Participants without cardiovascular disease but who were at increased risk were randomly assigned to receive a polypill (i.e. 1 statin with 3 blood pressure-lowering drugs) or placebo and to receive aspirin or placebo. With 4.6 years follow-up, the incidence of cardiovascular events was lower among participants receiving both the polypill and aspirin than among those receiving both placebos. Physician’s Weekly interviews the lead study investigator, Prof. Salim Yusuf (Population Health Research Institute, Hamilton, Canada) who presented the results of the TIPS-3 trial at the American Heart Association Scientific Sessions 2020 [1].

 TIPS-3 randomised 5,713 people, mostly of South Asian ancestry, who did not have cardiovascular disease but were classified as being at intermediate or high risk as measured by the INTERHEART Risk Score. The polypill contains 40 milligrams of simvastatin, 100 milligrams of atenolol, 25 milligrams of hydrochlorothiazide, and 10 milligrams of ramipril. One arm of the TIPS-3 trial tested the polypill versus placebo, another arm tested the polypill in combination with aspirin (75 mg daily) versus placebo, and a third arm tested just aspirin. The primary outcome of the trial was a composite score that included death from cardiovascular causes (stroke, heart attack) and heart failure, resuscitation from cardiac arrest, and revascularisation. The results were simultaneously published in the New England Journal of Medicine [2].

The mean follow-up was 4.6 years. Levels of low-density lipoprotein (LDL) cholesterol were lower by approximately 19 mg per decilitre and systolic blood pressure was lower by approximately 5.8 mmHg in the groups taking the polypill with or without aspirin when compared with group taking double placebo. The primary outcome showed a 21% difference in events in the polypill group (4.4%) versus the placebo group (5.5%; HR 0.79; 95% CI 0.63-1.00).

The difference in the primary outcome was slightly better when aspirin was added to the polypill, showing a 31% difference for the polypill + aspirin arm. In total, events occurred in 59 participants (4.1%) in the combined-treatment group as compared with 83 events (5.8%) in the double-placebo group (HR 0.69; 95% CI 0.50-0.97).

All treatment arms showed good safety profiles, although hypotension and dizziness were significantly  more common among subjects in the group taking the polypill and aspirin.

Physician’s Weekly interviewed Prof. Yusuf for his perspective on these findings:

What is the public health impact of the polypill and how does the reality compare with the expectations for the polypill? 

“Honestly, they were unrealistic expectations. The paper by Wald and Law published in 2003 [3] suggested that theoretically one could get an 80% reduction in strokes and ischemic heart disease with a polypill, but these projected results were very specific to those two events. Their predictions did not account for other relevant cardiovascular outcomes. Their thought exercise was based on the expectation that a polypill would reduce LDL cholesterol by nearly 2 mmol/l, whereas in reality, no large long-term trial was ever shown that much reduction of LDL cholesterol, only about half that. In addition, the reduction in blood pressure was overly optimistic as well; again, no large trial has shown that extent of risk reduction approaching the numbers they applied for their model.”

“That paper was theoretically pushing the limit. but if you adjust the expectations to 1 mmol/l difference in LDL cholesterol and about an 8 mmHg difference in diastolic blood pressure, you could probably get a 40%-50% treatment effect. That is realistic, and still very promising. Thus, there was an expectation of a very large effect, but that data was never actually there to support it.”

“In our trial, we found a more modest difference in blood pressure and LDL cholesterol, which is very similar to the PolyIran study (NCT01271985). PolyIran was another large study done in Iran and very similar to the TIPS- 3 study. PolyIran did not test a polypill, per se, but there were 2 blood pressure-lowering agents in one arm and in another arm had statin as a factorial, so a quarter of the subjects received 3 drugs analogous to a polypill [4]. I think the different studies are providing approximately the same results. A polypill or similar approach without aspirin seems to give about a 30% risk reduction, and when aspirin is combined, probably about a 40% risk reduction in clinical events, which is quite large when you think of the fact that, you are talking about primary prevention and you are also talking about inexpensive drugs that are relatively safe.”

Who is the ideal cohort to be taking this polypill? 

“Wald and Law proposed to give it to everybody over the age of 55 [3]. I do not think that is practical. But since the drugs included in the polypill are already indicated in people with hypertension, diabetes, multiple risk factors, as well as people who already have vascular disease, I would treat those groups first. In people requiring secondary prevention, I would certainly consider a polypill. These populations are relatively undisputed among professionals, that treating them would reduce the burden of cardiovascular disease overall. I would say on top of that, we should promote healthy living: avoiding smoking, being active, eating a lot of fruits and vegetables. My vision is that we should use the polypill as a vehicle to promote overall cardiovascular health.”

What kind of problems do you anticipate from regulatory bodies with regard to this? 

“It is important to realize that there are probably something like 20 or 25 polypills produced around the world. The ones approved are all safe and effective, and convenient to use. Whether this particular polypill that we studied will even be filed for regulatory purposes, I do not know. Because it is a small company in India and the regulatory filing fees in the US, for example, are about $1.5 million.”

“My feeling is that our study should be seen as a proof-of-concept. Existing polypills, as long as they have at least 2 blood pressure-lowering agents, and a statin, either with or without aspirin, are interchangeable.”

What are the next steps, and what will the next future polypill look like?

“The next step is to bring all the data together from all the 3 large studies together and by fostering different analysis we can look at specific events and specific patient subgroups. That work is already underway, and it probably will be completed in 6-9 months from now, in mid-2021. There are three big studies to consider: TIPS-3, PolyIran, and the Heart Outcomes Prevention Evaluation (HOPE)3 study (NCT00468923) [5-7].

“Secondly, we have a health economics analysis ongoing; this is essential research and will influence the impact of this work. Thirdly, a separate study is looking at cognitive decline, and its association with a reduction of vascular risk factors, blood pressure, as well as lipids. Further analyses from these existing trials and combining the trial data is the next step.”

“I also hope somebody will produce a stronger polypill in terms of something that will lower lipids to a greater extent and blood pressure to a greater extent. There will be some refinement in slightly different combinations of blood pressure lowering drugs and statins, or perhaps adding an ARB or ACE inhibitor help, and better diuretics with slightly improved blood pressure lowering effect. What we have shown is a proof of concept, upon which to build.”


  1. Yusuf S, et al. Aspirin Alone and in Combination With a Polypill in Cardiovascular Disease Primary Prevention: Results From the International Polycap Study (TIPS)-3. LBS.02, Late-Breaking Clinical Science Virtual AHA Scientific Sessions 2020, 13-17 Nov.
  2. Yusuf S et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. New Engl J Med, Nov 13, 2020.DOI: 10.1056/NEJMoa2028220.
  3. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. 2003 Jun 28;326(7404):1419.
  4. Roshandel G. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet. 2019 Aug 24;394(10199):672-683.
  5. Lonn EM, et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2009-20.
  6. Yusuf S, et al. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2021-31.
  7. Yusuf S, et al. Blood-Pressure and Cholesterol Lowering in Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2032-43.