New England Journal of Medicine JUNE 21, 2018

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

Ramón Estruch, Emilio Ros, Jordi Salas-Salvadó, et al. (PREDIMED Study Investigators)

Bottom Line

In this large, multicenter randomized trial involving high-risk individuals without prevalent cardiovascular disease, supplementation with a Mediterranean diet rich in extra-virgin olive oil or nuts resulted in a significant ~30% relative risk reduction in major cardiovascular events compared to a control diet.

Key Findings

1. Participants assigned to the Mediterranean diet with extra-virgin olive oil experienced a major cardiovascular event rate of 3.8% (96 events), and those assigned to the Mediterranean diet with nuts had a rate of 3.4% (83 events), compared to 4.4% (109 events) in the control group.

2. The multivariable-adjusted hazard ratios for the primary endpoint were 0.70 (95% CI, 0.54 to 0.92) for the olive oil group and 0.72 (95% CI, 0.54 to 0.96) for the nut group, relative to the control group.

3. The primary beneficial effect was driven predominantly by a significant reduction in the incidence of stroke, with no statistically significant differences observed for total mortality or myocardial infarction individually.

Study Design

Design

RCT

Open-Label

Sample

7,447

Patients

Duration

4.8 yr

Median

Setting

Multicenter, Spain

Population Adults 55 to 80 years of age, free of cardiovascular disease at baseline, with either type 2 diabetes or at least three major cardiovascular risk factors.

Intervention A Mediterranean diet supplemented with either extra-virgin olive oil (at least 4 tablespoons per day) or mixed nuts (30 g per day), provided free of charge.

Comparator A control diet consisting of advice to reduce dietary fat intake.

Outcome A composite of major cardiovascular events, defined as myocardial infarction, stroke, or cardiovascular death.

Study Limitations

• The trial was terminated early based on interim analysis, which can lead to an inflation of effect size estimates.

• Randomization procedures were found to have significant deviations, including non-random assignment of some household members and incorrect allocation at certain study sites, necessitating a post-hoc reanalysis to adjust for these factors.

• Reliance on self-reported dietary adherence and the open-label nature of the intervention introduce potential for recall and performance bias.

• The control arm diet (low-fat) may not have been strictly followed or clearly defined, potentially obscuring the relative benefit of the intervention groups.

Clinical Significance

The PREDIMED trial provides high-level evidence supporting the implementation of a Mediterranean-style diet as an effective, low-risk, population-wide strategy for the primary prevention of cardiovascular disease in high-risk individuals, emphasizing the importance of healthy fat sources like extra-virgin olive oil and nuts.

Historical Context

Before PREDIMED, the cardiovascular benefits of the Mediterranean diet were primarily supported by observational studies and one secondary prevention trial (the Lyon Diet Heart Study). PREDIMED served as a landmark primary prevention study, later undergoing significant scrutiny and a formal retraction and republication in 2018 due to flaws in the randomization protocol, though the corrected analysis ultimately reinforced the initial favorable conclusions.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the primary pathophysiological mechanisms by which the Mediterranean diet, specifically when supplemented with extra-virgin olive oil (EVOO) or nuts, reduces cardiovascular risk in high-risk individuals?

Key Response

The Mediterranean diet provides high concentrations of monounsaturated fatty acids (from EVOO) and polyunsaturated fatty acids (from nuts), along with polyphenols and antioxidants. These components work synergistically to improve the lipid profile, reduce systemic inflammation (measured by CRP), improve endothelial function, and lower blood pressure, thereby slowing the progression of atherosclerosis.

Resident

In a patient with high cardiovascular risk factors, such as Type 2 Diabetes or hypertension, how does the PREDIMED study inform your choice between recommending a Mediterranean diet versus a standard low-fat diet for primary prevention?

Key Response

The PREDIMED study demonstrated that a Mediterranean diet supplemented with EVOO or nuts resulted in a 30 percent relative risk reduction in major cardiovascular events compared to a control group advised on a low-fat diet. This suggests that the quality of fat intake is more clinically significant for primary prevention than the total quantity of fat.

