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Polypill strategy at the heart of cardiovascular secondary prevention
  1. Borja Ibañez1,2,3,
  2. José M Castellano1,4,5,
  3. Valentin Fuster1,6
  1. 1Clinical Research Department, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
  2. 2Cardiology Department, IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain
  3. 3CIBERCV, CIBER de enfermedades Cardiovasculares, Madrid, Spain
  4. 4Centro Integral de Enfermedades Cardiovasculares (CIEC), Hospital Universitario Montepríncipe, HM Hospitales, Madrid, Spain
  5. 5Facultad de Medicina, Universidad CEU San Pablo, Madrid, Spain
  6. 6Cardiology Department, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA
  1. Correspondence to Dr Borja Ibañez, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Madrid 28029 Spain ; bibanez{at}

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Over recent decades, cardiovascular disease (CVD) has overtaken infectious diseases as the leading cause of death worldwide.1 This shift is partly due to the great advances in the treatment of infectious diseases and the success of associated public health campaigns. General public awareness of the importance of both preventing high-risk exposure and early therapy initiation and adherence has helped reduce the burden of communicable (infectious) diseases. This contrasts sharply with the story of non-communicable diseases such as CVD. The incidence of atherosclerosis (the single largest underlying cause of CVD) has increased exponentially due to the immense lifestyle changes witnessed first in developed countries but lately also in low-income and middle-income countries. This rapid worldwide change in lifestyle has resulted in dramatic increases of obesity, sedentarism, dyslipidaemia and hypertension, all of which are risk factors for atherosclerosis.

The control of modifiable cardiovascular risk factors, such as lipid levels and blood pressure, has a clear impact in reducing the likelihood of experiencing a cardiovascular event, and this holds true for both primary and secondary prevention. The leading cardiovascular scientific societies dedicate major efforts to providing guidelines to enable clinicians to define specific targets for each of these modifiable factors based on a patient’s risk profile. The most recent European Society of Cardiology (ESC) ‘Guidelines on cardiovascular disease prevention in clinical practice’, released in 2016, established low-density lipoprotein (LDL) cholesterol targets of 70, 100 and 115 mg/dL for individuals at very high, high and low-to-moderate risk, respectively, and a blood pressure target of <140/90 mm Hg (140/85 mm Hg for most patients with diabetes).2 The identification of risk factors allows gross prediction of future cardiovascular events such as myocardial infarction (MI) and stroke.

Patients experiencing an acute cardiovascular event today have a high likelihood of surviving the episode thanks to the great therapeutic advances in MI and other acute conditions. However, these patients remain at high risk of subsequent events, with long-term consequences for the affected individuals (disability, absenteeism, etc) and for healthcare budgets. Clinical research over recent decades has identified several pharmacological routes to effectively reduce the incidence of adverse events in survivors of MI and other acute conditions. These therapeutic options all receive clinical practice guideline recommendations for specific conditions.3 4 Task forces commissioned to prepare these documents review available data about the efficacy of specific therapies. In devising these recommendations, the greatest weight is given to evidence from adequately powered randomised clinical trials. However, it is important to bear in mind that patients enrolled in clinical trials are monitored closely, and medication adherence is therefore usually high. In real life, treatment adherence is significantly lower than in controlled trials, with the result that the real-life efficacy of prescription drugs is lower than anticipated. Data from European cohort studies found that up to 9% of all CVD events can be attributed to poor adherence to cardiovascular medications.5 In a recent analysis of ≈4000 patients with post-MI, patients fully adhering to medication (taking prescribed drugs>80% of days) had a significantly lower incidence of major adverse cardiovascular events (MACE) than those with partial adherence (40%–80% of days covered) or non-adherence (<40%) (MACE incidence 19%, 25% and 26%, respectively).6 In addition, full treatment adherence results in lower per-patient annual direct medical costs for MI hospitalisation than partial or non-adherence.6 One major reason for non-adherence to secondary prevention medication is the complexity of treatment, which usually involves a high number of daily prescribed pills.7 This problem is by no means specific to CVD, but affects many other conditions requiring treatment combinations. The introduction of a polypill strategy for patients with infectious diseases (tuberculosis, HIV, etc) has successfully facilitated access and adherence to medication and has even reduced associated distribution costs.8 These polypills have become the mainstay therapy for most patients with these infectious diseases. Atherosclerosis seems a perfect scenario for the adoption of a polypill strategy, since clinical practice guidelines recommend a high number of medications after an acute event.3 4 Unexpectedly, although one secondary prevention cardiovascular polypill containing aspirin, ramipril and atorvastatin received approval from the European Medicines Agency (EMA) in 2014,9 this strategy has not been universally adopted.

