Effectiveness of Polypill for Primary and Secondary Prevention of Cardiovascular Diseases: A Pragmatic Cluster Randomized Controlled Trial

Background: A fixed-dose combination therapy ("polypill" strategy) has been proposed as an approach to reduce the burden of cardiovascular disease (CVD), 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 study population comprised of rural participants of the Golestan Cohort Study aged 50 years or older. Considering villages as clusters, the study participants were cluster randomized to a package of non-pharmacological preventive interventions either alone (minimal care arm) or together with a once daily polypill (polypill arm). Participants were followed for 60 months. The primary outcome was occurrence of major cardiovascular events (MCVE), which was compared between the two arms using Cox regression models with shared frailty. Findings: Overall, 6838 individuals were enrolled in the study, including 3417 (in 116 clusters) in the minimal care arm and 3421 (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 and minimal care arms, respectively, had one or more MCVE (adjusted hazard ratio [HR]=0.66; 95% confidence interval [CI]: 0.55-0.80). Polypill was effective for both primary and secondary prevention of CVD. When restricted to participants with high adherence, the risk of MCVE was further reduced (adjusted HR=0.43; 95%CI: 0.33-0.55). Overall, the frequency of adverse events was comparable between the two arms. Interpretation: Using polypill was effective in preventing MCVE. Medication adherence was high, and rates of adverse events were low. The polypill strategy may be considered as an additional effective component in controlling CVDs, especially in low resources settings. Trial Registration: Cllinicaltrials.gov identifier: NCT01271985. Funding Statement: The study was supported by and Alborz Darou, Barakat Foundation, and Tehran University of Medical Sciences. Golestan Cohort study was supported by Cancer Research UK (grant number: C20/A5860), Tehran University of Medical Sciences (grant number: 81/15), and the International Agency for Research on Cancer. Declaration of Interests: The authors disclose no conflicts. Ethics Approval Statement: The protocol of the PolyIran Study was reviewed and approved by Institutional Review Board (IRB) of Digestive Diseases Research Institute and Tehran University of Medical Sciences.