Researchers have found that combined treatment with a polypill plus aspirin led to a 31% lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease (CVD) who were at intermediate cardiovascular risk, according to the TIPS-3 study in the New England Journal of Medicine.
No excess of major bleeding events was not observed and the NEJM writes in an editorial that "the findings of TIPS-3 support the inclusion of multi-drug therapy for cardiovascular disease prevention in the World Health Organization “best buys” for noncommunicable disease prevention and control as the lone health-system approach that is potentially highly cost-effective."
The NEJM writes:
The polypill concept garnered substantial attention in 2003 after the publication of a modelling 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.
Notably, these models overestimated the effects of aspirin and folic acid and assumed full long-term adherence to the regimen. Subsequent randomised 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. 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 medicalisation of healthy populations. Without data on clinical outcomes, debates about the polypill remained unresolved.
In 2019, the PolyIran cluster-randomised trial reported the first long-term outcomes of any polypill study in a largely primary-prevention population. 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). 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.
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 bio-equivalence and long-term stability of polypill formulations should be shown. Finally, reasons for non-adherence to the polypill regimen due to preferences among physicians, patients, or both require further understanding.
Ischaemic heart disease and atherosclerotic stroke are among the leading causes of health loss globally. Yet, health systems either have not been sufficiently responsive or are unprepared to deliver equitable, high-quality primary care in cardiovascular disease prevention and control. The findings of TIPS-3 support the inclusion of multi-drug therapy for cardiovascular disease prevention in the World Health Organization “best buys” for noncommunicable disease prevention and control as the lone health-system approach that is potentially highly cost-effective.
Other population-based strategies still need to be implemented urgently to achieve global goals. However, patients with atherosclerotic cardiovascular disease and persons who are at risk for atherosclerotic cardiovascular disease can also derive health benefits from pharmacotherapy, and thus polypill therapy represents the most scalable intervention to date, given the totality of data.
Study details
Polypill with or without aspirin in persons without cardiovascular disease
Salim Yusuf, Philip Joseph, Antonio Dans, Peggy Gao, Koon Teo, Denis Xavier, Patricio López-Jaramillo, Khalid Yusoff, Anwar Santoso, Habib Gamra, Shamim Talukder, Courtney Christou, for the International Polycap Study 3 Investigators
Published in NEJM on 21 January 2021
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.
[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa2028220"]NEJM study (Restricted access)[/link]
[link url="https://www.nejm.org/doi/full/10.1056/NEJMe2033310?"]Full NEJM editorial: Polypills — A Central Strategy for Improving Cardiovascular Health (Restricted access)[/link]
See also from the MedicalBrief archives:
[link url="https://www.medicalbrief.co.za/archives/large-trial-produces-best-evidence-of-aspirin-benefits-in-reducing-cvd-risk/"]Preliminary TIP-3 data: Large trial produces ‘best evidence’ of aspirin benefits in reducing CVD risk (2020)[/link]
[link url="https://www.medicalbrief.co.za/archives/daily-4-1-polypill-cut-cvd-risk-low-income-countries/"]Daily 4-in-1 polypill could cut CVD risk in low-income countries[/link]