Fellow

While the PREDIMED trial showed a significant reduction in the composite primary endpoint of major adverse cardiovascular events (MACE), which specific component of the composite outcome was most significantly impacted, and how does this influence subspecialty counseling?

Key Response

The reduction in MACE was primarily driven by a significant reduction in the incidence of stroke (hazard ratios of approximately 0.61-0.67). The reductions in myocardial infarction and cardiovascular mortality were not statistically significant on their own, suggesting the Mediterranean diet has a particularly potent protective effect against cerebrovascular events.

Attending

The PREDIMED study shifted the dietary paradigm from 'nutrient-centric' to 'food-pattern-centric.' How do you incorporate the trial's use of 'supplementation' (providing actual olive oil and nuts) into clinical practice to improve patient adherence compared to traditional dietary advice?

Key Response

The provision of free EVOO or nuts in the trial likely increased adherence by reducing the financial and logistical barriers to following the diet. In practice, clinicians can emulate this by providing 'food prescriptions' or specific shopping lists rather than just general nutrient goals (like 'low cholesterol'), which often leads to better long-term dietary compliance.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The PREDIMED trial underwent a high-profile retraction and republication in 2018. What were the specific statistical concerns regarding randomization procedures, and how did the re-analysis accounting for non-randomized clusters impact the study's conclusions?

Key Response

Concerns arose regarding non-randomized assignment at certain sites (e.g., assigning entire households or clinics to one group). The re-analysis using mixed-effects models and adjusted hazard ratios found that while the study could no longer be claimed as purely randomized in all instances, the treatment effect size and statistical significance remained robust and consistent with the original findings.

Journal Editor

As a reviewer for PREDIMED, how would you evaluate the potential for 'performance bias' given that the control group received less frequent nutritional counseling sessions compared to the intervention groups during the first few years of the study?

Key Response

A critical reviewer would flag that the intervention groups received more intensive, personalized dietary counseling (quarterly) than the control group (annually at the start), which could confound the results. The 'extra attention' itself, rather than the specific food items, might have influenced health behaviors, necessitating a cautious interpretation of the specific dietary components versus the overall intervention intensity.

Guideline Committee

Based on the PREDIMED evidence, should the Mediterranean diet be elevated to a Class I recommendation for primary prevention in high-risk patients, and how does this align with current AHA/ACC and ESC guidelines?

Key Response

Current AHA/ACC 2019 guidelines and ESC 2021 guidelines already strongly endorse the Mediterranean diet (Class I or IIa). PREDIMED provides the highest level of RCT evidence (Level A) for these recommendations. A committee must decide if the stroke-specific benefit justifies a Class I recommendation for all high-risk primary prevention, or if the lack of significant reduction in total mortality keeps it at Class IIa.

Clinical Landscape

Noteworthy Related Trials

1997

DASH Trial

n = 459 · NEJM

Tested

Dietary Approaches to Stop Hypertension (DASH) diet

Population

Adults with hypertension or prehypertension

Comparator

Control diet low in fruits and vegetables

Endpoint

Reduction in systolic and diastolic blood pressure

Key result: The DASH diet, rich in fruits, vegetables, and low-fat dairy, significantly lowered blood pressure compared to the control diet.

1999

Lyon Diet Heart Study

n = 605 · Circulation

Tested

Mediterranean-style diet

Population

Patients with prior myocardial infarction

Comparator

Prudent Western diet

Endpoint

Recurrent major cardiovascular events

Key result: The Mediterranean-style diet significantly reduced the rate of recurrent cardiac events and mortality compared to a prudent Western diet.

2006

Women's Health Initiative (WHI) Dietary Modification Trial

n = 48,835 · JAMA

Tested

Low-fat dietary pattern

Population

Postmenopausal women

Comparator

Usual diet

Endpoint

Incidence of coronary heart disease

Key result: A low-fat dietary pattern did not significantly reduce the risk of coronary heart disease, stroke, or cardiovascular disease among postmenopausal women.

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