← Back
NeuroTrials.ai
Neurology Clinical Trial Database

PREDIMED

Prevención con Dieta Mediterránea - Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts

Share Share Copied! Compare

Year of Publication: 2018

Authors: Ramón Estruch, Emilio Ros, Jordi Salas-Salvadó, ..., for the PREDIMED Study Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2018;378:e34

Clinical Question

Does a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduce major cardiovascular events compared to a reduced-fat diet in high-risk individuals without established cardiovascular disease?

Bottom Line

In persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced major cardiovascular events by approximately 30% compared to a reduced-fat diet, with an absolute risk reduction of 1.7-2.1 percentage points over 5 years. Benefits were primarily driven by stroke reduction.

Major Points

  • Mediterranean diet with EVOO reduced primary endpoint by 31% (HR 0.69, 95% CI 0.53-0.91)
  • Mediterranean diet with nuts reduced primary endpoint by 28% (HR 0.72, 95% CI 0.54-0.95)
  • 5-year absolute risk: 3.6% (EVOO), 4.0% (nuts), 5.7% (control)
  • Stroke was significantly reduced: HR 0.65 (EVOO), HR 0.54 (nuts)
  • No significant reduction in MI or all-cause mortality individually
  • Per-protocol analysis showed even greater benefit (HR 0.42) with adherence
  • Results remained consistent after excluding participants with protocol deviations
  • Original 2013 publication was retracted and republished in 2018 after discovering randomization irregularities
  • Reanalysis with propensity score adjustment confirmed original findings

Design

Study Type: Parallel-group, multicenter, randomized controlled trial

Randomization: 1

Blinding: Open-label dietary intervention. Endpoint adjudication committee was blinded to group assignments. Protocol deviations identified: 425 household members assigned to same group as enrolled household member; 467 participants at Site D assigned by clinic rather than individually; 593 participants at Site B had inconsistent use of randomization tables.

Enrollment Period: June 25, 2003 - June 30, 2009

Follow-up Duration: Median 4.8 years (IQR 2.8-5.8 years)

Centers: 11

Countries: Spain

Sample Size: 7447

Analysis: Intention-to-treat. Cox proportional hazards models stratified by site, sex, and educational level, adjusted for 9 baseline covariates plus propensity scores based on 30 baseline variables. Robust variance estimators for intracluster correlations. O'Brien-Fleming stopping boundaries for interim analyses. Per-protocol analysis with inverse-probability weighting.

Inclusion Criteria

  • Men aged 55-80 years or women aged 60-80 years
  • No cardiovascular disease at enrollment
  • Type 2 diabetes mellitus OR at least 3 of the following major risk factors:
  • - Current smoking
  • - Hypertension (SBP ≥140 or DBP ≥90 mm Hg or antihypertensive therapy)
  • - Elevated LDL cholesterol (>160 mg/dL)
  • - Low HDL cholesterol (≤40 mg/dL in men, ≤50 mg/dL in women)
  • - Overweight or obesity (BMI ≥25)
  • - Family history of premature coronary heart disease

Exclusion Criteria

  • Documented cardiovascular disease
  • See Supplementary Appendix for detailed criteria

Arms

FieldControlMediterranean diet with extra-virgin olive oilMediterranean diet with nuts
InterventionAdvice to reduce dietary fat intake. Received leaflet with low-fat diet guidelines yearly for first 3 years. After October 2006 protocol amendment, received personalized advice and group sessions with same frequency as Mediterranean groups. Goals: low-fat dairy ≥3/day, bread/pasta/rice ≥3/day, fruits ≥3/day, vegetables ≥2/day, lean fish ≥3/week; limit vegetable oils ≤2 tbsp/day, nuts ≤1/week, red/processed meat ≤1/week. Received small nonfood gifts.Mediterranean diet plus free provision of extra-virgin olive oil (1 L/week per household). Goal: ≥4 tablespoons (50g) EVOO per day. Additional goals: olive oil ≥4 tbsp/day, nuts ≥3/week, fruits ≥3/day, vegetables ≥2/day, fish ≥3/week, legumes ≥3/week, sofrito ≥2/week, white meat instead of red meat, wine ≥7 glasses/week (optional for habitual drinkers). Quarterly educational sessions with dietitians. 14-item Mediterranean diet adherence questionnaire administered at each visit.Mediterranean diet plus free provision of mixed nuts (30g/day: 15g walnuts, 7.5g almonds, 7.5g hazelnuts). Same Mediterranean diet goals as EVOO group. Quarterly educational sessions with dietitians. 14-item Mediterranean diet adherence questionnaire administered at each visit.
DurationMedian 4.8 yearsMedian 4.8 yearsMedian 4.8 years

