Ramón Estruch1, Emilio Ros1, Jordi Salas-Salvadó1, Maria-Isabel Covas1, Dolores Corella1, Fernando Arós1, Enrique Gómez-Gracia1, Valentina Ruiz-Gutiérrez1, Miquel Fiol1, José Lapetra1, Rosa M Lamuela-Raventos1, Lluís Serra-Majem1, Xavier Pintó1, Josep Basora1, Miguel A Muñoz1, José V Sorlí1, J Alfredo Martínez1, Montserrat Fitó1, Alfredo Gea1, Miguel A Hernán1, Miguel A Martínez-González1. 1. From the PREDIMED (Prevención con Dieta Mediterránea) Network (RD 06/0045) (R.E., J.S.-S., F.A., E.G.-G., V.R.-G., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M., M.A.M.-G.) and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (R.E., E.R., J.S.-S., M.-I.C., D.C., F.A., M. Fiol, J.L., R.M.L.-R., L.S.-M., X.P., J.B., J.V.S., J.A.M., M. Fitó, A.G., M.A.M.-G.), Instituto de Salud Carlos III, Madrid, the Department of Internal Medicine, Hospital Clinic (R.E.), the Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomèdiques August Pi i Sunyer (E.R.), and the Department of Nutrition, Food Sciences, and Gastronomy, Faculty of Pharmacy and Food Sciences, Xarxa de Referència en Tecnologia dels Aliments, Instituto de Investigación en Nutrición y Seguridad Alimentaria (R.M.L.-R.), University of Barcelona, Institut Hospital del Mar d'Investigacions Mèdiques (M.-I.C., M. Fitó), the Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat (X.P.), and the Primary Care Division, Catalan Institute of Health, Institut Universitari d'Investigació en Atenció Primària (IDIAP)-Jordi Gol (M.A.M.), Barcelona, the Human Nutrition Department, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus (J.S.-S.), the Department of Preventive Medicine, University of Valencia (D.C., J.V.S.), and the Primary Care Division, Valencia Institute of Health (J.V.S.), Valencia, the Department of Cardiology, University Hospital of Álava, Vitoria (F.A.), the Department of Preventive Medicine, University of Malaga, Malaga (E.G.-G.), Instituto de la Grasa, Consejo Superior de Investigaciones Científicas (V.R.-G.), and the Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center (J.L.), Seville, the Institute of Health Sciences, University of the Balearic Islands, and Hospital Son Espases, Palma de Mallorca (M. Fiol), the Research Institute of Biomedical and Health Sciences, Instituto Universitario de Investigaciones Biomédicas y Sanitarias, University of Las Palmas de Gran Canaria, Las Palmas (L.S.-M.), the Primary Care Division, Catalan Institute of Health, IDIAP-Jordi Gol, Tarragona-Reus (J.B.), and the Departments of Nutrition and Food Sciences and Physiology (J.A.M.) and Preventive Medicine and Public Health (A.G., M.A.M.-G.), University of Navarra, Pamplona - all in Spain; and the Departments of Epidemiology and Biostatistics (M.A.H.) and Nutrition (M.A.M.-G.), Harvard T.H. Chan School of Public Health, and the Harvard-MIT Division of Health Sciences and Technology (M.A.H.), Boston.
Abstract
BACKGROUND: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. METHODS: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: aMediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. RESULTS: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. CONCLUSIONS: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639 .).
RCT Entities:
BACKGROUND: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. METHODS: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virginolive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virginolive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. RESULTS: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virginolive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virginolive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. CONCLUSIONS: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virginolive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639 .).
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