Carvedilol in Comparison and in Combination with Isosorbide Dinitrate Sustained Release in Patients with Chronic Stable Effort-Induced Angina Pectoris

Abstract

In a double-blind randomised 6-month multicentre study the antianginal and anti-ischaemic effects of carvedilol 25mg twice daily were assessed in comparison and in combination with isosorbide dinitrate (ISDN) SR (sustained release) 40mg twice daily in patients with chronic stable exercise-induced angina pectoris. After a placebo phase of 14 days during which two symptom-limited seated bicycle exercise tests were performed, 187 patients were randomly allocated to one of the two parallel treatment groups. After 3 months of therapy a further exercise test was performed, and patients were then switched to combination therapy for a further 3 months, at the end of which another exercise test was carried out. The patients were issued diary cards to document the daily numbers of anginal attacks and nitroglycerin applications. For the three major variables from exercise testing (total symptom-limited exercise time, time to angina and time to ST-segment depression), the statistical analysis confirmed the hypothesis that the efficacy of carvedilol was at least as good as that of ISDN SR. Indeed, the risk ratios from the Cox proportional hazards model indicated a trend, although not statistically significant, towards a slight advantage of carvedilol over ISDN SR for total exercise time and time to angina. This was also supported based on a comparison of the individual improvements between the groups. In patients with angiographically proven coronary artery disease, only carvedilol appeared to be effective. The number of daily anginal attacks and applications of short-acting nitrates were reduced by the two drugs to the same extent. Additional improvements in all efficacy variables were obtained after patients had been switched to combination therapy. The two drugs given in monotherapy and in combination were shown to be well tolerated. There were no unexpected adverse events. As monotherapy, carvedilol appeared to be somewhat better tolerated with fewer patients experiencing adverse events (14 vs 25.5%, respectively) and fewer dropouts because of adverse events (3 vs 6, respectively). In conclusion, carvedilol was at least as effective as ISDN SR in the treatment of patients with chronic stable exercise-induced angina pectoris and it appeared to be somewhat better tolerated. Combination therapy with both agents led to increased efficacy without any relevant changes in the tolerability profile.