Polypills — A Central Strategy for Improving Cardiovascular Health

Abstract

The polypill concept garnered substantial attention in 2003 after the publication of a modeling analysis that proposed that the use of fixed-dose combination therapy in persons with established atherosclerotic cardiovascular disease and in all other adults 55 years of age or older could reduce disease burden by 80% or more. 1 Notably, these models overestimated the effects of aspirin and folic acid and assumed full long-term adherence to the regimen. Subsequent randomized trials testing the effects of different polypills in small populations over short periods of time showed reductions in the cholesterol level and blood pressure and increases in the percentages of participants adhering to the regimen in both primary-prevention and secondary-prevention settings. 2 However, for primary prevention, concerns remained regarding the appropriateness of polypill components, including aspirin; the disadvantages of being unable to adjust the doses of individual drugs, potentially outweighing any benefits of a polypill approach; and the issue of medicalization of healthy populations. Without data on clinical outcomes, debates about the polypill remained unresolved. In 2019, the PolyIran cluster-randomized trial reported the first long-term outcomes of any polypill study in a largely primary-prevention population. 3 The tested combination included 81 mg of aspirin, 20 mg of atorvastatin, 12.5 mg of hydrochlorothiazide, and either 5 mg of enala-pril or 40 mg of valsartan. Among 6838 adults 50 to 75 years of age in Iran who were followed for a mean of 5 years, the polypill group had a 34% lower risk of major cardiovascular events than the group that received augmented usual care. This trial has now been closely followed by the publication in this issue of the Journal of TIPS-3 (the International Polycap Study 3), 4 which used a 2-by-2 factorial design to evaluate the efficacy and safety of a polypill containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril, administered daily with or without 75 mg of aspirin, as compared with matching placebos, in a primary-prevention population. Among 2850 intermediate-risk participants in nine countries who were followed for a mean of 4.6 years, those who had been randomly assigned to receive the polypill plus aspirin had a 31% lower risk of major cardiovascular events than those who had been randomly assigned to receive double placebo. After an active run-in phase, more participants in the polypill groups than in the placebo groups discontinued the trial regimen because of dizziness or hypotension (77 participants [2.7%] vs. 31 [1.1%]), but otherwise the incidence of adverse events was generally similar in the two pooled groups. The comparisons of the polypill alone with placebo and of aspirin alone with placebo showed a similar direction of effect with smaller effect-size estimates, as anticipated, although the results were not significant for the comparison of aspirin with placebo. The polypill groups had a significantly lower level of low-density lipoprotein (LDL) cholesterol and significantly lower systolic blood pressure than the placebo group. Although the benefit of the poly-pill was smaller than expected, this was largely explained by lower-than-anticipated long-term adherence to the polypill regimen, supply-chain barriers, or a combination thereof. 2 Nevertheless , the effect sizes seen in TIPS-3 are robust. Some important unresolved questions remain. An excess of major bleeding events was not observed in the comparison of polypill plus aspirin with double placebo in TIPS-3 (or in the comparison of the aspirin-containing polypill with usual care in the PolyIran trial), but these analyses were probably underpowered for detecting significant harms. Furthermore, the bioequiva-lence and long-term stability of polypill formulations should be shown. Of note, reductions in the LDL cholesterol level in TIPS-3 did not attenuate over time, although reductions in blood pressure did diminish. Finally, reasons for non-adherence to the polypill regimen due to preferences among physicians, patients, or both require further understanding.