Combination Therapy is superior to Sequential Monotherapy for the Initial Treatment of Hypertension: a double-blind randomised controlled trial

Background Guidelines for hypertension vary in their preference between Initial combination therapy and initial monotherapy, stratified by patient profile. We therefore compared the efficacy and tolerability of these approaches. Methods and Results We performed a 1-year double-blind, randomised, controlled trial in 605 untreated patients aged 18-79, systolic BP ≥ 150 mmHg or diastolic BP ≥ 95 mmHg. In phase 1 (weeks 0-16), patients were randomly assigned to initial monotherapy (losartan 50-100 mg, or hydrochlorothiazide (HCTZ) 12.5-25 mg crossing over at 8 weeks), or initial combination (losartan 50-100 mg + HCTZ 12.5-25 mg). In phase 2 (weeks 17-32), all patients received losartan 100 mg and HCTZ 12.5-25 mg. In phase 3 (weeks 33-52), amlodipine ± doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP (HSBP), averaged over phase 1 & 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in HSBP responses between tertiles of plasma renin. HSBP after initial monotherapy fell 4.9 mmHg (3.7, 6.0) less over 32 weeks (p <0.001) than after initial combination, but caught up at 32 weeks, (difference 1.2 mmHg (-0.4 to 2.8), p = 0.13). In phase 1, HSBP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform, and at least 5 mmHg more than to monotherapy. There were no difference in withdrawals due to adverse events. Conclusions Initial combination therapy can be recommended for patients with blood pressure >150/95 mmHg.