Verapamil Administered Twice Daily in Stable Angina Pectoris

Verapamil Administered Twice Daily in Stable Angina Pectoris* ArthurT.H. Tan, M.B., B.S.; and Susan Quek, M.B., B.S.

To assess whether verapamil taken orally twice daily (bel) was as effective as four times daily (qd) in patients With angina a placebo controlled double blind crossover bial was conducted in 1.2 patients. Each patient was randomized to verapamil, 160 mg bd, 80 mg qd, or corresponding placebo, each for three weeks. Patients \vere assessed subjectively and by treadmill exercise test. On both verapamil regimens, patients had less angina With delayed onset of ST segment depression during exercise compared to placebo, Without

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erapamil has been shown to be effective in stable effurt angina. l-3 In these studies, verapamil was given three to fuur times daily, as short-term single dose pharmacokinetic studies have shown a half life of three to seven hours. 4•5 Recent studies have suggested that less frequent administration may be adequate during long-term oral therapy.6-8 This study was designed to assess the antianginal efficacy of twice daily verapamil compared with fuur times daily in patients with stable effort angina. METHODS

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Twelve men (mean age 53 years, range 30 to 68 years) with a history of stable exertional angina for at least three months and having at least two anginal attacks a week participated in the study. Six patients had New York Association class 2 angina and six, class 3. Five patients had previous transmural myocardial infarction. All patients had a positive stress test defined as greater than 1 mm horizontal or downsloping ST segment depression of at least 0.08 second in duration in three consecutive beats at the time of angina. Patients with hypertension, valvular heart disease, unstable angina pectoris, cardiac failure, A-V nodal disease, diabetes mellitus, thyroid disorders, and resting ST segment abnormalities were not considered for the trial. All patients gave iriformed consent. The trial was placebo-controlled and double-blind. AlJ . previous anginal therapy was curtailed. Short acting nitrates were taken for symptomatic relief of angina with none taken at least six hours before each exercise test. Patients were randomized to verapamil, 160 mg twice daily (bd) or 80 mg four times daily (qd) or their Corresponding placebos for three weeks. Thus, each patient Went through four phases of therapy with subjective and objective assessment at the end of each phase. The protocol ensured that one half the patients started with verapamil 80 mg or placebo qd and one half with verapamil160 mg or placebo bd. This helps to exclude any training effect from repeated exercise tests. *From the University Department of Medicine, (Division of Cardiology); National University of Singapore. Manuscript received May 16; revision accepted JulY 27 Reprint requests: Dr. Tan, Depamnent of Medicine II, Singapore General Hospital, Singapore 0316

any differences between the two regimens. On bd verapamil, patients could increase their exercise capacity as much as on qd Without any increase in adverse effects. Angina threshold during exercise was increased by both regimens With a slightly higher threshold on qd verapamil compared to bd. Therefore, administration of verapamil twice daily is effedive in patients With stable angina pectoris, .With a similar efficacy to taking verapamil four times daily Without any increase in advene effects.

AssESSMENT

At the end of each three-week treatment phase, each patient underwent a symptom-limited inaximal exercise test on a treadmill (Avionics Model E-161-1) using the Bruce protocoP For each patient, the exercise test was done at the same time of the day just before the next dose was due. The ECG Was monitored using the modi6ed Mason lead system. 10 During exercise 1.2-lead ECGs, heart rate, blood pressure (measured by sphygomomanometer) and symptoms were recorded every minute. The end points of exercise were symptom limiting chest pain and/or breathlessness and!or filtigue. A tablet count was done at the end of each phase to verify compliance. Patients recorded anginal attacks during each three-week phase in a diary. Side effects were obtained by completion of a questionnaire and by inquiry. They were also asked to rank the order of preference for the four phases of therapy on completion of the trial. STATISTICAL METHODS

Results were analyzed by two-way analysis of variance. When a statistical signmcance was obtained between the four treatment phases (p <0.05), the treatment sum of squares was partitioned to identify the source of the statistical signi6cance. 11 Results are expressed as a mean ± SD unless otherwise indicated.

REsucrs Symptoms, Side Effects, and Preference Patients receiving verapamil had fewer anginal attacks than those receiving placebo. On verapamil, 160 mg bd, there were 12 ± 22 anginal episodes in three weeks compared to placebo 17 ± 25 episodes (p <0.05); on verapamil, 80 mg qd, 5 ± 5 episodes in three weeks compared to placebo 17±22 episodes (p<0.01). Patients takiilg verapamil fuur times daily had fewer anginal attacks than twice daily verapamil, but the difference was not significant. The incidence of side effects was low during each regimen of verapamil. Three patients complained of constipation on each dosage regimen. All patients preferred verapamil to placebo. Eight patients preferred taking verapamil, 80 mg qd and two 160 mg bd. CHEST I 85 I 1 I JANUARY, 1984

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On bd and qd regimens, exercise tests were performed 13 ± 3 and 5. 8 ± 0. 6 hours after the last dose of verapamil. Heart rate at rest was lower with verapamil than with placebo (Fig 1) being lower on qd compared to bd regimens (p <0.05). During exercise, the heart rate at each stage was lower on verapamil compared to placebo, with no significant difference between the two regimens. On both regimens of verapamil, blood pressure at rest and during exercise was not significantly different from placebo. The rate pressure product at each stage of exercise was lower with verapamil compared to placebo. While taking verapamil, patients Table 1-Effecta tfVerapamil on Mtuimum ST-Segment Depreuion and Eurciae Capacity

QD

BD

Verapamil Placebo Verapamil Placebo Exercise capacity HR at peak exercise

Mean BP at peak

6.5±2.5* 5.1±2.9 6 .2 ±2* 5.1±1.2 132±23 136±25 131±20 134±21 99± 15 100± 15 98± 13 95± 13

exercise

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*Verapamil vs placebo p <0.05.

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FIGURE 1. The effect of verapamil on heart rate and blood pressure at rest and during exercise (Heart rate during exercise: closed triangle is verapamil 80 mg qd, vs < closed circle placebo p <0.05; x, verapamil160 mg bd, vs
were able to exercise longer than with placebo (Table 1) with similar increases in exercise capacity in both regimens. The heart rate, blood pressure, and rate pressure product was, however, unchanged at peak exercise. Anginal Threshold and ST-Segment Depression

Receiving placebo, all patients developed angina at peak exercise with ST-segment depression. In contrast, during each regimen of verapamil therapy, seven patients developed angina with the other five limited by breathlessness at peak exercise. The time to onset of angina was longer with verapamil than with placebo (Table 2). Patients taking Table 2-Effecta tfVerapamil on Onset tf Angina and 1 mm ST-Segment Depreuion During Eurciae

QD

BD

Verapamil Placebo Verapamil Placebo Onsetofangina(min) 4.7±1.9* 3.5±2.5 3 .9 ±1.7* HR at onset of angina 123 ± 21 129 ± 20 123 ± 20 99± 15 96± 13 96± 14 BP (mean) at onset of angina 4.2±2.4* 2.8± 1.8 4.3±2.4* Onset ofl mm STdepression (min) 120±21 121± 16 123±20 HRat 1 mm STdepression 97±16 94±16 BP (mean) at 1 !11m ST- 94±14 depression

2.8±1.3 124 ± 21 100± 15 3.2±2 124±21 100±13

*Verapamil vs placebo p <0.05. 1\vlce Dally VerapamM In Stable Angina (Tan, Quek)

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verapamil fuur times daily could exercise longer befure onset of angina than those taking verapamil twice daily (p
Initial single dose pharmacokinetics have shown that verapamil has a half life of three to seven hours and should be given three to fuur times daily. 4 •5 More recent studies have shown that elimination kinetics of verapamil and its main metabolite norverapamil are prolonged after long-term oral administration,~ sug-

gesting that less frequent dose schedules may be possible. 8 This study was designed to establish the antianginal efficacy of verapamil given twice daily and to compare it with a more conventional regimen. In patients with stable effurt angina, this study has shown that verapamil taken twice daily is effective in the prevention of angina. Patients taking verapamil twice daily had fewer attacks ofangina than on placebo. They could exercise longer befure the onset of angina and ST-segment depression resulting in an increased exercise capacity. We compared the antianginal efficacy of verapamil given orally either twice daily (160 mg bd) or fuur times daily (80 mg qd). Though patients felt that the latter regimen was more effective in improving angina, we could not detect any differences in heart rate and blood pressure response to exercise, onset of 1 mm STsegment depression, and exercise capacity between the two regimens. These exercise tests were perfOrmed during the period when the expected plasma levels of verapamil from either regimen would have been at their trough. Furthermore, patients did not have any increase in adverse side effects from the CHEST I 85 I 1 I JANUARY, 1984

57

higher dosage. This study has shown that patients with stable effurt angina can be effectively and safely managed on a twice daily regimen. In some patients, however, a qd regimen may lead to slightly greater improvement and may be necessary. ACKNOWLEDGMENTS: We are peful to Professor D. T. Kelly, Hallstrom Institute ofCardiology, Sydney, fOr reviewing the manuscript, Mr. C. S. Kang fOr technk:al assistance, and Ms L. C. Chong fOr typing the manuscript.

REFERENCES 1 Andreasen F, Boye E, Christoffersen E, et al. Assessment of verapamil in the treatment of angina pectoris. Europ J Cardiol 1975; 2:433-52 2 Balasubramaniam VB, Lahiri A, Paramasivan R, Raferty EB. Verapamil in clm>nic stable angina. Lancet 1980; 841-44 3 1lm ATH, Sadick N, Kelly D1; Harris PJ, Freedman SB, Bautavich G. ·Verapamil in stable efiOrt angina: effects on left ventricular function evaluated with exercise radionuclide ventriculography. Am J Cardiol1982; 49:425-30

4 Singh BN, Ellroft G, Peter CT. Verapamil: a review of its pharmacological properties and therapeutic use. Drugs 1978; 15:169-97 5 Schomerus M, Spiegelhalder 8, Stieren 8 , Eichelbaum M. Physiological disposition of verapamil in man. Cardiovasc Res 1976; 10:605-12 6 Kates RE, Keefe OLD, Schwartz, Harapat S, Kirsten EB, Harrison DC. Verapamil disposition kinetics in chronic atrial Sbrilation. Clin Pharm Ther 1981; 30:44-51 7 Schwartz JB, Keefe DL, Kirsten E, Kates RE, Harrison DC. Prolongation of verapamil elimination kinetics during chronic oral administration. Am J Cardiol1982; 49(4 Part 2):942 8 Freedman SB, Richmond DR, Ashley JJ, Kelly DT. Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clin Pharm Ther 1981; 30:644-52 9 Bruce RA. Exercise testing of patients with coronary artery disease: Principles and normal standards for testing and evaluation. Ann Clin Res 1971; 3:323-32 10 Mason RE, Likar I, Biem RO, Ross RS. Multiple lead exercise electrocardiography. Circulation 1967; 36:517-25 11 Snedecor GW, Cochran WG. Statistical methods. Ames, lA: Iowa State University Press, 1967:308

Fourth International Symposium on Intensive Care and Emergency Medicine This symposium will be held March 28-30 in Brussels, Belgium. For infOrmation, please contact Jean-Louis Vincent, M.D., Department of Intensive Care, Universite Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium.

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1Wice Daly Verapeml In Stable Angina (Tan, Quek)