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
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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.
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Single-pill antihypertensive combinations may improve medication-taking behavior in some individuals.
“Single-pill antihypertensive combinations may improve medication-taking behavior in some individuals (60,61).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [61]
The Results (Adverse Effects and Tolerability; page not provided) report similar self-reported treatment adherence with low-dose combination therapy and active comparators, rather than an improvement. The paper does not report an adherence benefit for a subgroup of individuals. (LLM, conf=0.82)
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References 15 · Cited by 61
Research works printed but not linked: 13
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- Authors
- Wang, N., Rueter, P., Atkins, E., Webster, R., Huffman, M., de Silva, A., Chow, C., Patel, A., & Rodgers, A.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Northwestern University (US)
- Clinical Trials Unit, Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Kelaniya, Sri Lanka
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2023-06-01
- Volume
- 8
- Issue
- 6
- Pages
- 606
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC10134039
- OpenAlex
- W4367047784
- Cited by
- 61
- References
- 15
- Citations by year
- 2026: 22 · 2025: 22 · 2024: 13 · 2023: 4
- FWCI
- 12.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Cardiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- hypertension, triple combination therapy, monotherapy, blood pressure reduction, systolic blood pressure, antihypertensive efficacy, adverse effects, treatment withdrawal, antihypertensive drugs, antihypertensive monotherapy, combination antihypertensive therapy, antihypertensive withdrawal
- MeSH terms
- Antihypertensive Agents, Blood Pressure, Female, Humans, Hypertension, Male, Middle Aged
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