A once-daily polypill safely reduces the risk of major cardiovascular events such as heart attack, stroke, and heart failure by more than a third over five years compared with lifestyle advice alone (202/3,421 [6%] vs 301/3,417 [9%]), according to the first large randomised trial of its kind involving almost 7,000 individuals aged 50–75 years in Iran. The effects were seen in a wide range of individuals, including those with and without a history of cardiovascular disease (CVD).
The findings, published in The Lancet, demonstrate for the first time the effectiveness of a fixed-dose combination polypill—containing two commonly used blood pressure-lowering drugs, a cholesterol-lowering medicine, and aspirin—for both the primary and secondary prevention of CVD in the general population, and indicate that the benefits of widespread polypill use outweigh any known side effects.
Crucially, participants who took the polypill as directed (at least 70% of the time) saw the strongest protective effect against future cardiovascular events—cutting their risk by more than half (57%) compared with that given lifestyle advice only (86/2,144 [4%] vs 301/3,417 [9%]). Nevertheless, the authors did not observe a corresponding improvement in blood pressure.
This study is the first to have a sufficient sample size and follow-up time to assess the effect of the polypill on long-term fatal and non-fatal cardiovascular events in primary prevention.
“The idea of the polypill has always been appealing, and now we know that a fixed-dose polypill can achieve clinical benefits in practice,” says Professor Reza Malekzadeh from Tehran University of Medical Sciences in Iran who led the research. “Because the risks of side-effects from the components are very low, and the potential benefits are very high, the polypill is very safe. In terms of risk reduction, we can see the people who benefit most are those with high adherence. But the polypill is not an alternative to a healthy lifestyle and should be combined with physical activity, a healthy diet, and smoking cessation.”
“Polypills are commercially available in a number of countries for secondary prevention, but this is the largest trial confirming the value of the polypill and showing it is effective in primary prevention,” says co-author Professor Tom Marshall from University of Birmingham in the UK. “Because they have most to gain, the most efficient strategy would be to offer the polypill to those at highest risk of heart disease.”
Poor medication adherence is particularly common among patients with cardiovascular disease, with research suggesting that around a third of patients stop taking their medication as early as 90 days after having a heart attack. The polypill concept was first proposed almost 20 years ago as a simpler, cost-saving approach to improve medication adherence and reduce the cardiovascular disease burden. But evidence of the long-term effects of the polypill is lacking, particularly in primary prevention settings, and the polypill is still not widely used.
To provide more evidence, the PolyIran study recruited 6,838 individuals from the Golestan Cohort—a study tracking the health of over 50,000 adults from Golestan, a province in Iran. Between February, 2011, and April, 2013, participants aged 50 years or more living in rural areas were recruited. Around 1 in 10 had a history of CVD (737/6,838 participants), and over three-quarters of these (588/737) were using other cardiovascular drugs at the start of the study.
Researchers randomly assigned the villages in which participants lived to either lifestyle advice (116 villages; 3,417 participants) or a once-daily polypill plus lifestyle advice (120 villages; 3,421). They then looked at whether the individuals took the polypill, and how many major adverse clinical events (e.g., stroke, heart attack, or death) participants had over the next five years. Overall, participants showed high adherence to the polypill, with around 63% taking the polypill as recommended (at least 70% of the time).
Compared with lifestyle advice, taking the polypill reduced the risk of major cardiovascular events by 34% overall—and by around 40% in individuals without a history of CVD over five years (136/3,033 [4.5%] vs 229/3,068 [7.5%]), and by approximately 20% in those with previous CVD (66/388 [17%] vs 72/349 [21%]). The effects were similar in both men and women and the old and young. After adjusting for participants taking other cardiovascular drugs, the overall protective effect of the polypill was reduced to 22% (from 34%) but remained statistically significant.
Systolic and diastolic blood pressure did not differ significantly between the groups, but LDL cholesterol was significantly lower in polypill arm.
The findings suggest that 35 individuals would need to be treated with the polypill to prevent one person from having a serious cardiovascular event. In participants with high adherence to treatment (who took the polypill as directed at least 70% of the time), the number needed to treat was 21.
The study was not designed to look at mortality and more research is needed, but the findings indicate that the polypill was not associated with a significant reduction in overall mortality.
Overall, the polypill was well tolerated and adverse events were similar between the groups. Ten (0.3%) participants in the polypill group and 11 (0.3%) in the minimal care group had an intracranial hemorrhage, and there were similar diagnoses of peptic ulcer disease (34 [1.1%] vs 35 [1.2%]) and upper gastrointestinal bleeding (13 [0.4%] vs nine [0.3%]) over the five years. In total, 13% (440/3,421) of participants discontinued the polypill during follow-up—60% (267/440) for reasons related to the treatment.
“Given the polypill’s affordability, there is considerable potential to improve cardiovascular health and to prevent the world’s leading cause of death. Over three-quarters of the 18 million people who die from cardiovascular diseases each year live in low- and middle-income countries, and a fixed-dose polypill strategy, if adopted widely, could play a key part in achieving the bold UN target to reduce premature mortality due to cardiovascular disease by at least a third by 2030,” says co-author Dr Nizal Sarrafzadegan, Isfahan University of Medical Sciences, Iran.
The authors note several limitations, including that they used only two fixed-dose combination pills, and different dosages of each drug or different combinations might improve efficacy. Additionally, at the start of the study the enrolment team was aware of the allocation of 48 villages (2115 participants), which could have affected the behavior of the enrolling physicians—when these participants were excluded, the protective effect of the polypill was reduced to 22% (from 34%). They also point out that the study was done in a rural population in Iran, with a population largely of central Asian ethnicity, which could limit the generalisability of the findings to other countries.
Writing in a linked Comment, Professor Anushka Patel from The George Institute for Global Health, Australia, says: “Despite some limitations, this study makes a major contribution to the evidence-base for polypills in the prevention of CVD globally. The findings are particularly important for low- and middle-income countries where 80% of the global CVD burden resides and where, in general, even larger preventive treatment gaps exist than observed in this and other polypill trials…The widespread availability of low-cost polypills, with the inclusion of aspirin for people with established CVD, would likely facilitate global goals to provide effective and efficient access to essential CVD medicines to reduce CVD morbidity and mortality whether through initiation, step-up, or even substitution of individual medicines.”