Duration of effects of isradipine during twice daily therapy in angina pectoris

Summary

Isradipine, a 1,4 dihydropyridine calcium channel antagonist, is a potent coronary artery dilator that increases coronary blood flow with little effect on cardiac contractility. Isradipine is an approved antihypertensive agent, but its anti-anginal effects have not been well documented. In this placebo-controlled, double-blind, parallel-group design study we evaluated the duration of effects and safety of isradipine 10 mg bid in male patients with chronic stable angina pectoris. Seventy-two patients experiencing moderately severe angina between 3 and 7.5 minutes during a standard Bruce exercise test received placebo in a single-blind manner for 8–14 days. Sixty-one of these patients had reproducible treadmill exercise test results on three consecutive occasions and underwent further exercise tests at 3, 8, and 12 hours after a placebo period. Patients were then randomized (double blind) to either placebo or isradipine 10 mg bid for 2 weeks. Symptom-limited exercise tests were repeated predose and at 3, 8, and 12 hours after the 0800 hour dose dosing. Exercise duration increased significantly from baseline (last qualifying test during the single-blind placebo therapy, i.e., 0800 hours predose at visit 4) in the isradipine group compared to the placebo group prior to the administration of the 0800 hour dose (i.e., 12 hours after the 2000 hour dose) by 51 vs. 18 seconds, p=0.04; and after the administration of the 0800 hour dose at 3 hours by 78 vs. 29 seconds, p=0.005; and at 8 hours by 54 vs. 18 seconds, p=0.04. Similarly, statistical significance was achieved when exercise data were analyzed using visit 4 (single-blind placebo therapy) corresponding time points as baseline. At 12 hours after the 0800 hour dose, exercise tolerance did not increase significantly after isradipine compared to placebo. Time to 1-mm ST-segment depression increased significantly after isradipine at 3 hours post 0800 hour dose compared to placebo (87 vs. 7 seconds, p<0.01) but not at the 0, 8, or 12-hour postdose time points, regardless of which baseline was used. Isradipine therapy did not affect the rate-pressure double product. A significant correlation between the mean increase in total exercise time and mean plasma isradipine concentration was also present (p=0.0295). During double-blind treatment, drug-related adverse events were experienced by four patients in the isradipine group and two patients in the placebo group. None of the patients experienced ischemic complications during the study. In male patients with chronic stable angina, monotherapy with isradipine 10 mg twice a day significantly increased exercise duration for 8 hours after the 0800 hour dose. Of interest is the observation that isradipine significantly increased exercise duration at 12 hours post 2000 hour dose but not after post 0800 hour dose. These findings would suggest that three-time rather than twice-daily dosing with the standard formulation of isradipine, which has been recommended for the treatment of hypertension, may be required for optimal anti-anginal therapy.