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.     

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris

The antianginal and anti-ischemic effect of isosorbide dinitrate (ISDN), 120 mg once daily, and nifedipine, 20 mg twice daily, both in slow-release formulations, were compared in 17 patients with variant angina pectoris in a randomized, double-blind trial. The design included a placebo run-in period and two 6-week crossover periods of active treatment. Mean frequency of angina decreased significantly from 43 attacks per week during the placebo period to 4 per week with ISDN and 8 with nifedipine (p < 0.001). Sublingual nitroglycerin consumption decreased significantly from 37 tablets per week with placebo to 3 tablets per week with ISDN and 7 with nifedipine (p < 0.001). Both drugs reduced the silent and symptomatic ST-segment deviations on ambulatory electrocardiographic recording and increased maximal exercise tolerance. Episodes of coronary spasm could be provoked, by hyperventilation, in all patients during the placebo phase but in no patient during therapy with either active drug.Thus, both ISDN and nifedipine, in their slow-release formulations, are effective in the treatment of variant angina pectoris.     

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.     

A randomized double-blind crossover study of nicardipine and nifedipine in patients with angina pectoris and concomitant essential hypertension

Summary The two dihydropyridine calcium antagonists, nicardipine and nifedipine, were compared in 12 patients with both stable angina pectoris and systemic hypertension using a double-blind, crossover protocol. After a 2-week placebo run-in period, each patient was randomized to either nicardipine or nifedipine; each drug was titrated up to either blood pressure normalization, appearance of adverse effects, or maximal dosage (40 mg, three times a day with nicardipine and 30 mg, three times a day with nifedipine) and then administered for 4 weeks. Maximal symptom-limited exercise tests were performed at the end of the placebo run-in and each treatment period, 3 and 8 hours after drug administration. Nicardipine and nifedipine were used at the mean doses of 100±20 mg/day and 57±20 mg/day, respectively. Both drugs reduced, significantly and similarly, standing and supine blood pressure, frequency of anginal episodes, and nitroglycerin consumption. At 3 hours after drug administration, exercise duration and time to 1-mm ST depression increased significantly from 402±84 and 306±108 seconds, respectively, with placebo; to 533±135 and 442±138 seconds during nicardipine; and to 518±118 and 437±133 seconds during nifedipine, with a concomitant reduction of peak ST depression. Both submaximal and maximal exercise diastolic blood pressure were significantly reduced by the two calcium antagonists whereas systolic blood pressure was decreased only at submaximal but not at maximal exercise; the heart rate was not significantly modified by the two drugs at any exercise stage. The rate-pressure product decreased from 169±17 to 151±25 with nicardipine and 152±24 with nifedipine at submaximal exercise, but was not significantly modified at the onset of 1-mm ST depression and maximal exercise. Thus, nicardipine and nifedipine showed a similar hypotensive and antianginal activity; the only important difference between the two drugs emerged from the exercise tests performed 8 hours after drug administration; although nifedipine still maintained a slight antianginal activity, nicardipine showed a significantly greater anti-ischemic and hemodynamic activity at that time.We gratefully acknowledge the technical assistance of Chiara Pioselli in the performance of the exercise tests and preparation of this report.     

Interim report of multicenter double-blind, placebo-controlled studies of nifedipine in chronic stable angina

Preliminary results from multicenter double-blind placebo-controlled studies involving crossover and parallel designs were analyzed in 32 and 34 patients with stable angina pectoris entered respectively into the two protocols. The frequency of anginal attacks and the intake of nitroglycerin were decreased about 50 percent in patients receiving nifedipine, and the difference from those on placebo was statistically significant. Similarly, exercise tolerance was significantly increased with nifedipine, as evidenced by several variables, and the degree of ischemia was believed decreased, as reflected by lesser ST segment depression at peak exercise. The heart rate-blood pressure product, an approximation of myocardial oxygen consumption, was slightly but significantly decreased at equivalent workloads, but was not significantly different from placebo at the onset of angina or at maximal exercise. Adverse reactions to nifedipine, although frequent, were generally benign and usually responded to dose adjustment or improved spontaneously. These results suggest that the calcium antagonist nifedipine is effective and safe in the treatment of chronic stable angina.     

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.     

