Polypill strategy succeeds in preventing major cardiovascular events

Use of a polypill or fixed-dose combination of aspirin, atorvastatin, hydrochlorothiazide and enalapril appears to effectively cut the risk of major cardiovascular events, with high adherence and low adverse event (AE) rates, in individuals aged 50–75 years in a real-life setting, according to data from the PolyIran trial.

“To our knowledge, this is the first large-scale pragmatic trial with long-term follow-up to investigate the effects of a fixed-dose combination therapy on primary and secondary prevention of cardiovascular diseases (CVDs). The reduced major cardiovascular event risk in the [current] study suggests that a fixed-dose polypill strategy could help achieve the UN Sustainable Development Goal of reducing premature mortality due to CVD by at least a third before 2030,” the investigators said. [https://www.undp.org/content/undp/en/home/ sustainable-development-goals.html]

PolyIran was a two-group, pragmatic trial nested within the Golestan Cohort Study, which involved a cohort of 50,045 adult participants from the Golestan province in Iran. A total of 6,838 individuals were enrolled into the trial, among whom 3,417 were randomly assigned to the minimal care group given nonpharmacological preventive interventions alone and 3,421 to the polypill group.  

Over the 5-year follow-up, the primary endpoint of major CV events—hospitalization for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularization procedures, and nonfatal and fatal stroke—occurred with greater frequency in the minimal care group (5.9 percent vs 8.8 percent). Polypill was associated with about a 40-percent risk reduction (adjusted hazard ratio [HR], 0.66, 95 percent confidence interval [CI], 0.55–0.80). [Lancet 2019;394:672-683]

The cardioprotective advantage with polypill was consistently observed in individuals with pre-existing CVD (HR, 0.61, 95 percent CI, 0.49–0.75) and those without (HR, 0.80, 95 percent CI, 0.51–1.12; p-interaction=0.19). In the subgroup of individuals in the polypill group with high adherence, the reduction in the risk of major CV events proved even greater compared with the minimal care group (adjusted HR, 0.43, 95 percent CI, 0.33–0.55).

Median adherence rate to polypill tablets was 80.5 percent. There were two formulations used. One included hydrochlorothiazide 12.5 mg, aspirin 81 mg, atorvastatin 20 mg and enalapril 5 mg. The other, which was administered to participants who developed cough during the follow-up, included valsartan 40 mg instead of enalapril 5 mg.

In terms of safety, the frequency of AEs was similar between the polypill and minimal care groups. Intracranial haemorrhages occurred in 10 and 11 participants, respectively, while physician-confirmed diagnoses of upper gastrointestinal bleeding occurred in 13 and nine patients.

The investigators noted that polypill induced nonsignificant changes in blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) relative to minimal care after 5 years. They pointed out that healthy lifestyle education and probable use of LDL-C–lowering drugs in the minimal care group might have contributed to such a result, in addition to the insufficient dosing of the antihypertensive component in the polypill.

“Despite these relatively small changes in BP and LDL-C, our findings suggested greater effects of the polypill tablet on the risk of CVD outcomes when compared with previous similar studies, [such as] the HOPE-3 study,” the investigators said, pointing out that a risk reduction was only observed in individuals receiving rosuvastatin, although a larger difference in BP in those receiving the two antihypertensive agents was seen than in PolyIran. [N Engl J Med 2016;374:2009-2020]

“Therefore, we speculate that the beneficial effect of the polypill ... was probably attributable to atorvastatin and aspirin. This point should be considered in future studies investigating polypill strategy for reducing cardiovascular disease events,” they added.

In a linked commentary, Drs Anushka Patel and Mark Huffman from the University of New South Wales in Sydney, Australia, described PolyIran as a “monumental effort” to establish the potential value of combining multiple drugs in a single pill in fighting a major global health problem. [Lancet 2019;394:617-619]

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