Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind placebo-controlled comparison of verapamil and propranolol

The effectiveness and safety of the beta-adrenergic blocking agent propranolol and the calcium channel antagonist verapamil were compared in 22 patients with chronic stable angina pectoris using a double-blind randomized placebo-controlled crossover protocol. The double-blind phase was preceded by a 2 week single-blind placebo period, followed by randomization to either 4 weeks' therapy with verapamil, 360 mg/day, or propranolol, 240 mg/day, followed by crossover to the other drug. Both verapamil and propranolol increased exercise tolerance (5.5 +/- 0.4 minutes with placebo, 7.8 +/- 0.5 minutes with propranolol [p less than 0.001], and 9.1 +/- 0.5 minutes with verapamil [p less than 0.001]), but the increase with verapamil was significantly greater (p less than 0.01). Both drugs prolonged the exercise duration to 1 mm S-T depression (3.3 +/- 0.4 minutes with placebo, 5.7 +/- 0.5 minutes with propranolol [p less than 0.001] and 5.5 +/- 0.6 minutes with verapamil [p less than 0.001]); the degree of improvement was similar with both active drugs. Both drugs decreased the resting heart rate (76 +/- 3 beats/min with placebo, 56 +/- 2 beats/min with propranolol [p less than 0.001], and 71 +/- 3 beats/min with verapamil [p less than 0.01]), but the heart rate decreased more with propranolol than with verapamil (p less than 0.001). Neither drug produced significant adverse reactions. This study, along with 8 similar double-blind placebo-controlled randomized investigations which have compared verapamil with propranolol, indicate that verapamil is as effective and safe as propranolol in relieving symptoms and improving exercise tolerance in patients with chronic stable angina pectoris and may be considered a first-line therapeutic agent in patients with ischemic heart disease.     

Usefulness of bevantolol for chronic, stable angina pectoris

An objective assessment of the efficacy of bevantolol was performed in 21 patients with chronic, stable angina using computer-assisted exercise testing and ambulatory ST-segment monitoring. Given once daily, 200 mg of bevantolol was compared with 200 mg of bevantolol given twice daily and with placebo, using a double-blind crossover technique. The mean exercise time with placebo was 7.4 +/- 0.6 minutes; this increased to 10.6 +/- 0.9 minutes (p less than 0.001) with once-daily bevantolol and to 9.4 +/- 0.9 minutes (p less than 0.001) with twice-daily bevantolol. The mean heart rate at rest was 80 +/- 3 beats/min with placebo; it decreased to 63 +/- 2 beats/min (p less than 0.001) with once-daily bevantolol and to 66 +/- 2 beats/min (p less than 0.001) with twice-daily bevantolol. The maximum exercise heart rate of 118 +/- 6 beats/min with placebo was reduced to 99 +/- 4 beats/min (p less than 0.001) on once-daily and 101 +/- 4 beats/min (p less than 0.001) on twice-daily bevantolol. There was a corresponding decrease in the rate-pressure product. The corrected maximum ST-segment depression was reduced from 0.3 +/- 0.06 mm min-1 with placebo to 0.2 +/- 0.03 mm min-1 (p less than 0.02) with once-daily and 0.2 +/- 0.04 mm min-1 (p less than 0.05) with twice-daily bevantolol. The mean hourly ambulatory heart rate was significantly reduced for 21 hours with once-daily and 22 hours with twice-daily bevantolol. The lowest mean minimum heart rate was 55 beats/min during twice-daily treatment. The mean number of episodes of ST depression over 24 hours in lead CM5 was decreased from 6.89 +/- 1.7 with placebo to 2.50 +/- 0.6 (p less than 0.001) with once-daily and to 3.72 +/- 1.3 (p less than 0.001) with twice-daily bevantolol. Three patients were withdrawn during the once-daily bevantolol regimen due to adverse experiences, and another patient was admitted for coronary artery bypass surgery after 25 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of nicardipine and verapamil in the management of chronic stable angina

