A polypill that combines four cardiovascular drugs has been shown to reduce the risk of major cardiovascular events in the general population when taken in a low-dose once-daily. Findings from the PolyIran study, a five-year randomised controlled trial, were published in The Lancet, and are the first to demonstrate a role for such treatment in the primary as well as secondary prevention of heart disease.
The polypill used consists of two commonly used blood pressure lowering drugs, a cholesterol-lowering drug, and aspirin. It reduced rates of heart attack, stroke, and heart failure in participants both with and without a history of cardiovascular disease by more than one-third compared to lifestyle advice alone.
Authors Gholamreza Roshandel, Masoud Khoshnia, Hossein Poustchi (Shariati Hospital, and University of Medical Sciences, Tehran, Iran) et al speculate that the findings suggest a fixed-dose polypill strategy could help to achieve the UN Sustainable Development Goal to reduce premature mortality from cardiovascular disease by at least a third before 2030.
They write: “This pragmatic trial provides evidence that a low-cost polypill could be considered as part of preventive strategies to reduce cardiovascular disease burden among eligible adults, especially in low-income and middle-income countries.”
The PolyIran study was a two-group, cluster-randomised trial nested within the larger Golestan Cohort Study, which consisted of 50,045 participants aged 40–75 years from the Golestan province in Iran. Researchers randomised clusters (villages) 1:1 to either a package of non-pharmacological preventive interventions alone (minimal care group) or to a combination of a once-daily polypill tablet and non-pharmacological intervention (polypill group).
Statisticians at the University of Birmingham (Birmingham, UK) performed the randomisation independent of the local study team. Non-pharmacological preventive interventions (healthy lifestyle advice) were delivered by the PolyIran field visit team at three and six months, and every six months after that. There were two formulations of the polypill; polypill one (hydrochlorothiazide 12.5mg, aspirin 81mg, atorvastatin 20mg, and enalapril 5mg) was initially prescribed. Any subjects who developed a cough during follow-up were then changed to polypill two, in which enalapril 5mg was switched for valsartan 40mg. Follow-up was for 60 months.
The primary outcome—occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)—was centrally assessed by the GCS follow-up team, who were masked to allocation status, with an intention-to-treat analysis of all participants in the two study groups who met eligibility criteria.
The researchers enrolled 6838 participants between Feb 2011 and April 2013—3,417 (in 116 clusters) in the minimal care group and 3,421 (in 120 clusters) in the polypill group. Of these, 1761 (51.5%) in the polypill group and 1679 (49.1%) in the minimal care group were women. One in 10 had a history of cardiovascular disease (737/6,838), and more than three-quarters of these (588/737) were using other cardiovascular drugs at the beginning of the study. Systolic and diastolic blood pressure did not differ significantly between the groups, but low density lipoprotein (LDL) cholesterol was significantly lower in the polypill arm.
Median adherence to polypill tablets was 80.5% (interquartile range [IQR] 48.5–92.2). During follow-up, 301 (8.8%) participants in the minimal care group had major cardiovascular events compared with 202 (5.9%) in the polypill group (adjusted hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.55–0.80). Roshandel, Khoshnia, Poustchi et al found no statistically significant interaction with the presence (HR 0.61, 95% CI 0.49–0.75) or absence of pre-existing cardiovascular disease (HR 0.80, 95% CI 0.51–1.12, p interaction=0.19). An analysis of subjects participants in the polypill group with high adherence found an even greater reduction in risk of major cardiovascular events compared to the minimal care group (adjusted HR 0.43, 95% CI 0.33–0.55).
The frequency of adverse events was similar between the two study groups. During the five years of follow-up, 21 intracranial haemorrhages were reported—10 in the polypill group and 11 in the minimal care group. There were 13 instances of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group.
Roshandel, Khoshnia, Poustchi and colleagues say: “The number needed to treat (NNT) to prevent one major cardiovascular event was 34.5 (95% CI 25.9–56.1). The NNT to prevent one major cardiovascular event in participants with high adherence was 20.7 (95% CI 17.5–26.5). Our results did not show reductions in both systolic (p=0.08) and diastolic (p=0.09) blood pressure. Despite only small changes in blood pressure, our findings suggested greater effects of polypill tablets on the risk of cardiovascular disease outcomes when compared with previous similar studies (for example HOPE-3).”
They point out that the findings indicate that the benefits of widespread polypill use outweigh any known side-effects, that it is effective in preventing major cardiovascular events, and that it was not associated with a significant reduction in overall mortality, although the study was not designed to look at mortality and more research is needed.
However, the authors note that PolyIran performed in a rural population, consisting mainly of central Asian ethnicity, which could limit the generalisability of the findings. Additionally, they used only two fixed-dose combination pills, and different dosages of each drug or different combinations may improve efficacy.