Efficacy and harms associated with polypills for primary and secondary prevention of cardiovascular disease: a systematic review and meta-analysis

Introduction Few meta-analyses investigated polypills effects for both primary and secondary prevention of cardiovascular disease (CVD). Purpose We conducted a systematic review and meta-analysis to assess the efficacy and safety of polypills in these populations. Methods Five databases were searched until July 15th, 2024, for randomized controlled trials (RCTs) assessing effects of polypills vs. controls (usual care, active drugs, placebo). Primary outcomes were all-cause mortality (ACM), CV death, CV hospitalization (CVH), and all-cause hospitalization (ACH), myocardial infarction (MI), stroke, heart failure (HF) and revascularization. Secondary outcomes were blood pressure and cholesterol levels, adverse events (AE), and serious AE (SAE). We performed pairwise MAs and subgroup analyses by control type, polypill type, risk of bias (RoB), and prevention population. Effects were reported as risk ratios (RR) and hazard ratios (HR) for dichotomous outcomes and mean differences (MD) for continuous outcomes with 95% confidence intervals (CI). GRADE methods were used to assess quality of evidence (QoE) per outcome. Results Thirteen RCTs (n=27,836) were evaluated. Mean ages ranged between 54.0 and 75.1 years, and follow-up times between 1 and 96 months. Seven RCTs investigated primary prevention, three secondary prevention and three both populations. The evidence was very uncertain about the effect of polypills on ACM (RR 0.93, 95%CI 0.82-1.05, I2= 0%, 9 RCTs), stroke (RR 0.61, 95%CI 0.46-0.81, I2=63%, 4 RCTs), HF (RR 0.94, 95%CI 0.57-1.53, I2=0%, 4 RCTs) and revascularization (RR 0.73, 95%CI 0.49-1.10, I2=60%, 2 RCTs), vs. controls with very low QoE for all outcomes. Polypills may slightly reduce CV death (RR 0.69, 95%CI 0.57-0.83, I2=27%, 5 RCTs), CVH (RR 0.80, 95%CI 0.60-1.06, I2=0%, 2 RCTs) and ACH (RR 0.89, 95%CI 0.77-1.03, I2=1%, 3 RCTs) vs. controls with low QoE for all outcomes. Polypills probably reduced MI slightly (RR 0.69, 95%CI 0.50-0.95, I2=0%, 2 RCTs, moderate QoE). When compared to controls, polypills significantly reduced SBP (MD –3.25mmHg, 95%CI –5.36 to –1.14), DBP (MD –2.01mmHg, 95%CI –3.59 to –0.43), total cholesterol (MD –11.90mg/dL, 95%CI –22.94 to –0.86), LDL (MD –10.57mg/dL, 95%CI –18.15 to –2.99), and significantly increased AE (RR 1.16, 95%CI 1.04-1.30). Subgroup analyses were mostly consistent with main analyses. Conclusions In primary and secondary prevention populations, polypills had little to no effect on ACM, stroke, HF, and revascularization, slightly reduced CV death, CVH and ACH, and probably reduced MI slightly vs. controls. Polypills significantly reduced total cholesterol, LDL, SBP and DBP levels, and increased AE vs. controls.