Twenty-two patients with stable angina were studied in a randomised double-blind, placebo-controlled crossover trial to compare the antianginal effects of nicardipine (30 mg) and verapamil (120 mg), each given three times a day. Efficacy was assessed using treadmill exercise testing and 24-hour ambulatory electrocardiographic monitoring performed after an initial 2-week placebo phase and at the end of each 4-week active treatment period. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 min on placebo to 8.4 +/- 0.7 min on nicardipine (P less than 0.05) and to 9.9 +/- 0.7 min on verapamil (P less than 0.001). Resting heart rate was decreased by verapamil (P less than 0.002) and increased by nicardipine (P less than 0.02). Exercise heart rate was increased on nicardipine (P less than 0.005) but heart rate gain was higher on verapamil (P less than 0.01). Blood pressure and peak ST segment depression were unaltered by either drug but the time to 1 mm ST segment depression increased on both drugs. Ambulatory heart rates were lower on verapamil than on nicardipine and patient subjective preference was in favour of verapamil. This study confirms that both nicardipine and verapamil improve exercise capacity, but verapamil produces a greater improvement in exercise tolerance and indices of myocardial ischaemia whilst nicardipine is associated with an increase in the number of episodes of ST segment depression on ambulatory monitoring.     

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.     

Double-blind randomized crossover trial of verapamil and propranolol in chronic stable angina

Propranolol (240 mg daily) and verapamil (360 mg daily) were objectively compared for their respective efficacy in the treatment of chronic stable angina pectoris. Twenty-two patients were studied in a randomized placebo controlled, double-blind crossover trial with 4 weeks on each active drug treatment. Multistage treadmill exercise with computer-assisted ECG analysis was performed after 2 weeks on placebo and at the end of each 4-week active drug treatment. The mean exercise time to produce angina was 5.5 minutes (SEM +/- 0.4 minutes) on placebo and this increased to 7.8 (+/- 0.5) minutes on propranolol and 9.1 (+/- 0.5) minutes on verapamil. The improvement in exercise time of verapamil over propranolol was statistically significant (p less than 0.01). Ten patients became free of angina with verapamil and four with propranolol. Resting and maximal exercise heart rates were significantly reduced by propranolol; verapamil did not reduce the maximal heart rate but reduced the resting heart rate slightly. However, the heart rate increase per minute of exercise was significantly diminished (p less than 0.001). ST segment changes showed improvement with both drugs despite marked differences in heart rate profile. The overall efficacy of the slow calcium channel blocker, verapamil, compares favorably with that of a standard beta-adrenoreceptor blocking drug (propranolol), thus providing a new perspective in the management of angina pectoris. These two classes of drugs seem to act by different mechanisms and it is suggested that if patients are resistant or intolerant to one of these drugs, the other can be used to yield a beneficial response.     

Comparison of bevantolol and atenolol in chronic stable angina

A randomized, double-blind, parallel-group study design was used to compare the antianginal efficacy of bevantolol (200 to 400 mg) and atenolol (50 to 100 mg) each administrated once daily for 8 weeks in 39 patients with chronic stable angina. Assessments were made using 24-hour ambulatory monitoring and treadmill exercise testing performed 22 to 24 hours after the last dose of medication. Both groups were comparable at the end of the placebo phase. In the bevantolol group, exercise time increased from 7.9 +/- 0.7 minutes with placebo to 9.3 +/- 0.7 minutes with bevantolol (mean +/- standard error of the mean) (p less than 0.05). Time to 1 mm ST depression was unaltered. Rest and exercise heart rate decreased (p less than 0.0001 and less than 0.0005, respectively) as did exercise double product (p less than 0.0001). In the atenolol group exercise time increased from 7.1 +/- 0.7 minutes with placebo to 8.2 +/- 0.8 minutes with atenolol (p less than 0.02). Time to 1 mm ST depression increased (p less than 0.005) and rest and exercise heart rate and double product decreased (p less than 0.0001 and less than 0.05, respectively). When within-group differences between placebo and active drug were compared for bevantolol and atenolol, no significant differences were detected. Both drugs were well tolerated and reduced ambulatory heart rate throughout the 24 hours. This study confirms that both bevantolol and atenolol are effective antianginal agents. Bevantolol compares well with atenolol in the treatment of patients with chronic angina, and there was a similar response to exercise testing with the 2 drugs.     

