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Study Summary

The TIPS-3 trial was developed to determine the utility of a combination pill (polypill) of 40 mg simvastatin, 100 mg atenolol, 25 mg hydrochlorothiazide, and 10 mg ramipril in reducing a composite of cardiovascular events compared to placebo. This multicenter, multinational, double blind, randomized, placebo-controlled, trial incorporated a 2x2 factorial design assessing polypill versus placebo, aspirin versus placebo, and polypill plus aspirin versus placebo. Men aged ≥ 50 years and women aged ≥55 years with intermediate risk (INTERHEART risk score ≥10 or men and women aged ≥65 years with score ≥5) were included. A total of 5713 participants were randomized (mean age 64 years). After a follow-up period of 4.6 years, the presence of cardiovascular disease (defined as major cardiac events plus heart failure, resuscitated cardiac arrest, and arterial revascularization) was 4.4% in the polypill group versus 5.5% in the placebo group [21% reduction; (95% CI 0.63-1.00)], and 4.1% in the polypill plus aspirin group versus 5.8% in the double placebo group [31% reduction; (95% CI 0.50-0.97)] (see accompanying Hurst’s Central Illustration). Individually, mean systolic blood pressure decreased by 5.8 mmHg, heart rate by 4.6 bpm, and LDL by 19 mg/dL. Lastly, death from cardiovascular causes, stroke, and myocardial infarction were reduced by 14% (95% CI 0.67-1.10) in the aspirin group versus placebo.

Commentary

Study Strengths: This was a well-designed trial designed to study ideal effect of a polypill on a general population. This population was multinational (86 centers in 9 countries) and had a near split male to female ratio. Although the mean follow-up (4.6 years) was slightly shorter than comparative studies, collection of follow-up data was near perfect (99% of vital status and clinical outcome data at 4.6 years).

Study Limitations: The number of enrolled participants and study length was shortened by the COVID-19 pandemic (the initial plan was to include 7000 randomized patients). Additionally, this study used a run-in phase (those who demonstrated 80% adherence and were without adverse effects were randomized). This technique usually limits generalizability as it tends to overestimate adherence and underestimate adverse effects. Even with the use of this statistical method, discontinuation rates were high (20% at 2 years, 43% at study end), increasing the chance of a type II error (bias towards the null). While discontinuation was partially related to adverse effects, delays in drug supply chain as well as operational challenges due to the Covid-19 pandemic accounted for the majority of the reasons for discontinuation. The use of simvastatin may have had a more attenuated clinical benefit relative to the use of newer generation statins such as atorvastatin and rosuvastatin.

Next Steps/Clinical Perspective: This was a well-designed study that demonstrated combination polypill plus aspirin reduced the incidence of cardiovascular events in an intermediate risk population without established cardiovascular disease. While statistically significant, the reduction of cardiovascular events was modest, as were the reduction in individual risk factors (see above). Additionally, the polypill plus aspirin arm suggests that aspirin may have an synergistic effect in the prevention of cardiovascular disease in individuals at risk, as the aspirin only arm did not demonstrate significant reduction in events. Although higher incidences of hypotension, dizziness, and cough were noted for the treatment group, there was no difference in bleeding or myalgias. Given that the high discontinuation rate was mostly for reasons unrelated to adverse effects, the 31% reduction in cardiovascular disease is likely to be an underestimate of the true risk reduction.

Future directions may include additional formulations of a polypill that can result in greater differences in risk factors, or that include higher potency statins. Furthermore, cost-effective analysis could help determine the utility of this moderately effective regimen in a more generalizable study population that did not require a run-in phase.

Trial Reference

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Yusuf  S, Joseph  P, Dans  A,  et al. Polypill with or without aspirin in persons without cardiovascular disease. N. Engl. J. Med. doi:10.1056/NEJMoa2028220

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