Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris

A study was performed to compare isosorbide dinitrate and nifedipine as adjunctive therapy in 14 patients with coronary artery disease and stable angina pectoris taking maximal beta-blocking drugs. Drug titration phases ensured maximal therapy of propranolol, isosorbide or nifedipine. The combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing angina and increasing exercise capacity (323 vs 416 seconds, p less than 0.005) during exercise treadmill testing. Nifedipine produced a greater reduction in systolic blood pressure at submaximal exercise than isosorbide. Global and regional ejection fraction at rest and exercise was assessed with radionuclide ventriculography. The substitution of nifedipine for isosorbide depressed the global ejection fraction at rest (0.61 to 0.56 p less than 0.05) and produced a slight improvement in exercise ejection fraction (0.47 to 0.51, difference not significant). The decrease in ejection fraction from rest to exercise was 0.14 to 0.04 with nifedipine (p less than 0.005). The benefit of nifedipine compared with isosorbide occurred in regions with marked exercise-induced ischemia. In patients treated with maximal beta-blocking therapy, nifedipine is an effective alternative to isosorbide as a combination agent with propranolol. The salutary effects of nifedipine included afterload reduction with exercise and possible improvements in coronary blood supply.     

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.     

Effects of diltiazem alone or with isosorbide dinitrate or with atenolol both acutely and chronically for stable angina pectoris

To establish the contribution of combination therapy in stable angina, the short- and long-term effects of diltiazem (120 mg and 360 mg/day, respectively), and the additive effects of sublingual isosorbide dinitrate, 10 mg, and atenolol, 100 mg, were studied in 11 patients with chronic stable angina using an open-label sequential design. All patients underwent exercise testing without therapy, and with each drug and their combinations. Exercise time and heart rate-blood pressure product were measured at 1-mm ST-segment depression, or at peak exercise if the test result was negative. Exercise time increased from a control value of 8.0 +/- 2.3 minutes (mean +/- standard deviation) to 11.4 +/- 2.4 minutes (p less than 0.0001) after the administration of isosorbide dinitrate, to 11.3 +/- 1.8 minutes (p less than 0.001) after short-term diltiazem and to 12.4 +/- 1.5 minutes (p less than 0.001) after long-term diltiazem. The rate-pressure product increased from a control value of 19,070 +/- 3,564 to 24,431 +/- 4,795 beats/min X mm Hg (p less than 0.0001) after isosorbide dinitrate, to 22,287 +/- 4,753 beats/min X mm Hg (p less than 0.01) after short-term diltiazem and to 21,812 +/- 3,976 beats/min X mm Hg (p less than 0.007) after long-term diltiazem. The addition of atenolol to long-term diltiazem significantly reduced the rate-pressure product compared with long-term diltiazem alone (21,812 +/- 3,976 vs 13,926 +/- 2,880 beats/min X mm Hg, (p less than 0.002), although there was no further significant increase in exercise time (12.4 +/- 1.5 vs 13.3 +/- 1.6 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of high-dose sustained-action oral isosorbide dinitrate in stable angina

Hemodynamic effects of sustained-action oral isosorbide dinitrate (40 or 80 mg) were studied in 10 patients with stable angina for a period of 16 hours. Control hemodynamic parameters monitored for eight hours prior to the administration of isosorbide dinitrate showed no significant change. However significant reduction in mean arterial pressure, cardiac index, pulmonary artery wedge pressure, mean pulmonary artery pressure, double product (systolic pressure multiplied by heart rate), stroke volume index, and stroke work index occurred in the first two hours and persisted for 12 hours following the administration of isosorbide dinitrate. Heart rate did not change significantly for 12 hours. It can be concluded that the hemodynamic effects of sustained-action oral isosorbide dinitrate occur in the first two hours and last up to 12 hours. The predominant hemodynamic effect appears to be on the myocardial preload. The antianginal effect of the drug could be attributed to the reduction of myocardial oxygen demand reflected by a decrease in the double product and stroke work. The duration of the hemodynamic changes observed in this study indicates that high-dose oral isosorbide dinitrate could be administered conveniently two or three times daily.     

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.     

Prolonged salutary effects of isosorbide dinitrate and nitroglycerin ointment on regional left ventricular function.

