LACK OF PHARMACOLOGICAL 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 inc rease in anginal attacks in patients with stable angina pectoris. Desi gn: Multicenter, placebo-controlled, parallel-group, double-blind, ran domized study. Setting: Four university teaching hospitals and five pr ivate cardiology outpatient clinics. Patients: 116 patients with stabl e exertional angina who stopped treadmill exercise because of angina p ectoris. Intervention: After stopping all antianginal drugs with the e xception of beta-blockers, patients received single-blind placebo for 1 week followed by either 20 mg of IS-5-MN (n = 60 patients) or placeb o (n = 62 patients) twice daily at 0800 hours and 1500 hours for 2 wee ks. Measurements: Serial symptom-limited exercise tests and patients' diaries recording activity and date, time, and severity of anginal att acks. 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 increa sed 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-mor ning anginal attacks; increased during IS-5-MN therapy compared with p lacebo. Headaches occurred in 19 (32%) patients in the IS-5-MN group a nd in 9 (15%)- patients in the placebo group but necessitated disconti nuation of treatment in only 2 (3%) patients in the IS-5-MN group. Con clusion: Isosorbide-5-mononitrate, 20 mg twice daily given 7 hours apa rt, was well tolerated and improved exercise performance for 7 hours a fter the morning dose and for 5 hours after the afternoon dose without evidence of development of pharmacologic tolerance. No rebound increa se in anginal attacks was found.