.
ibefradil (Ro 40-5967) is a novel calcium antagonist that belongs to a new structural class of benzimidazolyl-substituted tetraline derivatives.1 Mibefradil binds to a unique receptor site,2 and is the first calcium antagonist with the ability to selectively block T-type calcium channels. The pharmacokinetic features of mibefradil include a high bioavailability (approximately 90%) and long plasma half-life (17 to 25 hours),3,4 making it suitable for once-a-day dosing. Clinical studies have demonstrated that mibefradil is an effective antihypertensive,5 antianginal,6 and anti-ischemic7,8 agent, and its clinical effects have been shown to be associated with a slight decrease in heart rate.5–7 Moreover, both preclinical8–10 and clinical11,12 studies have shown that mibefradil lacks negative inotropic effects at doses in the therapeutic range. The objective of this study was to evaluate the efficacy and safety of mibefradil at once-daily doses of 25 and 50 mg compared with placebo in patients with chronic stable angina pectoris receiving concomitant b-blocker therapy. The results of a previous monotherapy dose-ranging trial in patients with stable angina pectoris indicated that 50 mg/day was the lowest effective dose and 100 mg/day was the highest effective and well-tolerated From the Department of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona. This study was supported by a grant from F. Hoffmann-La Roche Ltd, Nutley, New Jersey. Manuscript received September 27, 1996; revised manuscript received and accepted December 17, 1996. Address for reprints: Joseph S. Alpert, MD, Department of Medicine, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, Arizona 85724-5035.
METHODS This multicenter, double-blind, placebo-controlled, parallel-group study was performed in 26 centers in the U.S. The protocol was approved by the local ethics committees at participating centers and conducted in accordance with the Helsinki Declaration, as amended in Tokyo, Venice, and Hong Kong. Patients: Male and female patients aged 18 to 70 years were eligible for inclusion in the study if they fulfilled the following criteria: (1) classic stress- or exercise-induced chronic stable angina pectoris for ¢2 months; (2) stable dose and regimen of b-blocker therapy for a minimum of 2 weeks before entry; and (3) resting heart rate ¢55 beats/min. Exclusion criteria were heart failure, cardiomyopathy, clinically relevant arrhythmias, uncontrolled hypertension, and any relevant clinical or laboratory abnormalities. Study protocol: Patients meeting the inclusion and exclusion criteria entered a 2-week washout and stabilization period, during which previous antianginal medications (with the exception of b blockers and tablet/spray nitroglycerin) were gradually stopped. A placebo run-in period of 1 week followed the washout period. To be eligible for randomization, patients were required to have 2 of 3 baseline exercise tol-
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Patients were asked to complete a diary throughout the trial to assess the total weekly nitroglycerin consumption and number of weekly anginal episodes. Safety was evaluated by continuous monitoring of adverse events (including intercurrent illnesses) by physical examination, and electrocardiographic and laboratory assessments. The study design and schedule of visits is depicted in Figure 1. Predose blood samples were also collected at the final visit, provided an ETT had been performed, for determination of plasma concentrations of mibefradil. Statistical analysis: The analysis of the intent-to-treat population was regarded as the main analysis of the study. The intentto-treat population included all randomized patients who received at least 1 dose of study medication, and had at least 1 baseline ETT and 1 postrandomization ETT. The primary efficacy variable was the change from baseline in symptom-limited ETT duration at week 2. Secondary efficacy variables included the changes from baseline to week 2 in: (1) time to persisFIGURE 1. Study design: BB Å b blocker; ETT Å exercise tolerance test; Mib Å tent 1-mm ST depression; (2) time to onmibefradil. set of angina; (3) blood pressure, heart rate, and heart rate–blood pressure proderance tests (ETTs) meet the following specific cri- uct during ETT; (4) number of weekly anginal atteria: (1) The duration of the first ETT had to be 3 tacks; and (5) weekly nitroglycerin consumption. to 8 minutes. (2) The duration of the second ETT The therapeutic response rate at week 2, defined as had to be 2.5 to 9.2 minutes and within { 15% of an increase in ETT duration of ¢60 seconds or an the previous one. If the second ETT was not within increase in ETT time without developing anginal { 15% of the first ETT, a third ETT could be per- symptoms, was also