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Original ArticleFree Preview

Polypill Strategy in Secondary Cardiovascular Prevention

List of authors.
  • Jose M. Castellano, M.D., Ph.D.,
  • Stuart J. Pocock, Ph.D.,
  • Deepak L. Bhatt, M.D., M.P.H.,
  • Antonio J. Quesada, Ph.D.,
  • Ruth Owen, M.Sc.,
  • Antonio Fernandez-Ortiz, M.D., Ph.D.,
  • Pedro L. Sanchez, M.D., Ph.D.,
  • Francisco Marin Ortuño, M.D., Ph.D.,
  • Jose M. Vazquez Rodriguez, M.D.,
  • Alexandra Domingo-Fernández, B.Sc.,
  • Iñigo Lozano, M.D.,
  • Maria C. Roncaglioni, M.Sc.,
  • Marta Baviera, Pharm.D.,
  • Andreana Foresta, M.Sc.,
  • Luisa Ojeda-Fernandez, Ph.D.,
  • Furio Colivicchi, M.D.,
  • Stefania A. Di Fusco, M.D.,
  • Wolfram Doehner, M.D., Ph.D.,
  • Antje Meyer, Ph.D.,
  • François Schiele, M.D., Ph.D.,
  • Fiona Ecarnot, Ph.D.,
  • Aleš Linhart, M.D., D.Sc.,
  • Jean-Claude Lubanda, M.D., Ph.D.,
  • Gyorgy Barczi, M.D., Ph.D.,
  • Bela Merkely, M.D., Ph.D., D.Sc.,
  • Piotr Ponikowski, M.D., Ph.D.,
  • Marta Kasprzak, Ph.D.,
  • Juan M. Fernandez Alvira, Ph.D.,
  • Vicente Andres, Ph.D.,
  • Hector Bueno, M.D., Ph.D.,
  • Timothy Collier, M.Sc.,
  • Frans Van de Werf, M.D., Ph.D.,
  • Pablo Perel, M.D., Ph.D.,
  • Moises Rodriguez-Manero, M.D., Ph.D.,
  • Angeles Alonso Garcia, M.D.,
  • Marco Proietti, M.D., Ph.D.,
  • Mikkel M. Schoos, M.D., Ph.D.,
  • Tabassome Simon, M.D., Ph.D.,
  • Jose Fernandez Ferro, M.D.,
  • Nicolas Lopez, M.D., Ph.D.,
  • Ettore Beghi, M.D.,
  • Yannick Bejot, M.D., Ph.D.,
  • David Vivas, M.D., Ph.D.,
  • Alberto Cordero, M.D., Ph.D.,
  • Borja Ibañez, M.D., Ph.D.,
  • and Valentin Fuster, M.D., Ph.D.
  • for the SECURE Investigators*



A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting–enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction.


In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke.


A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P=0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P=0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups.


Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE number, NCT02596126; EudraCT number, 2015-002868-17.)

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Funding and Disclosures

Supported by a grant (633765) from the European Union Horizon 2020 research and innovation program. Centro Nacional de Investigaciones Cardiovasculares (CNIC), a nonprofit public institution, is supported by Instituto de Salud Carlos III, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). CNIC receives royalties for the sales of the polypill from Ferrer International. In Spain, project management and monitoring was performed the Spanish Clinical Research Network, a public network funded by Instituto de Salud Carlos III (grant numbers PTC20/00018 and PT17/0017); the State Plan for Research, Development, and Innovation 2013–16; the State Plan for Scientific and Technical Research and Innovation 2017–20; and the Subdirectorate General for Evaluation and Promotion of Research, with cofunding from the European Regional Development Fund.

