A four-component polypill, including aspirin, atorvastatin, hydrochlorothiazide, and enalapril or valsartan, effectively reduced major cardiovascular events in a real-life setting study. The results of the PolyIran trial by Roshandel G. et al. was published in Lancet.
The PolyIran study is the first large-scale, long-term, pragmatic randomized trial aimed to investigate the effect of fixed-dose combination therapy for the primary or secondary prevention of cardiovascular diseases. The PolyIran study was designed as a two-group, cluster-randomized trial nested within the Golestan Cohort Study with approximately 50, 000 participants aged 40–75 years from the Golestan province of Iran. In this trial, villages (clusters) were randomly assigned to either the minimal care group, who received non-pharmacological preventive interventions alone (lifestyle modifications) or the polypill group, who received a once-daily polypill tablet in addition to preventive lifestyle interventions. In the polypill group, participants initially received polypill (hydrochlorothiazide 12•5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). For those intolerant to enalapril due to cough, a switch to polypill comprising valsartan 40 mg instead of enalapril was made.
A total of 6838 individuals (3417 in the minimal care group and 3421 in the polypill group) were enrolled in the study. Fifty percent of participants were women; and 10.8% had pre-existing cardiovascular disease, of whom 79.8% were taking cardiovascular medications at baseline. Median adherence to polypill, measured by pill count, was 80.5%, with 62.7% of the participants having a high medication adherence (70% or greater). The primary outcome was the occurrence of major cardiovascular events, including hospitalization for the acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularization procedures, and non-fatal and fatal stroke. Over a follow-up of 5 years, the primary outcome occurred in 202 (5.9%) of 3421 participants in the polypill group compared to the 301 (8.8%) of 3417 participants in the minimal care group, yielding a relative 34% risk reduction (adjusted HR 0.66; 95% CI: 0.55-0.80). The number needed to treat (NNT) to prevent one major cardiovascular event was 34.5 (95% CI: 25.9–56.1). The study also showed that participants with high adherence to polypill had an even lower risk of major cardiovascular events compared with the minimal care group (adjusted HR 0.43, 95% CI: 0•33–0•55), resulting in an NNT of 20.7 (17.5–26.5) to prevent one major cardiovascular event. The two study groups had a comparable frequency of adverse events, including intracranial hemorrhage and upper gastrointestinal bleeding.
“A polypill strategy could be considered as part of preventive measures to reduce cardiovascular disease burden among eligible adults, especially in low-income and middle-income countries…The reduced major cardiovascular event risk (and even greater risk reduction in those with high adherence) suggests that a fixed-dose polypill strategy could help achieve the UN Sustainable Development Goal to reduce premature mortality due to cardiovascular disease by at least a third before 2030.” – The investigators noted.
The main driver of the reduction in major cardiovascular events associated with polypill may be related to improved lipid-lowering (by atorvastatin) rather than blood pressure control (by hydrochlorothiazide and enalapril or valsartan) or atheroprotection (by aspirin). Of note, there was no significant difference in the decline of systolic or diastolic blood pressures between the two groups. In contrast, patients in the polypill group had a greater LDL cholesterol reduction from baseline to 60 months compared with the minimal care group (35.39 vs. 15.85 mg/dl, mean difference: 19.54 mg/dl, 95% CI: 17.74 to 21.33). With respect to aspirin, previous studies showed that its efficacy in primary cardiovascular prevention could be offset by bleeding side effects. Although increased hemorrhage was not observed in the polypill arm, the relative contribution to cardiovascular benefit by aspirin could not be estimated, as the study did not monitor the response to aspirin.
The study had some limitations. The enrollment team was not blinded at the start of the study. The study was conducted in a rural population in the Middle East; the widespread prescription of polypill to people of different ethnicities and nationalities would require further extended research, taking the regional prevalence of cardiovascular risk factors into account. Only one fixed-dose combination pills have been prescribed for all participants, both for primary and secondary prevention. “Flexible options (i. e., different dosages for each drug and different combinations tailored for specific clinical settings) might improve drug adherence and efficacy”, Roshandel et al. added.