Efficacy and safety of controlled-release isosorbide-5-mononitrate for patients with stable effort angina pectoris: A randomized, double-blind, placebo-controlled study

Abstract

Background A major limitation of the use of nitrates is the development of “nitrate tolerance”. The widely accepted treatment of preventing tolerance is to provide a period of “low nitrate interval”. Then, a new controlled-release isosorbide-5-mononitrate (I-CR) has been developed. Methods We conducted a randomized, double-blind, placebo-controlled study, which investigated the efficacy and safety of I-CR for 30 outpatients with stable angina pectoris. After consecutive exercise tests (ETs) for ascertaining the reproducibility of exercise tolerance during the placebo run-in period, patients were randomly assigned to either I-CR (40 mg once daily) or placebo groups (2:1) for 2 weeks. ETs were performed at 5, 12 and 24 hours after dosing on the final day. The primary efficacy variable was the change in exercise time to moderate angina from the baseline. Results The changes of exercise time to moderate angina were prolonged at 5 hours but not shortened at 24 hours. The subgroup analysis suggested that presence of concomitant use of insulin affected on this result. Headaches were the most frequent adverse effect but self-control levels in the I-CR group. The plasma concentration of I-CR at 24 hours was less than 100ng/mL. Conclusion These results suggest that I-CR improves exercise tolerance during the daytime and can be well tolerated in patients with stable effort angina without increasing adverse effect. (see Table) Clinical Pharmacology & Therapeutics (2005) 77, P53–P53; doi: 10.1016/j.clpt.2004.12.095 Table 1. Change in exercise time to moderate angina from baseline (seconds) Treatment N 5 hours 12 hours 24 hours I-CR 21 39.1 −7.5 27.5 All patients 14.7~63.6 −29.7~14.8 4.2~50.9 placebo 9 26.8 −17.2 65.4 −16.6~70.1 −61.7~27.3 26.1~104.8 Without insulin concomitant I-CR 16 52.9 5.0 38.8 28.0~77.9 −19.2~29.2 13.7~63.9 placebo 8 21.9 −24.5 65.4 −26.8~70.5 −72.4~23.4 19.7~111.1 Data are presented as mean values (95% confidence interval).