Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate.

OBJECTIVE

To determine whether isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, when given twice daily (in the morning and 7 hours later), prevents development of tolerance and reduction in exercise performance or is associated with a rebound increase in anginal attacks in patients with stable angina pectoris.

DESIGN

Multicenter, placebo-controlled, parallel-group, double-blind, randomized study.

SETTING

Four university teaching hospitals and five private cardiology outpatient clinics.

PATIENTS

116 patients with stable exertional angina who stopped treadmill exercise because of angina pectoris.

INTERVENTION

After stopping all antianginal drugs with the exception of beta-blockers, patients received single-blind placebo for 1 week followed by either 20 mg of IS-5-MN (n = 60 patients) or placebo (n = 62 patients) twice daily at 0800 hours and 1500 hours for 2 weeks.

MEASUREMENTS

Serial symptom-limited exercise tests and patients' diaries recording activity and date, time, and severity of anginal attacks.

RESULTS

Compared with placebo recipients, patients receiving IS-5-MN walked significantly longer at 2, 5, and 7 hours after the 0800-hour dose (P < 0.01) and at 2 and 5 hours after the 1500-hour dose (P < 0.01). Before the morning (0800-hour) dose, exercise duration increased by 0.53 minutes in placebo recipients and by 0.85 minutes in those receiving IS-5-MN therapy (P = 0.10). Neither nocturnal nor early-morning anginal attacks increased during IS-5-MN therapy compared with placebo. Headaches occurred in 19 (32%) patients in the IS-5-MN group and in 9 (15%) patients in the placebo group but necessitated discontinuation of treatment in only 2 (3%) patients in the IS-5-MN group.

CONCLUSION

Isosorbide-5-mononitrate, 20 mg twice daily given 7 hours apart, was well tolerated and improved exercise performance for 7 hours after the morning dose and for 5 hours after the afternoon dose without evidence of development of pharmacologic tolerance. No rebound increase in anginal attacks was found.