Polypill Therapy, Subclinical Atherosclerosis, and Cardiovascular Events – Implications for the Use of Preventive Pharmacotherapy: Multi-Ethnic Study of Atherosclerosis

Editor's Note: Commentary based on Bittencourt M, Blaha MJ, Blankstein R, et al. Polypill Therapy, Subclinical Atherosclerosis, and Cardiovascular Events—Implications for the Use of Preventive Pharmacotherapy: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2014;63:434-443.


The widespread use of a polypill has garnered a considerable amount of attention as a potentially attractive tool for the primary prevention of cardiovascular disease (CVD). This is largely due to the simplicity of the treatment selection algorithm and an estimate of up to an 80% lowering in cardiovascular disease burden.1 In general, proposed polypills include a low dose aspirin, beta-blocker, angiotensin converting enzyme inhibitor, and a statin all in one pill. However, the simplicity of this approach will also result in the expanded treatment to many individuals who are asymptomatic and have a very low probability of developing cardiovascular disease. In this article, Bittencourt et al. evaluate the potential implications of using coronary artery calcium (CAC) screening to refine the population treated with a polypill.


The Multi-Ethnic Study of Atherosclerosis (MESA) is composed of 6,814 patients who were 45-84 years old without known cardiovascular disease, and had a CAC scan performed at the start of study. The authors used the MESA cohort to identify participants who met the inclusion criteria for four different polypill distribution algorithms (the original article by Wald et al, The Indian Polycap Study [TIPS], Poly-Iran, and the Program to Improve Life and Longevity [PILL]) and then stratified them further based on CAC scores.1-4 They compared CVD event rates and the number needed to treat (NNT) within each polypill strategy stratified by CAC scores.


The number of MESA participants meeting inclusion criteria for the four polypill strategies ranged from 2,238 for the TIPS trial to 3,911 for the PILL trial. The majority of MESA subjects qualifying for the TIPS and Poly-Iran trials had a CAC score of zero (CAC=0), while the strategy proposed by Wald et al. had 39% of MESA participants with a CAC=0. In the CAC=0 group, the CVD events rates were approximately 2-4% per 1,000 person years for all four treatment strategies, while in the group with a CAC >100 the CVD event rates were 15-18% among the four treatment strategies. The NNT to prevent one CHD event in five years was between 81-130 for participants in the CAC=0 groups and between 18-20 among participants in the CAC >100 groups. Those with CAC scores of 1-100 had a NNT that was approximately two to three times higher than for those with a CAC >100, but about half as large compared to those with a CAC=0.


Very few CVD events occurred in the MESA participants with a CAC=0 and the majority of events occurred in those with a CAC >100 no matter the polypill treatment strategy. Using CAC=0 to identify a group that would not have a meaningful benefit from the polypill is a simple screening method that would significantly reduce the number of individuals treated and focus resources on the group at highest risk for CVD.


The polypill is an attractive public health concept, because the algorithms that have been used to determine who is treated are simple and easy for clinicians to remember and patients are only required to take one pill daily. It has been estimated that implementation of a polypill strategy could result in a reduction of up to 80% of CVD events, assuming an independent risk reduction of each component and that it is prescribed starting at age 55.1 If manufactured on a large scale as they are intended to be used, the cost should also be significantly less than the sum of each individual component. The medications included in the typical polypill also have relatively good side effect profiles and depending on the formulation and are estimated to cause side effects in only 8-15% of patients.1 Potential drawbacks include a cough in subjects taking an ACE-Inhibitor and less than optimal blood pressure and lipid lowering. In addition, there are limitations in the possible combinations/doses of medications and when implemented on a population level the cost would be substantial.

CAC screening is a simple, non-invasive method of CVD risk stratification and those with a CAC=0 have a very low event rate of approximately 2 per 1,000 person-years.5 In this article, Bittencourt et al. demonstrate that among patients eligible for polypill treatment the use of CAC screening could identify as many as 59% of the population with CAC=0. This novel algorithm for polypill distribution would eliminate the treatment of those very low risk individuals with CAC=0, while also reducing costs and potential treatment side effects by focusing treatment on those at the highest risk who are most likely to benefit from polypill therapy. However, it should be acknowledged that implementation of the polypill has generally been envisioned as a population wide public health endeavor in resource poor settings with treatment strategies based on clinical results that are already part of routine clinical practice. In this setting, it could be challenging to implement CAC screening even if available at the less than $100 which is typical of most metropolitan areas in the United States.6 Nevertheless, the use of CAC screening for the allocation of the polypill is an intriguing concept that would only add one additional step and a small cost to the polypill treatment algorithm with the potential to enhance its overall success.


  1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. Br Med J 2003;326:1419.
  2. Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009;373:1341-1351.
  3. Rastegarpanah M, Malekzadeh F, Thomas GN, Mohagheghi A, Cheng KK, Marshall T. A new horizon in primary prevention of cardiovascular disease, can we prevent heart attack by "heart polypill"? Arch Iran Med 2008;11:306-313.
  4. Malekzadeh F, Marshall T, Pourshams A, et al. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors. Int J Clin Pract 2010;64:1220-1227.
  5. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008;168:1333-1339.
  6. Blaha MJ, Budoff MJ, DeFilippis AP, et al. Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study. Lancet 2011;378:684-692.

Clinical Topics: Prevention

Keywords: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Cardiovascular Diseases, Coronary Vessels, Primary Prevention

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