Antianginal efficacy of carvedilol, a beta-blocking drug with vasodilating activity

The efficacy of carvedilol, a new vasodilating beta-blocking drug, was evaluated in 20 patients with chronic angina using a single-blind, placebo-controlled protocol. A 2-week placebo phase was followed by therapy with carvedilol, 25 mg twice daily for 2 weeks, after which the dose was doubled. There was then a second placebo phase lasting 2 weeks. Treadmill exercise testing, 24-hour ambulatory electrocardiographic monitoring and drug blood level assays were performed at the end of each phase. Exercise time (mean +/- standard error of mean) increased from 7.4 +/- 0.5 minutes during placebo to 9.0 +/- 0.5 minutes carvedilol, 25 mg twice daily (p less than 0.001), and to 9.2 +/- 0.4 minutes with 50 mg twice daily (p less than 0.001). Mean time to 1 mm of ST depression in both bipolar leads CM5 and CC5 increased significantly, but peak ST depression did not change. Heart rate at rest was reduced at both dose levels, from 86 +/- 4 beats/min during placebo to 70 +/- 2 beats/min with 25 mg twice daily (p less than 0.001) and to 67 +/- 3 beats/min with 50 mg twice daily (p less than 0.001). Systolic blood pressure at rest was significantly reduced at both doses (p less than 0.05; p less than 0.01), but blood pressure during exercise was decreased only with the larger dose (p less than 0.001). The exercise rate-pressure product was 182 +/- 9 with placebo and decreased to 153 +/- 5 with 25 mg twice daily (p less than 0.001) and to 138 +/- 6 with 50 mg twice daily (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Comparison of verapamil versus propranolol therapy in syndrome X

The effects of oral verapamil, 320 mg daily, propranolol, 120 to 160 mg daily, and placebo were compared in 16 patients presenting with transient myocardial ischemia without evidence of coronary atherosclerosis or vasospasm on angiography (syndrome X). Testing was done according to a randomized double-blind crossover placebo-controlled trial consisting of 3 consecutive 7-day treatment periods with verapamil or propranolol or placebo. Patients underwent continuous 48-hour electrocardiographic monitoring before therapy (run-in phase) and during the last 2 days of each treatment period. A total of 391 episodes of diagnostic (greater than or equal to 0.15 mV) ST depression was recorded during the trial. Of these, 23 were symptomatic. None of the episodes occurred while the patients were asleep, 25% during exercise, 35% during minimal physical activity and 40% at rest. Rest included activities demanding mental arousal (conversation, reading or watching television). Heart rate at the onset of ST depression was higher (greater than or equal to 10 beats/min) than that observed in the 5 minutes preceding ischemia in 95% of the episodes. In the group as a whole, the average number of ischemic episodes per 24 hours was significantly reduced during propranolol therapy compared with placebo (0.7 +/- 0.6 vs 3.9 +/- 1.8; p less than 0.0005). No significant differences were seen during verapamil treatment (3.4 +/- 1.7 vs 3.9 +/- 1.8). It is concluded that transient myocardial ischemia in syndrome X is mostly precipitated by an increase in oxygen consumption, presumably due to a heightened sympathetic activity. Accordingly, beta blockers may represent the first line of treatment.     

