PolyIran: Polypill Prevents Major Cardiovascular Events Over 5 Years

A polypill containing aspirin, a statin, and two antihypertensives reduced major cardiovascular events in a mostly primary prevention population, according to results of the cluster-randomized PolyIran trial.

Over 5 years, major CV events occurred in 5.9% of patients who were taking the polypill on top of a lifestyle intervention and 8.8% of those who received the lifestyle intervention alone, a relative 34% reduction in risk (adjusted HR 0.66; 95% CI 0.55-0.80). That works out to a number needed to treat (NNT) of 34.5.

There were no differences in adverse events, including intracranial hemorrhage and upper GI bleeding.

“To our knowledge, the PolyIran study is the first large-scale, long-term, pragmatic randomized trial to investigate the effects of a fixed-dose combination therapy on primary or secondary prevention of cardiovascular disease,” researchers led by Gholamreza Roshandel, PhD (Tehran University of Medical Sciences, Iran), say.

The findings, published in the August 24, 2019, issue of the Lancet, suggest “that a fixed-dose polypill strategy could help achieve the United Nations Sustainable Development Goal to reduce premature mortality due to cardiovascular disease by at least a third before 2030,” the investigators write.

“We found high medication adherence and the risk of adverse events was similar between the two study groups,” they continue. “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.”

Mark Huffman, MD (Northwestern University Feinberg School of Medicine, Chicago, IL, and the George Institute for Global Health, Sydney, Australia), told TCTMD that PolyIran is unique in its size, scope, and ability to evaluate a polypill’s effect on hard clinical endpoints. Prior polypill studies, he explained, have been smaller, have had shorter durations, and have been powered only to assess effects on risks factors like LDL cholesterol and blood pressure.

Asked about the impact of the PolyIran findings, Huffman, who co-wrote an accompanying editorial with Anushka Patel, MBBS, PhD (The George Institute for Global Health), said, “I think these results will stimulate or renew broader interest in fixed-dose combination therapy for cardiovascular disease prevention and control.”

Benefits Seen Across Subgroups

The concept of a polypill—a fixed-dose combination of medications targeting multiple risk factors—to reduce CVD was introduced more than 15 years ago. Prior studies have tested various fixed-dose combinations, but the long-term effects on hard clinical endpoints have remained unclear.

The PolyIran researchers previously performed a pilot study of a polypill containing aspirin, atorvastatin, hydrochlorothiazide, and enalapril, showing that it was well tolerated and led to reductions in blood pressure and lipids. They designed the trial to further assess its impact on clinical outcomes over longer-term follow-up.

PolyIran was a cluster-randomized trial nested within the Golestan Cohort Study, which involved more than 50,000 participants ages 40 to 75 from the Golestan province in Iran. In the trial, villages were randomly assigned to either a nonpharmacological lifestyle intervention alone or the lifestyle intervention plus a once-daily polypill. The final analysis included 6,838 people ages 50 and older randomized in 236 clusters. Half of the participants were women, and 10.8% had preexisting cardiovascular disease.

The nonpharmacological intervention involved educational training about healthy lifestyle habits delivered periodically by a field team and supported by text messages and a pamphlet.

In the polypill group, all people received a fixed-dose combination containing aspirin 81 mg, atorvastatin 20 mg, hydrochlorothiazide 12.5 mg, and enalapril 5 mg. Those who developed cough during follow-up were switched to a pill that contained valsartan 40 mg instead of enalapril. Both tablets were made by Alborz Darou Pharmaceutical Company in Tehran.

Adherence based on pill count was high at 80.5%, with 62.7% of participants having an adherence of 70% or greater.

While there may be some debate about the magnitude of effect, the authors provide compelling evidence about the direction of effect. Mark Huffman

The primary composite endpoint of major cardiovascular events encompassed hospitalization for ACS, fatal MI, sudden death, heart failure, coronary artery revascularization procedures, and nonfatal and fatal stroke.

The reduction in risk over 5 years in the polypill group was consistent across subgroups defined by age, sex, baseline cholesterol, smoking status, whether group allocation was concealed from the enrollment team (it wasn’t for the first 48 clusters), and preexisting hypertension, diabetes, or CVD. The investigators found, however, that only the patients with adherence of at least 70% derived a benefit (adjusted HR 0.43; 95% CI 0.33-0.55; NNT 20.7).

