The Growing Importance of Polypills in the Management of Cardiovascular Diseases

By Jose Maria Castellano, MD*

The worldwide epidemic of cardiovascular disease sparked nearly 15 years ago the concept of a CV polypill. It seems counterintuitive that in the time of personalized medicine, a cardiovascular polypill would be deemed as one of the most escapable strategies to contain atherosclerotic cardiovascular disease pandemic. The polypill offers significant solutions to the current prevention landscape, including:

  1. Improved worldwide accessibility: nearly 80% of all CV deaths take place in low and middle income countries, where access to medication is dismal (reports from the PURE studies show 8-14% accessibility to antiplatelets, statins and antihypertensive medication in secondary prevention with figures dropping to the low single digits in rural areas).
  2. Improved adherence: the polypill has been consistently shown in clinical trials including different populations to be the single most efficient (and certainly scalable) strategy to significantly improve adherence. Four trials reported the effect of polypills on adherence, which was 44% higher in the polypill group than in the comparator group (p<0.001). Interestingly, participants with low baseline adherence were more likely to show improvements in adherence with polypills than were participants with high baseline adherence levels. This finding supports the position that polypills can be used to reduce inequities that manifest in lower baseline medication adherence rates in disadvantaged populations.
  3. Improved risk factor control: thirteen trials (7638 participants) reported the effect on systolic blood pressure, which was 6.3 mm Hg lower in the polypill group than in the comparator group (p<0.001). Eleven trials (6565 participants) reported the effect on total cholesterol, which was 0.6 mmol/L lower in the polypill group (p<0.001). Because most trials that included risk factor changes had short-term follow-up, the differences seen between the polypill and comparator groups were not maintained long enough to manifest differences in clinical event rates.
  4. Patient preference: Four trials of polypills versus usual care have reported data on acceptability of the polypill concept to physicians or patients, or both, participating in these trials. Although subject to social desirability bias (whereby participants might report favourably to be seen in a better light), the overwhelming response was favourable towards use of a polypill in routine clinical practice. Five additional studies surveyed patients and physicians who were not involved in clinical trials with similar positive response to the polypill concept. The most commonly mentioned advantages were the ease and convenience of taking pills, cost-saving benefits, and improved safety from simplifying, and therefore decreasing confusion about, pill regimens.
  5. Cost effectiveness: various pharmaco economic models have been published comparing the use of a polyill strategy versus usual care. The polypill has been shown to be cost effective even in the most adverse models due to its effect on clinical outcomes based on improved adherence, and risk factor control.
  6. Adverse effects: Frequency of side-effects (including serious adverse effects) for patients taking the polypill has been measured in multiple trials. In the Single Pill to Avert Cardiovascular Events (SPACE) Collaboration20 group of three trials (and eventually pooled for analysis), 23% of patients reported adverse events (compared with 20% of patients in the polypill group). In the FOCUS trial adverse events were fewer, at 6% in the polypill group compared with 6.6% in the comparator group.

One of the main disadvantages in the use of polypills cited by prescribers is inflexibility to prescribe. While there is a case for personalized prescribing, it can also be argued that all patients in secondary prevention (and many high risk primary prevention), require treatment with aspirin, statin, and an ACEi. Secondly, prescribing a polypill does not prevent from adding-on all needed medication in order to effectively control the risk factor profile of an individual patient. Thirdly, patients receiving a polypill containing atorvastatin 20 have shown better LDL control than those with stating of higher potency, based on better adherence. Finally, the polypill may not be the ultimate solution and certainly not perfect for all patients, but based on its inherent strengths, it is certainly better than the current pandemic of cardiovascular disease worldwide.


Real world experience in implementation is mainly derived from the Fuster-CNIC-Ferrer (a public-private partnership between the National Center for Cardiovascular Research in Madrid and Ferrer Group in Barcelona, led by Dr. Valentin Fuster), polypill project for secondary prevention, Trinomia, containing aspirin, statin and ACEi. Trinomia is approved for commercialization in nearly 50 countries. Regulatory approval is based on the evidence of bioequivalence to individual products and bridging to the existing safety and efficacy data for the polypill components. There should be no need to require extensive outcome studies for regulatory approval of the polypill if bioequivalence is shown, because this requirement is an unwarranted and substantial barrier to development, however lack of clinical trials demonstrating reduction of hard outcomes has been a significant barrier for implementation. Proof of an effect of a polypill on clinical outcomes is not a requirement for regulatory approval among people who have had a cardiovascular disease event because of the strength of the evidence and consistency in international guideline recommendations supporting the use of the component medications.

According to WHO’s guidelines for the regulation of fixed-dose medicinal products, fixed-dose combinations have advantages when there is an identifiable patient population for whom treatment with a particular combination of active drugs in a fixed ratio of doses has been shown to be safe and effective, and when all of the drugs contribute to the overall therapeutic effect. A cardiovascular polypill for secondary prevention and high-risk primary prevention meets these criteria in all respects.

The public health implications of polypill use are potentially substantial, especially in low-resource settings but also in all settings where adherence to secondary prevention is low. The large treatment gaps in secondary prevention, especially in LMICs, are well documented. Despite the demonstrated benefits of effective and inexpensive drug therapy for secondary prevention of recurrent cardiovascular events, these therapies are underused in many LMICs where the greatest burden of cardiovascular disease occurs. The grave burden of non-communicable diseases has not escalated in the health agenda of various policy makers, precisely because of the chronicity of these diseases. There needs to be a conceptual adaptation to the reality of non-communicable diseases by all stakeholders (societal, patients’ associations, policy makers, scientific associations, industry, insurers, and policy makers) to adopt and implement simple, cost effective, scalable strategies, the so-called best-buy public health interventions, such as the cardiovascular polypill for secondary prevention. The cardiovascular polypill, used as an important component of a comprehensive public health approach for secondary prevention and high-risk primary prevention, is a vital strategy for treatment expansion. The future prospects for the widespread use of the polypill as a crucial public health intervention will depend on key strategies to address the clinical, regulatory, and systemic barriers.

*Dr. Castellano is the Director of the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Coordinator of the Cardiovascular Health Program of the University Hospital HM Monteprincipe in Madrid, Spain. He is working with Valentin Fuster in several studies with Polypills, and has published important articles in that field.