Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris.

According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.     

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.     

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.     

Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris

Sixteen patients with chronic stable angina pectoris were studied to compare the hemodynamic and antianginal effects of buccal nitroglycerin (GTN) in a dose of 3 mg administered 3 times daily and oral isosorbide dinitrate (ISDN) in a dose of 30 mg administered 4 times daily. Compared with placebo, both oral ISDN and buccal GTN treatment induced a decrease in systolic blood pressure at rest over a 5-hour period during acute but not during sustained therapy. Neither buccal GTN nor oral ISDN modified the changes in systolic blood pressure during exercise. Both treatment programs were associated with a higher exercise heart rate during acute therapy. During sustained treatment with buccal GTN, the heart rate during exercise remained greater than that during placebo throughout the 5-hour test period, but during treatment with oral ISDN, only the exercise heart rate at 1 hour was greater than that seen with placebo. Treadmill walking time to the onset of angina and to the development of moderate angina increased significantly during acute therapy with both buccal GTN and oral ISDN. The clinical efficacy of buccal GTN was maintained after 2 weeks of 3-times-daily therapy. In contrast, during 4-times-daily therapy with oral ISDN, treadmill walking time was prolonged for only 1 hour after drug administration. This investigation indicates that tolerance develops during 4-times-daily therapy with oral ISDN, but 3 times daily therapy with buccal GTN is not associated with diminished antianginal effects.     

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.     

Combination propranolol and bepridil therapy in stable angina pectoris

The safety and efficacy of bepridil plus propranolol therapy were investigated in a placebo-controlled, parallel-design, double-blind trial in 56 patients who were not responding to propranolol alone. Patients entering the study were receiving an average propranolol dosage of 131 mg/day (range 20 to 240). For the first 2 weeks of the study they were given placebo in addition to their propranolol dose, and then were randomized to receive continued placebo plus propranolol or bepridil plus propranolol therapy. The bepridil dosage was adjusted over the 8 weeks of active treatment to an average of 273 mg/day (range 200 to 400). The double-blind treatment period was followed by a 3-week washout period during which all patients received propranolol and placebo. The effects of treatment on the frequency of angina attacks, nitroglycerin consumption, exercise performance (treadmill-modified Bruce protocol) and Holter electrocardiogram (ECG) were assessed. Propranolol and bepridil plasma levels also were obtained. Improved antianginal efficacy and reduced nitroglycerin consumption were noted when bepridil was added to propranolol (p less than 0.01). During 8 weeks of combination treatment, exercise tolerance increased 1.0 +/- 1.2 minutes from a baseline of 7.3 +/- 2.2 with bepridil plus propranolol compared with an increase of 0.02 +/- 1.3 minutes from a baseline of 7.6 +/- 2.9 with placebo plus propranolol (p less than 0.01). With bepridil plus propranolol, there were also increases in exercise time to onset of angina (p less than 0.04), exercise time to 1-mm electrocardiographic ST-segment depression (p less than 0.06) and total work (p less than 0.03) compared with placebo plus propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transdermal isosorbide dinitrate in angina pectoris: Effect of acute and sustained therapy

Twelve patients with chronic, stable angina pectoris underwent hemodynamic investigations and treadmill exercise testing before and during a 24-hour period after the application of 100 mg of transdermal isosorbide dinitrate (ISDN) and matching placebo. Compared with placebo, there were no changes in systolic blood pressure or heart rate at rest or during exercise; but treadmill walking time to the onset of angina and to the development of moderate angina was significantly prolonged at 2,4 and 8 hours, but not at 24 hours, after drug application. Patients subsequently received these same treatment regimens for 7 to 10 days and underwent repeat exercise testing. During this sustained phase of the investigation, treadmill walking time to the onset of angina and to the development of moderate angina was similar 4, 8 and 24 hours after application of ISDN and placebo. Thus, transdermal ISDN in a dose of 100 mg is effective for 8 hours during acute therapy, but during sustained therapy tolerance developed and no antianginal effects of ISDN persisted.     

Enhancement of the efficacy of isosorbide dinitrate by captopril in stable angina pectoris.