calculated. Baseline ETT was formed within 1 to 3 days. In such a case, the du- defined as the last ETT before randomization. Evaluation of the changes from baseline in preration of the third ETT had to be 2.5 to 9.2 minutes and { 15% of the second ETT. (3) The reason for dose ETT parameters was performed by analysis of stopping exercising of all baseline ETTs had to be covariance using a model containing treatment, centhe onset of moderate angina. Qualified patients were ter, and treatment-by-center as fixed factors, and randomized to receive once-daily treatment with 25 baseline ETT duration as a covariant. To compare mg of mibefradil, 50 mg of mibefradil, or matching the active treatments with placebo, estimated treatplacebo for 2 weeks. Throughout the placebo run-in ment effects were defined as the paired difference and double-blind treatment periods, patients contin- between both groups in the center-adjusted mean ued to receive daily stable b-blocker therapy. An change from baseline (calculated from the analysis ETT was performed at the end of the 2-week double- of covariance model). Because of the abnormal disblind treatment period or when patients withdrew tribution of the data, anginal diary variables were from the study. All ETTs were performed according analyzed using nonparametric methods (Mannto the Bruce protocol 22 to 24 hours after drug ad- Whitney U test with Hodges-Lehmann estimate). With use of a high-performance liquid chromaministration. Heart rate and blood pressure were measured before starting the ETT, every 3 minutes tography technique, plasma samples obtained before during the ETT, at the time of appearance of at least dosing at the final visit were analyzed for concentra1-mm ST-segment depression, at onset of angina, at tions of mibefradil. The relationships between miexercise termination, and every 2 minutes for 10 befradil-plasma concentration and the changes in (1) minutes during recovery. During treatment, ETTs time to onset of angina during ETT, (2) time to onset could be stopped because of moderate angina or of persistent 1-mm ST-segment depression during other symptoms (e.g., dyspnea or weakness) or for ETT, (3) total exercise time, (4) heart rate, and (5) safety concerns (e.g., arrhythmia or hypotension), PR interval were evaluated using the nonlinear whichever came first (defined as symptom-limited mixed-effect model. Noneffect, linear, and EMAX ETT). were the models tested. 1026
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or were unable to proceed for administrative or other reasons. The Placebo Mibefradil 25 mg Mibefradil 50 mg remaining 205 patients with reproVariable (n Å 70) (n Å 67) (n Å 68) ducible exercise-induced moderate angina were randomized to receive Men:women 52:18 55:12 51:17 Age (yr) 62.1 { 9.8 62.6 { 8.9 64.5 { 8.0 either placebo (n Å 70), mibefradil Weight (kg) 84.4 { 15.1 85.9 { 14.5 84.3 { 15.8 25 mg (n Å 67), or mibefradil 50 White:black:other 55:6:9 53:7:7 55:9:4 mg (n Å 68). The 3 groups were Myocardial infarction 25 (36) 27 (40) 20 (29) well matched in terms of demoCoronary angioplasty 19 (27) 18 (27) 12 (18) graphic and baseline characteristics Coronary bypass 13 (19) 12 (18) 16 (24) (Tables I and II). Three patients in *Does not include data from 2 patients excluded from intention-to-treat efficacy analyses. the mibefradil group withdrew preValues for age, weight and exercise tolerance test duration are mean { SD. maturely from the study: 1 for an adverse event (25 mg), 1 because of asymptomatic bradycardia (50 mg), TABLE II Change from Baseline in Exercise Tolerance Test Variables After Two and 1 for administrative reasons Weeks of Treatment (50 mg). Placebo Mibefradil 25 mg Mibefradil 50 mg Exercise performance: Four paVariable (n Å 70) (n Å 65) (n Å 66) tients (2 each in the 25- and 50-mg Exercise duration mibefradil groups), including 3 who Baseline (sec) 351 { 99 355 { 87 356 { 87 failed to complete the study, were Change from baseline 16 { 58 30 { 51 36 { 51* not included in the intent-to-treat ef(sec) ficacy analyses because of missing Change 4.5% 8.6% 10.2% Onset of angina postrandomization ETT measureBaseline (sec) 263 { 99 270 { 96 281 { 98 ments. † Change from baseline 16 { 83 40 { 83 48 { 65 The effects of each treatment on (sec) ETT variables are summarized in Change 6.1% 14.8% 17.2% Time to persistent ST-segment Table II. Compared with placebo, depression the addition of once-daily treatment Baseline (sec) 289 { 110 276 { 100 284 { 106 with mibefradil 50 mg to existing bChange from baseline 19 { 69 38 { 68 47 { 77‡ blocker therapy for 2 weeks resulted (sec) in statistically significant increases Change 6.6% 13.8% 16.7% in exercise duration (p Å 0.036), *p Å 0.036; p Å 0.002; p Å 0.004, all versus placebo as treatment effect (mibefradil-placebo). time