A double-blind, crossover study of the antihypertensive efficacy of angiotensin II-receptor antagonists and their activation of the renin-angiotensin system

Objective: The objectives of this study were to assess the effects of 4 angiotensin II-receptor antagonists-losartan, valsartan, irbesartan, and candesartan-on blood pressure (BP) and plasma active renin (PAR), and to determine whether equipotent antihypertensive doses of these drugs produce different degrees of reactive activation of the renin-angiotensin system (RAS). Methods: This double-blind, crossover study included 40 patients with mild to moderate hypertension (diastolic BP [DBP] >90 and <105 mm Hg). After a 4-week placebo run-in period, 20 patients were randomized to receive the recommended starting doses of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), and candesartan (8 mg) once daily for 12 weeks with 4 crossover periods (4 x 4 Latin square design). The other 20 patients were treated with the same doses according to the same protocol, but after 6 weeks, the dose of each drug was doubled for patients with a DBP >90 mm Hg or a reduction in DBP of <10 mm Hg. BP and PAR were measured at the end of the placebo period and of each treatment period. Results: In the group treated with standard initial doses of the 4 drugs, BP was consistently lower than during the placebo period; however, the decrease in BP was greater after treatment with valsartan 80 mg (-13.8/-9.8 mm Hg) and irbesaptan 150 mg (-14.1/-9.9 mm Hg) than after treatment with losartan 50 mg (-9.9/-6.9 mm Hg; P < 0.05 for systolic BP and DBP). All 4 drug treatments increased PAR, and no differences were found between the treatments. In the group of patients whose drug dose was doubled, all 4 agents were equally effective in reducing BP. The equipotent antihypertensive doses were 80.5 mg for losartan, 115.5 mg for valsartan, 216.6 mg for irbesartan, and 13.7 mg for candesartan. Although PAR was always higher at the end of the treatment periods than during the placebo period, it was higher during treatment with candesartan than during treatment with losartan or valsartan (P < 0.05). Conclusions: Losartan, valsartan, irbesartan, and candesartan are not equipotent in lowering BP when used at the initial doses recommended by their respective manufacturers. At equipotent doses, there appears to be no correlation between the antihypertensive efficacy of these drugs and the degree of reactive activation of the RAS.