The National Heart, Lung, and Blood Institute, in partnership with the National Cancer Institute and Office of Disease Prevention, convened a Working Group in Bethesda, Maryland, to discuss the feasibility of and provide recommendations for testing the effects of a Mediterranean dietary pattern on cardiovascular and other disease morbidity and mortality in adults in the United States in a large lower-cost trial.
In 2013, investigators of the Prevención con Dieta Mediterránea (PREDIMED) trial reported that a Mediterranean diet supplemented with extra virgin olive oil or nuts reduced the incidence of major cardiovascular events among adults at high risk. This trial, conducted in Spain, randomized 7447 men (55-80 years of age) and women (60-80 years of age) to receive either 1L/week (per family) of olive oil (50 g/day), 30g/day of mixed nuts, or small non-food gifts (control) at no cost for a median follow up of 4.8 years. The olive oil and mixed nuts group also received advice and coaching to follow a Mediterranean dietary pattern while the control group received advice to follow a low-fat diet . Similarly, the Lyon Diet Heart Study found a protective effect of a Mediterranean dietary pattern on cardiac events and nonfatal acute myocardial infarction in patients with previous myocardial infarctions.
It is not known whether such a Mediterranean diet intervention could have similar profound benefits in the U.S. population. Prospective cohort studies have found strong associations between reduced CVD risk and higher adherence to a Mediterranean-style dietary pattern . Randomized controlled trials and prospective cohort studies have both shown beneficial effects of Mediterranean-style dietary patterns on blood pressure and mixed effects on blood lipids [3-5]. However, no large clinical trial in the United States has assessed the benefits of a Mediterranean-style dietary pattern on cardiovascular disease morbidity and mortality.
For these reasons, the Division of Cardiovascular Sciences at NHLBI, in partnership with the NIH Office of Disease Prevention and the National Cancer Institute, convened a Working Group to discuss key challenges and opportunities for conducting lower cost clinical trials to test the effects of a Mediterranean dietary pattern on CVD and other disease morbidity and mortality in the United States.
Holly Nicastro, PhD, MPH
Division of Cardiovascular Sciences
Janet de Jesus, MS, RD
Center for Translational Research and Implementation Science
Catherine (Cay) Loria, PhD, MS, MA
Division of Cardiovascular Sciences
Jacques E. Rossouw, MbChB, FCP (SA), MD
Division of Cardiovascular Sciences
Penny Kris-Etherton, PhD, RD, FAHA, FNLA, FASN; The Pennsylvania State University
Frank Sacks, MD; Harvard University
Christine Albert, MD, MPH; Brigham and Women’s Hospital
Garnet Anderson, PhD; Fred Hutchinson Cancer Research Center
Lawrence J. Appel, MD, MPH; Johns Hopkins Medical Institutions
Deborah Bowen, PhD; University of Washington
John Buse, MD, PhD; University of North Carolina
Janelle W. Coughlin, PhD; Johns Hopkins School of Medicine
Alan S. Go, MD; Kaiser Permanente Northern California
Frank Hu, MD, PhD; Harvard University
Victor Kipnis, PhD; National Cancer Institute
Benoît Lamarche, PhD; Université Laval
Alice H. Lichtenstein, DSc; Tufts University
JoAnn E. Manson, MD, MPH, DrPH; Brigham and Women’s Hospital
Miguel A. Martínez González, MD, PhD, MPH; Universidad de Navarra
Robert Mentz, MD; Duke University
Martha Clare Morris, ScD; Rush University
Marian L. Neuhouser, PhD, RD; Fred Hutchinson Cancer Research Center
Ross Prentice, PhD; Fred Hutchinson Cancer Research Center
David Reboussin, PhD; Wake Forest University
Linda Van Horn, PhD, RD; Northwestern University
Mara Vitolins, DrPH, MPH, RDN, FAND; Wake Forest University
NIH Staff Planning Group
Tanya Agurs-Collins, PhD, RD; NCI
Susan Czajkowski, PhD; NCI
Kevin Dodd, PhD; NCI
Mary Evans, PhD; NIDDK
Lawrence J. Fine, MD, DrPH, FAHA; NHLBI
Stephanie George, PhD, MPH, MA; ODP
Susan Krebs-Smith, PhD, MPH; NCI
Barbara Linder, MD, PhD; NIDDK
Kathryn McMurry, MS; NHLBI
Charlotte Pratt, PhD; NHLBI
Jill Reedy, PhD, MPH, RD; NCI
Sharon Ross, PhD, MPH; NCI
Jacqueline Wright, DrPH; NHLBI
Susan Yanovski, MD; NIDDK
NIH Staff Participants
Rachel Ballard, MD, MPH; ODP
Josephine Boyington, PhD; NHLBI
Rebecca Costello, PhD; ODS
Abby Ershow, ScD, RD, FAHA; ODS
Rachel Fisher, MS, MPH, RD; NIDDK
Sheila Fleischhacker, PhD, JD; NIDDK
Kathy Helzlsouer, MD; NCI
Claudia Moy, PhD; NINDS
Nancy Potischman, PhD; ODS
Nicole Redmond, MD, PhD, MPH; NHLBI
Karen Regan, MS, RD; NIDDK
Marcel Salive, MD; NIA
Barbara Sorkin, PhD; ODS
Gina Wei, MD, MPH; NHLBI
The Working Group meeting brought together experts in nutritional science, clinical trials, cardiology, chronic disease, biostatistics, and public health. NIH staff with broad expertise also participated in the meeting.