Effect of propranolol on indices of intermittent myocardial ischemia, assessed by exercise testing and ambulatory ST-segment monitoring

Seventy three patients (63 males and 10 females) aged 41-75 years with established stable exertional angina pectoris were studied in a double-blind fashion to confirm the efficacy of 80 mg propranolol administered three times daily and also to examine its effect on ST-segment changes in the electrocardiogram by ambulatory ST-segment monitoring and exercise testing using on-line computer analysis. During ambulatory monitoring, episodes of ST-segment depression in lead CM5 were significantly reduced from 6.5 +/- 0.7 during placebo to 3.4 +/- 0.6 during propranolol therapy (p less than 0.001). The total duration of ST-segment depression was also significantly reduced and the maximal depth of ST-segment depression improved from 2.6 +/- 0.2 mm during placebo to 1.7 +/- 0.2 mm during propranolol therapy (p less than 0.001). The mean +/- SEM exercise time of 5.5 +/- 0.2 minutes on placebo increased to 8.6 +/- 0.4 minutes on propranolol 240 mg daily (p less than 0.001). The 1 mm ST-segment depression time of 3.5 +/- 0.2 minutes on placebo in lead CM5 was prolonged to 6.2 +/- 0.3 minutes during propranolol therapy (p less than 0.001). Propranolol treatment significantly reduced the resting and maximal heart rates (p less than 0.001). The maximal ST-segment depression during exercise in lead CM5 was reduced from 2.3 +/- 0.1 mm on placebo to 1.9 +/- 0.1 mm with propranolol (p less than 0.01). Similarly, the rate-pressure product at peak exercise of 188 +/- 5 units on placebo was reduced to 144 +/- 3 units with propranolol (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination of verapamil and beta blockers in systemic hypertension

The efficacy and safety of verapamil and propranolol were examined in 14 hypertensive patients (mean age 51.2, range 30 to 65) in a double-blind, randomized, crossover study of verapamil, 360 mg, propranolol, 240 mg, these 2 formulations in combination and placebo, each given for 4 weeks. Supine blood pressure, heart rate, atrioventricular conduction (PR interval) and left ventricular function were measured. All treatments reduced diastolic blood pressure (mean +/- standard deviation) (p less than 0.001): placebo to 106.6 +/- 8.1 mm Hg; propranolol to 93.8 +/- 7.7; verapamil to 89.8 +/- 7.8; the combination to 84.1 +/- 6.1, but the effect of the combination was significantly greater than that of either drug alone (p less than 0.05). Heart rate at rest (placebo, 80.2 +/- 12.2 beats/min) was reduced by propranolol (63.3 +/- 9.4, p less than 0.001), but not by verapamil (79.0 +/- 8.9). However, the addition of verapamil to propranolol led to a further reduction in heart rate (56.9 +/- 8.4, p less than 0.005). PR interval was prolonged significantly by the combination (185.5 +/- 35.3 ms) when compared with placebo (154.0 +/- 22.7); propranolol (159.1 +/- 21.2) and verapamil (165.5 +/- 32.4) (p less than 0.005 for each). The active drugs increased end-diastolic dimension and end-systolic dimension. For each variable, the effect of the combination was statistically significant (p less than 0.01). Fractional shortening was not altered significantly by any of the treatments. Thus verapamil plus propranolol is a very effective antihypertensive combination but heart rate, atrioventricular conduction and left ventricular function may be affected adversely, necessitating careful monitoring of therapy.     

Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris

The effects of L-carnitine (900 mg, p.o. daily) on exercise performance were studied in 12 patients with stable effort angina using a multistage treadmill exercise test. Exercise tests were performed at the end of the placebo period and after 4 and 12 weeks of carnitine therapy. While 12 patients experienced angina during treadmill tests in the placebo period, 2 patients were free of angina after treatment with carnitine. The mean exercise time was 11.4 +/- 0.7 min (mean +/- SE) in the placebo period. This increased significantly to 12.2 +/- 0.5 min (p less than 0.05) after 4 weeks and 12.8 +/- 0.5 min (p less than 0.01) after 12 weeks of treatment with carnitine. The time required for 1 mm ST depression to occur was 6.4 +/- 0.9 min in the placebo period. This increased significantly to 7.6 +/- 0.9 min (p less than 0.01) after 4 weeks and 8.8 +/- 1.0 min after 12 weeks of treatment with carnitine. There was significantly less ST segment depression during the same exercise load after 12 weeks of treatment as compared with that in the placebo period (p less than 0.05). The heart rate and the pressure rate product at the same work load showed no significant difference among the 3 testing periods. The results of this study suggest that L-carnitine may improve exercise tolerance in patients with effort angina.     

Diltiazem dose responses in sustained therapy for stable angina pectoris

Fifteen patients with stable effort angina were treated for 2 weeks with each of diltiazem 120 mg, 240 mg, 360 mg or placebo in a double-blind crossover protocol. The frequency of angina was decreased from 7.2 +/- 1.1 (mean +/- S.D.) episodes per 2 weeks with placebo to 5.9 +/- 5.2 (N.S.), 4.1 +/- 1.1 (p less than 0.01) and 1.5 +/- 0.8 (p less than 0.005) with 120 mg, 240 mg and 360 mg diltiazem respectively. Similar decreases occurred in nitroglycerin consumption. Ten hours after the last dose of each treatment period, each patient was challenged with 120 mg diltiazem. Treadmill exercise testing was carried out at 0, 1, 2, 4 and 8 hours. Time to onset of angina and 0.1m V ST depression increased at 1 hour, was maximal at 2 and 4 hours, and remained elevated at 8 hours. Two weeks of sustained treatment with diltiazem did not alter the responses in treadmill performance to 120 mg diltiazem. Hemodynamic changes were consistent with decreased myocardial oxygen demand and increased myocardial oxygen supply by diltiazem. There was no significant attenuation of hemodynamic response with sustained therapy. Trough plasma levels of diltiazem at 10 hours following the last dose of sustained therapy varied in a dose-dependent manner. However, corresponding exercise tolerances were identical regardless of the plasma level. Peak drug levels at 4 hours following 120 mg aldo did not correlate with exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Usefulness of severity of myocardial ischemia on exercise testing in predicting the severity of myocardial ischemia during daily activities

To determine the relation between myocardial ischemic indexes on exercise testing and on ambulatory Holter recording, 60 patients with stable coronary artery disease who exhibited an ischemic response to both testing procedures were studied. All patients performed a Bruce protocol exercise test and underwent 24-hour Holter recording within 2 weeks without antianginal medications. Mean exercise duration was 7.4 +/- 2.8 minutes, mean heart rate at 1-mm ST depression was 118 +/- 20 beats/min and mean maximal ST depression during exercise was 2.2 +/- 1 mm. During Holter recording the average number of ischemic episodes was 4.7 +/- 2.6 per patient, mean duration of daily ischemia was 62 +/- 54 minutes, mean maximal ST depression was 3.2 +/- 1.3 mm and average heart rate at 1-mm ST depression was 93 +/- 17 beats/min. Overall, the correlations between ischemic indexes on both testing procedures were very weak (mean r2 = 0.054). The only exercise variable that had a significant correlation (p less than 0.05) with all Holter variables was heart rate at 1-mm ST depression, yet it correlated very weakly (0.064 less than or equal to r2 less than or equal to 0.125) with most Holter covariates and had a better correlation (r2 = 0.256) only with average heart rate at 1-mm ST depression during Holter. Thus, ischemic indexes on exercise testing cannot accurately predict ischemic indexes on ambulatory Holter recording in patients with stable coronary artery disease who exhibit ischemic changes on both tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of nicardipine and propranolol for chronic stable angina pectoris

