Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra‐Virgin Olive Oil or Nuts

The New England Journal of Medicine

Jun 2018

DOI: 10.1056/NEJMoa1800389

Citations:2510

Influential Citations:88

Interventional (Human) Studies

Enhanced Details

Methods

Design: parallel-group, multicenter, randomized trial conducted in Spain. Participants: 7,447 adults aged 55-80 years at high cardiovascular risk but without cardiovascular disease at enrollment; diabetes or at least three major risk factors (smoking, hypertension, elevated LDL, low HDL, overweight/obesity, or family history of premature CHD). Follow-up median 4.8 years. Three dietary arms: Mediterranean diet with extra-virgin olive oil, Mediterranean diet with nuts, or a control low-fat diet.

Intervention

Mediterranean diet with extra-virgin olive oil: olive oil provided; 1 liter per week per household; consume at least 4 tablespoons per day per person; polyphenol-rich oil; free supply (15 liters every 3 months); no total calorie restriction; oil consumed with meals. Mediterranean diet with mixed nuts: 30 g of mixed nuts per day per person (15 g walnuts, 7.5 g almonds, 7.5 g hazelnuts); free supply (2 kg walnuts, 1 kg almonds, 1 kg hazelnuts every 3 months); no total calorie restriction. Duration: follow-up about 4.8 years.

Results

Primary end point events: 96 (3.8%) in EVOO group, 83 (3.4%) in nuts group, 109 (4.4%) in control. Hazard ratio vs control: 0.69 (0.53-0.91) for EVOO and 0.72 (0.54-0.95) for nuts after adjustment for baseline factors and propensity scores. Five-year absolute risks: 3.6% (EVOO), 4.0% (nuts), 5.7% (control). Per-protocol hazard ratio for Mediterranean diets vs control: 0.42 (0.24-0.63). In high-risk individuals, energy-unrestricted Mediterranean diets supplemented with either EVOO or nuts reduced major cardiovascular events compared with a low-fat diet, with greater benefit with higher adherence.

Limitations

Protocol deviations in randomization: enrollment of household members without randomization, assignment to a study group without randomization at one of 11 sites; 467 participants at Site D assigned by clinic; 593 participants at Site B with nonrandomized assignment; 425 participants shared a household with a previously enrolled participant and were not randomly assigned. Excluding these deviations yielded similar results. Generalizability to lower-risk populations uncertain. Event rates were lower than expected, reducing power to analyze component endpoints.

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: a Mediterranean 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.) show less