Association of Mediterranean Diet With Peripheral Artery Disease: The PREDIMED Randomized Trial

The role of nutrition in preventing peripheral artery disease (PAD) remains elusive.¹

Mediterranean diets reduce the risk of myocardial infarction and stroke.^2,3 They also may reduce the risk of PAD, but this hypothesis has never been tested in a randomized trial. We assessed the association of Mediterranean diets with the occurrence of symptomatic PAD in an exploratory, nonprespecified analysis of a randomized trial.

The Prevención con Dieta Mediterránea (PREDIMED) was a multicenter, randomized, primary prevention feeding trial with blinded assessment of end points conducted in Spain between October 2003 and December 2010.^3,4

Eligible participants were men aged 55 to 80 years and women aged 60 to 80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least 3 cardiovascular risk factors.

Participants were randomized in a 1:1:1 ratio to 1 of 3 groups: a Mediterranean diet supplemented with extra-virgin olive oil; a Mediterranean diet supplemented with nuts; or counseling on a low-fat diet (control group). All participants received a comprehensive dietary educational program on a quarterly basis. The intensity of the program delivered to the control group was increased in October 2006.

The protocol was approved by institutional review boards and written informed consent was obtained from all participants.

New symptomatic PAD events were confirmed by a central end-point adjudication committee that was blinded to the allocated group. A confirmed diagnosis of PAD in symptomatic patients required at least 1 of the following criteria: an ankle-brachial index of less than 0.9 at rest, a clinical diagnosis of arterial occlusive disease based on imaging tests (duplex ultrasonography, magnetic resonance angiography, computed tomographic angiography, or catheter–based radiocontrast angiography), or an endovascular or open surgical procedure (revascularization or amputation).

We used Stata version 12.1 (StataCorp) for statistical analyses. Kaplan-Meier curves and Cox proportional hazards models adjusted for baseline factors were used to compare the risk of PAD for each diet group vs the control group on an intention-to-treat basis. Departures from the individual randomization protocol have been reported in detail elsewhere.³ Briefly, in the overall trial 425 members of the same household of a previous participant were directly allocated during all the duration of the trial to the same group as their previously randomized relative. In addition, 441 individual participants and 26 participant members of the same household from 1 of the 11 recruiting centers were allocated by clusters (clinics) instead of using individual randomization. To address these issues, we additionally adjusted for propensity scores that used 30 variables to estimate the probability that a participant would be allocated to each of the 3 intervention groups and used robust variance estimators to account for intra-cluster correlations.

The number needed to treat (NNT) was estimated for each diet group vs control group. As a sensitivity analysis, we used multiple imputation algorithms for participants without any events or study contact for at least 2 years.

Of 8713 eligible candidates, 7447 were initially included and randomized in the PREDIMED trial.³ Among them, 12 participants were excluded for intermittent claudication symptoms at baseline.

The mean (SD) age of included participants was 67 (6.2) years, and 58% were women. We observed 89 confirmed new cases of clinical PAD after a median follow-up of 4.8 years.

Both Mediterranean diet interventions were associated with a lower risk of PAD compared with the control group (Table). In the model adjusted for classic atherosclerotic risk factors, the hazard ratio (HR) was 0.34 (95% CI, 0.20-0.58) for participants in the Mediterranean diet plus extra-virgin olive oil group and 0.50 (95% CI, 0.30-0.81) for the Mediterranean diet plus nuts group vs control group. The overall results remained unchanged in the multivariable analyses as well as when we additionally adjusted for propensity scores and used robust variance estimators to account for intra-cluster correlations. The results also remained unchanged in secondary analyses after excluding all participants with departures from the individual randomization process (second members of the same household and all site D) (Table).

The multiple imputation procedure rendered similar estimates. No statistically significant difference between the 2 active intervention groups was apparent (adjusted HR, 0.71; 95% CI, 0.38-1.33).

The Kaplan-Meier curves diverged early in the trial (Figure). The NNT to prevent 1 case of PAD per year was 336 (95% CI, 269-566) for the Mediterranean diet plus extra-virgin olive oil group and 448 (95% CI, 316-1536) for the Mediterranean diet plus nuts group.

To our knowledge, this is the first randomized primary prevention trial to suggest an association between a dietary intervention and PAD. These results are consistent with previous observational studies and relevant from a public health perspective.^5,6

Because PAD was not a prespecified end point in the trial protocol, this is only an exploratory analysis. Other potential limitations include that the observed number of events was small and the study was restricted to clinically symptomatic cases. Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn.

The randomized design, blinded assessment and adjudication of events, and adjustment for a large number of potential confounders minimize the threat of biases in this study.

We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD.

Correction: This article was corrected on November 5, 2018, to report departures from the original protocol and updated results in the text and table.

Corresponding Author: Miguel A. Martínez-González, MD, PhD, University of Navarra, Irunlarrea, 1, 31008 Pamplona, Spain (mamartinez@unav.es).

Author Contributions: Dr Martínez-González had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Ruiz-Canela, Martinez-Gonzalez.

Acquisition of data: Estruch, Corella, Salas-Salvadó.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Ruiz-Canela, Martínez-González.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Martínez-González.

Obtained funding: Estruch, Corella, Salas-Salvadó, Martínez-González.

Administrative, technical, and material support: Estruch, Corella, Salas-Salvadó, Martínez-González.

Study supervision: Estruch, Martínez-González.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Salas-Salvadó reported receiving grant funding from the International Nut Council and serving as a consultant to the International Nut Council. No other disclosures were reported.

Funding/Support: The work was supported by RTIC G03/140 from Instituto de Salud Carlos III (Estruch) and RD 06/0045 from the PREDIMED Research Network (Martinez-Gonzalez). The authors also received grants from Centro Nacional de Investigaciones Cardiovasculares, Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional, Consejería de Salud de la Junta de Andalucía, Ministerio de Ciencia e Innovación, Fundación Mapfre, Consejeria de Salud de la Junta de Andalucia, Agencia Canaria de Investigación, Innovación y Sociedad de la Información-EU FEDER, Public Health Division of the Department of Health of the Autonomous Government of Catalonia and Generalitat Valenciana, and Ministerio de Economía. The supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and La Morella Nuts.

Role of the Sponsors: The funding sources played no role in the study design and conduct; data collection, management, and analysis; manuscript preparation, review, and approval; or the decision to submit the manuscript for publication.

PREDIMED Group: All of the authors are affiliated with the Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y la Nutrición (CIBERobn) and are members of the PREDIMED group. CIBERobn and PREDIMED are initiatives of Instituto de Salud Carlos III (ISCIII) in Spain. The members of the PREDIMED group and the steering and clinical end-point committees are listed in the reference article by Estruch et al.³

Trial Registration: isrctn.org Identifier: ISRCTN35739639