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Overall, the Polycap polypill (simvastatin, atenolol, hydrochlorothiazide, ramipril) falls well short of the high expectations for the polypill approach to cardiovascular disease risk reduction.
When Nicholas Wald and Malcolm Law proposed the polypill in 2003, they projected that it could lower the risk of stroke and heart attack by 80%.
Results reported today at the American Heart Association (AHA) Scientific Sessions 2020 meeting showed a much lower reduction of serious cardiovascular events even when aspirin was given with the polypill.
This outcome may not mean the end of the road for the polypill, but it does put a damper on expectations for what was seen as a simple, low-cost way of ratcheting down elevated cardiovascular disease risk.
The Polycap polypill made by Cadila Pharmaceutials, an Indian company headquartered in Ahmedabad, consists of 40 milligrams of simvastatin, 100 milligrams of atenolol, 25 milligrams of hydrochlorothiazide and 10 milligrams of ramipril. One arm of the TIPS-3 trial tested the Polycap pill against a placebo, and another arm tested the Polycap pill in combination with aspirin against a placebo. A third arm tested just aspirin. The primary outcome of the trial was a composite score that include death from cardiovascular causes (stroke, heart attack) and heart failure, resuscitation from cardiac arrest, and revascularization.
The results, as presented in the New England Journal of Medicine today, showed a 21% difference (a hazard ratio of .79) in the primary outcome between the study volunteers who were randomized to take the Polycap pill and those randomized to take the placebo (126, or 4.4%, in the Polycap group compared with 157, or 5.5%, in the placebo group).
The difference in the primary outcome was slightly better when aspirin was added. The results reported by the investigators show a 31% difference (a hazard ratio of .69) between those randomized to take the Polycap pill and a low dose of aspirin (75 milligrams daily) and those randomized to take a placebo (there were 59 instances of the primary outcome, or 4.1%, in the Polycap-plus-aspirin group compared with 83 instances, or 5.8%, in the placebo group).
Hypotension and dizziness was more common among those in Polycap-plus-aspirin group
than they were in the group randomized to the placebo, according to the research team led by Salim Yusuf, D.Phil., executive director of the Population Health Research Institute in Hamilton, Ontario, Canada, and Prem Pais, M.D., of St. John’s Medical College in Bangalore, India.
Despite falling short of Wald and Law’s projections, Yusuf and Pais and their colleagues make case for the polypill approach in the discussion section of their NEJM article .
Wald and Law called for including vitamins B12 and B6 and folate in a polypill as a way of lowering homocysteine levels. Polycap doesn't include those vitamins, and Yusuf, Pais and their colleagues said homocysteine-lowering was not a goal in their trial because the benefits of it are unclear.
“The benefits we observed are nonetheless likely to be of clinical and population-wide importance especially if the polypill is inexpensive,” they say in the NEJM article, adding that a similar formulation of Polycap in India costs $15.
The TIPS-3 trial included 5,713 people, most of them recruited to participate either in India or the Philippines. The study volunteers did not have cardiovascular disease but were classified as being at intermediate or high risk for it as measured by the INTERHEART Risk Score.
Cadila Pharmaceuticals provided the polypill and the placebo for the study. Other funding came from the Wellcome Trust.