Efficacy and safety of dual combination therapy of blood pressure-lowering drugs as initial treatment for hypertension: A systematic reviewandmeta-analysis of randomized controlled trials

Objective: To assess the efficacy and tolerability of dual combination of blood pressure (BP)-lowering drugs as initial treatment for hypertension. Methods: MEDLINE, Embase, CENTRAL were searched until August 2017 for randomized, double-blind trials of dual combination therapy vs. monotherapy in adults with hypertension who were either treatment naive or untreated for at least 4 weeks. Regimens were classified with reference to usual daily 'standard-dose'; for example, <1R<1 for a combination of two drugs both at less than one standard-dose. Random-effects models were used for meta-analysis. Results: Thirty-three trials (13 095 participants) with mean baseline mean BP 155/100mmHg were included. Compared with standard-dose monotherapy, dual combinations of <1R<1, 1R<1 and 1R1 (i.e. low-tostandard dose), showed a dose-response relationship in reducing SBP [mean differences (95% confidence interval) of 2.8 (1.6-4.0), 4.6 (3.4-5.7) and 7.5 (5.4-9.5)mmHg, respectively], and in improving BP control [risk ratio (RR) (95% confidence interval) 1.11 (0.92-1.34), 1.25 (1.16-1.35) and 1.42 (1.27-1.58), respectively]. Withdrawals due to adverse events were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy [2.9 vs. 2.2%; RR 1.28 (0.85 to 1.92)]. There were fewer data for higher dose dual combinations, which did not appear to produce substantial additional efficacy and could potentially be less tolerable. Conclusion: Compared with standard-dose monotherapy, initiating treatment with low-to-standard dose dual combination therapy is more efficacious without increasing withdrawals due to adverse events.