Objectives: Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events. Methods:We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90mmHg) with calcium channel blocker (CCB) benidipine 4mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), β-blocker, or thiazide diuretic in addition to benidipine. Results: Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-β-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-β-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P=0.3505) and 1.54 in the benidipine-β-blocker (P=0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P=0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P=0.0240) compared with benidipine and β-blocker. All trial treatments were safe and well tolerated. Conclusion: CCB combined with ARB, β-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.
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