Efficacy and Safety of Low-Dose Triple and Quadruple Combination Pills vs Monotherapy, Usual Care, or Placebo for the Initial Management of Hypertension: A Systematic Review and Meta-analysis

Abstract

Importance: Low-dose combination (LDC) antihypertensives consisting of 3 or 4 blood pressure (BP)-lowering drugs have emerged as a potentially important therapy for the initial management of hypertension.

Objective: To assess the efficacy and safety of LDC therapies for the management of hypertension.

Data sources: PubMed and Medline were searched from date of inception until September 2022.

Study selection: Randomized clinical trials comparing LDC consisting of 3 or 4 BP-lowering drugs compared to either monotherapy, usual care, or placebo.

Data extraction and synthesis: Data were extracted by 2 independent authors and synthesized using both random and fixed-effects models using risk ratios (RR) for binary outcomes and mean differences for continuous outcomes.

Main outcomes and measures: The primary outcome was mean reduction in systolic BP (SBP) between LDC and monotherapy, usual care, or placebo. Other outcomes of interest included the proportion of patients achieving BP less than 140/90 mm Hg, rates of adverse effects, and treatment withdrawal.

Results: Seven trials with a total of 1918 patients (mean [mean range] age, 59 [50-70] years; 739 [38%] female) were included. Four trials involved triple-component LDC and 3 involved quadruple-component LDC. At 4 to 12 weeks follow-up, LDC was associated with a greater mean reduction in SBP than initial monotherapy or usual care (mean reduction, 7.4 mm Hg; 95% CI, 4.3-10.5) and placebo (mean reduction, 18.0 mm Hg; 95% CI, 15.1-20.8). LDC was associated with a higher proportion of participants achieving BP less than 140/90 mm Hg at 4 to 12 weeks compared to both monotherapy or usual care (66% vs 46%; RR, 1.40; 95% CI, 1.27-1.52) and placebo (54% vs 18%; RR, 3.03; 95% CI, 1.93-4.77). There was no significant heterogeneity between trials enrolling patients with and without baseline BP-lowering therapy. Results from 2 trials indicated LDC remained superior to monotherapy or usual care at 6 to 12 months. LDC was associated with more dizziness (14% vs 11%; RR 1.28, 95% CI 1.00-1.63) but no other adverse effects nor treatment withdrawal.

Conclusions and relevance: The findings in the study showed that LDCs with 3 or 4 antihypertensives were an effective and well-tolerated BP-lowering treatment option for the initial or early management of hypertension.

Figure 1.. Mean Systolic Blood Pressure (SBP) During Baseline and Follow-up in Trials of Low-Dose Combination (LDC) Blood Pressure–Lowering Drugs Containing 3 or 4 Agents

Error bars represent 95% CIs. QUARTET indicates the Quadruple Ultra-Low-Dose Treatment for Hypertension trial; TRIUMPH, the Treatment for Immune Mediated Pathophysiology trial. ^aWald et al did not report blood pressure levels in the placebo arm.

Figure 2.. Low-Dose Combination (LDC) Therapy vs Active Comparator for Reducing Systolic Blood Pressure (SBP)

Squares represent individual studies, with the size proportional to the weight in the meta-analysis. Horizontal lines and width of diamonds show 95% CIs. RR indicates risk ratio. ^aWald et al was a crossover randomized trial design and did not report BP levels in the placebo arm.