Comparison of atenolol and nifedipine in chronic stable angina pectoris

The antiangina effects of atenolol, 50 to 200 mg once daily, or nifedipine, 10 to 30 mg 3 times daily, were evaluated in a multicenter, randomized, double-blind, parallel study of 39 patients with known symptomatic coronary artery disease. Treatment was titrated to produce at least a 30% increase in treadmill exercise duration over placebo baseline and then maintained at that dosage for an additional 3 weeks. Both treatments produced significant (p less than 0.001) increases in duration of exercise, total work and exercise capacity when compared with placebo baseline. These improvements in exercise performance were obtained with significant (p less than 0.001) reductions in both ST-segment depression and rate-pressure product for atenolol compared with nifedipine. Furthermore, the total angina attack rate and rate at rest were significantly (p less than 0.01) less frequent with atenolol than with nifedipine. Hence, the antiischemic effects of atenolol exceeded those of nifedipine, based on ST-segment depression and rate-pressure product at comparable workloads.     

Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled, randomized study

The effect of nicardipine hydrochloride, a calcium-channel blockingagent, was studied in 46 patients with stable angina in a double-blind,placebo-controlled, randomized, repeated cross-over protocol,using a 30 or 40 mg dose of nicardipine or placebo three timesa day. Mean resting heart rate and blood pressure did not changesignificantly with 30 mg nicardipine; heart rate increased from81 ±10 to 88 ±13 beats min^–1, systolic bloodpressure decreased from 129±18 to 119±16mmHg,and diastolic blood pressure from 81 ±12 to 74±11mmHg (P < 0·01 for all three variables) with a 40mg dose. Using a treadmill exercise protocol, mean exerciseduration increased from 5·4±1·8 to 6·0±1·8min (P<0·01) with 30 mg nicardipine, and from 5·8+1·7to 616+1·9 min (P<0101) with 40 mg. Time to onsetof angina increased from 4·6+1·9 to 5·2±1·7min(P<0·05) with 30 mg and from 5·1 ± 1·8to 5·7+1·8 min (P = NS) with 40 mg. Mean anginalfrequency and sublingual nitroglycerin consumption were lowduring the cross-over placebo period and did not change significantlyduring therapy with nicardipine. Non-cardiac side-effects weremild and required the withdrawal of only one patient from thestudy. However, during nicardipine therapy four patients hadunstable angina and two developed a non-Q wave myocardial infarction.Of these patients, five were receiving a ß-adrenergicblocker that was discontinued prior to the study. It is concludedthat nicardipine had only a mild positive effect on exerciseduration. As observed with other dihydropyridines, nicardipinehas the potential to precipitate important ischaemic eventsin patients with stable angina, particularly when started afterdiscontinuing a ß-adrenergic blocking agent.     

A randomized double-blind comparison of diltiazem and nifedipine in stable angina

A double-blind crossover trial comparing diltiazem (360 mg/day) and nifedipine (120 mg/day) for treatment of stable angina was conducted in 21 of 27 patients with proven coronary artery disease who completed the trial. All patients started with a 2 week placebo period followed by a random assignment to either drug treatment for 3 weeks and subsequent crossover to the other treatment. The two drug treatment periods were separated by a 1 week placebo washout phase and the study was completed with a 1 week placebo phase. There were no significant differences between patients' responses to diltiazem and nifedipine in relation to time to onset of angina, ST depression responses to exercise, heart rate or systolic or diastolic blood pressure. A total of 37 adverse effects were reported with nifedipine compared with 9 with diltiazem in the 22 patients in whom drug safety was analyzed. Additionally, two patients treated with nifedipine were withdrawn from study participation before crossover. There was a significant (p less than 0.05) difference with respect to incidence of edema (7 of 22 patients taking nifedipine, 1 of 22 taking diltiazem) and dizziness (7 of 22 patients taking nifedipine, 0 of 22 taking diltiazem). The most frequent adverse effect reported with diltiazem was rash (3 of 22 patients). Severe adverse effects were reported in four patients: in one with diltiazem (rash) and in three with nifedipine (palpitation in two and headache in one). A reduction in prescribed dosage was required in 37% of nifedipine-treated compared with 6% of diltiazem-treated patients. Efficacy measures were significantly improved above placebo levels by both diltiazem and nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm

Twelve patients were entered prospectively into a randomized double-blind study comparing the efficacy of nifedipine and isosorbide dinitrate (ISDN) in the treatment of variant angina pectoris due to coronary artery spasm. Using the diary technique, both anginal episodes and nitroglycerin tablets consumed were recorded during the pretrial, no drug period, and both active drug phases. During the baseline pretrial period, an average of 1.1 anginal episodes/day occurred with reduction to 0.28/day during nifedipine treatment and 0.39/day during ISDN treatment. Headache was the major side effect during ISDN treatment, occurring in 9 of 11 (81%) patients; and nonheart failure related pedal edema during nifedipine treatment, occurring in 4 of 12 (33%) patients. Intolerable side effects necessitating cessation of treatment occurred in two patients during nifedipine treatment and in three patients during ISDN treatment. Patients preferred nifedipine over ISDN because of increased efficacy and fewer uncomfortable side effects. We conclude that both nifedipine and ISDN are effective therapy for coronary spasm, but that nifedipine was more effective and was preferred by the majority of patients.     

