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To compare the efficacy and tolerability of angiotensin II (Ang II) antagonist losartan and the β-blocker atenolol in the treatment of patients with isolated systolic hypertension (ISH) after 16 weeks of treatment.A double-blind, randomized, multi-country study was carried out in 273 patients with ISH. Patients with a sitting systolic blood pressure (SiSBP) of 160–205 mmHg, and a sitting diastolic blood pressure (SiDBP) <90 mmHg at screening and at placebo baseline were subjected to a 4-week placebo period and then randomly grouped to receive 50 mg losartan or 50 mg atenolol once daily for 16 weeks. At 8 and 12 weeks, patients not controlled (SiDBP ≥ 160 mmHg) were given additional treatment of 12.5 mg hydrochlorothiazide (HCTZ) once daily.Similar significant reductions in SiSBPs (mean ± SD) were obtained with 50 mg losartan and 50 mg atenolol, from 173.7 ± 10.3 and 173.5 ± 10.7 mmHg at baseline to 149.0 ± 15.5 and 148.2 ± 15.3 mmHg after 16 weeks of losartan or atenolol treatment, respectively. Sixty-seven percent of the losartan-treated and 64% of the atenolol-treated patients remained on monotherapy throughout the study. Only 1.5% of the losartan-treated patients withdrew because of a clinical adverse event (CAE) compared with 7.2% in the atenolol-treatment group (P = 0.035). Drug-related CAEs were observed significantly more frequently with atenolol than with losartan treatment (20.3 versus 10.4%; P = 0.029).It is concluded that 50 mg losartan and 50 mg atenolol produced comparable reductions in SiSBP in patients with ISH but losartan was better tolerated. This is the first demonstration of the therapeutic value of selective Ang II receptor blockade with losartan in the treatment of ISH.