A MULTIFACTORIAL TRIAL DESIGN TO ASSESS COMBINATION THERAPY IN HYPERTENSION - TREATMENT WITH BISOPROLOL AND HYDROCHLOROTHIAZIDE

Background: The safety and effectiveness of different dosages and comb inations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Di vision of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3x4 factorial trial of bisoprolol, a beta(1)-selective adrenergic blocking agent, and hydrochlorothiazide . Methods: A total of 512 patients with mild to moderate essential hyp ertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all p ossible combinations. Diastolic and systolic blood pressures were moni tored during this 12-week trial. Results: The effects of bisoprolol an d hydrochlorothiazide were additive with respect to reductions in dias tolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisop rolol (or hydrochlorothiazide) produced an incremental reduction in bl ood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contr ibuted a significant antihypertensive effect. A hydrochlorothiazide do sage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg /d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably wit h that of placebo. Conclusions: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonst rated. The combination of low dosages of bisoprolol and hydrochlorothi azide may be a rational alternative to conventional stepped-care thera py for the initial treatment of patients with mild to moderate hyperte nsion.