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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 [[beta].sub.1]-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.

SUMMARYIn the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial, the efficacy of rosuvastatin calcium (Crestor) was compared with that of atorvastatin (Lipitor †), simvastatin (Zocor‡), and pravastatin (Pravachol§) for lowering plasma low-density lipoprotein cholesterol (LDL-C) after 6 weeks of treatment. In this multicenter, parallel-group, open-label trial, adults with hypercholesterolemia were randomized to treatments with rosuvastatin 10, 20,40, or 80 mg, atorvastatin 10, 20,40, or 80 mg, simvastatin 10,20,40, or 80 mg, or pravastatin 10, 20, or 40 mg. Efficacy and safety results from this trial have been previously published. The additional analyses included in this report show that 53 (83/156) to 80 (125/157) of patients in the rosuvastatin 10- to 40-mg groups achieved LDL-C levels <100 mg dl−1(<2.6 mmol l−1), compared with 18 (28/158) to 70 (115/165) of patients who received atorvastatin, 8 (13/165) to 53 (86/163) of patients who received simvastatin, and 1 (1/160) to 8 (13/161) of patients who received pravastatin. Other additional analyses showed that more patients in the rosuvastatin 10- to 40-mg groups than in the comparator groups who were at high risk of coronary heart disease according to National Cholesterol Education Program Adult Treatment Panel (ATP) III, Joint European Societies, or Canadian guidelines achieved the LDL-C goals of <100 mg dl−1(<2.6 mmol l−1) (55 to 77 compared with 0 to 64), <3.0 mmol l−1(<116 mg dl−1) (76 to 94 compared with 6 to 81), and <2.5 mmol l−1(<97mg dl−1) (47 to 69 compared with 0 to 53), respectively. Results favoring rosuvastatin versus the comparators were also reported for patients: (a) who had triglycerides >200 mg dl−1(>2.3 mmol l−1), and achieved both ATP III LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) goals (80 to 84 versus 15 to 84); (b) overall who achieved the Canadian LDL-C goals of <2.5 (<97 mg dl−1) to <5.0 mmol l−1(< 193mg/dl) (85 to 91 versus 44 to 86); and (c) who achieved all 3 Canadian goals for LDL-C, triglycerides (<3.0 mmol l−1[< 266 mg dl−1] to < 2.0 mmol l−1[<177 g dl−1]), and the total cholesterol/high-density lipoprotein-cholesterol ratio (<4 to <7) (70 to 83 versus 35 to 79). Crestor is a registered trademark of the AstraZeneca group of companies and is licensed to AstraZeneca from Shionogi & Co, Ltd, Osaka, Japan.†Lipitor is a registered trademark of Pfizer Inc.‡Zocor is a registered trademark of Merck & Co., Inc.§Pravachol is a registered trademark of Bristol-Myers Squibb Company.