to onset of angina (p Å 0.002), Values are expressed as mean { SD. and time to persistent 1-mm STsegment depression (p Å 0.004). Whereas treatment with mibefradil TABLE III Changes from Baseline at Week Two in Hemodynamic Variables During 25 mg was also associated with Exercise Tolerance Test at Rest and Upon Termination of Exercise improvements in all 3 ETT paramVariable Placebo Mibefradil 25 mg Mibefradil 50 mg eters, the values compared with plaRest cebo were not statistically signifiDiastolic blood pressure (mm Hg) 00.4 { 10.1* 01.6 { 8.8† 04.2 { 8.9† cantly better. More patients in the Systolic blood pressure (mm Hg) 02.1 { 17.2* 01.5 { 15.3† 09.6 { 16.9† mibefradil dose groups were able to ‡ † § Heart rate (beats/min) 02.0 { 8.8 03.8 { 10.9 06.0 { 10.3 increase their exercise tolerance Double product (mm Hg 0435 { 1,984‡ 0619 { 1,919† 01,450 { 1,883† time without developing angina 1 beats/min) Termination of exercise than those in the placebo group. Diastolic blood pressure (mm Hg) 00.5 { 10.8x 01.2 { 9.5§ 03.0 { 11.2‡ Hemodynamic effects: Treatment x § ‡ Systolic blood pressure (mm Hg) 01.7 { 20.8 04.4 { 21.7 07.2 { 21.2 with mibefradil was associated with Heart rate (beats/min) 00.9 { 11.8x 05.8 { 13.4§ 09.5 { 15.9‡ a dose-dependent decrease in heart Double product (mm Hg 0417 { 3,433x 01,439 { 3,848§ 02,297 { 4,276‡ 1 beats/min) rate and blood pressure at rest and at termination of ETT at week 2 *n Å 68; n Å 64; n Å 66; n Å 65; n Å 69. (Table III), leading to a larger reValues are expressed as mean { SD. duction in double product in both mibefradil groups than in the plaAll tests were 2-sided and performed using an cebo group. Similar results were apparent for hemoalpha level of 0.05. Data are expressed as the mean dynamic measurements obtained at the onset of angina and onset of ischemia. { SD unless otherwise stated. TABLE I Demographic and Baseline Characteristics
†
†
‡
‡
§
x
Anginal symptoms and nitroglycerin consumption:
RESULTS Patients: A total of 230 patients entered the placebo run-in period. Of these, 25 failed to meet the final selection criteria with respect to ETT variables,
The changes from baseline in diary parameters are summarized in Table IV. The number of anginal episodes per week was reduced in a dose-dependent manner; the decrease in the number of anginal epi-
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from the 25- to the 50-mg dose group was higher than a dose-proMibefradil 50 mg portional increase. A linear corre(n Å 67) lation was observed for mibefradil plasma concentration and the 3.3 { 5.8 change from baseline in time to on02.1 { 4.0* set of ischemia. 064% Tolerability and safety: All 205 patients randomized to receive pla1.6 { 3.4 cebo or mibefradil treatment were 00.9 { 2.9 056% included in the safety analyses. The combination of mibefradil and b blockers was well tolerated. The incidence of adverse events, including those assessed by the investigators as unrelated to treatment, was slightly higher in the mibefradil groups compared with the placebo group. Table V lists the incidence of treatment-related adverse events in each treatment group for those events reported by ¢2 patients in any group. Dizziness and lightheadedness were the only treatment-related adverse events not reported in the placebo group that were reported by ¢2 mibefradil-treated patients. The other 2 common treatment-related adverse events— hypotension and headache—were reported with a higher frequency in the placebo group than in the mibefradil treatment groups. Approximately two thirds of all treatment-related adverse events were judged to be mild in severity by the investigators, and only 1 adverse event was considered serious. An escape junctional rhythm at a rate of 52 beat/min was noted on an electrocardiogram recorded 2 hours after the last visit (26 hours after the final dose of mibefradil 50 mg) in a 71-year-old man; the nodal rhythm resolved upon cessation of all medication. One patient, a 65-year-old woman, died of an acute myocardial infarction that developed subsequent to coronary angioplasty performed 7 days after study completion; the death was considered unrelated to study treatment (mibefradil 50 mg). One patient was withdrawn from the study because of postural hypotension accompanied by dizziness, chest pain, and dyspnea that developed after the first dose of 25 mg. A second patient was prematurely withdrawn after 7 days of treatment with mibefradil 50 mg because of symptomatic bradycardia (36 beats/ min) noted on electrocardiogram. Mibefradil treatment was associated with a mean dose-related decrease in heart rate (Table III) and a slight, dose-related increase in the PR interval (Table VI). No consistent pattern of laboratory changes or individual abnormalities was observed during this trial.