To assess the long-term effects of orally and topically administered nitrates on left ventricular function, 11 patients with previous myocardial infarction were studied with use of isosorbide dinitrate, 20 mg orally, nitroglycerin ointment, 12.5 to 40 mg and placebo ointment. Both nitrates produced a sustained decrease in systolic blood pressure and estimated left ventricular wall stress but no change in heart rate during 4 hours of study. The triple product of heart rate, systolic blood pressure and left ventricular ejection time decreased by 21 percent after administration of isosorbide dinitrate (P < 0.001) and 19 percent after administration of nitroglycerin ointment (P < 0.001). The echocardiographic left ventricular end-diastolic dimension decreased significantly after isosorbide dinitrate (from 52.4 to 49.2 mm at 2 hours, P < 0.01) and nitroglycerin ointment (from 52.4 to 50.5 mm, P < 0.01). The end-systolic dimension was similarly reduced. Left ventricular sites showing abnormally small excursion (less than 3 mm) on wall motion videotracking showed improved motion after the administration of each nitrate, and the velocity of systolic inward motion was consistently increased after each. Thus, determinants of myocardial oxygen consumption, such as systolic blood pressure, left ventricular ejection time, left ventricular size and triple product appear to be consistently reduced for at least 4 hours after administration of isosorbide dinitrate and nitroglycerin ointment, and impairment of left ventricular wall motion appears to be significantly decreased.     

Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol

A double-blind crossover study was performed on 27 patients with proved fixed coronary artery disease and stable angina pectoris. The study was designed to compare the relative efficacy of two combination therapies, nifedipine plus propranolol and isosorbide dinitrate plus propranolol, in terms of antianginal response and effect on exercise tolerance by evaluation of treadmill testing. The combination of nifedipine and propranolol was superior to the combination of isosorbide and propranolol in reducing the number of anginal attacks (p = 0.03), increasing total exercise time (p less than 0.02), increasing oxygen consumption achieved at end of exercise (p less than 0.03), increasing time to onset of pain (p = 0.003) and increasing oxygen consumption achieved at onset of pain (p = 0.003). Analysis of the rate-pressure products suggests that the difference in these results may be explained by the greater effect of nifedipine on afterload reduction. Although nitroglycerin consumption was reduced from baseline levels during combination nifedipine therapy (p less than 0.001), there was no statistical difference between nifedipine combination therapy and isosorbide combination therapy. In conclusion, although both combination therapies were superior to propranolol therapy alone, the combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing the incidence of angina and improving exercise performance. Side effects were experienced at a similar frequency during both combination therapies.     

The effects of dyslipidemia on left ventricular systolic function in patients with stable angina pectoris.

Large-scale clinical trials have shown that long-term treatment with lipid-lowering therapy results in a significant reduction in the occurrence of heart failure among patients with coronary artery disease without previous evidence of congestive heart failure, suggesting dyslipidemia may have an adverse effect on left ventricular performance. To examine whether dyslipidemia has a detrimental effect on left ventricular systolic function and whether this effect is dependent on the corresponding severity of coronary atherosclerosis, 114 consecutive patients with stable angina and a positive exercise thallium-201 myocardial perfusion single-photon emission computed tomography were studied. All patients underwent measurement of serum lipid profiles, right-sided heart catheterization, left ventriculography, and selective coronary arteriography. Mean serum levels of total cholesterol and triglycerides were 4.5 and 1.4 mmol/l, respectively. In univariate analysis, a significant positive correlation between serum high-density lipoprotein (HDL) cholesterol and left ventricular ejection fraction (LVEF) (r = 0.49, P<0.0001) was found. Patients in the lower tertile of serum HDL cholesterol had a significantly lower mean LVEF than those in the upper tertile (55.9+/-15.2 vs. 72.8+/-6.8%, P<0.0001). Stepwise multiple linear regression analysis revealed that LVEF significantly correlated with HDL cholesterol (P<0.0001), the Gensini score (P = 0.008), and diabetes mellitus (P = 0.08) (r = 0.55, P<0.0001). In subgroup analysis of patients with angiographically normal coronary arteries, serum HDL cholesterol was still significantly associated with LVEF. The present study demonstrated an independent association between low HDL cholesterol and subclinical left ventricular systolic dysfunction in Chinese patients with stable angina whose serum levels of total cholesterol and triglycerides were relatively low. Moreover, this correlation remained significant even in patients with normal coronary angiograms, suggesting HDL cholesterol might influence left ventricular systolic performance through extra-atherosclerotic mechanisms.     

