Can this one pill save your life?

A low-cost polypill—a combination of four different drugs currently used to treat hypertension and hypercholesterolemia—may effectively prevent major cardiovascular events, according to the results of a large study published in The Lancet. And, in a related study, it was shown to do so cost-effectively.

“Cardiovascular diseases are major causes of mortality worldwide. A fixed-dose combination therapy—the so-called polypill—was proposed more than 15 years ago as an acceptable and cost-saving approach to reduce cardiovascular disease risk. Since then, different formulations of polypill have been used in several studies worldwide. However, long-term effects of the polypill on fatal and non-fatal hard endpoints (such as mortality or cardiovascular events) have not yet been firmly established, particularly in primary prevention settings,” wrote the authors, led by Gholamreza Roshandel, MD, PhD, associate professor, Golestan University of Medical Sciences, Gorgan, Iran.

The polypill is comprised of four drugs: aspirin, atorvastatin, hydrochlorothiazide, and enalapril or valsartan.

To assess the efficacy of the polypill strategy as primary and secondary prevention of cardiovascular disease, researchers conducted the PolyIran Study, which was nested within the Golestan Cohort Study of 50,045 participants aged 40-75 years in Iran.

Participants were randomized—according to clusters of villages—to either the polypill once daily (n = 3,421) or non-pharmacologic interventions (n = 3,417; minimal care group) that included educational training on maintaining a healthy lifestyle provided at months 3 and 6 and then every 6 months thereafter.

The initial polypill patients received consisted of hydrochlorothiazide (12.5 mg), aspirin (81 mg), atorvastatin (20 mg), and enalapril (5 mg). Those who developed a cough were switched to a second variation of the polypill that included valsartan (40 mg) instead of enalapril. Follow-up was 5 years.

Patients who took the polypill regularly—at least 70% of the time—reduced their risk of a major cardiovascular event by up to 57%, and of cardiovascular events such as heart attack, stroke, and heart failure by one-third.

During follow-up, 5.9% of those in the polypill group had major cardiovascular events compared with 8.8% of those in the minimal care group. Upon conducting a post hoc analysis, Dr. Roshandel and colleagues found that the longer the polypill was used, the stronger its protective effects became. Over the 5-year follow-up, 27.4% of those in the extended polypill group had a new major cardiovascular event compared with 35.9% in the extended minimal care group.

In addition, participants treated with the polypill who had a high adherence to the medication protocol demonstrated significantly greater reductions in their risk of major cardiovascular events compared with the minimal care group (adjusted HR: 0.43; 95% CI: 0.33–0.55).

At 5 years, researchers also observed greater changes in systolic blood pressure levels from baseline in the polypill group compared with the minimal care group (-5.58 vs -4.18 mmHg, respectively; P = 0.079), as well as in diastolic pressure levels (-4.31 vs -2.91 mmHg; P = 0.093) and LDL cholesterol levels (-35.39 vs -15.85 mg/dL; P < 0.0001).

Adverse events were similar between the two groups. Intracranial hemorrhages occurred in 10 participants in the polypill group compared with 11 in the minimal care group. Physician-confirmed upper gastrointestinal bleeding occurred in 13 vs 9 participants, respectively.  

“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. Our results showed a significant reduction in major cardiovascular event risk in the polypill group compared with the minimal care group (adjusted hazard ratio [HR]: 0.66, 95% CI: 0.55–0.80),” noted Dr. Roshandel and colleagues.

“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),” they concluded.

In a related study, researchers found that the polypill was undeniably cost-effective in patients who suffered previous myocardial infarction or stroke. They published their findings in Lancet Global Health.

Upon constructing a simulation model, senior author Dhruv S. Kazi, MD, MSc, MS, associate director, Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center (BIDMC), Boston, MA, and fellow researchers used real-world data to model the current rates of medication use and cardiovascular outcomes to determine results if patients currently treated with one or more evidence-based therapies for cardiovascular disease were switched to the polypill.

They chose to apply their model to countries representing a wide range of economic development, which included India, China, Mexico, Nigeria, and South Africa. All have a large burden of cardiovascular disease.

In each country, Dr. Kazi and colleagues found that the polypill would be cost-effective compared with standard of care. The greatest benefits arose from the fact that doctors needed to prescribe only a single pill, ensuring that patients received all four therapies, thus making medication compliance easier and higher.

They cautioned, however, that the polypill must be used in tandem with other measures to stem the huge burden of cardiovascular disease in these countries.

“In order to achieve meaningful improvements in health outcomes, [low- and middle-income countries] adopting the polypill must also make strategic investments in high-quality health infrastructure and effective supply chains to ensure that patients with a prior history of heart disease or stroke have reliable access to an affordable cardiovascular polypill,” concluded Dr. Kazi.

Dr. Roshandel’s study was funded by the Tehran University of Medical Sciences, the Barakat Foundation, and Alborz Darou. Dr. Kazi’s work was supported in part by the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology at BIDMC, a Hellman Family Foundation award at UCSF, the Veterans Affairs Office of Academic Affiliations Advanced Fellowship in Health Services Research and Development, the UCSF Global Health Pathways grant, and the UCSF Resident Clinical and Translational Research Funding Program.