This study was designed to assess whether the angiotensin-converting enzyme inhibitor captopril could potentiate the efficacy of a single dose of oral isosorbide dinitrate (ISDN) in patients with coronary artery disease. Fourteen men (mean age 53 years) with stable angina pectoris were studied. In each patient the efficacy of placebo, captopril (50 to 100 mg), ISDN (10 mg), and a combination of captopril (50 to 100 mg) and ISDN (10 mg) was assessed by repeated exercise treadmill tests performed before and 1, 2, 3 and 6 hours after administration of a single dose. A single-blind, randomized technique was applied. According to the mean data in the whole group of 14 patients, captopril alone produced no improvement in exercise duration to the onset of angina and to angina of moderate severity compared with placebo. The magnitude of ST-segment depression did not significantly change after captopril administration. ISDN alone significantly increased exercise duration to onset of angina and to angina of moderate severity (antianginal effect) and decreased the magnitude of ST-segment depression (antiischemic effect) 1 to 3 hours after administration. Combined administration of ISDN and captopril resulted in more expressed antianginal and antiischemic effects; at 2, 3 and 6 hours these effects with ISDN plus captopril were significantly more pronounced than those with ISDN alone. According to individual data, the most marked potentiation of ISDN efficacy was observed in patients who had poor response to ISDN alone. In all 6 patients in whom ISDN alone was ineffective, after the addition of captopril the desired antianginal effect was obtained.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of antianginal drugs on left ventricular function in patients with effort angina pectoris. Comparison among isosorbide dinitrate, nifedipine and propranolol by PANOVA

To study the acute effects of ISDN, nifedipine, propranolol and placebo on cardiac function in patients with myocardial ischemia and to characterize their hemodynamic effects by PANOVA, we repetitively performed exercise radionuclide angiography (RNA) following random assignment of each drug in 20 patients with effort angina pectoris. We obtained exercise response curves of hemodynamic parameters determined by RNA. ANOVA was performed to analyze the sizes (average height) of those response curves, and PANOVA (principal component analysis, PCA, combined with ANOVA) to analyze differences in the profiles (patterns) of the curves. By conventional analysis of variance followed by a Scheffé type multiple comparison, end-diastolic volume after ISDN, which was significantly smaller than those after the other drugs at rest (p less than 0.01), was similar to those after nifedipine and propranolol during exercise (96.4 +/- 4.6 ml/m2 vs. 94.8 +/- 5.1 ml/m2 and 97.1 +/- 4.9 ml/m2, respectively). Systemic vascular resistance after nifedipine, which was also significantly lower than those after the other drugs at rest (p less than 0.05), was not different from that after placebo during exercise (16.9 +/- 1.1 units vs. 18.7 +/- 1.3 units). Thus, this analysis was considered insufficient to fully differentiate the characteristics of each drug. By PANOVA, the profiles of LVEF with these three antianginal drugs were similar, and significantly differentiated from that of placebo (p less than 0.05). This indicated that the antianginal effect could be represented by the profiles of the response curves of LVEF, using PANOVA. Evaluating the underlying hemodynamic mechanisms of these drugs by PANOVA, ISDN was significantly differentiated from nifedipine and propranolol by the profile of end-diastolic volume (p less than 0.05). The characteristics of nifedipine were clearly demonstrated by the size and profile of systemic vascular resistance, and those of propranolol were also differentiated by the size and profile of the double product and P-V index. Hence, it is concluded that with the aid of PANOVA, the changes in hemodynamic parameters during ischemia can be evaluated in a manner that is highly effective in differentiating the characteristics of the effects of antianginal drugs in patients with angina pectoris.     

Clinical response and effects on left ventricular function of isosorbide dinitrate added to propranolol or diltiazem monotherapy in patients with chronic stable angina

Twenty-four patients were randomized to a double-blind, triple placebo controlled, latin square protocol to examine the relative efficacy of propranolol or diltiazem given as monotherapy or in combination with isosorbide dinitrate. Treatment phases were preceded and followed by placebo control periods. At the end of each phase, symptom-limited treadmill exercise stress tests were performed, as well as rest and exercise radionuclide ventriculography. Both forms of monotherapy were effective in reducing episodes of angina and nitroglycerin use, and in improving exercise tolerance. Diltiazem monotherapy was associated with slightly higher treadmill times (509.9 +/- 123 s) compared to propranolol (462.7 +/- 131 s, P less than 0.05). The addition of isosorbide dinitrate to either form of monotherapy allowed no further improvement in any of the measured clinical responses. Radionuclide ventriculography showed no significant difference in resting left ventricular function. The addition of isosorbide dinitrate to propranolol showed a reduction in end diastolic volume in keeping with a reduction in preload. In response to exercise, stress-induced left ventricular dysfunction was equal in all groups except for the diltiazem-nitrate combination, which was associated with a higher ejection fraction (56.2 +/- 8.6%) compared to monotherapy (52.6 +/- 10.9%, P less than 0.01). A higher cardiac output could be achieved in the groups treated with diltiazem; this was related to increased heart rate and maintenance of stroke volume. It was concluded that diltiazem is equally effective as propranolol for the treatment of chronic stable angina and, in terms of exercise capacity and cardiac output, superior to beta-blockade. The addition of isosorbide dinitrate appears to impart no overt benefits, but some evidence suggests a reduction in left ventricular decompensation in the face of stress.     