TABLE IV Changes from Baseline at Week Two in Diary Parameters Variable Anginal episodes (no./wk) Baseline Change from baseline Change Nitroglycerin consumption Baseline Change from baseline Change
Placebo (n Å 70)
Mibefradil 25 mg (n Å 64)
2.9 { 3.3 00.4 { 1.8 014%
2.3 { 3.4 00.8 { 1.8 035%
1.9 { 3.0 00.4 { 2.1 021%
1.3 { 2.7 00.4 { 1.6 031%
*p Å 0.020 versus placebo as treatment effect (mibefradil-placebo). Values are expressed as mean { SD.
TABLE V Overview of Adverse Events Excluding Those Unrelated to Treatment Mibefradil (mg/day)
Patients with adverse events [no. (%)] Patients with treatment-related adverse events [no. (%)] Leg edema Headache Dizziness Hypotension Lightheadednes
Placebo (n Å 70)
25 mg (n Å 67)
50 mg (n Å 68)
16 (22.9)
17 (25.4)
21 (30.9)
9 (12.9)
10 (14.9)
12 (17.6)
1 (1.4) 3 (4.3) — 2 (2.9) —
1 2 1 4
— (1.5) (3.0) (1.5) (6.0)
2 1 3 1
(2.9) (1.5) (4.4) (1.5) —
TABLE VI Overview of Most Common Treatment-Emergent Electrocardiographic Changes by Dose Group
Sinus bradycardia [no. (%)]* ST-T changes First-degree atrioventricular block† Ventricular premature contractions Left-axis deviation Left ventricular hypertrophy Total patients with ¢1 electrocardiogram change
Placebo (n Å 70)
Mibefradil 25 mg (n Å 67)
Mibefradil 50 mg (n Å 68)
17 (24) 11 (16) 2 (3)
16 (24) 6 (9) 10 (15)
22 (32) 6 (9) 9 (13)
4 (6)
1 (1)
6 (9)
2 (3) 0 29 (41)
5 (7) 2 (3) 32 (48)
1 (1) 0 37 (54)
*Sinus bradycardia: heart rate õ55 beats/min with ú10 beats/min decrease from baseline, or heart rate õ45 beats/min. † First-degree atrioventricular block: PR interval ú200 ms.
