Methods:

Publication databases, clinical trial registries and regulatory agency websites were searched until April 2018 for double-blind randomized controlled trials (RCTs) comparing triple with dual therapy of BP-lowering drugs, for at least 3 weeks, among patients with hypertension. Meta-analyses for efficacy and safety outcomes were performed using random-effects model. Regimen efficacy was predicted using the Therapeutic Intensity Score (TIS) and the Law et al. method (which predict dose doubling increases efficacy by 100% and around 20%, respectively), and compared with observed efficacy.

Results:

Fourteen RCTs (11 457 participants) were included. Overall, triple compared with dual therapy reduced BP by 5.4/3.2 mmHg (P< 0.001), and improved BP control by 58 versus 45%[relative risk (RR) 1.33 (95% CI 1.25–1.41)], whereas incidence of withdrawals because of adverse events were 3.3 versus 3.4%[RR 1.24 (95% CI 1.00–1.54), P= 0.05]. Law et al.'s method was superior to TIS in predicting differences in efficacy between triple and dual therapies. For patients uncontrolled on submaximal dose dual therapy, adding a third drug achieved on average approximately four times more BP reduction than doubling the dose of dual therapy component drugs (6.0/3.6 versus 1.5/0.8 mmHg, respectively).

Conclusion:

Addition of a third drug is likely to be more efficacious without increasing adverse events, compared with increasing dose of existing dual therapy. Early use of triple therapy can significantly improve hypertension control.