Michael J. Bowles

Combined therapy with verapamil and propranolol in chronic stable angina

The comparative efficacy of verapamil (360 mg daily) and propranolol (240 mg daily) was evaluated with computerized treadmill exercise in 22 patients with chronic stable angina in a placebo-controlled double-blind crossover study with 4 weeks on each active phase. Fourteen of these patients still had angina despite active drug therapy and they were further treated with a combination of verapamil (360 mg) and propranolol (120 mg) for 4 weeks. The mean exercise time for these patients taking placebo was 4.8 +/- 0.22 minutes (mean +/- standard error of the mean) and this increased to 6.8 +/- 0.64 minutes with propranolol and 8.0 +/- 0.5 minutes with verapamil. A further increase to 10.1 +/- 0.88 minutes was observed with the combination of both drugs and seven patients became symptom-free. S-T segment criteria improved with both drugs, and combination therapy produced a further reduction in peak S-T depression. Electrocardiographic ambulatory monitoring showed no evidence of conduction defects and mean hourly heart rates were similar to those seen with propranolol alone. Left ventricular function indexes were not significantly different from those obtained with propranolol. Combination therapy with verapamil and propranolol appears to be efficacious in the treatment of selected patients with severe chronic stable angina. The patients need to be carefully monitored for adverse effects.

Randomized double-blind comparison of verapamil and nifedipine in chronic stable angina

A randomized double-blind crossover trial was performed in 32 patients with chronic stable angina to compare the antianginal actions of verapamil (120 mg 3 times daily) and nifedipine (20 mg 3 times daily). Efficacy was assessed using objective end points obtained by computer-assisted exercise testing and 24 hour ambulatory monitoring for S-T segment shift. Twenty-eight patients completed the trial. The mean exercise time to produce angina improved from 5.7 +/- 0.3 minutes (mean +/- standard error of the mean) in patients on placebo, to 7.9 +/- 0.5 minutes in those on nifedipine and 10.0 +/- 0.7 minutes in those on verapamil. Similar improvement was seen in all other objective variables. Generally verapamil produced mild bradycardia and nifedipine mild tachycardia. Four patients complained of palpitations and angina after ingestion of nifedipine and were identified by ambulatory monitoring to have tachycardia and persistent S-T depression. These opposite effects on heart rate may explain the differences in efficacy between these 2 potent calcium ion antagonists.

Objective evaluation of three dose levels of diltiazem in patients with chronic stable angina.

Twenty-one patients with chronic stable angina were treated with the calcium antagonist diltiazem. Dose titration studies involving 180, 270 and 360 mg/day were conducted using a blinded objective protocol. Improvement in exercise tolerance was observed at all dose levels, but the best reduction of anginal attacks and glyceryl trinitrate consumption, enhancement of exercise capacity and improvement of objective ischemic variables were observed with the 360 mg/day dose. The mean exercise time to produce grade II angina on treadmill walking increased from 5.6 +/- 0.7 minutes on placebo to 7.9 +/- 0.8 minutes on diltiazem 180 mg/day (probability [p] less than 0.001), 8.0 +/- 0.8 minutes on 270 mg/day and 9.5 +/- 0.9 minutes on 360 mg/day (p less than 0.001 as compared with 270 mg/day). One patient was withdrawn at the 360 mg/day dosage because of pedal edema. The 24 hour Holter monitoring data confirmed the findings on exercise testing, and left ventricular function was not altered with any dose level. Diltiazem in doses ranging from 180 to 360 mg/day is another powerful antianginal agent in the calcium antagonist group producing excellent therapeutic benefit in chronic stable angina with no adverse effects on left ventricular function.

Short- and long-term efficacy of nicardipine, assessed by placebo-controlled single- and double-blind crossover trials in patients with chronic stable angina