sodes per week from baseline to the end of therapy in the 50-mg mibefradil group versus that in the placebo group was statistically significant (p Å 0.020). There was no significant difference in the mean change from baseline in weekly nitroglycerin usage between the placebo and the 25- or 50-mg mibefradil dosage groups. Concentration-effect relations: After 2 weeks of treatment, the mean trough plasma concentrations of mibefradil were 83.9 { 49.7 ng/ml in the 25-mg dosage group and 297.1 { 139.2 ng/ml in the 50-mg group. The increase in trough plasma concentration 1028
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DISCUSSION The results of the present study clearly indicate that the addition of mibefradil 50 mg to chronic bblocker monotherapy is associated with significant improvement in multiple ETT variables including exercise duration, time to onset of angina, and APRIL 15, 1997
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number of anginal episodes. Treatment with the 25-mg dose of mibefradil was also associated with antianginal and anti-ischemic effects, but these did not reach statistical significance. This observation is in accord with the results shown by Bakx et al6 in patients with chronic stable angina pectoris who were not receiving chronic background therapy, thus confirming that the 50-mg dose of mibefradil is the lowest proven effective dose in patients with chronic stable angina pectoris. The increased efficacy observed with the addition of mibefradil to b-blocker therapy was not achieved at the expense of safety or tolerability; the combination was as well tolerated as b-blockers alone. Clinical experience with other calcium antagonists suggests caution in the concomitant use of calcium antagonists and b-blockers because of the possibility of symptomatic bradycardia, conduction defects, hypotension, and impaired cardiac contractility.6,13 – 18 However, clinical benefits, including improved exercise capacity and reduced frequency of anginal episodes, have been observed when patients with symptomatic ischemic heart disease receive combined b-blocker and calcium antagonist therapy.19 – 22 The magnitude of the benefits observed with the combination of mibefrdil and b blockers was similar to that reported from earlier calcium antagonist/b-blocker combination therapeutic trials.19 – 22 Although the combination of mibefradil and a b blocker was associated with a dose-related decrease in heart rate (reaching a mean of 06.0 beats/ min with 50 mg of mibefradil at week 2), the incidence of bradycardia was only slightly higher in the mibefradil groups than in the placebo group, and the percentage of patients whose heart rate was õ45 or 40 beats/min was similar in mibefradil- and placebo-treated patients. The additive effect of mibefradil and b blockers on lowering heart rate in this study was similar in magnitude to that observed with similar doses in studies where there was no concomitant b-blocker treatment.5 – 7 Whereas no safety concern regarding heart rate was identified in the trial, the number of patients was small, and patients with heart rates õ55 beats/ min at baseline were excluded. Further studies that include patients with low heart rates at baseline are needed to elucidate the effect of this combination therapy on heart rate. Combining mibefradil with a b blocker had an additive lowering effect on resting diastolic blood pressure. However, the decrease was small. The lack of hypotension and postural hypotension with the mibefradil– b-blocker combination may be due to mibefradil’s gradual onset of action and consistent 24-hour antihypertensive effect.5,23 The addition of mibefradil to b-blocker treatment was associated with a slight dose-related increase in the PR interval that was similar in magnitude to that observed with mibefradil alone.5 – 7 This effect resulted in an increased incidence of first-degree atrioventricular block with the combination. No cases
of second- or third-degree atrioventricular block were observed. No patient developed heart failure during the trial. Interpretation of the plasma concentration and drug effect data demonstrated an absence of a relationship for plasma concentrations and total exercise time and time to onset of angina. However, a linear relation was found for plasma concentrations of mibefradil and time to onset of ischemia. An explanation for these findings could be that ST-segment depression is an objective measure, while exercise duration and time to onset of angina are both highly subjective variables. Acknowledgment: We thank F. Hoffmann-La Roche Ltd: Robert Pordy, MD, Maurizio Rainisio, and Catherine Ward, on behalf of the Ro 40-5967 International Study Group, Basel, Switzerland.
APPENDIX Contributing Investigators: Stephen Archer, MD; Steven G. Chrysant, MD; Clinton Corder, MD; Robert Detrano, MD; William H. Frishman, MD; W. Thomas Garland, MD; Stephen Glasser, MD; General Hillard, MD; Lawrence D. Horowitz, MD; Michael Koren, MD; Benjamin Levy, MD; Thomas Martin, MD; Felix Mestas, MD; John R. Morse, MD; Paul Ogden, MD; Jeffrey Osborn, MD; John Setaro, MD; William Smith, MD; Henry Stratmann, MD; William Strauss, MD; George J. Taylor, MD; Robert Weiss, MD; John Wertheimer, MD; Charles Wilmer, MD; Laurence Yellen, MD; Kamen Zakov, MD.
