DOUBLE-BLIND, DOSE-RESPONSE, PLACEBO-CONTROLLED MULTICENTER STUDY OF NISOLDIPINE - A NEW 2ND-GENERATION CALCIUM-CHANNEL BLOCKER IN ANGINA-PECTORIS

Background. Nisoldipine is a potent 1:4 dihydropyridine calcium channel antagonist, and doses of 5 or 10 mg administered either once or twice daily have been claimed to exert antianginal effects. There is, however, little information regarding the dose-response relation and whether the drug exerts any consistent effects throughout the dosing interval. In this placebo-controlled, parallel-design study, the dose-response relation of monotherapy with nisoldipine administered twice daily was studied in patients with stable angina pectoris. Methods and Results. Two hundred thirty-one patients received single-blind placebo for 2 weeks; of these, 185 patients who reproducibly stopped treadmill exercise because of angina of moderate severity and had greater-than-or-equal-to 1 mm ST segment depression during exercise and experienced an average of three episodes of anginal attacks per week were randomized in a double-blind manner to one of the four treatment groups: placebo (n = 48), nisoldipine 2.5 mg (n = 47), nisoldipine 5 mg (n = 44), or nisoldipine 10 mg (n = 46). Nisoldipine or placebo was administered twice daily for 4 weeks and symptom-limited exercise tests were repeated at 2 and 10-14 hours after the double-blind medication. One hundred sixty-eight patients completed the study and 181 patients were valid for efficacy analysis. Compared with double-blind placebo, there were marginally significant trends toward increases for time to onset of angina for the 10-mg-b.i.d. group (83 versus 108 seconds, p = 0.08), time to 1 mm ST segment depression for the 5-mg-b.i.d. group (54 versus 83 seconds, p = 0.08), and total exercise time for the 5- (30 versus 50 seconds, p = 0.10) and 10-mg-b.i.d. (30 versus 58 seconds, p = 0.06) groups at 2 hours after the dose (peak effect) after 4 weeks of therapy. At 10-14 hours after the dose (trough effect), no differences between placebo and any of the nisoldipine doses on any of the exercise parameters were found after 4 weeks of therapy. A subset analysis of patients who stopped exercise within 10 minutes because of angina of moderate severity during single-blind placebo therapy (n = 123) revealed significant increase in total exercise duration and time to 1 mm ST segment depression at 2 hours after the dose in the 5- and 10-mg-b.i.d. dose groups compared with double-blind placebo (p < 0.04). No significant trough effects, however, were observed even in this subgroup after any of the doses of nisoldipine. The frequency of anginal attacks decreased by 44%, 41%, 30%, and 41% after twice-daily therapy with 2.5 mg, 5 mg, 10 mg nisoldipine, and placebo groups, respectively (p = NS, nisoldipine versus placebo). The incidence of adverse events (minor and major) was 43.8% in the placebo group and 42.6%, 45.5%, and 56.5% in the nisoldipine 2.5-, 5-, and 10-mg-b.i.d. groups, respectively (p = NS compared with placebo). However, four patients developed unstable angina while on nisoldipine therapy (two in the 2.5-mg, one in the 5-mg, and one in the 10-mg-b.i.d. group) and two patients died suddenly in the nisoldipine 10-mg-b.i.d. group. Conclusions. Monotherapy with 2.5, 5, and 10 mg nisoldipine twice a day was not superior to placebo therapy in treating patients with angina pectoris, and the 10-mg-b.i.d. therapy resulted in a statistically insignificant but clinically important increase in the incidence of serious adverse events.