The safety and efficacy of quadruple ultra-low-dose combination (quadpill) for hypertension treatment: a meta-analysis of randomized controlled trials

Abstract

Abstract Background Hypertension is a significant healthcare burden, with an average global prevalence of 1.28 billion adults aged between 30 -79 years old. Using antihypertensive drug combinations is considered more effective in controlling elevated blood pressure than monotherapy; however, psychological factors of the patients and the physicians’ caution from the drugs' adverse effects are still barriers against antihypertensive drug combinations. Quadpill, a single pill containing a quadruple combination of quarter doses of four antihypertensive agents, has been investigated for hypertension treatment. Purpose We aim to evaluate the efficacy and safety of the quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) in patients with hypertension. Methods We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs) evaluating quadpill versus monotherapy or placebo in patients with hypertension, which were retrieved by systematically searching: PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane through February 17th, 2023. Continuous and dichotomous outcomes were pooled using mean difference (MD) and risk ratio (RR) along with confidence interval (CI), using Revman V. 5.4 software. Results Four RCTs with a total of 781 patients (372 in the quadpill group and 425 in the control group) were included in our analysis. Quadpill was effective in controlling automated systolic blood pressure on the short-term (4-6 weeks) (RR: -13.00 with 95% CI [-17.22, -8.78], P= 0.00001) and on the long-term (12 weeks) (RR: -6.18 with 95% CI [-9.35, -3.01], P= 0.0001). Quadpill was also effective in controlling automated diastolic blood pressure on the short-term (4-6 weeks) (MD: -8.15 with 95% CI [-9.42, -6.89], P= 0.00001) and on the long-term (12 weeks) (MD: -6.35 with 95% CI [-10.37, -2.33], P= 0.002). Moreover, patients in the quadpill group significantly achieved target blood pressure < 140/90 (RR: 1.77 with 95% CI [1.26, 2.51], P= 0.001), compared to the control group. Finally, there was no difference between the quadpill and the control groups regarding the safety outcomes, including the incidence of any adverse events (RR: 1.36 with 95% CI [0.86, 2.15], P= 0.19), any serious adverse events (RR: 1.13 with 95% CI [0.56, 2.25], P= 0.74), and any adverse events leading to drug discontinuation (RR: 0.89 with 95% CI [0.19, 4.11], P= 0.88). Conclusion Quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) was effective and safe for hypertension treatment. However, further large-scale multicenter RCTs are still warranted before endorsement in the clinical practice as current evidence is based on a small number of RCTs and quadpill holds a promising strategy for hypertension treatment.Figure 1Figure 2