Presentations and discussions were organized into 5 sessions and a final discussion/synthesis section. In session 1, “Introductory session,” speakers introduced the Mediterranean diet, presented key findings from previous studies, and provided recommendations and issues related to conducting a PREDIMED-type trial in the United States. In session 2, “Possible intervention approaches,” speakers discussed the provision of substitution foods or vouchers, the use of behavioral counseling to consume a Mediterranean diet, and what the appropriate control/comparison group would be. In session 3, “Low-cost models for intervention delivery,” the VITAL trial’s hybrid mail-order and in-clinic model and the POWER Hopkins trial’s remote behavioral intervention model were discussed. Pros and cons of each model were debated. In session 4, “Study design,” participants presented recommendations related to the study population, statistical issues, sample size, power considerations, monitoring adherence to a Mediterranean diet, and measurement error in assessing a Mediterranean dietary pattern. A 5th session on “Outcome measurements related to a Mediterranean diet intervention” focused on low-cost outcomes ascertainment methods, cardiovascular outcomes, and other disease co-primary/secondary/exploratory outcomes including cancers, diabetes, and cognition. This session also had discussion on other outcomes, mediators, surrogate endpoints, and important ancillary studies to consider.
Working Group Discussion Themes, Issues Raised, and Recommendations
Participants agreed that the topic is important and that a large U.S.-based trial to test the effects of a Mediterranean dietary pattern compared to a usual dietary pattern on disease outcomes, including CVD and cancer, is timely and would help to advance our understanding of the role of dietary patterns in CVD prevention. The participants also recognized that vanguard, pilot, or ancillary studies could be useful to inform the experimental design of such a trial.
Recommendations, key issues, and research gaps include:
Session 1: Introductory session
- A U.S. Mediterranean-style diet should be rich in fruits and vegetables and limited in red and processed meats, should use extra virgin olive oil as the predominant fat/oil, should include fish, legumes, nuts, and seeds, should predominantly use whole grains over refined grains, and should include low- and non-fat dairy products.
- Questions were raised about acceptability of extra virgin olive oil in the United States. If a different type of oil is featured, it is no longer a Mediterranean diet but may be more acceptable. How important is promotion of a Mediterranean-style diet (i.e., a diet rich in extra virgin olive oil) vs. other similar healthy dietary patterns that use other liquid vegetable oils that are popular in the United States?
Session 2: Possible intervention approaches
- The use of “substitution foods” (foods that would be provided to the intervention group with instructions to replace currently consumed foods with these items) is an important strategy to promote adherence. Substitution foods to consider include extra virgin olive oil and nuts, and vouchers for key food items like fruits, vegetables, pulses, and seafood.
- Important questions that will need to be answered during study design, study planning, and a possible vanguard phase include:
- Can the intervention change participants’ diet?
- Are provided “substitution foods” acceptable to participants?
- Can participants adhere to the intervention diet?
- Does the intervention diet change cardiovascular disease risk factors (e.g., blood pressure, blood lipids/lipoproteins, body weight/BMI) within 3-6 months?
- The control group should be a usual diet group and not an active diet treatment, but there should be consideration to provide enough attention to the control group in such a way that it balances attention in the active treatment arm. Examples of ways to provide attention to the control group include the use of self-monitoring or the provision of generic retail vouchers. Such efforts could also encourage retention and minimize differential reporting of outcomes.
- Questions were raised about the level of intensity required from a behavioral intervention to complement the provision of substitution foods and vouchers.
Session 3: Low-cost models for intervention delivery
- A hybrid design (remote or mail-based intervention with serial in-clinic visits in a subsample) has advantages, including quality and cost-efficiency.
- Training and oversight of interventionists/coaches is an indispensable component of intervention implementation.
- Behavioral approaches to achieve adherence with intervention goals (e.g., self-monitoring, feedback/support, etc.) should remain the cornerstone of an intervention.
Session 4: Study design
- A trial should target a diverse population that is broadly representative of the United States and has at least moderate CVD risk.
- The trial should have >80% power to detect a >20% effect size and should include interim testing.
- Creating large enough differences in the diets of the control and intervention groups and minimizing crossover will be critical to observe a large enough effect size between groups.
- Dietary assessment will play an important role in both the intervention and in assessing adherence.
- Should high baseline consumption of a Mediterranean dietary pattern (determined by a questionnaire) be an exclusion criterion for a trial?
Session 5: Outcome measurements related to a Mediterranean diet intervention
- The primary endpoint should be a composite cardiovascular outcome that includes CVD mortality, non-fatal MI, non-fatal stroke, and heart failure. Any other component considered should be a ‘hard CVD outcome’ that, based on available evidence, will be affected by the intervention.
- Components should not be included in a composite outcome if available evidence suggests no effect of the intervention or if there is the potential for biased ascertainment.
- Electronic health records have the potential to streamline identification and recruitment of eligible patients, and with appropriate validation studies, to ascertain certain clinical outcomes.
- The use of Centers for Medicare & Medicaid Services data to collect outcome measures could be an important cost saving measure.
- Data on cancer risk factors and cancer endpoints should be collected in a uniform and standardized manner.
- Cancer endpoints should be included and should be restricted to the most common cancers with potential diet etiology.
- Diabetes and cognitive endpoints are important exploratory endpoints to consider.
- It is not clear what role co-treatment (e.g., statin usage) will play in a large trial.
The working group plans to prepare a manuscript(s) for publication in a peer-reviewed journal.
- Estruch, R., et al., Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med, 2013. 368(14): p. 1279-90.
- Trichopoulou, A., et al., Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med, 2003. 348(26): p. 2599-608.
- Strazzullo, P., et al., Changing the Mediterranean diet: effects on blood pressure. J Hypertens, 1986. 4(4): p. 407-12.
- Esposito, K., et al., Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA, 2004. 292(12): p. 1440-6.
- Psaltopoulou, T., et al., Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr, 2004. 80(4): p. 1012-8.