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.     

Enhanced effectiveness of combined sustained-release forms of isosorbide dinitrate and diltiazem for stable angina pectoris

In 14 patients with documented coronary artery disease, the extent and duration of acute anti-ischemic, antianginal and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate and diltiazem were compared; their combined therapy administered once daily in the morning with diltiazem given again in the evening were also compared according to a randomized, double-blind, crossover, placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST decreases) at an identical work load, exercise capacity and determination of plasma concentrations of both substances. Comparison of individual substances revealed more marked and sustained effects of isosorbide dinitrate (ST decreases at 2 hours, -66%; at 6 hours, -50%; p less than or equal to 0.05 for both), remaining statistically significant up to 12 hours (-24%) than of diltiazem (2 hours, -30%; 6 hours, -16%; p less than 0.05). Combined therapy resulted in increased effects (ST decreases at 2 hours, -80%; 6 hours, -76%; 12 hours, -30%; p less than or equal to 0.05) as opposed to individual substances for a period of up to 12 hours. However, therapeutic coverage over 24 hours could not be demonstrated, even with renewed administration of sustained-release diltiazem in the evening. Plasma concentrations of isosorbide-5-mononitrate were greater than 250 ng/ml for 12 hours on days when isosorbide dinitrate was given, decreasing to less than 100 ng/ml at 24 hours. On days when diltiazem was given, plasma levels greater than 50 ng/ml were detected only at 2 and at 6 hours, and at 24 hours only after a second tablet was given.     

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.     

Intravenous isosorbide dinitrate infusion in the management of unstable angina pectoris refractory to conventional medical therapy

During the past 2 years, 102 patients were treated for unstable angina pectoris (AP) in our department. Fifteen of them had recurrent chest pain at rest despite treatment with various anti-anginal agents, or prolonged chest pain unresponsive to sublingual nitroglycerin; they received intravenous isosorbide dinitrate (ISDN) infusion. A rapid bolus injection of 2 to 6 mg followed by an infusion of 2 to 5 mg/hr was given to 10 patients with acute chest pain, and 5 patients, who were free of chest pain at the time, but had repeated episodes of angina in the past 24 hours, were given ISDN infusion without a bolus injection. Chest pain disappeared completely in 13 patients, but recurred in 2 of them when the dose was tapered. Two other patients experienced recurrent chest pain during ISDN infusion, and additional boluses were given. The hospital course was uneventful in 11 patients. Four patients who had recurrent anginal attacks underwent emergency coronary cineangiography under intraaortic ballon counterpulsation and aorto-coronary bypass surgery. There were no hospital deaths, no one had subsequent acute myocardial infarctions, and only 2 patients had mild to moderate headache as a side effect. Although the patient population is small, intravenous ISDN infusion is useful in the management of severe unstable AP.     

Comparison of nifedipine alone with propranolol alone for stable angina pectoris including hemodynamics at rest and during exercise

The effects of nifedipine (60 to 90 mg/day) and propranolol (240 mg/day) on symptoms, angina threshold and cardiac function were compared in a placebo-controlled, double-blind, crossover study. Five-week treatment periods with nifedipine and propranolol were compared with 2 weeks of placebo treatment in 21 men with chronic stable angina pectoris, 13 of whom had symptoms both at rest and on exertion. Compared with placebo, New York Heart Association functional class improved in patients equally with nifedipine (p = 0.001) and propranolol (p = 0.006). Frequency of chest pain decreased with nifedipine (p = 0.001) and propranolol (p = 0.01), and nitroglycerin consumption similarly decreased with both treatments. Nifedipine significantly delayed the onset of chest pain (p = 0.01) and 1 mm of ST-segment depression (p = 0.002) during bicycle exercise; smaller increases with propranolol were not statistically significant. A preferential clinical response to nifedipine (9 patients) or propranolol (6 patients) was unrelated to the presence or absence of pain at rest or to any baseline hemodynamic finding. Nifedipine and propranolol were equally effective in relieving exertional ischemia as shown by improvements in ejection fraction at identical workloads, from 0.48 +/- 0.11 to 0.58 +/- 0.12 (p less than 0.001) and 0.56 +/- 0.14 (p less than 0.001), respectively. Exercise wall motion, assessed by a semiquantitative wall motion score, also improved with both drugs. Propranolol treatment decreased exercise cardiac output by 14% (p = 0.01) through its effect on heart rate. In contrast, nifedipine treatment had no effect on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)