Treatment of chronic stable angina pectoris with angiotensin converting enzyme inhibition--a randomized, placebo-controlled, double-blind cross-over study

To investigate the potential anti-ischaemic effects of benazepril (10 mg bid) in comparison to placebo, this new ACE-inhibitor was given to 11 patients with chronic stable angina, reproducible exercise-induced ST-segment depression and angiographically verified coronary artery disease. Blood pressure at rest, plasma renin activity, and plasma concentration of atrial natriuretic peptide were measured after treatment periods of two weeks. Bicycle exercise tests at the same time should evaluate ST-segment depression at comparable maximal workload, work capacity, blood pressure, and heart rate at exercise. In comparison to placebo, benazepril reduced arterial blood pressure significantly from 140 +/- 14/90 +/- 11 mm Hg to 125 +/- 16/84 +/- 10 mm Hg (p less than 0.05) and increased plasma renin activity from 2.19 +/- 3.76 ng/ml/h to 9.62 +/- 8.49 ng/ml/h (p less than 0.005). In contrast, ST-segment depression decreased only slightly and not significantly from 2.09 +/- 1.22 mm to 1.91 +/- 1.00 mm. Benazepril had neither an effect on the frequency of episodes of angina pectoris nor did it reduce the amount of GTN-consumption. Also, work capacity and plasma concentration of atrial natriuretic peptide were not changed in comparison to placebo. Although the significant reduction of blood pressure and the highly significant increase of plasma renin activity demonstrate the specific action of benazepril, a significant anti-ischaemic effect could not be established.     

Labealol in the treatment of stable exertional angina pectoris: a comparison with nifedipine

Labetalol, a combined alpha-and beta-receptor antagonist, wascompared with nifedipine in a placebocontrolled, randomizeddoubled-blind cross over study (four week treatment periods) of 11 normotensive patients with stable exertional anginapectoris. Standard recomended doses of both drugs (labetalol200–400 mg twice daily, nifedipine 10–20 mg threetimes daily) were used. Angina frequency was similar duringthe placebo washout period and treatment with the two drugs.The duration of treadmill exercise to angina, ischaemia (>1mm ST segment depression), and end of exercise was increasedby both labealol and nifedipine when compared with placebo,but there was no difference between the drugs. Ambulatory STsegment monitoring demonstrated that the frequency, durationand magnitude of ST segment depression, whether painful or silent,were unaffected by either drug. Labetalol is an effective agent in improving exercise tolerancein normotensive patients with stable exertional angina pectoris,with an efficacy similar to that of nifedipine.     

A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris

Summary The antianginal activities of nicorandil, 10 and 20 mg bid, and metoprolol, 100 mg bid, were compared in patients with stable effort angina pectoris in a randomized, double-blind parallel group study lasting 7 weeks. Twenty patients were enrolled into the trial and 16 patients completed the study. To evaluate the antiischemic effects of the two drugs, a treadmill exercise test was performed after a 1-week placebo run-in period and 6 weeks of treatment. On the same occasions, weekly sublingual nitroglycerine consumption and the number of anginal attacks were also recorded in the patient's diary. The total duration of exercise increased significantly with both nicorandil, 10 and 20 mg, and metoprolol (p<0.01). Similar improvements were observed in the time to onset of ischemia with both treatments (p<0.01). The double product at maximal comparable workload (MAX 1) was reduced with the two drugs (p<0.05 for nicorandil and p<0.01 for metoprolol), while at the maximal exercise time (MAX 2) it was reduced with metoprolol (p<0.01) and slightly but not significantly increased with both doses of nicorandil. Weekly sublingual nitroglycerine consumption and anginal attacks were also significantly reduced a similar manner by both treatments (p<0.01). In conclusion, nicorandil, 10 and 20 mg bid, exerted an antiischemic effect comparable with that of metoprolol in patients with stable effort angina pectoris.     

Beta-adrenoceptor antagonists plus nifedipine in the treatment of chronic stable angina pectoris

The antianginal effects of beta-adrenoceptor antagonists are achieved by a reduction in myocardial oxygen demand. This is a rational approach to treatment in patients whose angina is caused by a fixed stenosis. However, dynamic coronary vasospasm is an important factor in patients with chronic stable angina. Nifedipine increases myocardial oxygen supply by reducing coronary vascular tone and is a logical approach to treatment in these patients. For monotherapy of angina, nifedipine is less effective than the beta-adrenoceptor antagonists, but the combination has additive effects in reducing the frequency of anginal episodes and improving exercise tolerance.Plasma concentrations of nifedipine are closely related to clinical efficacy, and the variable first-pass metabolism of the drug leads to wide interindividual differences in peak concentrations and duration of action. Increasing the size of individual doses of nifedipine carries a risk of enhanced side effects due to high peak plasma concentrations. Optimal treatment may be more appropriately achieved in some patients by a slow release formulation, but with an increased frequency of administration.     