In a double-blind, randomized, crossover clinical trial, a new calcium antagonist, nicardipine (90 mg/day in 3 divided doses), was compared with propranolol (120 mg/day in 3 divided doses) in 25 patients with chronic stable angina. The mean weekly frequency of angina episodes decreased from 7.8 +/- 1.2 (+/- standard error of the mean) with placebo to 3.8 +/- 1.2 with nicardipine treatment and 3.5 +/- 1 with propranolol treatment (p less than 0.001). With exercise testing, 5 patients receiving nicardipine and 3 receiving propranolol had no angina or ST-segment changes. Comparing paired samples of both drugs with placebo, significant improvement occurred in exercise duration (nicardipine, 1.3 +/- 0.3 minutes, p less than 0.001; propranolol, 1.0 +/- 0.4 minutes, p less than 0.01), time to onset of angina (nicardipine, 1.5 +/- 0.4 minutes, p less than 0.001; propranolol, 1.5 +/- 0.5 minutes, p less than 0.001), maximal ST-segment changes (nicardipine, 0.7 +/- 0.1 mm, p less than 0.01; propranolol, 0.06 +/- 0.1 mm, p less than 0.01) and time to 1 mm of ST depression (nicardipine, 2.5 +/- 0.4 minutes, p less than 0.01; propranolol, 2.0 +/- 0.3 minutes, p less than 0.01). One patient receiving propranolol and 2 receiving nicardipine withdrew from the study because of transient side effects. Mild side effects occurred in 10 patients receiving propranolol and 5 receiving nicardipine. Nicardipine proved to be safe and effective for patients with chronic stable angina; it had fewer side effects than propranolol in the doses used.     

Effects of nicorandil on exercise tolerance in patients with stable effort angina: a double-blind study

Effects of nicorandil, a recently introduced 2-nicotinamidethyl nitrate, on exercise performance were studied in 11 patients with stable effort angina. The duration of exercise before the onset of angina and time to the onset of ischemic ST depression 30 minutes after 20 mg of oral nicorandil were compared with events 30 minutes after oral placebo and 5 minutes after 0.3 mg of sublingual nitroglycerin. Nicorandil and placebo were given according to the randomized double-blind method. Nicorandil prolonged the duration of exercise in all 11 patients by 2.3 +/- 2.2 minutes (mean +/- SD, p less than 0.01) and delayed the onset of ischemic ST depression by 2.3 +/- 1.7 minutes compared to placebo (p less than 0.01). The increment of the duration of exercise and the time to the onset of ischemic ST depression following 20 mg of oral nicorandil were almost equivalent to findings after sublingual nitroglycerin (by 2.0 +/- 1.8 and 2.5 +/- 1.7 minutes, respectively). Nicorandil also increased the pressure-rate product at the time of angina compared with placebo (20,420 +/- 480 vs 17,480 +/- 370, p less than 0.05). These results indicate that oral administration of nicorandil should be considered for the clinical treatment of effort angina.     

Randomized double-blind placebo-controlled comparison of nicardipine and nifedipine in patients with chronic stable angina pectoris

Forty-one patients were studied in a randomized double-blind placebo-controlled crossover trial to compare the antianginal actions of nicardipine 30 mg thrice daily and nifedipine 10 mg thrice daily. Efficacy was assessed using objective criteria from computer-assisted multistage graded exercise testing, performed after a two-week placebo run-in period and at the end of each four-week active treatment period. Thirty-seven patients completed both legs of the crossover trial. The mean (+/- standard error of the mean) baseline exercise time to development of angina was 6.7 +/- 0.4 min and this increased to 9.5 +/- 0.6 min on nicardipine (p less than 0.001) and 9.5 +/- 0.5 min on nifedipine (p less than 0.001 vs baseline; NS vs nicardipine). Both drugs significantly prolonged the time to the development of 1mm ST segment depression. The baseline resting heart rate of 83 +/- 2 beats/min increased to 87 +/- 3 beats/min during nicardipine (p less than 0.05) and remained unaltered at 83 +/- 2 beats/min during nifedipine therapy (p = NS vs baseline and p less than 0.02 vs nicardipine). Similarly, both drugs increased significantly the maximal heart rate at peak exercise. One patient was lost to follow-up during the placebo run-in period and four patients (two each on nicardipine and nifedipine) were withdrawn due to adverse effects. Our results indicate that nicardipine is comparable in efficacy to nifedipine and has a similar adverse effect profile and can also be considered a useful therapeutic agent for the treatment of chronic stable angina pectoris.     