Improved left ventricular performance during exercise with verapamil or nifedipine in patients with chronic stable angina

To examine the effects of chronic oral therapy with verapamil, 120 mg three times a day, and nifedipine, 20 mg four times daily, on left ventricular ejection fraction and regional wall motion at rest and exercise, 10 patients with chronic stable angina pectoris underwent serial rest and exercise radionuclide angiography. Pre drug control study revealed a resting left ventricular ejection fraction (LVEF) of 0.62 +/- 0.08, falling to 0.54 +/- 0.12 at peak exercise (p less than 0.05). Wall motion score deteriorated from a resting value of 13.8 +/- 2.3 to 10.6 +/- 1.8 (p less than 0.01) with exercise. Patients were subsequently randomized to verapamil or nifedipine for 4 weeks each in an open-labeled crossover design. Rest and exercise radionuclide angiography were repeated at the end of each 4-week period. Neither verapamil nor nifedipine had a significant effect on resting LVEF (verapamil LVEF = 0.61 +/- 0.10, nifedipine LVEF = 0.64 +/- 0.02). Likewise, they had no significant effect on resting wall motion score (verapamil = 14.2 +/- 2.2, nifedipine = 14.4 +/- 1.6). Both verapamil and nifedipine significantly increased LVEF at peak exercise (verapamil = 0.63 +/- 0.09, nifedipine = 0.65 +/- 0.08, p less than 0.05 vs pre drug control) and improved peak exercise wall motion score (verapamil = 13 +/- 1.9, nifedipine = 13.8 +/- 1.6, p less than 0.05 vs pre drug control). Both drugs significantly reduced maximal ST depression at peak exercise and prolonged exercise duration. Episodes of angina and nitroglycerin use were also significantly reduced. In summary, verapamil and nifedipine improved left ventricular performance at exercise in patients with angina pectoris.     

Nifedipine and isosorbide dinitrate alone and in combination for patients with chronic stable angina: a double-blind crossover study

Since not all patients tolerate beta-blockers, the efficacy of nifedipine and isosorbide dinitrate was evaluated alone and in combination in patients with stable angina pectoris. The study was a randomized double-blind crossover design with patients titrated to maximally tolerated doses of both drugs. Phases included isosorbide dinitrate alone, nifedipine alone, and isosorbide dinitrate plus nifedipine in combination, with efficacy determined by stress testing. Eleven men and one woman patient with a mean age of 60 years and a mean of five anginal episodes/week completed the study. Patients were in New York Heart Association (NYHA) classes I, II, and III. With nifedipine alone compared with isosorbide dinitrate alone, patients had fewer angina attacks/week (p less than 0.02), exercised longer before experiencing angina (p less than 0.03), and had less ST segment depression during (p less than 0.03) or after (p less than 0.05) exercise. When patients received isosorbide dinitrate plus nifedipine, only time to onset of angina during exercise (p less than 0.05) was significantly different from the response with isosorbide dinitrate alone. Analysis of variance between nifedipine and isosorbide dinitrate plus nifedipine was not significant. Diastolic blood pressure with isosorbide dinitrate plus nifedipine (p less than 0.04) was lower than with isosorbide dinitrate alone. No significant differences in systolic blood pressure were noted between the treatment groups. The drugs alone and in combination were relatively well tolerated. Nifedipine alone may be superior to isosorbide dinitrate alone. The combination of isosorbide dinitrate plus nifedipine demonstrated no advantage over nifedipine alone compared with isosorbide dinitrate alone.     

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.     

Comparative effects of propranolol and diltiazem on systolic and diastolic left ventricular function in essential hypertension

The effects of propranolol and diltiazem on left ventricular systolic and diastolic function in hypertensive subjects (DBP 90-114 mmHg) were examined with M-mode and 2D echocardiograms in 21 patients in a double-blind fashion prior to and after 4 months of treatment. Systolic function was assessed by measurement of fractional shortening, mean velocity of fibre shortening, peak systolic pressure/end systolic dimension ratio, and end systolic stress/end systolic dimension ratio. To assess diastolic function, maximal rate of change in left ventricular dimension (MAXD), maximal rate of change in posterior wall thinning (MAX PWT) and early diastolic (EDD) and late diastolic dimension changes (LDD) were calculated using digitised M-mode images of mid-wall diameter. Both propranolol and diltiazem reduced systolic and diastolic pressures similarly. No significant changes were observed in any of the parameters of systolic function with either drug. Similarly neither propranolol nor diltiazem altered MAXD or EDD significantly. Although changes in maximal rate of posterior wall thinning (MAX PWT) were not significant with either drug, diltiazem improved MAX PWT in 7 of 8 patients. The results of the study demonstrate that both propranolol and diltiazem reduce blood pressure without significant deleterious effects on systolic or diastolic function. Diastolic functional parameters, which were not abnormal at baseline, showed no consistent change with either propranolol or diltiazem.     