In their Heart paper, Selak and colleagues10 present an individual participant data meta-analysis of three randomised clinical trials comparing a polypill strategy (containing aspirin, a statin and an antihypertensive drug) with standard care. The main goal of the analysis was to determine the proportion of patients in the polypill and usual care arms meeting 2016 ESC prevention guideline2 targets for LDL cholesterol, blood pressure and antiplatelet use. The analysis included 3140 patients with a prior CVD event (secondary prevention) or who were at high risk of their first event (primary prevention). The trials included in the meta-analysis were IMProving Adherence using Combination Therapy (IMPACT) (n≈500 patients), The Kanyini Guidelines Adherence with the Polypill (Kanyini-GAP) (n≈600) and Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) (n≈2000). The three trials were conducted between 2010 and 2013 as part of the pre-established Single Pill to Avert Cardiovascular Events (SPACE) collaboration. The three trials thus followed the same protocol, with only minor regional adaptations.11 The SPACE consortium already published the results of an individual participant data meta-analysis of these trials,12 showing that the polypill strategy significantly improved medication adherence, resulting in a significant improvement in systolic blood pressure and LDL cholesterol levels compared with usual care.12 In the present study, Selak and colleagues used the same database to determine if these improvements resulted in a higher proportion of patients meeting the targets set by the ESC prevention guidelines.2 The main finding of the present study is that a higher proportion of patients in the polypill arm achieved the recommended targets for LDL cholesterol (39% in polypill vs 34% in usual care) and blood pressure (62% vs 58%). Adherence to antiplatelet therapy (only applicable to secondary prevention patients) did not differ (96% in both arms). The proportion of patients meeting the three targets simultaneously was significantly higher in patients included in the polypill arm than in those in the usual care arm (24% vs 19%). Despite being a not prespecified analysis, these results are very important and provide significant incremental information to their previous meta-analysis.12 One limitation of this analysis is that it only presents data collected in the SPACE collaboration trials, which were conducted 5–8 years ago. Relevant data from more recent trials, like the Fixed-Dose Combination Drug for Secondary Cardiovascular Prevention (FOCUS) trial13 were not included. In the European Union FP7-funded FOCUS trial, ≈700 patients with post-MI were randomised to a polypill strategy (aspirin, statin and ramipril) or to usual care. Adherence to medication was significantly higher in the polypill strategy group (51% vs 41% in usual care group).13 After completion of the FOCUS trial, the cardiovascular ‘Fuster polypill’—containing aspirin, ramipril and a statin—received approval for clinical use in 2014 and is currently available in more than 30 countries.9

As the Salek study confirms, the evidence supporting the benefits of a cardiovascular polypill strategy in high-risk patients is compelling. Given that this strategy results in higher treatment adherence and better control of modifiable risk factors, the 2016 ESC cardiovascular prevention guidelines included for the first time a recommendation for its use.2 A year later, the 2017 ESC guidelines for the treatment of patients with ST-segment elevation MI4 included the same recommendation, in line with the prevention guidelines. In these two major ESC guideline documents, the class of recommendation for the cardiovascular polypill is set at IIb, with a level of evidence B. Given the consistent benefits across trials, one might question why the class of recommendation for this strategy is not stronger. The main reason is the lack of direct data showing that the increased adherence and better control of risk factors associated with the use of the cardiovascular polypill result in significant reductions in hard endpoints. To date, no trial has had the power to test this hypothesis. To address this need, the European commission (H2020)-funded Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial is being conducted under the coordination of the Spanish National Centre for Cardiovascular Research in Spain ( Identifier: NCT02596126). The ongoing SECURE trial will randomise 3200 patients with post-MI in seven European countries (Spain, Italy, Czech Republic, Germany, France, Poland and Hungary) to receive the ‘Fuster polypill’ (aspirin, ramipril and atorvastatin) or to usual care (the three medications separately). This study is powered to identify differences in MACE (cardiovascular death, non-fatal MI, non-fatal ischaemic stroke and urgent revascularisation) over a minimum 2 year follow-up. The bad news is that results of this trial will not be available before 2022.

In summary, there is robust evidence that the use of a cardiovascular polypill strategy results in increased adherence to treatments, to better control modifiable risk factors and to a higher proportion of patients meeting ESC guideline targets for LDL cholesterol and blood pressure. Although there is still no data showing that these benefits translate into a reduction in hard endpoints, adoption of this strategy can now be considered in daily practice.



  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests BI and VF have no personal conflicts of interest to declare. JMC has received speaker fees and travel support from Ferrer. The CNIC is a non-profit public institution that receives royalties for the sales of a polypill (Trinomia) composed of aspirin, ramipril and atorvastatin, but no CNIC researcher has direct interests or receives any personal benefits.

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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