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Macrovascular Residual Risk Studies

22 March 2021
The International Polycap Study-3 (TIPS-3) showed that the combination of a polypill and aspirin reduced cardiovascular events in primary prevention patients
Treatment with a polypill targeting elevated low-density lipoprotein cholesterol and high blood pressure, together with aspirin reduced cardiovascular events by 31% in intermediate-risk individuals without pre-existing cardiovascular disease.
Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med 2021; 384:216-228.
Objective: To investigate whether administration of a polypill, containing simvastatin 40 mg, atenolol 100 mg, hydrochlorothiazide 25 mg, and ramipril 10 mg, with or without aspirin 75 mg, reduces cardiovascular events in intermediate-risk individuals without cardiovascular disease.
Study design: Randomized controlled trial. Following consent, eligible subjects underwent a 3-to-4-week run-in phase, with a low-dose polypill and low-dose aspirin daily. Subjects who tolerated the study medications were randomized using a 2-by-2-by-2 factorial design to treatment with the polypill or placebo daily, aspirin or placebo daily, and the polypill plus aspirin or double placebo daily. Random allocation used a central randomization process that was stratified by centre. Subjects were followed-up at 6 weeks, 3, 6 and 9 months, 1 year, and at 6-monthly intervals thereafter until the end of the study.
Study population: Subjects without cardiovascular disease aged ≥50 years (men) and ≥55 years (women) with an INTERHEART risk score ≥ 10, or men and women aged ≥65 years with an INTERHEART risk score of ≥5.
Study outcome:

· For the polypill-alone and polypill-plus-aspirin comparisons, the primary endpoint was a composite of 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.

Methods: The study was analyzed on an intention-to-treat basis. The primary analysis was the time to a confirmed primary outcome event using the Cox proportional hazards model.

In total, 5713 participants (mean age 63.9 years, 53% female) were randomized. The mean INTERHEART risk score was 16.8, which is consistent with a study population at intermediate risk. Most subjects were recruited in India (48%) and the Philippines (29%). Compared with placebo alone, the polypill (either alone or in combination with aspirin), lowered low-density lipoprotein cholesterol level by ~19 mg/dL and systolic blood pressure by 5.8 mmHg.

Over the mean follow-up of 4.6 years, a primary endpoint was reported for 126 (4.4%) subjects in the polypill arm and 157 (5.5%) in the placebo arm (Hazard ratio 0.79, 95% confidence interval [CI] 0.63 to 1.00). In the polypill-plus-aspirin versus double placebo comparison, there was a significant difference for the primary endpoint, which occurred in 59 (4.1%) subjects and 83 (5.8%) subjects, respectively (Hazard ratio 0.69, 95% CI 0.50 to 0.97). The comparison of aspirin alone versus placebo did not show a significant reduction in major adverse cardiovascular events.

Conclusion: 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.


The polypill concept aims to target the major modifiable risk factors for cardiovascular disease, notably elevated LDL-C and high blood pressure, using generic therapies. In addition to effectiveness, the key benefit is convenience, as patients only need to take one medication per day, which should improve treatment adherence (1).  First mooted nearly 20 years ago (2), this  strategy offers a low-cost approach to reducing the burden of cardiovascular disease in low- and middle-income regions, where 80% of cardiovascular disease is now occurring (3).

TIPS-3 is the first large clinical trial to investigate whether this fixed-dose polypill is effective in the primary prevention of cardiovascular disease in individuals at increased risk (4). The study showed that the combination of a polypill with three generic blood pressure medications and simvastatin, together with aspirin, significantly reduced the primary endpoint by 31%; the comparison of the polypill alone versus placebo was not statistically significant. The results show benefit but also suggest that there may be room for improvement in the doses employed in the combination. 


1. Truelove M, Patel A, Bompoint S, et al. The effect of a cardiovascular polypill strategy on pill burden. Cardiovasc Ther 2015; 33:347-52.

2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419.

3. World Health Organization. Cardiovascular diseases. Fact Sheets.

4. Joseph P, Pais P, Dans AL, et al. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J 2018; 206:72-79.

Key words polypill; primary prevention; International Polycap Study-3 (TIPS-3)