1. Osterrieder W, Holck M. In vitro pharmacologic profile of Ro 40-5967, a novel Ca2/ channel blocker with potent vasodilator but weak inotropic action. J Cardiovasc Pharmacol 1989;13:754–759. 2. Rutledge A, Triggle D. The binding interaction of Ro 40-5967 at the L-type C channel in cardiac tissue. Eur J Pharmacol 1995;290:155–158. 3. Clozel J-P, Osterrieder W, Kleinbloesem C, Welker HA, Schla¨ppi B, Tudor R, Hefti F, Schmitt R, Eggers H. Ro 40-5967: a new nondihydropyridine calcium antagonist. Cardiovasc Drug Rev 1991;9:4–17. 4. Welker H, Eggers H, Kleinbloesem C. Ro 40-5967, pharmacokinetics of a new calcium antagonist (abstr). Eur J Clin Pharmacol 1989;36:A304. 5. Bernink PJLM, Prager G, Schelling A, Kobrin I. Antihypertensive properties of the novel calcium antagonist mibefradil (Ro 40-5967). Hypertension 1996;27:426–432. 6. Bakx AL, van der Wall EE, Braun S, Emanuelsson H, Bruschke AV, Kobrin I. Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: a multicenter, placebocontrolled study. Ro 40-5967 International Study Group. Am Heart J 1995;130:748–757. 7. Braun S, van der Wall EE, Emanuelsson H, Kobrin I. Effects of a new calcium antagonist, mibefradil (Ro 40-5967), on silent ischemia in patients with stable chronic angina pectoris: a multicenter placebo-controlled study. J Am Coll Cardiol 1996;27:317–333. 8. Clozel J-P, Ve´niant M, Osterrieder W. The structurally novel Ca2/ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drugs Ther 1990;4:731–736. 9. Ve´niant M, Clozel J-P, Hess P, Wolfgang R. Ro 40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction. J Cardiovasc Pharmacol 1991;17:277–284. 10. Ve´niant M, Clozel J-P, Hess P, Wolfgang R. Hemodynamic profile of Ro 40-5967 in conscious rats: comparison with diltiazem, verapamil, and amlodipine. J Cardiovasc Pharmacol 1991;18(suppl 10):S55–S58. 11. Rousseau MF, Hayashida W, van Eyll C, Hess OM, Benedict CR, Ahn S, Chapelle F, Kobrin I, Pouleur H. Hemodynamic and cardiac effects of the selective T-type and L-type calcium channel blocker, mibefradil, in patients with varying degrees of left ventricular systolic dysfunction. J Am Coll Cardiol; 1996;28:972–979. 12. Portegies MC, Schmitt R, Kraaij CJ, Braat SH, Gassner A, Hagemeijer F, Pozenel H, Prager G, Viersma JW, van der Wall EE. Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris. J Cardiovasc Pharmacol 1991;18:746–751. 13. Anastassiades C. Nifedipine and b-blocker drugs. Br Med J 80;281:1251– 1252.
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14. Opie L, White D. Adverse interaction between nifedipine and b-blockade. Br Med J 1980;281:1462. 15. Ishikawa T, Imamura T, Koiwaya Y, Tanaka K. Atrioventricular dissociation and sinus arrest induced by oral diltiazem. N Engl J Med 1983;309:1124– 1125. 16. Hossack K. Conduction abnormalities due to diltiazem. N Engl J Med 1982;307:953–954. 17. McGourty J, Silas J. b-blockers and verapamil: a cautionary tale. Br Med J 1984;289:1624. 18. Misra M, Thakur R, Bhandari K. Sinus arrest caused by atenolol–verapamil combination. Clin Cardiol 1987;10:365–367. 19. Strauss WE, Parisi AF. Combined use of calcium-channel and b adrenergic blockers for the treatment of chronic stable angina. Ann Intern Med 1988;109:571–581.
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20. Packer M. Combined b-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med 1989;320:709–718. 21. Packer M, Meller J, Medina N, Yushak M, Smith H, Holt J, Guererro J, Todd GD, McAllister RG Jr, Gorlin R. Hemodynamic consequences of combined b-adrenergic and slow calcium-channel blockade in man. Circulation 1982;65:660–668. 22. Johnston D, Lesoway R, Humen D, Kostuk W. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine, and diltiazem in exertional angina pectoris: a placebo-controlled, double-blind randomized, crossover study. Am J Cardiol 1985;55:680–687. 23. Schmitt R, Kleinbloesem C, Belz GG, Schroeter V, Feifel U, Pozenel H, Kirch W, Halabi A, Woittiez A-J, Welker HA, van Brummelen P. Hemodynamic and humoral effect of the novel calcium antagonist Ro-5967 in patients with hypertension. Clin Pharmacol Ther 1992;52:314–323.
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