Polypill with or without Aspirin in Persons without Cardiovascular Disease

Abstract

Background: A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease.

Methods: Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed.

Results: A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups.

Conclusions: Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.).

Figure 1. Effects of the Polypill, as Compared with Placebo, on Systolic Blood Pressure, Heart Rate, and the Low-Density Lipoprotein (LDL) Cholesterol Level.

I bars indicate 95% confidence intervals (CIs).

Figure 2. Effects of the Polypill, as Compared with Placebo, on Clinical Outcomes.

Panel A shows the cumulative incidence of a first composite-primary-outcome event (death from cardiovascular causes, myocardial infarction, stroke, heart failure, resuscitated cardiac arrest, or arterial revascularization) for the comparison of the polypill with placebo. Panel B shows the cumulative incidence of first and recurrent events of the primary composite outcome. Insets show the same data on an enlarged y axis.

Figure 3. Effects of the Aspirin, as Compared with Placebo, on Clinical Outcomes.

Panel A shows the cumulative incidence of a first composite-primary-outcome event (death from cardiovascular causes, myocardial infarction, or stroke) for the comparison of aspirin with placebo. Panel B shows the cumulative incidence of the first event of cancer (component of the secondary outcome; a prespecified outcome). Insets show the same data on an enlarged y axis.

Figure 4. Effects of the Polypill plus Aspirin, as Compared with Double Placebo, on Clinical Outcomes.

Panel A shows the cumulative incidence of a first composite-primary-outcome event (death from cardiovascular causes, myocardial infarction, stroke, heart failure, resuscitated cardiac arrest, or arterial revascularization) for the comparison of combination therapy with a polypill plus aspirin with placebo. Panel B shows the cumulative incidence of first and recurrent events of the primary composite outcome. Insets show the same data on an enlarged y axis.