A recent trial by Dr. Salim Yusuf, published in The New England Journal of Medicine, indicated that combination therapy with aspirin plus a polypill (consisting of a statin plus three blood-pressure-lowering drugs) can reduce the incidence of cardiovascular events compared with placebo among participants without established cardiovascular disease, but at moderate cardiovascular risk.
Cardiovascular diseases are the leading causes of mortality worldwide. To lower the risk of cardiovascular disease, high blood pressure and hypercholesterolemia are important modifiable risk factors. A “polypill” that includes both lipid-lowering and blood-pressure-lowering medications may theoretically reduce the risk of cardiovascular disease to a greater extent than either medication used in isolation. Aspirin has also been proven to be an effective medication for decreasing the risk of cardiovascular diseases in patients with established disease. The use of aspirin alone or combined with a polypill for the prevention of cardiovascular disease should be elucidated. The International Polycap Study 3 (TIPS 3) compared the incidence of cardiovascular diseases among those taking polypill alone compared to matching placebo, those taking polypill combined with aspirin compared with double placebo, and those who take aspirin alone compared with matching placebo.
The TIPS-3, a prospective, multicenter, double-blind trial, recruited men aged 50 years or older and women aged 55 years or older without known established cardiovascular disorders, but with an increased INTERHEART Risk Score. Participants were randomized in a 2-by-2-by-2 factorial design to receive either polypill (consisting of 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) with aspirin, or polypill alone, or aspirin alone, or double placebo. For the comparison of polypill-aspirin with double placebo and polypill with placebo, the primary endpoint was a composite of major cardiovascular events, which included: death from cardiovascular causes, stroke, myocardial infarction, heart failure, resuscitated cardiac arrest, and arterial revascularization. For the comparison of aspirin with placebo, the primary endpoint was death from cardiovascular causes, myocardial infarction, or stroke. The participants were followed for a mean of 4.6 years.
A total of 5713 participants were assigned to polypill combined with aspirin (n=1429) or polypill alone (n=1432) or aspirin alone (n=1431) or double placebo (n=1421). In the primary intention-to-treat analysis, no significant differences were observed in the primary composite outcome of the aspirin compared with the placebo group (4.1% versus 4.7%; Hazard ratio (HR):0.86, 95% confidence interval (CI): [0.67–1.10]). A total of 126 out of 2861 participants in the polypill group and 157 out of 2852 in the receptive placebo group developed the primary outcome of interest (HR: 0.79, 95% CI:[0.63–1.00]). Polypill with aspirin led to a 31% reduction in the primary outcome compared to double placebo (HR: 0.69 (95% CI: [0.50–0.97]). Polypill plus aspirin use was associated with a higher incidence of hypotension, dizziness, and cough, but no excess of bleeding events compared to double placebo.
The TIPS-3 trial included a run-in phase where of the 7534 patients initially enrolled, 715 (9.5%) and 560 (7.4%) participants did not undergo randomization due to side effects and non-adherence to the trial-medication, respectively. This should be taken into account while generalizing the findings of the study, as the results may underestimate non-adherence to polypill plus aspirin treatment.
In conclusion, the TIPS-3 trial demonstrated that a combination of aspirin and polypill leads to a lower incidence of cardiovascular events among patients at intermediate risk of cardiovascular disease, but who do not have established CV disease.