Use of Quadruple Therapy in the Management of Hypertension: A Systematic Review of Randomized Controlled Trials

Abstract

Background and objectives: Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with suboptimal blood pressure (BP) control despite available treatments. Monotherapy often fails to achieve target BP, necessitating combination therapies. Quadruple low-dose combination therapy (quadpill) has emerged as a potential strategy to enhance efficacy while minimizing side effects. This systematic review evaluates the effectiveness and safety of quadpill therapy compared to standard monotherapy and dual therapy. Methods: A systematic search was conducted in PubMed, Web of Science, and Scopus from inception till January 2025 for randomized controlled trials (RCTs) investigating quadruple therapy in hypertensive patients. Studies comparing quadpill therapy with monotherapy, dual therapy, or placebo were included. Data on BP reduction, achievement of target BP, and adverse events were extracted and analyzed. The Cochrane Risk of Bias tool (RoB-2) was used to assess study quality. Results: Five RCTs were included in the current systematic review. Quadpill therapy resulted in greater reductions in systolic BP (SBP and diastolic BP (DBP) compared to monotherapy and dual therapy across all time points. The proportion of patients achieving target BP (<140/90 mmHg) was significantly higher in the quadpill group. The safety profile was favorable, with adverse event rates comparable to those in monotherapy and dual therapy groups. Notable adverse effects included mild dizziness, edema, and biochemical alterations (elevated fasting glucose and uric acid levels), but these did not lead to significant treatment discontinuation. Conclusions: Quadruple low-dose combination therapy is a promising approach for improving BP control while maintaining a favorable safety profile. Early initiation of quadpill therapy could mitigate treatment inertia and improve long-term cardiovascular outcomes.

Keywords: combination; diastolic blood pressure; hypertension; quadruple; systolic blood pressure.

Figure 1

PRISMA flow diagram of searching and screening.

Figure 2

Risk of bias assessment of RCTs using Rob-2 [16,21,26,27,28].