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Composite of myocardial infarction, stroke, and death from cardiovascular causesPrimary109 events (4.4%); 11.2 per 1000 person-years; 5-year absolute risk 5.7% (95% CI 4.6-6.9%)<0.05 for both comparisons
StrokeSecondary58 events; 5.9 per 1000 person-years; 5-year risk 3.0%
Myocardial infarctionSecondary38 events; 3.9 per 1000 person-years; 5-year risk 2.1%Not significant
Death from cardiovascular causesSecondary30 events; 3.1 per 1000 person-years; 5-year risk 1.6%Not significant
Death from any causeSecondary114 events; 11.7 per 1000 person-years; 5-year risk 5.4%Not significant
Primary endpoint - Combined Mediterranean diets vs control (adjusted)Secondary109 events0.7<0.05
Primary endpoint - Excluding Sites D, B and second household membersSecondary83/1906
Per-protocol (adherence-adjusted) analysis - Combined Mediterranean vs controlSecondary0.42
Diet-related adverse effectsAdverse

Subgroup Analysis

Prespecified subgroup analyses were conducted according to sex, age, BMI, cardiovascular risk factor status, and baseline adherence to the Mediterranean diet. Results were consistent across subgroups. Analysis by recruitment timing (before vs after October 2006 protocol change for control group): HR 0.77 (95% CI 0.59-1.00) for participants recruited before October 2006; HR 0.49 (95% CI 0.26-0.92) for those recruited after (P=0.21 for heterogeneity).

Criticisms

  • Randomization protocol deviations: 425 household members assigned to same group as enrolled member; 467 participants at Site D assigned by clinic not individually; 593 participants at Site B had inconsistent randomization table use
  • Original 2013 publication was retracted due to these irregularities; republished in 2018 with propensity score adjustments
  • Open-label design - no blinding of dietary intervention
  • Higher dropout rate in control group (11.3%) than Mediterranean groups (4.9%)
  • Control group received less intensive intervention in first 3 years (yearly contact vs quarterly)
  • Spanish population with baseline Mediterranean-style diet may limit generalizability to other populations
  • Lower than expected event rates required sample size recalculation and extended follow-up
  • Underpowered for individual secondary endpoints (MI, CV death, total mortality)
  • Major between-group differences were primarily in supplemental items (EVOO, nuts) rather than overall dietary pattern
  • Participants at high CV risk; may not generalize to lower-risk populations

Funding

Instituto de Salud Carlos III, Spanish Ministry of Health (grants RTIC G03/140, RTIC RD 06/0045); Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición; multiple other Spanish government and regional grants. Supplemental foods donated: extra-virgin olive oil (Hojiblanca, Patrimonio Comunal Olivarero), walnuts (California Walnut Commission), almonds (Borges), hazelnuts (Morella Nuts). Dr. Hernán supported by Patient-Centered Outcomes Research Institute grant ME-1503-28119. Sponsors had no role in study design, data analysis, or reporting.

Based on: PREDIMED (New England Journal of Medicine, 2018)

Authors: Ramón Estruch, Emilio Ros, Jordi Salas-Salvadó, ..., for the PREDIMED Study Investigators

Citation: N Engl J Med 2018;378:e34

Content summarized and formatted by NeuroTrials.ai.