Study Design

The PREDIMED trial (Prevención con Dieta Mediterránea) was a parallel-group, multicenter, randomized trial. Details of the trial design are provided elsewhere.10-12 The trial was designed and conducted by the authors, and the protocol was approved by the institutional review boards at all study locations. The authors vouch for the accuracy and completeness of the data and all analyses and for the fidelity of this report to the protocol, which is available with the full text of this article at NEJM.org.

Supplemental foods were donated, including extra-virgin olive oil (by Hojiblanca and Patrimonio Comunal Olivarero, both in Spain), walnuts (by the California Walnut Commission), almonds (by Borges, in Spain), and hazelnuts (by La Morella Nuts, in Spain). None of the sponsors had any role in the trial design, data analysis, or reporting of the results.

Participant Selection and Randomization

Eligible participants were men (55 to 80 years of age) and women (60 to 80 years of age) with no cardiovascular disease at enrollment, who had either type 2 diabetes mellitus or at least three of the following major risk factors: smoking, hypertension, elevated low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease. Detailed enrollment criteria are provided in the Supplementary Appendix, available at NEJM.org. All participants provided written informed consent.

Beginning on October 1, 2003, participants were randomly assigned, in a 1:1:1 ratio, to one of three dietary intervention groups: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Randomization was performed centrally by means of a computer-generated random-number sequence.

Interventions and Measurements

Table 1. Table 1. Summary of Dietary Recommendations to Participants in the Mediterranean-Diet Groups and the Control-Diet Group.

The dietary intervention8,10-13 is detailed in the Supplementary Appendix. The specific recommended diets are summarized in Table 1. Participants in the two Mediterranean-diet groups received either extra-virgin olive oil (approximately 1 liter per week) or 30 g of mixed nuts per day (15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds) at no cost, and those in the control group received small nonfood gifts. No total calorie restriction was advised, nor was physical activity promoted.

For participants in the two Mediterranean-diet groups, dietitians ran individual and group dietary-training sessions at the baseline visit and quarterly thereafter. In each session, a 14-item dietary screener was used to assess adherence to the Mediterranean diet8,14 (Table S1 in the Supplementary Appendix) so that personalized advice could be provided to the study participants in these groups.

Participants in the control group also received dietary training at the baseline visit and completed the 14-item dietary screener used to assess baseline adherence to the Mediterranean diet. Thereafter, during the first 3 years of the trial, they received a leaflet explaining the low-fat diet (Table S2 in the Supplementary Appendix) on a yearly basis. However, the realization that the more infrequent visit schedule and less intense support for the control group might be limitations of the trial prompted us to amend the protocol in October 2006. Thereafter, participants assigned to the control diet received personalized advice and were invited to group sessions with the same frequency and intensity as those in the Mediterranean-diet groups, with the use of a separate 9-item dietary screener (Table S3 in the Supplementary Appendix).

A general medical questionnaire, a 137-item validated food-frequency questionnaire,15 and the Minnesota Leisure-Time Physical Activity Questionnaire were administered on a yearly basis.10 Information from the food-frequency questionnaire was used to calculate intake of energy and nutrients. Weight, height, and waist circumference were directly measured.16 Biomarkers of compliance, including urinary hydroxytyrosol levels (to confirm compliance in the group receiving extra-virgin olive oil) and plasma alpha-linolenic acid levels (to confirm compliance in the group receiving mixed nuts), were measured in random subsamples of participants at 1, 3, and 5 years (see the Supplementary Appendix).

End Points

The primary end point was a composite of myocardial infarction, stroke, and death from cardiovascular causes. Secondary end points were stroke, myocardial infarction, death from cardiovascular causes, and death from any cause. We used four sources of information to identify end points: repeated contacts with participants, contacts with family physicians, a yearly review of medical records, and consultation of the National Death Index. All medical records related to end points were examined by the end-point adjudication committee, whose members were unaware of the study-group assignments. Only end points that were confirmed by the adjudication committee and that occurred between October 1, 2003, and December 1, 2010, were included in the analyses. The criteria for adjudicating primary and secondary end points are detailed in the Supplementary Appendix.

Statistical Analysis

We initially estimated that a sample of 9000 participants would be required to provide statistical power of 80% to detect a relative risk reduction of 20% in each Mediterranean-diet group versus the control-diet group during a 4-year follow-up period, assuming an event rate of 12% in the control group.10,17 In April 2008, on the advice of the data and safety monitoring board and on the basis of lower-than-expected rates of end-point events, the sample size was recalculated as 7400 participants, with the assumption of a 6-year follow-up period and underlying event rates of 8.8% and 6.6% in the control and intervention groups, respectively. Power curves under several assumptions can be found in Fig. S1 in the Supplementary Appendix.

Yearly interim analyses began after a median of 2 years of follow-up. With the use of O'Brien–Fleming stopping boundaries, the P values for stopping the trial at each yearly interim analysis were 5×10−6, 0.001, 0.009, and 0.02 for benefit and 9×10−5, 0.005, 0.02, and 0.05 for adverse effects.18 The stopping boundary for the benefit of the Mediterranean diets with respect to the primary end point was crossed at the fourth interim evaluation; on July 22, 2011, the data and safety monitoring board recommended stopping the trial on the basis of end points documented through December 1, 2010.

All primary analyses were performed on an intention-to-treat basis by two independent analysts. Time-to-event data were analyzed with the use of Cox models with two dummy variables (one for the Mediterranean diet with extra-virgin olive oil and another for the Mediterranean diet with nuts) to obtain two hazard ratios for the comparison with the control group. To account for small imbalances in risk factors at baseline among the groups, Cox regression models were used to adjust for sex, age, and baseline risk factors. We tested the proportionality of hazards with the use of time-varying covariates. All analyses were stratified according to center. Prespecified subgroup analyses were conducted according to sex, age, body-mass index (BMI), cardiovascular-risk-factor status, and baseline adherence to the Mediterranean diet. Sensitivity analyses were conducted under several assumptions, including imputation of data for missing values and participants who dropped out (see the Supplementary Appendix).