Enhanced effectiveness of combined sustained-release forms of isosorbide dinitrate and diltiazem for stable angina...

In 14 patients with documented coronary artery disease, the extent and duration of acute anti-ischemic, antianginal and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate and diltiazem were compared; their combined therapy administered once daily in the morning with diltiazem given again in the evening were also compared according to a randomized, double-blind, crossover, placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST decreases) at an identical work load, exercise capacity and determination of plasma concentrations of both substances. Comparison of individual substances revealed more marked and sustained effects of isosorbide dinitrate (ST decreases at 2 hours, -66%; at 6 hours, -50%; p less than or equal to 0.05 for both), remaining statistically significant up to 12 hours (-24%) than of diltiazem (2 hours, -30%; 6 hours, -16%; p less than 0.05). Combined therapy resulted in increased effects (ST decreases at 2 hours, -80%; 6 hours, -76%; 12 hours, -30%; p less than or equal to 0.05) as opposed to individual substances for a period of up to 12 hours. However, therapeutic coverage over 24 hours could not be demonstrated, even with renewed administration of sustained-release diltiazem in the evening. Plasma concentrations of isosorbide-5-mononitrate were greater than 250 ng/ml for 12 hours on days when isosorbide dinitrate was given, decreasing to less than 100 ng/ml at 24 hours. On days when diltiazem was given, plasma levels greater than 50 ng/ml were detected only at 2 and at 6 hours, and at 24 hours only after a second tablet was given.