V.Bala Subramanian

VERAPAMIL IN CHRONIC STABLE ANGINA: A Controlled Study with Computerised Multistage Treadmill Exercise

Abstract The efficacy of verapamil (360 mg daily) in the treatment of patients with chronic stable angina pectoris was compared with placebo. 28 patients were studied in a placebo-controlled double-blind crossover trial of 2 weeks each and afterwards on long-term verapamil. Exercise tests were performed at the end of the placebo period, and after 2 weeks and 4 weeks on verapamil. On placebo, angina developed in all 28 patients during treadmill tests; the mean exercise time was 6·6 min (SEM ±0·5 min). The mean exercise time increased to 9·2 (±0·8) min at 2 weeks, and 11·2 (±0·8) min at 4 weeks on verapamil. In 15 and 20 patients out of the 28 angina did not develop during treadmill exercise at 2 and 4 weeks respectively. Trinitrin consumption also decreased. There was a significant improvement in ST-segment changes. Constipation (in 7 patients) and reversible PR-interval prolongation (in 2 patients) were the only side effects. No patient had clinical signs of heart-failure. Thus verapamil (360 mg daily) may be useful in the management of chronic stable angina.

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.

Hemodynamic and clinical effects of combined verapamil and propranolol therapy in angina pectoris

Abstract Because of their common negative chronotropic and inotropic effects, combined therapy of beta-adrenergic blocking drugs and calcium channel antagonists has long been feared to produce synergistic cardiodepressant effects. To evaluate whether such fears are justified when such therapy is used in patients with angina pectoris, five hemodynamic and clinical studies were reviewed. These studies indicated that in patients with preserved ventricular function treated with low or moderate doses of propranolol, verapamil produced little change in cardiac performance; this finding was not significantly different from the effects of verapamil in the absence of beta-blockade. In patients receiving large doses of propranolol, verapamil produced modest but significant cardiodepressant effects; these could be avoided by withdrawal of propranolol for 24 hours. Adverse reactions, when they occurred, were primarily hemodynamic rather than electrophysiologic. Short-term (48 hours) and long-term (4 weeks) randomized controlled trials, which objectively evaluated exercise tolerance in patients with angina pectoris, demonstrated that combined therapy of verapamil and propranolol was superior not only to placebo but also to either drug alone. In patients with preserved left ventricular function, the incidence of adverse effects with combined therapy was small (less than 10%) but increased to 25% in patients with poor left ventricular performance (ejection fraction less than 30%). Combined therapy of nifedipine and propranolol also produced adverse hemodynamic and clinical reactions. Combined therapy of beta-adrenergic and calcium channel antagonists can provide substantial clinical benefits for patients with angina pectoris who remain symptomatic with either agent used alone. Because adverse effects can occur, however, patients being considered for such treatment need to be carefully selected and observed.

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)

Comparison of diltiazem at two dose levels with propranolol for treatment of stable angina pectoris

Two dose levels of diltiazem with propranolol were compared in the management of chronic stable angina. Two groups of patients were treated for alternate periods of 4 weeks with each drug in a double-blind crossover with computer-assisted maximal treadmill tests and ambulatory ST-segment monitoring for evaluation of efficacy and safety. In 12 patients who received diltiazem, 180 mg/day, the time to development of angina increased from 5.9 +/- 0.7 minutes (+/- standard error of the mean) during placebo treatment to 8.3 +/- 0.8 minutes during diltiazem treatment and to 9.2 +/- 0.8 minutes with propranolol, 240 mg/day. Three patients became angina-free when they were treated with both drugs. Among 12 patients who received diltiazem, 360 mg/day, 1 patient became angina-free during treatment with both drugs and 1 became angina-free with diltiazem only. The mean exercise time increased from 5.8 +/- 0.7 minutes with placebo to 8.6 +/- 1.0 minutes with diltiazem, 360 mg/day, and to 8.2 +/- 0.6 minutes with propranolol, 240 mg/day. Analysis of variance showed no difference in efficacy between the 2 doses of diltiazem or between the 2 drugs. Ambulatory heart rate was reduced both during the day and at night with both drugs and significantly more with propranolol than with diltiazem treatment. Except for 1 patient in whom a rash developed when given diltiazem, 180 mg/day, and another who had both a rash and first-degree heart block with diltiazem, 360 mg/day, both drugs were well tolerated. Thus, diltiazem in a daily dose of 180 or 360 mg/day is as effective as propranolol for the treatment of chronic stable angina.

Changes of Q wave amplitude during exercise for the prediction of coronary artery disease

We have examined the changes of Q wave amplitude during exercise in 156 patients with chest pain with a view to improving the accuracy of stress testing for the diagnosis of coronary artery disease. Coronary arteriography showed significant disease in 127 patients and normal arteries or minimal disease in 29. The Q wave amplitude was measured in lead CM5 from the computer-derived average of 25 consecutive beats immediately before and at the peak of maximal treadmill exercise. The amplitude was greater in the normal subjects at rest and increased with exercise, but the reverse occurred in those with coronary disease. Using the criterion of decrease or no change of Q wave amplitude during exercise as indicating a positive test, the discriminative capacity of Q wave changes was equivalent to that of ST segment depression and was maintained when patients with myocardial infarction were excluded. Using either an abnormal Q wave or ST segment response to exercise improved the tests sensitivity with a loss of specificity but no change of predictive value. In 42% of patients with coronary disease when both the Q wave and ST segment exercise responses were abnormal coronary disease was predicted with an accuracy of 91%. Analysis of subgroups of patients with coronary artery disease suggested a possible explanation for the observed changes in Q wave amplitude, measurement of which can improve the stress tests accuracy for predicting obstructive coronary artery disease.