Disclosure forms provided by the authors are available with the full text of this article at

This article was published on August 26, 2022, at

A data sharing statement provided by the authors is available with the full text of this article at

Author Affiliations

From Centro Nacional de Investigaciones Cardiovasculares (J.M.C., S.J.P., A.J.Q., A.F.-O., J.M.F.A., V.A., H.B., J.F.F., B.I., V.F.), Centro Integral de Enfermedades Cardiovasculares, Hospital Universitario Monteprincipe, Grupo HM Hospitales (J.M.C.), Hospital Clínico San Carlos, Universidad Complutense (A.F.-O., D.V.), Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (A.F.-O., P.L.S., F.M.O., J.M.V.R., V.A., H.B., A.C., B.I.), Unidad de Investigación Clínica y Ensayos Clínicos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (A.D.-F.), Health Research Institute, October 12 Hospital (H.B.), Fundación Jiménez Díaz University Hospital (J.F.F., B.I.), and Universidad Autonóma de Madrid (J.F.F.), Madrid, the Department of Cardiology, Hospital Universitario Salamanca, Salamanca (P.L.S.), Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia (F.M.O.), Servicio de Cardiología, Hospital Universitario A Coruña, Instituto de Investigación Biomédica A Coruña, La Coruña (J.M.V.R.), Servicio de Cardiología, Hospital Universitario de Cabueñes, Gijón (I.L.), the Cardiovascular Area and Coronary Unit, University Clinical Hospital of Santiago de Compostela, Santiago (M.R.-M.), the Department of Neurology, Hospital Universitario Rey Juan Carlos, Getafe (J.F.F.), and Servicio de Neurología, Hospital General Universitario de Alicante (N.L.), and the Department of Cardiology, Hospital Universitario de San Juan (A.C.), Alicante — all in Spain; the Department of Medical Statistics (S.J.P., R.O., T.C.) and the Centre for Global Chronic Conditions (P. Perel), London School of Hygiene and Tropical Medicine, and Imperial College NHS Trust (A.A.G.), London, and Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool (M.P.) — all in the United Kingdom; Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School (D.L.B.) — both in Boston; the Laboratory of Cardiovascular Prevention (M.C.R., M.B.P.D., A.F., L.O.-F.) and Laboratorio di Malattie Neurologiche, Dipartimento di Neuroscienze (E.B.), IRCCS, the Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri (M.P.), and the Department of Clinical Sciences and Community Health, University of Milan (M.P.), Milan, and the Clinical and Rehabilitation Cardiology Unit, Emergency Department, San Filippo Neri Hospital, Rome (F.C., S.A.D.F.) — all in Italy; Berlin Institute of Health–Center for Regenerative Therapies, the Department of Internal Medicine and Cardiology (Virchow Klinikum), German Center for Cardiovascular Research, and the Center for Stroke Research Berlin, Charité Universitätsmedizin — all in Berlin (W.D., A.M.); the Department of Cardiology, University Hospital Besançon (F.S., F.E.), and University of Burgundy Franche-Comté (F.S., F.E.), Besançon, the Department of Clinical Pharmacology–Clinical Research Platform, Assistance Publique–Hôpitaux de Paris, Hôpital Saint Antoine, French Alliance for Cardiovascular Trials, Sorbonne Université, Paris (T.S.), the Department of Neurology, University Hospital of Dijon Burgundy (Y.B.), the Medical School of Dijon, University of Burgundy (Y.B.), and Hôpital François Mitterrand (Y.B.), Dijon — all in France; the 2nd Department of Medicine, Department of Cardiovascular Medicine of the 1st Faculty of Medicine, Charles University, and General University Hospital — both in Prague (A.L., J.-C.L.); Semmelweis Egyetem Városmajori Szív És Érgyógyászati Klinika, Budapest (G.B., B.M.); the Department of Heart Disease, Medical University, Wrocław, Poland (P. Ponikowski, M.K.); the Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium (F.V.W.); the Department of Cardiology, Zealand University Hospital, Roskilde, Denmark (M.M.S.); and the Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (V.F.).

Dr. Fuster can be contacted at or at Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain.

A list of the SECURE investigators is provided in the Supplementary Appendix, available at