Verapamil therapy for stable exertional angina pectoris

Clinical and exercise responses to therapy with the calcium-channel blocking agent verapamil were assessed in 26 patients with stable exertional angina pectoris using a double-blind, placebo-controlled, randomized crossover study design. Verapamil, 480 mg daily, reduced the frequency of angina attacks (5.6 +/- 7.3 to 2.2 +/- 3.0 attacks per week, p less than 0.001) and number of nitroglycerin tablets consumed (3.4 +/- 4.9 to 1.2 +/- 2.5 tablets per week, p less than 0.05), and increased exercise duration (6.4 +/- 2.1 to 7.5 to 1.8 minutes, p less than 0.001) (all data are mean +/- standard deviation). These changes were significantly better than those seen with placebo. These beneficial effects of verapamil were related to significant reduction in the heart rate-systolic blood pressure product during submaximal exercise. Adverse effects from verapamil were few and consisted primarily of constipation in 6 patients. A total of 193 patients had been entered in 6 independent clinical trials, which have compared verapamil with placebo for the treatment of stable exertional angina pectoris, using a similar study design. The combined evidence from all these studies indicates that verapamil is a highly effective and safe drug for the treatment of stable effort-related angina pectoris.     

Increased exercise tolerance and reduced duration of ischemia after isosorbide dinitrate oral spray in angina pectoris

The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 +/- 1.4 minutes with placebo to 7.2 +/- 1.3 minutes with the active drug (p less than 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 +/- 1.5 minutes with placebo to 10.2 +/- 1.2 minutes with ISDN (p less than 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 +/- 0.7 to 2.1 +/- 0.8 minutes (p less than 0.001), and the time of disappearance of electrocardiographic changes from 4.2 +/- 0.6 to 2.5 +/- 0.8 minutes (p less than 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.     

Effects of theophylline, atenolol and their combination on myocardial ischemia in stable angina pectoris

The effects of theophylline (400 mg twice a day), atenolol (50 mg twice a day) and their combination on myocardial ischemia were studied in 9 patients with stable angina pectoris in a randomized, single-blind, triple crossover trial. Placebo was administered to the patients during the run-in and the run-off periods. A treadmill exercise test and 24-hour ambulatory electrocardiographic monitoring were obtained at the end of each treatment period. Compared with placebo, theophylline significantly improved the time to onset of myocardial ischemia (1 mm of ST-segment depression) from 7.8 +/- 3.7 to 9.5 +/- 3.7 minutes (p less than 0.03) and the exercise duration from 9 +/- 3.4 to 10.1 +/- 3.5 minutes (p less than 0.04). During atenolol and during combination treatment, the time to the onset of ischemia and the exercise duration were similar (10.8 +/- 4.2 and 11.2 +/- 3.2 minutes, 11.2 +/- 3.6 and 11.5 +/- 3.2 minutes, respectively) and longer than during theophylline administration (p less than 0.05). Ambulatory electrocardiographic monitoring showed that, during theophylline administration, the heart rate was higher than during placebo throughout the 24 hours (p less than 0.05). During atenolol and during combination treatment the heart rate was similar and in both cases lower than during placebo (p less than 0.05). Compared with placebo, theophylline decreased the total ischemic time from 97 +/- 110 to 70 +/- 103 minutes (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)