Effect of beta blockade with betaxolol on left ventricular systolic function in chronic stable angina pectoris and left ventricular dysfunction

To assess the effect of beta blockade on left ventricular (LV) performance in patients with LV dysfunction and stable angina pectoris, 18 subjects taking a placebo followed by incremental doses of the cardioselective beta-adrenergic blocking agent betaxolol (5, 10, 20, 40 and 80 mg/day) were studied. The study ended with the achievement of optimal clinical beta blockade (heart rate at rest 50 to 60 beats/min, a 20% or smaller increase in heart rate during stage 1 of symptom-limited treadmill exercise using the modified Bruce protocol). Optimal clinical beta blockade produced a decrease in mean frequency of angina, from 6.8 +/- 1.7 to 0.7 +/- 0.8 episodes per week (p less than 0.0005) and an increase in mean treadmill exercise capacity, from 3.1 +/- 1.7 to 7.7 +/- 2.8 minutes (p less than 0.0005). LV systolic function was assessed at rest and during symptom-limited exercise with radionuclide left ventriculography. Mean LV ejection fraction (EF) during therapy with placebo was 39 +/- 7% at rest and 40 +/- 8% at peak exercise. Mean LVEF during optimal clinical beta blockade was 43 +/- 11% at rest and 45 +/- 10% at peak exercise. Neither of these changes was statistically significant. No patient had clinical or radiographic signs of LV failure. The results suggest that optimal clinical beta blockade with betaxolol, in doses sufficient to significantly reduce the frequency of angina and improve exercise capacity in patients with stable angina pectoris and mild to moderate LV systolic dysfunction, does not cause significant deterioration of LV systolic function or produce LV failure.     

Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectoris

The antianginal effects of diltiazem 180 mg/day and propranolol 240 mg/day, alone and in combination, were investigated in 15 patients with effort related angina in a double blind placebo controlled crossover trial, with each period of treatment lasting four weeks. Patients performed a symptom limited treadmill exercise test at the end of each period of treatment. Mean (SEM) time to onset of angina was increased from 293(32) s when receiving placebo to 347(38) s when receiving diltiazem alone, to 350(30) s when receiving propranolol alone, and further to 421(34) s when receiving diltiazem and propranolol combined. Similar changes occurred in the duration of exercise testing and time to 1 mm ST segment depression. The sum of ST segment depression at peak exercise was reduced by both diltiazem and propranolol alone compared with placebo, and combination treatment produced a further significant improvement. Rate pressure product was significantly reduced at rest and at peak exercise after propranolol alone and combination treatment. The study clearly showed the superior value of diltiazem and propranolol combined in effort related angina when compared with either drug used alone.     

Improvement in left ventricular diastolic function in patients with stable angina after chronic treatment with verapamil and nicardipine

A placebo-controlled double-blind randomized crossover studywas carried out to assess the effects of chronic therapy withtwo calcium antagonists on left ventricular diastolic functionin patients with stable angina. Ventricular function was assessedusing equilibrium radionuclide angiography and the data wasanalysed using an automated algorithm. The mean±SD ejectionfraction on placebo was 59±10% and this remained unchangedon both verapamil (59 ±9%; P = NS) and nicardipine (58±7%; P = NS). Verapamil increased the peak filling rateindex (P<0.001) and first one-third filling fraction (P<0.005).Nicardipine increased the peak filling rate index (P < 0.005),but did not alter the other diastolic indices. Early fillingrate index was not altered by either drug. Comparison of theeffects of nicardipine and verapamil revealed no significantdifferences in ejection fraction, peak filling rate index orearly filling rate index. However, verapamil showed a greaterimprovement in time to peak filling rate and first one-thirdfilling fraction (P<0.01, P<0.01, respectively) comparedwith nicardipine. Heart rate (P<0.002) and systolic bloodpressure (P<0.01) were also lower on verapamil than on nicardipine.These data suggest that left ventricular ‘relaxation’abnormalities may be detected in patients with chronic anginapectons before systolic dysfunction becomes apparent and thatthese abnormalities may be partially corrected by calcium antagonists.     

Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectoris.

The antianginal effects of diltiazem 180 mg/day and propranolol 240 mg/day, alone and in combination, were investigated in 15 patients with effort related angina in a double blind placebo controlled crossover trial, with each period of treatment lasting four weeks. Patients performed a symptom limited treadmill exercise test at the end of each period of treatment. Mean (SEM) time to onset of angina was increased from 293(32) s when receiving placebo to 347(38) s when receiving diltiazem alone, to 350(30) s when receiving propranolol alone, and further to 421(34) s when receiving diltiazem and propranolol combined. Similar changes occurred in the duration of exercise testing and time to 1 mm ST segment depression. The sum of ST segment depression at peak exercise was reduced by both diltiazem and propranolol alone compared with placebo, and combination treatment produced a further significant improvement. Rate pressure product was significantly reduced at rest and at peak exercise after propranolol alone and combination treatment. The study clearly showed the superior value of diltiazem and propranolol combined in effort related angina when compared with either drug used alone.