Initial triple low-dose combination therapy improves blood pressure control without increased adverse events: a systematic review and meta-analysis

Background/Introduction

Single-pill triple low-dose combination (triple-LDC) antihypertensive drugs have become available for clinical use as an alternative initial therapy for hypertension, expanding the range of validated treatment strategies beyond established monotherapies.

Purpose

We hypothesized that initial triple-LDC therapy would achieve superior blood pressure (BP) reduction compared with placebo and standard-dose monotherapy, with preserved tolerability.

Methods

This systematic review and meta-analysis were conducted according to a prespecified PROSPERO-registered protocol and PRISMA guidelines. Randomized controlled trials comparing triple-LDC therapy (<=50% of the standard dose per component) with placebo or standard-dose monotherapy were identified through MEDLINE, EMBASE, and CENTRAL. Pooled estimates were calculated using random-effects inverse-variance models with restricted maximum likelihood, applying the Hartung–Knapp–Sidik–Jonkman (HKSJ) method for primary inference and Wald-type confidence intervals for sensitivity analyses. Within-study pooling was performed for multi-arm trials, and robustness was assessed using leave-one-out analyses.

Results

Eight randomized controlled trials from seven publications (1,749 participants) were included. Compared with placebo, triple-LDC therapy significantly reduced systolic BP by -13.76 mmHg (95% CI, -19.28 to -8.23) and diastolic BP by -7.45 mmHg (95% CI, -10.85 to -4.04), with more than a twofold increase in BP control rates (risk ratio [RR] 2.27, 95% CI, 1.37 to 3.75).

Compared with standard-dose monotherapy, triple-LDC therapy achieved an additional systolic BP reduction of -3.65 mmHg (95% CI, -7.40 to 0.11). Although not statistically significant in the primary HKSJ model, the effect was significant in Wald-based sensitivity analyses (95% CI, -6.53 to -0.77). Diastolic BP reduction was numerically greater but did not reach statistical significance (-1.39 mmHg; 95% CI, -3.35 to 0.58). BP control rates were higher with triple-LDC therapy (RR 1.25, 95% CI, 1.00 to 1.56). Findings were robust in sensitivity and leave-one-out analyses. Treatment-emergent adverse events and withdrawal rates were comparable between treatment groups.

Conclusion

Triple-LDC therapy provides substantial BP reduction compared with placebo and modest additional benefit over standard-dose monotherapy without increased adverse events, supporting its role as an effective initial treatment strategy for hypertension.ESC2026_triple_ldc_meta_forest.jpg