The polypill also reduced risks of several secondary outcomes, including fatal and nonfatal ischemic heart disease and fatal and nonfatal stroke. No differences were seen between groups for overall and non-CV mortality, sudden death, and heart failure.

Minimal Changes in Risk Factors

The significant impact on cardiovascular events was seen despite the lack of large effects on risk factors. Blood pressure was reduced modestly and to a similar degree in both groups through 5 years. The reduction in LDL cholesterol was greater in the polypill arm by 19.54 mg/dL.

“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 (eg, HOPE-3),” Roshandel et al write, speculating that the observed benefit “was probably attributable to atorvastatin and aspirin.”

Speaking with TCTMD, Patel, one of the editorialists, said the magnitude of the reported reduction in cardiovascular events is likely larger than the true effect. She based that assessment on the disconnect between the changes in blood pressure and LDL cholesterol and the effect on the primary endpoint as well as the fact that group allocation was not concealed at the beginning of the trial.

“I think the effect is real. I think there probably is an effect of the polypill strategy. It’s probably a bit more modest than reported,” she said, noting that the greater benefits seen in the high-adherence group should be interpreted cautiously because the participants most likely to take the polypill were compared with the entirety of the control arm.

Huffman agreed with Patel’s assessment. “While there may be some debate about the magnitude of effect, the authors provide compelling evidence about the direction of effect,” he said, “and that’s what makes this a remarkable study.”

What’s Holding Polypills Back?

Asked about why polypills haven’t gained strong traction in the clinical practice, Patel pointed to regulatory challenges as one issue. She said the space occupied by polypills falls somewhere between the purviews of brand-name pharmaceutical manufacturers and makers of generics. “The push to get this sort of product through those regulatory hurdles hasn’t really had a strong backer,” she said, noting that the George Institute and a few other groups around the world are working on that.

Another issue is that up until now, there hasn’t been solid evidence that a polypill strategy can improve clinical outcomes, Patel said.

“People were waiting for this kind of evidence. Most of the trials to date have been based on surrogate outcomes,” she said. “I would hope that this sort of trial impacts others that are being undertaken at the moment, might move things further along that pipeline and lead to some more regulatory trials and to this becoming more widely available.”

And after the evidence is accumulated, implementation challenges need to be addressed, Patel said.

People were waiting for this kind of evidence. Anushka Patel

Huffman agreed that the PolyIran data will likely spur ongoing commercial development of various fixed-dose combinations for the prevention of CVD. But the world is not likely to see uptake similar to what has been seen for combination antiretroviral therapy for HIV because of the lack of “larger social mobilization” around the issue of CVD in the community, he predicted.

“There are few grassroots organizations that are really calling for broader access to cardiovascular disease preventive medicines as a means to achieve people’s rights to health,” Huffman said. “And so the global cardiovascular health community needs to engage beyond the health sector to be more effective, to demonstrate the scope of the problem of cardiovascular diseases, the potential gains through interventions such as these and others related to disease prevention, and the pathways for implementation in existing health systems, which continue to be fragmented and underfunded in many low- and middle-income country settings.”

Growing support for fixed-dose combination therapy among guideline writers will help increase uptake as well, he said.

The potential implications in terms of CVD burden around the world, particularly in low- and middle-income countries, are huge, Patel and Huffman indicate in their editorial.

“The widespread availability of low-cost polypills, with the inclusion of aspirin for people with established cardiovascular disease, would probably facilitate global goals to provide effective and efficient access to essential medicines to reduce cardiovascular disease morbidity and mortality, whether through initiation, step-up, or even substitution of individual medicines,” they write.

“Achievement of this goal requires substantial progress in overcoming regulatory and system-level barriers and developing effective implementation strategies across diverse settings,” they continue. “While the scientific community, policy makers, and public ask, ‘What’s next for polypills?’, the PolyIran trial helps to accelerate research, progress, and debate about how polypills can improve global cardiovascular health outcomes.”