University of Birmingham Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran)

Background: Cardiovascular diseases (CVDs) continues to be the leading cause of death worldwide. A fixed-dose combination therapy (“polypill” strategy) was proposed as a costsaving method for CVD prevention, especially in lower resource settings. We conducted the PolyIran Study to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide and either enalapril or valsartan, for primary and secondary prevention of CVD. Methods: The PolyIran study is a two-arm pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). The sampling frame for the PolyIran study was rural GCS participants aged 50 years or older. Considering villages as clusters, and using a cluster randomization, the study participants were allocated to a package of non-pharmacological preventive interventions either alone (minimal care arm) or together with a once daily polypill (polypill arm). All participants were followed for 60 months and the primary outcome was occurrence of major cardiovascular events (MCVE). The risk of MCVE between the two arms was compared using Cox regression models, with shared frailty models. Findings: Overall, 6841 individuals were enrolled in the study, including 3,417 (in 116 clusters) in the minimal care arm and 3,421 (in 120 clusters) in the polypill arm. Median (interquartile range) adherence to polypill tablets was 80.5% (48.5-92.2). During the follow up, 202 and 301 participants in the polypill arm and minimal care arm respectively had one or more MCVE, representing a 34% reduction (adjusted hazard ratio [HR]=0.66; 95% confidence interval [CI]: 0.55-0.80) in risk of MCVE in the polypill arm. The risk of MCVE in participants with high adherence was significantly lower when compared with the minimal care arm (adjusted HR=0.43; 95%CI: 0.33-0.55). The effect of polypill was stronger in participants without pre-existing CVD (primary prevention group) (HR=0.61, 95% CI: 0.490.75) than those with history of CVD (secondary prevention group) (HR=0.80, 95% CI: 0.571.12) (p-value for interaction=0.19). Overall, the frequency of adverse events was comparable between the two arms. Interpretation: The PolyIran study is the first large scale pragmatic trial with long term follow up demonstrating the effectiveness of a fixed-dose combination therapy in primary and secondary prevention of CVDs. Our results showed high medication adherence and the risk of adverse events was similar between the two arms. The polypill strategy may be considered as an additional effective component in controlling CVDs, especially in low resources settings.