Efficacy of combination therapy with trandolapril and verapamil SR in primary hypertension: A 4x4 trial design

The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril - an ACE inhibitor, and verapamil SR - a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters: lowered diastolic blood pressure (at trough) more than placebo, p < 01 (except the 120 mg verapamil SR, NS, 0.5 mg trandolapril, 0.5/180 and 2/120 combinations, p < 05), yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo. Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. Trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg.