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The CNIC-Polypill reduces recurrent major cardiovascular events in real-life secondary prevention patients in Spain: The NEPTUNO study

  • José R. González-Juanatey
    Correspondence
    Corresponding author at: Cardiology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
    Affiliations
    Cardiology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain

    CIBERCV (Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares), Madrid, Spain

    IDIS (Instituto de Investigación Sanitaria de Santiago de Compostela), Santiago de Compostela, Spain
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  • Alberto Cordero
    Affiliations
    CIBERCV (Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares), Madrid, Spain

    Cardiology Department, Hospital Universitario de San Juan, Alicante, Spain
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  • José Mª. Castellano
    Affiliations
    Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain

    Centro Integral de Enfermedades Cardiovasculares (CIEC), Hospital Universitario Montepríncipe, Grupo HM Hospitales, Madrid, Spain
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  • Luis Masana
    Affiliations
    Universitat Rovira i Virgili.Hospital Universitario Sant Joan de Reus, Vascular Medicine and Metabolism unit, Reus, Spain

    IISPV (Institut d'Investigació Sanitària Pere Virgili), Reus, Spain

    CIBERDEM (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas), Madrid, Spain
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  • Regina Dalmau
    Affiliations
    Cardiology Department, University Hospital La Paz, Madrid, Spain

    IdiPAZ (Instituto de Investigación Hospital Universitario la Paz), Madrid, Spain
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  • Emilio Ruiz
    Affiliations
    Ferrer International, Barcelona, Spain
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  • Antonio Sicras-Mainar
    Affiliations
    Athrys Health, Barcelona, Spain
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  • Valentín Fuster
    Affiliations
    Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain

    Mount Sinai Medical Center, New York, USA
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Open AccessPublished:May 12, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.05.015

      Highlights

      • In secondary prevention patients the occurrence of new CV events is common.
      • The CNIC-Polypill contains ASA 100 mg, atorvastatin 20/40 mg and ramipril 2.5/5/10 mg.
      • The CNIC-Polypill reduces recurrent MACE in secondary prevention.
      • The CNIC-Polypill improves BP, lipids and medication persistence.

      Abstract

      Background

      To evaluate the effectiveness of a cardiovascular polypill including aspirin, ramipril and atorvastatin (CNIC-Polypill), on the incidence of recurrent major cardiovascular events (MACE) and risk factor control in patients with established atherosclerotic cardiovascular disease (ASCVD) vs different pharmacological therapeutic strategies.

      Methods

      Retrospective, observational study using data from electronic-health records. Patients were distributed into 4 different cohorts: CNIC-Polypill (case cohort) vs 3 control cohorts: same monocomponents taken separately (Monocomponents), equipotent drugs (Equipotent) and other drugs not included in the previous cohorts (Other therapies). Patients were followed for 2 years or until MACE or death.

      Results

      After propensity score matching, a total of 6456 patients (1614 patients per cohort) were analysed. After 2 years, the risk of recurrent MACE was lower in the CNIC-Polypill cohort compared to the control groups (22%; p = 0.017, 25%; p = 0.002, 27%; p = 0.001, higher in the Monocomponents, Equipotent and Other therapies cohorts, respectively). The incremental proportion of patients who achieved blood pressure (BP) and low-density lipoprotein cholesterol (LDLc) control from baseline was higher in the CNIC-Polypill cohort vs control cohorts (BP controlled patients: +12.5% vs + 6.3%; p < 0.05, +2.2%; p < 0.01, +2.4%; p < 0.01, LDLc controlled patients: +10.3% vs + 4.9%; p < 0.001, +5.7%; p < 0.001, +4.9%; p < 0.001, respectively). Medication persistence was higher in patients treated with the CNIC-Polypill (72.1% vs 62.2%, 60.0% and 54.2%, respectively; p < 0.001) at study end.

      Conclusions

      In secondary prevention patients, compared with control groups, treatment with the CNIC-Polypill was associated with significant reductions in the accumulated incidence of recurrent MACE, improved BP and LDLc control rates, and increased medication persistence.

      Keywords

      1. Background

      Patients with prior atherosclerotic cardiovascular disease (ASCVD) have a high risk of recurrent Major Acute Cardiovascular Events (MACE). It has been estimated that up to 50–75% of patients with previous myocardial infarction will have a recurrent CV event within 1–3 years after the acute cardiac event. Therefore, the long-term prognosis among patients with a previous cardiovascular event remains poor [
      • Andres E.
      • Cordero A.
      • Magan P.
      • Alegria E.
      • Leon M.
      • Luengo E.
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      Longterm mortality and hospital readmission after acute myocardials infarction: an eight-year follow-up study.
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      • Soldati S.
      • Di Martino M.
      • Castagno D.
      • Davoli M.
      • Fusco D.
      In-hospital myocardial infarction and adherence to evidence-based drug therapies: a real-world evaluation.
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      • Zabawa C.
      • Cottenet J.
      • Zeller M.
      • Mercier G.
      • Rodwin V.G.
      • Cottin Y.
      • et al.
      Thirty-day rehospitalizations among elderly patients with acute myocardial infarction: Impact of postdischarge ambulatory care.
      ].
      Atherosclerosis, the main underlying cause of cardiovascular disease, has a multifactorial origin, including non-modifiable cardiovascular risk factors, and others like hypertension, dyslipidaemia, diabetes or prothrombotic state, that might be modified by lifestyle changes and appropriate pharmacologic treatment [
      • Visseren F.L.J.
      • Mach F.
      • Smulders Y.M.
      • Carballo D.
      • Koskinas K.C.
      • Bäck M.
      • et al.
      ESC scientific document group. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice.
      ]. As these cardiovascular risk factors cluster in a high proportion of patients with established ASCVD, they usually need therapies that target the different cardiovascular risk factors. Low-dose acetyl salicylic acid (ASA), angiotensin-converting enzyme inhibitors (ACEI), and statins are recommended in guidelines to reduce MACE in patients with established ASCVD [
      • Visseren F.L.J.
      • Mach F.
      • Smulders Y.M.
      • Carballo D.
      • Koskinas K.C.
      • Bäck M.
      • et al.
      ESC scientific document group. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice.
      ,
      • Aboyans V.
      • Ricco J.B.
      • MEL Bartelink
      • Björck M.
      • Brodmann M.
      • Cohnert T.
      • et al.
      2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries Endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
      ,
      • European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee
      Guidelines for management of ischaemic stroke and transient ischaemic attack 2008.
      ].
      The concept of cardiovascular polypills, aimed at targeting several risk factors at the same time with a single pill including various drugs, was first proposed in 2003 [
      • Wald N.J.
      • Law M.R.
      A strategy to reduce cardiovascular disease by more than 80%.
      ]. Since then, a number of clinical trials with different cardiovascular polypills have demonstrated improved adherence and risk factor control compared to usual care [
      • Bahiru E.
      • de Cates A.N.
      • Farr M.R.
      • Jarvis M.C.
      • Palla M.
      • Rees K.
      • Ebrahim S.
      • Huffman M.D.
      Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases.
      ,
      • Joseph P.
      • Roshandel G.
      • Gao P.
      • Pais P.
      • Lonn E.
      • Xavier D.
      • et al.
      Polypill Trialists’ Collaboration
      Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.
      ,
      • Castellano J.M.
      • Sanz G.
      • Peñalvo J.L.
      • Bansilal S.
      • Fernández-Ortiz A.
      • Alvarez L.
      • et al.
      A polypill strategy to improve adherence: results from the FOCUS project.
      ,
      • Muñoz D.
      • Uzoije P.
      • Reynolds C.
      • Miller R.
      • Walkley D.
      • Pappalardo S.
      • et al.
      Polypill for cardiovascular disease prevention in an underserved population.
      ,
      • Castellano J.M.
      • Verdejo J.
      • Ocampo S.
      • Rios M.M.
      • Gómez-Álvarez E.
      • Borrayo G.
      • SORS investigators
      • et al.
      Clinical effectiveness of the cardiovascular polypill in a real-life setting in patients with cardiovascular risk: the SORS study.
      ]. A limited number of clinical trials have shown benefits in terms of preventing MACE in primary and secondary prevention patients [
      • Joseph P.
      • Roshandel G.
      • Gao P.
      • Pais P.
      • Lonn E.
      • Xavier D.
      • et al.
      Polypill Trialists’ Collaboration
      Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.
      ,
      • Roshandel G.
      • Khoshnia M.
      • Poustchi H.
      • Hemming K.
      • Kamangar F.
      • Gharavi A.
      • et al.
      Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial.
      ,
      • Yusuf S.
      • Joseph P.
      • Dans A.
      • Gao P.
      • Teo K.
      • Xavier D.
      • International Polycap Study 3 Investigators
      • et al.
      Polypill with or without aspirin in persons without cardiovascular disease.
      ].
      The CNIC-Polypill, designed by the Spanish National Centre for Cardiovascular Diseases (CNIC), contains ASA 100 mg, atorvastatin 20/40 mg and ramipril 2.5/5/10 mg []. The CNIC-Polypill is approved for use in secondary prevention of cardiovascular events as substitution therapy in adult patients adequately controlled with the monocomponents given concomitantly at equivalent therapeutic doses []. Clinical data to date with the CNIC-Polypill include a prospective randomized clinical trial which showed a significant improvement in adherence, as well as various real world studies which demonstrated significant risk factor control [
      • Castellano J.M.
      • Sanz G.
      • Peñalvo J.L.
      • Bansilal S.
      • Fernández-Ortiz A.
      • Alvarez L.
      • et al.
      A polypill strategy to improve adherence: results from the FOCUS project.
      ,
      • Castellano J.M.
      • Verdejo J.
      • Ocampo S.
      • Rios M.M.
      • Gómez-Álvarez E.
      • Borrayo G.
      • SORS investigators
      • et al.
      Clinical effectiveness of the cardiovascular polypill in a real-life setting in patients with cardiovascular risk: the SORS study.
      ,
      • Gómez-Álvarez E.
      • Verdejo J.
      • Ocampo S.
      • Ruiz E.
      • Martinez-Rios M.A.
      Reaching blood pressure guideline targets with the CNIC polypill in patients with a previous cardiovascular event in Mexico: a post hoc analysis of the SORS study.
      ,
      • Becerra V.
      • Gracia A.
      • Desai K.
      • Abogunrin S.
      • Brand S.
      • Chapman R.
      • et al.
      Cost-effectiveness and public health benefit of secondary cardiovascular disease prevention from improved adherence using a polypill in the UK.
      ,
      • González-Juanatey J.R.
      • Tamargo J.
      • Torres F.
      • Weisser B.
      • Oudovenko N.
      Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?.
      ,
      • Gómez-Álvarez E.
      • Verdejo J.
      • Ocampo S.
      • Ponte-Negretti C.I.
      • Ruíz E.
      • Ríos M.M.
      • SORS investigators
      The CNIC-polypill improves atherogenic dyslipidemia markers in patients at high risk or with cardiovascular disease: results from a real-world setting in Mexico.
      ,
      • Ros-Castelló V.
      • Natera-Villalba E.
      • Gómez-López A.
      • Sánchez-Sánchez A.
      • Chico-García J.L.
      • García-Madrona S.
      • et al.
      Use of the cardiovascular polypill in secondary prevention of cerebrovascular disease: a real-life tertiary hospital cohort study of 104 patients.
      ]. In addition, a pharmacodynamic study has shown that there might be a synergistic effect between ramipril and atorvastatin in the CNIC-Polypill as there is an additional 7% decrease in low-density lipoprotein cholesterol (LDLc) levels compared to atorvastatin alone [
      • González-Juanatey J.R.
      • Tamargo J.
      • Torres F.
      • Weisser B.
      • Oudovenko N.
      Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?.
      ]. Although a long-term prospective randomized clinical trial, the SECURE study (Secondary prevention of cardiovascular disease in the elderly) it is currently ongoing, for the time being, data about the efficacy of the CNIC-Polypill on MACE in secondary prevention patients are lacking.
      The NEPTUNO study aimed to evaluate the effectiveness of the CNIC-Polypill on the incidence of recurrent MACE compared to three other therapeutic options in patients with ASCVD treated according to clinical practice. Secondary objectives included the effect of the CNIC-Polypill on cardiovascular risk factor control and on persistence to treatment.

      2. Methods

      2.1 Study design

      NEPTUNO is a retrospective and non-interventional analysis of an anonymized medical history dataset covering patients contained in the BIG-PAC® administrative database during the years 2015–2018. The validity and the representativeness of this database have been demonstrated previously [
      • Sicras-Mainar A.
      • Enriquez J.L.
      • Hernández I.
      • Sicras-Navarro A.
      • Aymerich T.
      • Leon M.
      PMU146 validation and representativeness of the Spanish BIG-PAC database: integrated computerized medical records for research into epidemiology, medicines and health resource use (real world evidence).
      ,
      • Escobar C.
      • Varela L.
      • Palacios B.
      • Capel M.
      • Sicras A.
      • Sicras A.
      • et al.
      Costs and healthcare utilisation of patients with heart failure in Spain.
      ].
      The study included adults with a diagnosis of ASCVD, defined as coronary heart disease (acute myocardial infarction, stable/unstable angina), cerebrovascular disease (ischaemic stroke, transient ischaemic attack), or peripheral artery disease (intermittent claudication, ischaemia, amputation), who initiated treatment for secondary prevention between January 1st 2015 and December 31st 2018 (index date).
      Included patients were required to have available data from 1 year before and 2 years after the index date. By contrast, patients with any contraindication for use of any of the components of the CNIC-Polypill (haemodialysis, severe renal or hepatic impairment, gastrointestinal bleeding, peptic ulcer, cerebrovascular haemorrhage, history of angioedema, atrial fibrillation, severe mental disorders, or end-stage kidney disease) were excluded from the study.

      2.2 Study cohorts

      Patients were allocated into 4 different cohorts according to their therapy: Cohort 1: CNIC-Polypill (case cohort); patients treated with the CNIC-Polypill. The index date was the date of the first prescription of the CNIC-Polypill after a cardiovascular event between 2015 and 2018. Cohort 2: Monocomponents: identical monocomponents, but taken as loose medications. Cohort 3: Equipotent medication: patients treated with ASA, a statin (simvastatin or rosuvastatin) and an ACEI or an angiotensin II receptor blocker (ARB) (Enalapril or Valsartan, respectively). Supplementary Table 1 reports the equipotent doses of these drugs. The index date for cohorts 2 and 3 was the date of the first prescription of the last of the three drug classes. Cohort 4: Other therapies: patients treated with different drug combinations to those described in the prior cohorts or not receiving all three drug classes concomitantly. In this cohort, the date of the first dispensation of the last of the prescribed drug classes (some patients could receive only one or two drug classes) was considered as the index date (Supplementary Fig. 1). Patients were followed for 2 years from the index date or until the development of recurrent MACE or death (maximum follow-up until 31 December 2020). Cohorts 2, 3 and 4 were considered control cohorts.

      2.3 Variables estimated at baseline

      At baseline, biodemographic and comorbidity data, including age, gender, Charlson comorbidity index (high risk >3 points) [
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • Mackenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ], hypertension, diabetes, obesity, smoking status, renal impairment, heart failure, thromboembolism and HbA1c levels, as well as data from physical examination (body mass index [kg/m2]), were collected.
      Previous CV events (including coronary heart disease [acute myocardial infarction, stable/unstable angina], cerebrovascular disease [ischaemic stroke, transient ischaemic attack], peripheral artery disease [intermittent claudication, ischaemia, amputation]) were retrieved based on ICD-9 codes (https://eciemaps.mscbs.gob.es) (Supplementary Table 2). Additionally, cardiovascular risk factors (blood pressure, lipid profile [total cholesterol, LDLc, high-density lipoprotein cholesterol (HDLc) and triglycerides] recorded at baseline, defined as the last available data in the database before the index date, were included. Furthermore, concomitant treatments at baseline were also collected from the registries of dispensed medicines, according to the Anatomical Therapeutic Chemical Classification System [

      The anatomical therapeutic chemical classification system with defined daily doses (ATC/DDD): World Health Organization. Available at: https://www.who.int/classifications-/atcddd/en/. Last accessed: 10 June 2020.

      ].

      2.4 Evaluation of variables during follow-up

      The primary endpoint of the study was the accumulated incidence of recurrent MACE during 2 years of follow-up in all cohorts. Secondary endpoints were time to first recurrent cardiovascular event or death, blood pressure and LDLc control and persistence to therapy.
      Changes in systolic/diastolic blood pressure and lipid variables from baseline until the last data available in the database were analysed. Additionally, the proportion of patients attaining the blood pressure goal of <130/80 mmHg, the LDLc target of <70 mg/dL (the target recommended by the guidelines at the time when the study was conducted) and the triglycerides goal of <150 mg/dL, were also estimated [
      • Piepoli M.F.
      • Hoes A.W.
      • Agewall S.
      • Albus C.
      • Brotons C.
      • Catapano A.L.
      • ESC Scientific Document Group
      • et al.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      ].
      Persistence to treatment during the study was defined as the time, measured in days, without abandonment of initial treatment or without change to another medication at least 30 days after the initial prescription.

      2.5 Study approval and consent

      The study was approved by the Ethics Committee of Research of the Consorci Sanitari de Terrassa. As data were completely anonymized, which was in accordance with local applicable legal requirements, informed consent from patients was not required.

      2.6 Statistical analysis

      As this was a descriptive study, data for all patients available in the database that met the inclusion/exclusion criteria were collected. Propensity score matching (PSM) was performed to minimize possible confounding variables and to allow comparability of the study cohorts. A 1:1 pairing was performed, i.e. for each case (CNIC-Polypill cohort), one control was obtained (matching) in each of the three control cohorts according to 23 prespecified variables (Supplementary Table 3). As a result, three PSM procedures were performed (cohort 1 vs cohorts 2, 3 and 4, respectively). The PSM was developed according to the greedy nearest neighbour algorithm, with replacement (substitution) and accepting a calliper (tolerance) of 0.20. Exact matches were prioritized (randomly). The homogeneity of the cohorts was tested using a logistic regression model. After conducting the PSM procedure, standardized coefficients (standardized differences) were provided in subsequent comparisons.
      A univariate-descriptive analysis was performed. For qualitative data, absolute and relative frequencies were calculated and, for quantitative date, mean, standard deviation (SD), median and percentiles were provided. The 95% CI was calculated to estimate population parameters.
      Bivariate analysis (comparison between cohorts), ANOVA (quantitative variables) and Chi-square test (qualitative variables) were used for independent groups. In addition, the Student's t-test and McNemar tests were used for paired samples or repeated measurements.
      The raw incidence of MACE is presented in Kaplan-Meier survival curves. A Cox proportional risk regression model was performed to compare the incidence of recurrent MACE during the 2-year follow-up period. The risk of MACE was estimated as the hazard ratio [HR] and 95% confidence interval [CI]. Additionally, a bivariate regression analysis (successive steps procedure; Wald test) was performed to determine which variables recorded at baseline (independent variables), such as demographic variables, comorbidities, time from diagnosis and concomitant medications, were associated with the development of MACE during the follow-up period (dependent variable). The persistence/duration of treatment was analysed using a Kaplan-Meier survival analysis (procedure: log-rank test). A 0.05 level of statistical significance was applied in all statistical tests. Data were analysed using the SPSS (v27.0) statistical package (SPSS Inc., Chicago, Illinois, USA).

      3. Results

      3.1 Flow chart of patients

      Out of 1.8 million people included in the BIG-PAC® database in 2015, 1.2 million sought medical attention during the 2015–2018 period and had data registered, of whom 980,682 were aged ≥18 years. Of these, 13,239 had a previous cardiovascular event. Overall, 4293 patients were excluded due to different reasons (i.e. inconsistent data, inactive in the database, follow-up not guaranteed, mental/terminal disease, atrial fibrillation, contraindications for the CNIC-polypill), with 8946 patients being enrolled in the study (1614 in the CNIC-Polypill cohort; 2475 in the Monocomponents cohort; 2193 in the Equipotent cohort; and 2664 in the Other therapies cohort). As these cohorts were not homogeneous (Supplementary Tables 4 and 5), PSM was performed. After PSM, a total of 6456 patients (1614 patients in each cohort) were finally analysed (Supplementary Fig. 2).

      3.2 Baseline characteristics

      After PSM, all cohorts were comparable in relation to baseline clinical characteristics. Approximately 60% of patients were male, nearly two-thirds had hypertension, 26% diabetes, 16% obesity, and 12% renal impairment. Nearly 70% of patients had ischaemic heart disease and the majority of patients had had only one cardiovascular event (Table 1).
      Table 1Baseline data after propensity score matching (PSM).
      CNIC-Polypill cohort (N = 1614)Monocomponents cohort (N = 1614)Equipotent cohort (N = 1614)Other therapies cohort (N = 1614)pSC
      Biodemographic data and comorbidities
      Age, years, mean (SD)

      ≥75 years (%)
      63.5 (11.2)

      17.7
      63.1 (12.0)

      17.3
      63.5 (13.1)

      19.7
      63.0 (13.9)

      18.0
      0.550

      0.119
      0.036

      0.040
      Gender, male (%)60.560.360.360.60.9980.002
      Hypertension (%)64.164.964.664.10.9510.007
      Diabetes mellitus (%)26.826.326.526.10.9820.005
      Obesity (%)16.516.116.516.10.9740.006
      Current smoker (%)15.415.815.415.60.9830.005
      Charlson index, mean (SD)2.1 (1.0)2.1 (1)2.1 (1)2.1 (1)0.8750.007
      Heart failure (%)10.410.810.710.20.9350.008
      Renal impairment (%)12.612.611.812.00.8470.009
      Thromboembolism (%)2.52.52.42.50.9990.002
      HbA1c, % (SD)8.1 (1.5)8.0 (1.5)8.3 (1.6)8.4 (1.5)<0.0010.234
      Physical examination
      Body mass index, kg/m2(SD)28.6 (4.4)28.8 (4.4)28.8 (4.3)28.8 (4.4)0.2940.087
      Prior cardiovascular events
      Cardiovascular events (%)
       Ischaemic heart disease69.566.968.369.10.0880.091
       Cerebrovascular disease21.923.921.720.70.0640.055
       Peripheral artery disease8.69.21010.20.1150.031
      Number of previous events, mean (SD)1.1 (0.3)1.1 (0.3)1.1 (0.4)1.1 (0.3)0.2640.082
       1 event (%)88.587.985.487.6
       2 events (%)11.411.81412.20.0910.074
       3 events (%)0.10.30.60.2
      Time from diagnosis, days, mean (SD)324.1 (176)258.6 (127.2)269.5 (119.9)274.2 (161)<0.0010.257
      Median (P25 – P75)297 (181–-430)255 (151-369)268 (166-374)271 (130-417)
      Treatments
      Number of drugs, mean (SD)4.6 (1.2)4.6 (1.3)4.6 (1.2)4.5 (1.4)0.2550.057
      Antithrombotic therapy (%)10010010092.6<0.0010.238
      Lipid-lowering drugs (%)10010010093.1<0.0010.230
      Renin-angiotensin-aldosterone (%)10010010087.7<0.0010.309
      Insulin (%)5.75.65.65.30.9570.007
      Antidiabetic (%)23.624.524.023.70.9350.008
      Cardiac therapy (%)8.89.49.19.20.9440.008
      Antihypertensive drugs (%)51.251.151.751.50.9860.005
      Diuretic (%)19.418.918.618.50.9090.009
      Beta blockers/calcium channel blockers (%)51.650.751.751.70.9350.008
      p: statistical significance; SC: standardized coefficient; SD: standard deviation. P: percentile.
      Baseline treatments after PSM showed that whereas in the CNIC-Polypill, Monocomponents and Equipotent cohorts, all patients were receiving ASA 100 mg, a statin and an ACEI/ARB, in the Other therapies' cohort, only 86.1% were taking antiplatelet agents, 70.7% statins, and 87.7% ACEI/ARBs. Further information about the specific prescribed drugs from the three therapeutic classes (antithrombotic agents, statins and ACEI/ARBs) is presented in Supplementary Table 6 and Supplementary Fig. 3.

      3.3 Results after 2 years of follow up

      3.3.1 Recurrent MACE

      After 2 years of follow up, the incidence of recurrent MACE was lower in the CNIC-Polypill cohort vs the three control cohorts (19.8% vs 23.3%, 25.5% and 26.8%; p < 0.001). The risk of experiencing recurrent MACE was 22%, 25% and 27% higher in the Monocomponents, Equipotent and Other therapies cohorts compared with the CNIC-Polypill cohort (Monocomponents: HR 1.22; 95% CI 1.06–1.45; p = 0.017; Equipotent: HR 1.25; 95% CI 1.08–1.43; p = 0.002; and Other therapies: HR 1.27; 95% CI 1.10–1.41; p = 0.001) (Fig. 1).The most common type of cardiovascular event was ischaemic heart disease (44%), followed by peripheral artery disease (30%) and cerebrovascular disease (26%) (Table 2).
      Fig. 1
      Fig. 1Cumulative incidence of recurrent MACE after 2 years of follow up in patients with established ASCVD treated with CNIC-Polypill and three other active treatment cohorts.
      The figure shows the cumulative incidence of a first recurrent outcome event (death from cardiovascular causes, myocardial infarction, angina, ischaemic stroke, transient ischaemic attack or peripheral artery disease) for the comparison of the CNIC-Polypill with three active medication control cohorts (Monocomponents, Equipotents and Other therapies).
      ASCVD: atherosclerotic cardiovascular disease; CI: confidence interval; MACE: major adverse cardiovascular event; HR: Hazard Ratio.
      Table 2Proportion of patients with cardiovascular events or death and time to events after 2 years of follow up (post-PSM cohorts).
      Total eventsCNIC-Polypill cohort (N = 1614)Monocomponents cohort (N = 1614)Equipotent cohort (N = 1614)Other therapies cohort (N = 1614)p
      Patients with recurrent MACE, % (95% CI)19.8 (17.9–21.7)23.3 (21.2–25.4)25.5 (23.4–27.6)26.8 (24.4–28.8)<0.001
      Mean number of cardiovascular events (SD) *0.2 (0.4)0.2 (0.5)0.3 (0.5)0.3 (0.5)<0.001
       0 events, %80.276.774.573.2
       1 event, %18.321.723.624.7<0.001
       ≥2 events, %1.51.51.92.1
      Time to CV event, days, mean (SD)274.8 (195.5)249.2 (201.5)226.4 (203.4)217.8 (184.5)<0.001
      Median (P25 - P75)236 (107–413)204 (76–373)160 (50–351)173 (57–337)
      Type of recurrent MACE, %
       Ischaemic heart disease8.710.71212.90.001
       Cerebrovascular disease5.66.96.77.90.08
       Peripheral artery disease77.28.780.256
      Death, % (95% CI)

      Time to death, days, mean (SD)

      Median (P25 - P75)
      8.1 (6.8–9.4)

      406.3 (183)

      392 (246–568)
      8.1 (6.8–9.4)

      395.6 (203.6)

      322 (222–472)
      8.9 (7.5–10.3)

      387.2 (205.1)

      333 (188–461)
      9.2 (7.8–10.6)

      386.6 (196.1)

      367 (225–452)
      0.357

      0.828
      CI: confidence interval; CV: cardiovascular; MACE: major acute CV event. p: statistical significance; SD: standard deviation. P: Percentile *Categorized variable within the multivariate model.
      Bivariate logistic regression showed that age (odds ratio [OR] 1.03, 95% CI 1.02–1.04), more than one previous cardiovascular event (OR 1.32, 95% CI 1.21–1.44), and diabetes (OR 1.21, 95% CI 1.05–1.39) were independent predictors of experiencing subsequent cardiovascular events during the follow-up period. Among patients included in the CNIC-Polypill cohort, the independent variables of recurrent MACE were male sex (OR 1.54, 95% CI 1.15–2.1), more than one previous cardiovascular event (OR 1.28, 95%CI 1.05–2.07), and persistence with treatment (OR 1.71, 95% CI 1.31–2.23).
      In addition, mean time to recurrent MACE was longer in the CNIC-Polypill cohort compared to control cohorts (Table 2 and Fig. 1). No significant differences were observed regarding death rates or time to death between cohorts (Table 2).

      3.3.2 Cardiovascular risk factors

      After 2 years of follow up, systolic and diastolic blood pressure decreased from baseline in all four cohorts, but this decrease was significantly higher in the CNIC-Polypill cohort compared to the control cohorts (systolic blood pressure: −14.1 vs − 11.7; −10.4; and −10.4 mmHg; [p < 0.001] and diastolic blood pressure: −4.5 vs − 2.5, −2.1 and −1.2 mmHg; [p < 0.001]) and also in the one-to-one comparison with each of the control cohorts (Table 3 and Supplementary Fig. 4). The proportion of patients achieving the blood pressure control goal of <130/80 mmHg increased significantly from baseline in the CNIC-Polypill and monocomponents cohorts, but was not significant in the other two cohorts. The incremental proportion of patients with controlled blood pressure after 2 years of therapy was significantly higher in the CNIC-Polypill cohort compared to each of the other cohorts [SBP/DBP <130/80mmHg: 44.1% vs 37.9 % (p<0.05); 34.6% (p< 0.01) and 32.4% (p<0.01) in the CNIC-Polypill cohort compared to monocomponents, equipotents and other therapies, respectively.] (Supplementary Table 7 and Supplementary Fig. 5).
      Table 3Evolution of blood pressure and lipid parameters after 2 years of follow-up (post-PSM cohorts).
      CNIC-Polypill (n = 1614)Monocomponents (n = 1614)Equipotents (n = 1614)Other Therapies (n = 1614)
      ParametersBaselineFinalDifferenceBaselineFinalDifferenceBaselineFinalDifferenceBaselineFinalDifference
      SBP, mmHg, mean (SD)140.7 (21.0)126.5 (20.8)−14.1 (24.8)*139.9 (21.3)128.3 (20.9)−11.7 (23.9)* ‡139.4 (21.5)129.1 (21.4)−10.4 (24.3)* †140.6 (22.4)130.1 (21.6)−10.4 (23.6)* †
      DBP, mmHg, mean (SD)81.8 (12.7)77.3 (12.0)−4.5 (13.3)*82.1 (12.3)79.5 (12.2)−2.5 (12.0)* †82.5 (12.5)80.4 (12.0)−2.1 (12.4)* †82.3 (12.5)81.1 (12.4)−1.2 (12.7)* †
      Total cholesterol, mg/dL, mean (SD)229.4 (48.9)174.6 (50.6)−54.9 (43.2)*230 (51.6)187.2 (51.9)−42.8 (45.2)* †229.7 (46.9)198.0 (48.0)−31.7 (43.3)* †229.8 (46.9)198.1 (47.2)−31.7 (42.4)* †
      LDL cholesterol, mg/dL, mean (SD)128.1 (41.1)108.3 (40.3)−19.6 (38.2)*128.9 (43.6)115.9 (43.0)−12.9 (42.2)* ‡130.1 (40.3)117.4 (41.5)−12.3 (39.7)* †128.6 (40.0)119.2 (41.5)−9.1 (41.2)* †
      HDL cholesterol, mg/dL, mean (SD)48.9 (12.0)55.4 (12.2)6.5 (10.2)*48.5 (12.3)53.0 (12.5)4.6 (10.5)*†49.2 (13.6)53.0 (13.5)3.8 (11)*‡48.9 (13.4)51.8 (13.5)2.8 (11.0)* †
      Triglycerides, mg/dL, mean (SD)235.8 (104.8)168.3 (95.6)−67.5 (98.7)*236.8 (103.7)176.9 (81.4)−59.9 (80.3)* ‡236.1 (93.2)180.1 (86.3)−56.1 (77.1)* †236.2 (96.7)181.7 (80.9)−54.4 (79.5)* †
      DBP: diastolic blood pressure; HDL: high-density lipoprotein: LDL: low-density lipoprotein; SBP: systolic blood pressure; SD: standard deviation.
      *p < 0.001 vs baseline; †p < 0.001 and ‡p < 0.01 vs reference cohort: CNIC-Polypill.
      In relation to the lipid profile, there was a significant reduction from baseline in total cholesterol, LDLc and triglycerides in all cohorts and this decrease was significantly higher in the CNIC-Polypill cohort when compared to the control cohorts (total cholesterol: −54.9 vs − 42.8, −31.7 and − 31.7 mg/dL [p < 0.001]; LDLc: −19.6 vs − 12.9, −12.3 and − 9.1 [p < 0.001]; triglycerides: −67.5 vs − 59.9, −56,1 and − 54.4 mg/dL [p < 0.001]), and also in the one-to-one comparison with each of the control cohorts (Table 3 and Supplementary Fig. 6). HDLc increased significantly from baseline in the CNIC-Polypill cohort when compared to the control cohorts (HDLc: 6.5 vs 4.6, 3.8 and 2.8 mg/dL; [p < 0.001] and when compared to each of the control cohorts (Table 3 and Supplementary Fig. 6). The proportion of patients achieving the LDLc goal of <70 mg/dL increased significantly from baseline in all four cohorts. The incremental proportion of patients with controlled LDLc after 2 years of therapy was significantly higher in the CNIC-Polypill cohort compared to each of the other cohorts [LDLc <70mg/dL: 15.4% vs 12.5 % (p<0.001); 12.8% (p< 0.001) and 11.6% (p<0.001) in the CNIC-Polypill cohort compared to monocomponents, equipotents and other therapies, respectively.] (Supplementary Table 7 and Supplementary Fig. 7). Similar results were obtained for triglycerides and HDLc (Table 3, Supplementary Table 7 and Supplementary Figs. 6 and 8).

      3.3.3 Treatment persistence

      More patients in the CNIC-polypill cohort remained on treatment compared with all other cohorts (72.1% vs 62.2%, 60,0% and 54,2%, respectively; p < 0.001) after 2 years of follow up. Consequently, treatment duration was significantly longer in the CNIC-Polypill cohort [627 vs 596.2, 590.2 and 573.3 days, respectively; p < 0.001] (Supplementary Table 10).
      All patients in the four cohorts were also taking additional medications, such as ezetimibe, fibrates or other blood pressure-lowering agents from other therapeutic classes, with no differences at baseline. After 2 years of follow up, concomitant therapy was intensified in all cohorts similarly, with higher use of calcium channel blockers in the Other therapies cohort. There was not a use of a higher amount of medication in the CNIC-Polypill cohort. The total mean number of treatments by the end of follow-up was significantly lower in the CNIC-Polypill cohort compared to the control cohorts (4.7 vs 4.8, 4.9 and 4.8. [p = 0.042]) (Supplementary Table 8). Further information about the specific prescribed drugs and doses from the different therapeutic classes can be found in Supplementary Fig. 9 and Supplementary Table 9.

      4. Discussion

      The NEPTUNO study is, to our knowledge, the first study that has shown that the use of the CNIC- Polypill is associated with a significant reduction in the incidence of recurrent MACE, together with a delay to time to event, in a large sample of real-world patients with a history of ASCVD compared with three different active treatment control groups (Monocomponents, Equipotent and Other therapies). In addition, the CNIC-Polypill provides greater blood pressure and lipid control rates, as well as higher medication persistence. These results may reinforce the utility of these strategy for secondary CV prevention in clinical practice.
      Results in reduction in MACE following a therapeutic approach with a polypill strategy have been recently published [
      • Joseph P.
      • Roshandel G.
      • Gao P.
      • Pais P.
      • Lonn E.
      • Xavier D.
      • et al.
      Polypill Trialists’ Collaboration
      Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.
      ] but this was a meta-analysis conducted in primary prevention population and the control cohorts were placebo or a non-pharmacologic intervention, thus the results are not comparable.
      Baseline clinical characteristics and the prevalence of established cardiovascular disease (cardiovascular, cerebrovascular or peripheral artery disease) were in line with other published studies that included patients with established ASCVD [
      • Kotseva K.
      • De Backer G.
      • De Bacquer D.
      • Rydén L.
      • Hoes A.
      • Grobbee D.
      • et al.
      Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry.
      ,
      • Ray K.K.
      • Molemans B.
      • Schoonen W.M.
      • Giovas P.
      • Bray S.
      • Kiru G.
      • et al.
      EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study.
      ]. Of note, in our study time from diagnosis was different after PMS between cohorts. But it should be taken into account that the CNIC-Polypill was launched on 2015 in Spain and its regular use in clinical practice started later.
      The improvement in CV risk factors (BP and lipid profile) with the CNIC-Polypill compared with prior therapy had already been documented in a real-world study carried out in Mexico where marked reductions in blood pressure (from 147/89 mmHg to 128/80 mmHg; p < 0.001) and LDLc levels (from 132 mg/dL to 108 mg/dL; p < 0.001) after 1 year of treatment with the CNIC-Polypill were shown [
      • Castellano J.M.
      • Verdejo J.
      • Ocampo S.
      • Rios M.M.
      • Gómez-Álvarez E.
      • Borrayo G.
      • SORS investigators
      • et al.
      Clinical effectiveness of the cardiovascular polypill in a real-life setting in patients with cardiovascular risk: the SORS study.
      ,
      • Gómez-Álvarez E.
      • Verdejo J.
      • Ocampo S.
      • Ruiz E.
      • Martinez-Rios M.A.
      Reaching blood pressure guideline targets with the CNIC polypill in patients with a previous cardiovascular event in Mexico: a post hoc analysis of the SORS study.
      ]. Remarkably, in the case of the Neptuno study, the significant improvement took place compared to the treatment with the identical monocomponents or equipotent drugs after 2 years of follow up.
      Reasons that could explain this fact are, in the first place, the significant increase in treatment persistence in the CNIC-Polypill cohort compared to the other 3 cohorts. This is in line with other prior studies in which higher adherence to the CNIC-Polypill therapy was assessed [
      • Castellano J.M.
      • Sanz G.
      • Peñalvo J.L.
      • Bansilal S.
      • Fernández-Ortiz A.
      • Alvarez L.
      • et al.
      A polypill strategy to improve adherence: results from the FOCUS project.
      ,
      • Becerra V.
      • Gracia A.
      • Desai K.
      • Abogunrin S.
      • Brand S.
      • Chapman R.
      • et al.
      Cost-effectiveness and public health benefit of secondary cardiovascular disease prevention from improved adherence using a polypill in the UK.
      ]. The importance of full adherence to medication (≥80%) in post-MI patients was shown in another claim database study in over 4000 patients in which those patients who were fully adherent to their prescribed secondary prevention medications had significantly better event-free survival, with a 27% risk reduction of MACE [
      • Bansilal S.
      • Castellano J.M.
      • Garrido E.
      • Wei H.G.
      • Freeman A.
      • Spettell C.
      • et al.
      Assessing the impact of medication adherence on long-term cardiovascular outcomes.
      ]. In the second place, the patient's preferences could also be involved, as in a recent study, patients preferred the CNIC-Polypill compared to the same individual drugs, which translates into greater medication adherence rates [
      • Cosin-Sales J.
      • Murcia-Zaragoza J.M.
      • Pereyra-Rico H.O.
      • la Guía-Galipienso F.
      • Hermans K.
      • Rubio G.
      Evaluating patients’ satisfaction and preferences with a secondary prevention cardiovascular polypill: the Aurora study.
      ]. Finally, a synergistic effect between the polypill components (ramipril and atorvastatin vs atorvastatin alone) that would increase the beneficial effect on LDLc reduction without increasing the adverse event rate has been suggested [
      • González-Juanatey J.R.
      • Tamargo J.
      • Torres F.
      • Weisser B.
      • Oudovenko N.
      Pharmacodynamic study of the cardiovascular polypill. Is there any interaction among the monocomponents?.
      ]. This is concordant with another study that also showed the synergistic effect of combining ACEI and statins in patients with coronary heart disease, resulting in a lower incidence of cardiovascular events in this subgroup [
      • Athyros V.G.
      • Mikhailidis D.P.
      • Papageorgiou A.A.
      • Bouloukos V.I.
      • Pehlivanidis A.N.
      • Symeonidis A.N.
      • et al.
      Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease.
      ]. In the Neptuno study, the improvement in CV risk factors cannot be attributed to a higher amount of concomitant medication in the CNIC-Polypill cohort, as the intensification in therapy was very similar in all four cohorts during the follow up of the study.
      Although the LDLc and BP control rate achieved by the end of the two years of follow up in the Neptuno study was significantly higher in the CNIC-Polypill cohort compared to the other 3 cohorts, a great amount of patients in all the cohorts did not reach the treatment goals recommended by the guidelines and not even the 32% LDLc or 50% BP control rate observed in the EUROSPIRE V study [
      • Kotseva K.
      • De Backer G.
      • De Bacquer D.
      • Rydén L.
      • Hoes A.
      • Grobbee D.
      • et al.
      Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry.
      ]. Due to its retrospective design, the NEPTUNO study reflects the real-world clinical practice. The fact that patients still remain uncontrolled, even after the addition of supplementary medication in all cohorts indicates that in Spain, intensification of therapies for CV prevention in these very high-risk patients is urgently warranted.
      Thus, the CNIC-Polypill used as baseline therapy following the stepwise approach recommended by the 2021 CV prevention guidelines [
      • Visseren F.L.J.
      • Mach F.
      • Smulders Y.M.
      • Carballo D.
      • Koskinas K.C.
      • Bäck M.
      • et al.
      ESC scientific document group. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice.
      ] could help in achieving CV risk factor goals, as there is the possibility of intensifying therapy by adding further antihypertensive drugs in single or double combination to attain blood pressure goals and/or adding ezetimibe alone, or in combination with atorvastatin or PCSK9 inhibitors, to obtain LDLc targets in a second step [
      • Visseren F.L.J.
      • Mach F.
      • Smulders Y.M.
      • Carballo D.
      • Koskinas K.C.
      • Bäck M.
      • et al.
      ESC scientific document group. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice.
      ]. This strategy assures that patients take at least the three fundamental drugs once a day and provides additional flexibility to build the complete therapy for patients.
      Our study might have some limitations. As this study had a retrospective design, with data collected from electronic health records, some diagnoses or treatments (i.e. dose modifications) may not have been recorded adequately. However, the retrospective analysis is the best design to determine the role of a therapeutic approach in current clinical practice, as no specific intervention was used in the study. Furthermore, the high number of included patients and the quality of the recorded data, may reduce any potential bias. In addition, the BIG-PAC® database has been validated in previous studies [
      • Sicras-Mainar A.
      • Enriquez J.L.
      • Hernández I.
      • Sicras-Navarro A.
      • Aymerich T.
      • Leon M.
      PMU146 validation and representativeness of the Spanish BIG-PAC database: integrated computerized medical records for research into epidemiology, medicines and health resource use (real world evidence).
      ,
      • Escobar C.
      • Varela L.
      • Palacios B.
      • Capel M.
      • Sicras A.
      • Sicras A.
      • et al.
      Costs and healthcare utilisation of patients with heart failure in Spain.
      ].Remarkably, the time from the previous event to the index date was not considered as matching variable. Although analysis of propensity matching by average treatment effect in the treated (ATT) could have added power by improving SE magnitudes [
      • Austin P.C.
      The performance of different propensity score methods for estimating marginal hazard ratios.
      ], analysis by average treatment effect (ATE) was performed as it is also considered acceptable to show comparability between cohorts. On the other hand, all patients, except those that died, were followed during 2 years in all cohorts of the study. Persistence referred only to treatment, but the estimation of parameters was calculated at the end of the follow up (2 years). This was the same for all cohorts and no heterogeneity was observed between them. However, although PSM was performed to homogenize the cohorts, patients were not assigned randomly to different treatment arms. Consequently, only indirect causality may be suggested. In any case, specific prospective studies should be conducted to confirm the results obtained in our study. In this context, the SECURE trial (NCT02596126) is an ongoing prospective randomized trial to evaluate whether the CNIC-Polypill will reduce the rate of death from CV causes, nonfatal myocardial infarction, stroke, and hospitalization requiring revascularization, when compared to usual care among patients with type 1 myocardial infarction aged ≥65 years from seven European countries.

      5. Conclusions

      The NEPTUNO study has shown that, in patients with established ASCVD, the CNIC-Polypill (ASA 100 mg, atorvastatin 20/40 mg and ramipril 2.5/5/10 mg) is associated with significant reductions in recurrent MACE, improvements in blood pressure, lipids and medication persistence, reducing the total number of pills, compared with three control groups (Monocomponents, Equipotent or Other therapies). For that reason, these results reinforce the use of the CNIC-Polypill as a baseline treatment for patients with established ASCVD, contemplating the addition of other drugs to achieve CV risk factor control and consequently decrease the incidence of recurrent MACE.

      Funding

      This study was funded by Ferrer .

      Data availability

      The data that support the findings of this study are available from the corresponding author upon reasonable request.

      Authors' contributions

      All authors have contributed significantly to the conception, design, or acquisition of data, or analysis and interpretation of data. All authors have participated in in drafting, reviewing, and/or revising the manuscript and have approved its submission.

      Declaration of Competing Interest

      José Ramón González-Juanatey has received honoraria for consulting and lectures from: Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, MSD, Daichii-Sankyo, Ferrer International, Novartis, Lilly, Sanofi y Servier.
      Alberto Cordero reports a) honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim, MSD, and Bristol-Myers Squibb and AMGEN; b) consulting fees from AstraZeneca, Ferrer and AMGEN.
      José Mª Castellano reports grants from H2020 related to conducting the ongoing SECURE trial as well as receiving honoraria and reimbursement for travel expenses from Ferrer, Pfizer, Bayer, and Servier.
      Luis Masana has received honoraria for lectures and/or consulting work from Amgen, Sanofi, Novartis, Ferrer, Servier, Daiichi-Sankyo, Amarin, Amryt.
      Regina Dalmau has received consulting fees from Ferrer International.
      Emilio Ruiz is current worker of Ferrer International.
      Antonio Sicras-Mainar is current worker of Athrys Health.
      Valentín Fuster reports grants from H2020 related to conducting the ongoing SECURE trial.

      Acknowledgements

      Editorial support was provided by Content Ed Net , with funding from Ferrer.

      Appendix A. Supplementary data

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      Linked Article

      • Is Polypill the magic pill?
        International Journal of CardiologyVol. 364
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          Three are the main pillars of cardiovascular disease prevention based on medical therapy: an appropriate drug prescription, accessibility to drugs, adherence to medication. All of them need specific programs of implementation to concretely improve cardiovascular morbidity and mortality both in the primary and secondary prevention settings.
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