A double-blind dose-response study of amlodipine in patients with stable angina pectoris

Sixty patients (31 male, 29 female) were studied in a 4-weekdouble-blind parallel dose-response study. Patients receivedamlodipine 1.25 mg (n = 12), 2.5 mg (n = 12), 5 mg (n = 12),10 mg (n=12) or placebo (n = 12) once a day. Anti-anginal efficacywas assessed by sequential treadmill testing 24 h post-dose,frequency of anginal attacks and consumption of nitroglycerin,patient and investigator assessment. In the analysis of thefinal vs baseline total exercise time, the difference betweenthose on amlodipine and those on placebo was significant (P<0.01),(all doses). Mean total exercise time increased by 24% in theamlodipine 10 mg group compared with a 20% decrease in the placebogroup. The time to onset of angina increased by 37% in the amlodipine10 mg group, compared with a 16.5% decrease in the placebo group.Differences were statistically significant for the 1.25, 5 and10 mg amlodipine groups vs placebo. ST-segment charges and rate-pressureproduct were not affected significantly. There was a statisticallysignificant difference in angina attack frequency and nitroglycerintablet consumption (P<0.05) for all dose groups vs placebo.The majority of patients receiving amlodipine reported improvementin angina symptoms. Side-effects were frequent but mild anddose-related. Amlodipine has significant anti-anginal efficacy.The mechanisms underlying the anti-ischaemic effects of amlodipineare still under discussion.     

Nifedipine in chronic stable angina: a double-blind placebo-controlled crossover trial

Thirty patients with chronic stable angina pectoris were randomized in a double-blind prospective placebo-controlled crossover trial to assess the efficacy of nifedipine (30 to 60 mg/day orally) in controlling symptoms and objective signs of myocardial ischemia using a symptom-limited treadmill exercise test. Adverse effects that occurred during both nifedipine and placebo treatment were minor and generally well tolerated. Twenty-three patients were analyzed from the crossover phase of the study. Nifedipine significantly reduced the frequency of angina by 55% and nitroglycerin consumption by 59%, and increased exercise time by 34%. These changes were significantly greater than those in the placebo group. Hemodynamic evaluation during exercise revealed a significant reduction in systolic and diastolic blood pressures in the nifedipine group at the onset of angina and at maximal exercise without significant differences in heart rate responses in the nifedipine and placebo groups. The pressure-rate product during submaximal exercise was significantly smaller in the nifedipine group than in the placebo group, but did not differ significantly in the 2 groups at the onset of angina or on maximal exercise. Furthermore, S-T segment depressions that occurred during exercise at the same pressure-rate products were smaller in the nifedipine period than in the placebo period. Thus, it appears that the antianginal effects of nifedipine are caused by a reduced myocardial oxygen demand for a specific work load and possibly by an increased blood supply to ischemic myocardium.     

Effects of nifedipine on myocardial perfusion during exercise in chronic stable angina pectoris

Nifedipine may be effective in the treatment of stable angina by both decreasing myocardial oxygen demand and increasing myocardial oxygen supply. To determine the mechanism of action of nifedipine and its dose-response relation, 14 patients with stable angina were treated with nifedipine 10, 20 and 30 mg 4 times daily as single-agent therapy in a double-blind, randomized, placebo-controlled crossover trial. Treatment was continued for 1 week on each dose regimen and efficacy was determined using an exercise test at the end of each phase. Compared to placebo, a significant decrease of systolic blood pressure at peak exercise occurred with the nifedipine 20- and 30-mg regimens (p less than 0.05), accompanied by an increase in heart rate on the 10- and 20-mg regimens (p less than 0.005). There was no significant effect on the rate-pressure product compared to placebo at any exercise time on any of the nifedipine regimens. The times to onset of ST-segment depression and to angina were delayed significantly by all 3 dose regimens compared to placebo (p less than 0.02). There was a significant decrease in the magnitude of ST-segment depression at all exercise times by all dosage schedules of nifedipine compared with placebo (p less than 0.05), although there were no significant differences among the 3 dosage schedules. Data indicate that since nifedipine was effective in improving manifestations of myocardial ischemia during exercise without altering the double product at submaximal or maximal exercise, its beneficial mechanism of action may have been due to enhancing blood flow to ischemic zones or to favorably altering determinants of myocardial oxygen demand, which were not measured.