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PREDIMED

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

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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

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

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Original 2013 publication was retracted and republished in 2018 after discovering randomization irregularities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

Baseline Characteristics

Control:

N: 2450
Sex - Female: 59.7%
Age - mean (SD), years: 67.3 (6.3)
Race - White European: 96.9%
Race - Hispanic: 1.6%
Smoking - Never: 62.3%
Smoking - Former: 23.8%
Smoking - Current: 13.8%
BMI - mean (SD): 30.2 (4.0)
Waist circumference - mean (SD), cm: 101 (11)
Waist-to-height ratio - mean (SD): 0.63 (0.07)
Hypertension: 83.7%
Type 2 diabetes: 48.5%
Dyslipidemia: 72.0%
Family history of premature CHD: 22.9%
ACE inhibitors: 49.6%
Diuretics: 22.9%
Other antihypertensives: 30.9%
Statins: 40.1%
Other lipid-lowering agents: 5.1%
Insulin: 5.5%
Oral hypoglycemic agents: 30.9%
Antiplatelet therapy: 20.9%

Active (EVOO):

N: 2543
Sex - Female: 58.7%
Age - mean (SD), years: 67.0 (6.2)
Race - White European: 97.1%
Race - Hispanic: 1.4%
Smoking - Never: 61.8%
Smoking - Former: 24.3%
Smoking - Current: 13.9%
BMI - mean (SD): 29.9 (3.7)
Waist circumference - mean (SD), cm: 100 (10)
Waist-to-height ratio - mean (SD): 0.63 (0.06)
Hypertension: 82.1%
Type 2 diabetes: 50.4%
Dyslipidemia: 71.6%
Family history of premature CHD: 22.7%
ACE inhibitors: 48.6%
Diuretics: 21.0%
Other antihypertensives: 28.5%
Statins: 40.9%
Other lipid-lowering agents: 4.8%
Insulin: 4.9%
Oral hypoglycemic agents: 30.2%
Antiplatelet therapy: 18.7%

Active (Nuts):

N: 2454
Sex - Female: 54.0%
Age - mean (SD), years: 66.7 (6.1)
Race - White European: 97.4%
Race - Hispanic: 1.2%
Smoking - Never: 59.7%
Smoking - Former: 25.8%
Smoking - Current: 14.5%
BMI - mean (SD): 29.7 (3.8)
Waist circumference - mean (SD), cm: 100 (10)
Waist-to-height ratio - mean (SD): 0.63 (0.06)
Hypertension: 82.5%
Type 2 diabetes: 46.6%
Dyslipidemia: 73.3%
Family history of premature CHD: 21.7%
ACE inhibitors: 49.8%
Diuretics: 19.4%
Other antihypertensives: 28.9%
Statins: 39.3%
Other lipid-lowering agents: 5.9%
Insulin: 5.1%
Oral hypoglycemic agents: 27.7%
Antiplatelet therapy: 20.0%

Arms

Field	Control	Mediterranean diet with extra-virgin olive oil	Mediterranean diet with nuts
Intervention	Advice 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.
Duration	Median 4.8 years	Median 4.8 years	Median 4.8 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of myocardial infarction, stroke, and death from cardiovascular causes	Primary	109 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
Stroke \| Intervention (EVOO): 49 events; 4.1 per 1000 person-years; 5-year risk 1.7%; Intervention (Nuts): 32 events; 3.1 per 1000 person-years; 5-year risk 1.5%; HR/OR (EVOO): 0.65; HR/OR (Nuts): 0.54; 95% CI (EVOO): 0.44-0.95; 95% CI (Nuts): 0.35-0.82; Combined Mediterranean HR: 0.58; Combined 95% CI: 0.42-0.82	Secondary	58 events; 5.9 per 1000 person-years; 5-year risk 3.0%
Myocardial infarction \| Intervention (EVOO): 37 events; 3.1 per 1000 person-years; 5-year risk 1.4%; Intervention (Nuts): 31 events; 3.0 per 1000 person-years; 5-year risk 1.6%; HR/OR (EVOO): 0.82; HR/OR (Nuts): 0.76; 95% CI (EVOO): 0.52-1.30; 95% CI (Nuts): 0.47-1.25	Secondary	38 events; 3.9 per 1000 person-years; 5-year risk 2.1%			Not significant
Death from cardiovascular causes \| Intervention (EVOO): 26 events; 2.2 per 1000 person-years; 5-year risk 1.0%; Intervention (Nuts): 31 events; 3.0 per 1000 person-years; 5-year risk 1.4%; HR/OR (EVOO): 0.62; HR/OR (Nuts): 1.02; 95% CI (EVOO): 0.36-1.06; 95% CI (Nuts): 0.63-1.67	Secondary	30 events; 3.1 per 1000 person-years; 5-year risk 1.6%			Not significant
Death from any cause \| Intervention (EVOO): 118 events; 10.0 per 1000 person-years; 5-year risk 4.4%; Intervention (Nuts): 116 events; 11.2 per 1000 person-years; 5-year risk 5.4%; HR/OR (EVOO): 0.9; HR/OR (Nuts): 1.12; 95% CI (EVOO): 0.69-1.18; 95% CI (Nuts): 0.86-1.47	Secondary	114 events; 11.7 per 1000 person-years; 5-year risk 5.4%			Not significant
Primary endpoint - Combined Mediterranean diets vs control (adjusted) \| Intervention (Combined): 179 events; 95% CI: 0.55-0.89	Secondary	109 events		0.7	<0.05
Primary endpoint - Excluding Sites D, B and second household members \| Intervention (EVOO): 73/1976; Intervention (Nuts): 62/1977; HR/OR (EVOO): 0.71; HR/OR (Nuts): 0.68; HR/OR (Combined): 0.69; 95% CI (Combined): 0.53-0.92	Secondary	83/1906
Per-protocol (adherence-adjusted) analysis - Combined Mediterranean vs control \| Events: 111/7356; 95% CI: 0.24-0.63	Secondary			0.42
Diet-related adverse effects	Adverse		All groups: No relevant diet-related adverse effects reported

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)