The efficacy of nicardipine, a new calcium ion antagonist, was studied in 39 patients aged 42 to 70 years with chronic stable angina in two different placebo-controlled single- and double-blind crossover trials and with long-term follow-up, using serial quantitated exercise testing and ambulatory ST segment monitoring. In the first study the minimal effective dose was determined, and in the repeat study the effects of three different dose levels were evaluated. Treadmill exercise testing was performed at the end of each 2 week treatment period with on-line computer analysis of the electrocardiogram. The mean (+/- standard error of the mean) exercise time was 6.8 +/- 0.7 minutes on placebo and 7.0 +/- 0.8 minutes during treatment with nicardipine, 60 mg/day (p = NS). This increased to 8.7 +/- 0.8 (p less than 0.001) and 9.2 +/- 0.9 minutes (p less than 0.001) with 90 and 120 mg/day, respectively. The mean heart rate at rest during placebo administration was 75 +/- 2 beats/min and increased to 85 +/- 3, 84 +/- 2 and 88 +/- 3 beats/min (p less than 0.02, p less than 0.01, p less than 0.01, respectively) at each dose level. The time taken to develop 1 mm of ST segment depression was prolonged from 4.8 +/- 0.6 minutes during placebo administration to 5.3 +/- 0.7 (p = NS), 6.4 +/- 0.7 (p less than 0.01) and 6.7 +/- 0.8 minutes (p less than 0.001), respectively, at each dose level. The improvement achieved after 2 weeks of nicardipine, 120 mg daily, was maintained over a period of 6 months of follow-up. Three patients were withdrawn, one taking 60 mg of nicardipine, one taking 90 mg of nicardipine and one taking placebo, but the overall incidence of side effects was low. Nicardipine is an effective antianginal agent with an optimal dose of 90 to 120 mg/day.

Randomized double-blind comparison of gallopamil and propranolol in stable angina pectoris

A new calcium ion antagonist, gallopamil, 150 mg/day, was compared with propranolol, 240 mg/day, in 20 patients with stable chronic angina. The patients were studied in a randomized, placebo-controlled, double-blind, crossover trial. Multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and at the end of each 4-week active treatment period. The mean (+/- standard error of the mean) exercise time to development of angina was 5.4 +/- 0.3 minutes with placebo; this increased to 9.4 +/- 0.7 minutes with propranolol (p less than 0.001) and 10.1 +/- 0.7 minutes with gallopamil (p less than 0.001 vs placebo; difference not significant vs propranolol). Both drugs significantly prolonged the time to development of 1 mm of ST depression. Five patients became free of angina during treadmill testing with gallopamil therapy and 2 with propranolol. Both drugs decreased the heart rate at rest; propranolol also decreased the maximal exercise heart rate, which was slightly increased with gallopamil. With the exception of 1 patient in whom raised liver enzymes developed, gallopamil was well tolerated. Thus, gallopamil is an effective antianginal agent that has few of the unwanted effects associated with other calcium channel-blocking drugs.

Rationale for the choice of calcium antagonists in chronic stable angina

The effectiveness and safety of verapamil, nifedipine, and placebo in patients with chronic stable angina pectoris were evaluated and compared in two double-blind randomized crossover trials. In the first study, nifedipine (10 mg 3 times daily) was compared with placebo in 24 patients with chronic effort-related angina pectoris; no significant differences in exercise performance were observed with nifedipine compared with placebo. In the second study, the effects of verapamil (120 mg 3 times daily), nifedipine (20 mg 3 times daily), and placebo were compared in 32 patients with chronic stable angina using a double-blind crossover study design. Compared with placebo, both nifedipine and verapamil prolonged exercise duration (5.7 +/- 0.3 minutes with placebo, 7.9 +/- 0.5 minutes with nifedipine [p less than 0.001], and 10.0 +/- 0.7 minutes with verapamil [p less than 0.001]), but the improvement with verapamil was greater than that seen with nifedipine (p less than 0.01). Seven patients had increasing angina with nifedipine, none did with verapamil; the exacerbation of angina during nifedipine therapy appeared related to our observation that, compared with placebo, patients receiving nifedipine had higher heart rates, while patients receiving verapamil had slower heart rates. This study indicates that, at the doses used, verapamil was more effective and better tolerated than nifedipine in patients with chronic stable angina pectoris.

Long-term antianginal action of verapamil assessed with quantitated serial treadmill stress testing

The long-term efficacy of verapamil in a dose of 360 mg daily in patients with chronic stable angina pectoris was assessed by quantitated serial treadmill exercise tests. Twenty-eight patients were investigated with a placebo-controlled, double-blind, crossover protocol of 2 weeks each and afterward all patients were put on long-term therapy. Exercise tests were performed at the end of the placebo period and after 2, 4, 8, 16, 24 and 52 weeks of verapamil therapy. All 28 experienced angina during treadmill tests on placebo and the mean (+/- standard error of the mean) exercise time was 6.6 +/- 0.5 minutes. This increased to 9.2 +/- 0.8 minutes at 2 weeks and 50 11.2 +/- 0.8 minutes at 4 weeks. Fifteen and 20 of the 28 patients became angina-free during treadmill exercise at 2 and 4 weeks, respectively. The consumption of nitroglycerin showed a similar improvement. The improvement was maintained at 1 year of follow-up. The on-line computer-analyzed S-T segment changes showed a statistically significant improvement at all follow-up periods. Withdrawal of verapamil produced a return to pretreatment levels. The adverse effects noted were constipation in seven patients and reversible P-R interval prolongation in two. No heart failure occurred in any patient. These findings suggest that verapamil possesses a powerful and sustained antianginal action and, in a dose of 360 mg daily, merits a place as a primary therapeutic agent in the management of chronic stable angina.

