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Treatment With Bisoprolol and Hydrochlorothiazide

William H. Frishman, MD; Brian S. Bryzinski, MD; Lewis R. Coulson, MD; Vincent L. DeQuattro, MD; Nicolas D. Vlachakis, MD; William J. Mroczek, MD; Gary Dukart, MD; Judith D. Goldberg, ScD; Demissie Alemayehu, PhD; Kenneth Koury, PhD

Arch Intern Med. 1994;154(13):1461-1468.

Abstract
Background
The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3x4 factorial trial of bisoprolol, a β₁-selective adrenergic blocking agent, and hydrochlorothiazide.

Methods
A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial.

Results
The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage 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 with 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 demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

(Arch Intern Med. 1994;154:1461-1468)

Author Affiliations
From the Departments of Medicine and Epidemiology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY (Dr Frishman); the Departments of Cardiovascular Clinical Research (Dr Bryzinski), US Regulatory Affairs (Dr Dukart), Statistics and Data Management (Dr Goldberg), and Clinical Statistics (Drs Alemayehu and Koury), American Cyanamid Co, Pearl River, NY; the Department of Medicine, University of Illinois College of Medicine, Chicago (Dr Coulson); the Department of Medicine, University of Southern California School of Medicine, Los Angeles (Drs DeQuattro and Vlachakis); and the Cardiovascular Center of Northern Virginia, Alexandria (Dr Mroczek).

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