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PREDIMED (Prevención con Dieta Mediterránea (Prevention with Mediterranean Diet)) was a large Spanish primary prevention trial which included 7,447 Spanish participants (55–80 years, 58% women) who were at high risk for cardiovascular disease, but otherwise healthy (initially free of cardiovascular disease). They were randomly assigned to receive interventions with intensive education to one of three diets:
- Mediterranean diet supplemented with extra-virgin olive oil.
- Mediterranean diet supplemented with nuts.
- Control diet encouraging low-fat food items.
The trial was planned for six years, but it was terminated early after a median follow-up of 4.8 years, and demonstrated that both Mediterranean diet groups reached a statistically significant reduction in the rate of the composite cardiovascular primary end-point of myocardial infarction, stroke, or cardiovascular death. This corresponded to an absolute reduction in 3 less cardiovascular events per 1000 patient-years, or a 30% relative risk reduction. Other important observed benefits included a strong reduction in peripheral artery disease, breast cancer, and atrial fibrillation (only associated with the consumption of extra-virgin olive oil).
Some criticisms included that the protocol for the low-fat control group was changed during the trial, there were losses to follow up in the low-fat group which may have biased the results and, very specially, that a true low-fat diet was not achieved by the control group. Additionally, participants lived in a Mediterranean country. Thus, it is unclear if the results will be applicable to other non-Mediterranean settings. Despite these criticisms, there is no other dietary pattern with such a strong evidence of cardiovascular benefit, supported by this major trial and by the Lyon Diet-Heart Study but also reinforced by a multitude of other large and well-conducted observational studies. The transferability of the Mediterranean diet to other geographical regions far from the Mediterranean Sea represents the next main challenges.
Arnav Agarwal and John Ioannidis note that "[r]epublication may not solve multiple problems that remain, including the inappropriateness of stopping early given the revised results and the effects on over 200 secondary publications [and] [m]ultiple contradictions between data reported across PREDIMED publications suggest a more generic problem with the trial’s quality".
The trial was multicenter with eleven field centers:
- Barcelona, two centers
- Two other centers were late incorporations (Belvitge and Canary Islands).
The field work started in 2003 in the vanguard center of PREDIMED-NAVARRA (University of Navarra) and the trial was completed in 2011 following the recommendation of the Data and Safety Monitoring Board, Xavier Pi-Sunyer, Frank B. Hu, Joan Sabaté and Carlos A. González). The main paper with the final cardiovascular results was published in 2013, but retracted and immediately republished in 2018 because of errors in statistical methodology, which were revised in the republished paper.
The coordinators and principal investigators of the PREDIMED Research Networks were R. Estruch (2003–2005) from Hospital Clinic (Barcelona) and M.A. Martinez-González (2006–2013) from University of Navarra (Spain).
- Martínez-González, Miguel A.; Salas-Salvadó, Jordi; Estruch, Ramón; Corella, Dolores; Fitó, Montse; Ros, Emilio; PREDIMED INVESTIGATORS (2016-08-01). "Benefits of the Mediterranean Diet: Insights From the PREDIMED Study". Progress in Cardiovascular Diseases. 58 (1): 50–60. doi:10.1016/j.pcad.2015.04.003. hdl:10230/25644. ISSN 1873-1740. PMID 25940230.
- Estruch, Ramón; Ros, Emilio; Salas-Salvadó, Jordi; Covas, Maria-Isabel; Corella, Dolores; Arós, Fernando; Gómez-Gracia, Enrique; Ruiz-Gutiérrez, Valentina; Fiol, Miquel (2013-04-04). "Primary prevention of cardiovascular disease with a Mediterranean diet". The New England Journal of Medicine. 368 (14): 1279–1290. doi:10.1056/NEJMoa1200303. hdl:10171/28216. ISSN 1533-4406. PMID 23432189. This article has been retracted "[b]ecause of irregularities in the randomization procedures". Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90.
- Ruiz-Canela, Miguel; Estruch, Ramón; Corella, Dolores; Salas-Salvadó, Jordi; Martínez-González, Miguel A. (2017-01-22). "Association of Mediterranean diet with peripheral artery disease: the PREDIMED randomized trial". JAMA. 311 (4): 415–417. doi:10.1001/jama.2013.280618. hdl:2445/119828. ISSN 1538-3598. PMID 24449321.
- Toledo, Estefanía; Salas-Salvadó, Jordi; Donat-Vargas, Carolina; Buil-Cosiales, Pilar; Estruch, Ramón; Ros, Emilio; Corella, Dolores; Fitó, Montserrat; Hu, Frank B. (2015-11-01). "Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial: A Randomized Clinical Trial". JAMA Internal Medicine. 175 (11): 1752–1760. doi:10.1001/jamainternmed.2015.4838. hdl:10230/33360. ISSN 2168-6114. PMID 26365989.
- Martínez-González, Miguel Á; Toledo, Estefanía; Arós, Fernando; Fiol, Miquel; Corella, Dolores; Salas-Salvadó, Jordi; Ros, Emilio; Covas, Maria I.; Fernández-Crehuet, Joaquín (2014-07-01). "Extravirgin olive oil consumption reduces risk of atrial fibrillation: the PREDIMED (Prevención con Dieta Mediterránea) trial". Circulation. 130 (1): 18–26. doi:10.1161/CIRCULATIONAHA.113.006921. ISSN 1524-4539. PMID 24787471.
- Trichopoulou, Antonia; Martínez-González, Miguel A.; Tong, Tammy Yn; Forouhi, Nita G.; Khandelwal, Shweta; Prabhakaran, Dorairaj; Mozaffarian, Dariush; de Lorgeril, Michel (2014-07-24). "Definitions and potential health benefits of the Mediterranean diet: views from experts around the world". BMC Medicine. 12: 112. doi:10.1186/1741-7015-12-112. ISSN 1741-7015. PMC 4222885. PMID 25055810.
- Martínez-González, Miguel A. (2016-10-14). "Benefits of the Mediterranean diet beyond the Mediterranean Sea and beyond food patterns". BMC Medicine. 14 (1): 157. doi:10.1186/s12916-016-0714-3. ISSN 1741-7015. PMC 5064779. PMID 27737657.
- Ioannidis, John P. A.; Agarwal, Arnav (2019-02-07). "PREDIMED trial of Mediterranean diet: retracted, republished, still trusted?". BMJ. 364: l341. doi:10.1136/bmj.l341. ISSN 0959-8138. PMID 30733217.
- García-Calzón, Sonia; Zalba, Guillermo; Ruiz-Canela, Miguel; Shivappa, Nitin; Hébert, James R.; Martínez, J. Alfredo; Fitó, Montserrat; Gómez-Gracia, Enrique; Martínez-González, Miguel A. (2015-10-01). "Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study: cross-sectional and longitudinal analyses over 5 y". The American Journal of Clinical Nutrition. 102 (4): 897–904. doi:10.3945/ajcn.115.116863. ISSN 1938-3207. PMC 4588745. PMID 26354530.