Reproducibility of multistage graded exercise testing in patients with chronic stable angina

Exercise testing is widely used for the diagnosis of ischaemic heart disease and for the evaluation of antianginal drugs. To assess reproducibility, analysis was carried out on 128 paired graded exercise tests from 103 patients performed at the same time of day and under identical conditions. Six different parameters were evaluated and compared between the basal test (no treatment) and the placebo test. During the basal period the mean (+/- SEM) exercise time to the development of angina was 6.0 (+/- 0.2) min and the 1 mm ST depression time was 4.1 (+/- 0.2) min. After 2 weeks of placebo the exercise time was 6.1 (+/- 0.2) min (P = NS) and the 1 mm ST depression time was 4.2 (+/- 0.2) min (P = NS). There was no significant difference between the resting or maximum heart rate on either test and the maximum ST segment depression (leads CM5 and CC5) was unaltered. In a second group of 17 patients where the basal tests were performed in the afternoon and the placebo tests in the morning, heart rate and ST segment were found to be reproducible but there was a significant difference in exercise time: 5.7 (+/- 0.7) min for the basal test and 8.3 (+/- 0.5) min for the placebo test (P less than 0.001); and of the 1 mm ST depression time: 2.7 (+/- 0.4) min for the basal test, and 5.4 (+/- 0.5) min for the placebo test (P less than 0.001). We conclude that exercise tests done under standardised conditions in the morning are highly reproducible in patients with chronic stable angina and therefore provide a valuable test for the evaluation of antianginal drugs.

Long-term efficacy of diltiazem assessed with multistage graded exercise tests in patients with chronic stable angina pectoris

The long-term efficacy of diltiazem, 360 mg/day, in patients with grade II or III stable exertional angina pectoris (Canadian Cardiovascular Society criteria) was assessed by multistage graded exercise tests. Seventeen patients undertook a placebo-controlled, double-blind, dose-titration protocol and all received long-term therapy. Exercise tests were performed at the end of 2 weeks of placebo treatment and after 6, 18, 26, 40 and 52 weeks of diltiazem, 360 mg/day. All patients had angina during treadmill testing with placebo and the mean (+/- standard error of the mean) exercise time was 5.8 +/- 0.7 minutes. This increased to 10.8 +/- 1.0 minutes after 6 weeks, 11.3 +/- 1.1 minutes after 18 weeks, 11.4 +/- 1.1 minutes after 26 weeks, 12.9 +/- 1.2 minutes after 40 weeks and 11.6 +/- 1.3 minutes after 52 weeks of continuous diltiazem therapy (p less than 0.001 vs placebo at all stages). Four patients were withdrawn after 26 weeks of treatment; one patient underwent coronary artery bypass surgery and 3 patients required the addition of beta-adrenoreceptor blocking agents. In 1 patient an irritant rash developed on the torso, legs and arms after 39 weeks of diltiazem and disappeared after discontinuing the drug. One patient complained of swelling and stiffness of the fingers and 3 patients complained of shoulder and elbow pain. Another patient had a myocardial infarction after 8 weeks of diltiazem treatment and died. No other adverse effects were observed during this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Does placebo improve indexes of effort-induced myocardial ischemia? An objective study in 150 patients with chronic stable angina pectoris

The effects of placebo were studied in 150 patients (135 men, 15 women) aged 42 to 75 years with stable exertional angina pectoris, using multistage graded exercise testing. Treadmill exercise, using on-line computer analysis of the electrocardiogram, was performed after a basal period, during which time the patients had no treatment for 2 weeks, and after 2 weeks of placebo therapy. Mean exercise time during no treatment was 6.0 +/- 0.2 minutes and during placebo was 6.1 +/- 0.2 minutes (difference not significant). Similarly, time to development of 1 mm of ST-segment depression of 4.0 +/- 0.2 minutes without treatment was 4.1 +/- 0.2 minutes after 2 weeks of placebo therapy (difference not significant). Placebo failed to show any effect on rest or maximal heart rate or on maximal ST-segment depression. It also failed to increase exercise tolerance or to improve other objective indexes of effort-induced myocardial ischemia in both single-and double-blind protocols in patients with stable exertional angina pectoris. Therefore, placebo control of antianginal drug trials that use exercise testing for evaluation of effect is unnecessary and can be omitted.