Background: Vegetarian dietary patterns are recommended for cardiovascular disease (CVD) prevention and management due to their favorable effects on cardiometabolic risk factors, however, the role of vegetarian dietary patterns in CVD incidence and mortality remains unclear. Objective: To update the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy, we undertook a systematic review and meta-analysis of the association of vegetarian dietary patterns with major cardiovascular outcomes in prospective cohort studies that included individuals with and without diabetes using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Methods: MEDLINE, EMBASE, and Cochrane databases were searched through September 6th, 2018. We included prospective cohort studies ≥1 year of follow-up including individuals with or without diabetes reporting the relation of vegetarian and non-vegetarian dietary patterns with at least one cardiovascular outcome. Two independent reviewers extracted data and assessed study quality (Newcastle-Ottawa Scale). The pre-specified outcomes included CVD incidence and mortality (total CVD, coronary heart disease (CHD) and stroke). Risk ratios for associations were pooled using inverse variance random effects model and expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I 2-statistic). The overall certainty of the evidence was assessed using GRADE. Results: Seven prospective cohort studies (197,737 participants, 8,430 events) were included. A vegetarian dietary pattern was associated with reduced CHD mortality [RR, 0.78 (CI, 0.69, 0.88)] and incidence [0.72 (0.61, 0.85)] but were not associated with CVD mortality [0.92 (0.84, 1.02)] and stroke mortality [0.92 (0.77, 1.10)]. The overall certainty of the evidence was graded as "very low" for all outcomes, owing to downgrades for indirectness and imprecision. Conclusions: Very low-quality evidence indicates that vegetarian dietary patterns are associated with reductions in CHD mortality and incidence but not with CVD and stroke mortality in individuals with and without diabetes. More research, particularly in different populations, is needed to improve the certainty in our estimates. Clinical Trial Registration: Clinicaltrials.gov, identifier: NCT03610828.

CIBER Fisiopatología de la Obesidad y Nutrición Instituto de Salud Carlos 3 Madrid Spain

Clinical Nutrition and Risk Factor Modification Center St Michael's Hospital Toronto ON Canada

College of Pharmacy and Nutrition University of Saskatchewan Saskatoon SK Canada

Department of Medicine Faculty of Medicine University of Toronto Toronto ON Canada

Department of Nutritional Sciences University of Toronto Toronto ON Canada

Division of Endocrinology and Metabolism St Michael's Hospital Toronto ON Canada

Human Nutrition Department IISPV Universitat Rovira i Virgili Reus Spain

Institute for Clinical and Experimental Medicine Prague Czechia

Li Ka Shing Knowledge Institute St Michael's Hospital Toronto ON Canada

Physicians Committee for Responsible Medicine Washington DC United States

School of Medicine University of Zagreb Zagreb Croatia

Toronto 3D Knowledge Synthesis and Clinical Trials Unit St Michael's Hospital Toronto ON Canada

Vuk Vrhovac University Clinic for Diabetes Endocrinology and Metabolic Diseases Merkur University Hospital Zagreb Croatia

Zobrazit více v PubMed

Satija A, Hu FB. Plant-based diets and cardiovascular health. Trends Cardiovasc Med. (2018) 28:437–41. 10.1016/j.tcm.2018.02.004 PubMed DOI PMC

Dinu M, Abbate R, Gensini GF, Casini A, Sofi F. Vegetarian, vegan diets and multiple health outcomes: a systematic review with meta-analysis of observational studies. Crit Rev Food Sci Nutr. (2017) 57:3640–9. 10.1080/10408398.2016.1138447 PubMed DOI

Yokoyama Y, Nishimura K, Barnard ND, Takegami M, Watanabe M, Sekikawa A, et al. . Vegetarian diets and blood pressure: a meta-analysis. JAMA Intern Med. (2014) 174:577–87. 10.1001/jamainternmed.2013.14547 PubMed DOI

Yokoyama Y, Levin SM, Barnard ND. Association between plant-based diets and plasma lipids: a systematic review and meta-analysis. Nutr Rev. (2017) 75:683–98. 10.1093/nutrit/nux030 PubMed DOI PMC

Viguiliouk E, Kendall CW, Kahleova H, Rahelic D, Salas-Salvado J, Choo VL, et al. . Effect of vegetarian dietary patterns on cardiometabolic risk factors in diabetes: a systematic review and meta-analysis of randomized controlled trials. Clin Nutr. (2018) 38:1133–45. 10.1016/j.clnu.2018.05.032. PubMed DOI

USDA . Dietary Guidelines for Amercians 2015-2020. (2015). Available online at: https://health.gov/dietaryguidelines/2015/resources/2015-2020_Dietary_Guidelines.pdf.

Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, et al. . 2016 Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. (2016) 32:1263–82. 10.1016/j.cjca.2016.07.510 PubMed DOI

Sievenpiper JL, Chan CB, Dworatzek PD, Freeze C, Williams SL. Nutrition therapy. Can J Diabetes. (2018) 42 (Suppl. 1):S64–79. 10.1016/j.jcjd.2017.10.009 PubMed DOI

ADA 4 Lifestyle management: standards of medical care in diabetes-2018. Diabetes Care. (2018) 41(Suppl. 1), S38–50. 10.2337/dc18-S004 PubMed DOI

Dyson PA, Twenefour D, Breen C, Duncan A, Elvin E, Goff L, et al. . Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes. Diabet Med. (2018) 35:541–7. 10.1111/dme.13603 PubMed DOI

Mann JI, De Leeuw I, Hermansen K, Karamanos B, Karlstrom B, Katsilambros N, et al. . Evidence-based nutritional approaches to the treatment and prevention of diabetes mellitus. Nutr Metab Cardiovasc Dis. (2004) 14:373–94. 10.1016/S0939-4753(04)80028-0 PubMed DOI

Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. (1998) 339:229–34. 10.1056/NEJM199807233390404 PubMed DOI

Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. (2006) 368:29–36. 10.1016/S0140-6736(06)68967-8 PubMed DOI

Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. (2011). Available online at: www.cochrane-handbook.org (accessed September 8, 2018).

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. . Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. (2000) 283:2008–12. 10.1001/jama.283.15.2008 PubMed DOI

Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. (2014). Ottawa: Ottawa Hospital Research Institute; Available online at: www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed May 8, 2018).

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. (1986) 7:177–88. PubMed

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. . GRADE guidelines: 7. Rating the quality of evidence—inconsistency. J Clin Epidemiol. (2011) 64:1294–302. 10.1016/j.jclinepi.2011.03.017 PubMed DOI

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. (1994) 50:1088–101. PubMed

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. (1997) 315:629–34. PubMed PMC

Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. (2000) 56:455–63. 10.1111/j.0006-341X.2000.00455.x PubMed DOI

Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, et al. . GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. (2011) 64:401–6. 10.1016/j.jclinepi.2010.07.015 PubMed DOI

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. (2011) 64:383–94. 10.1016/j.jclinepi.2010.04.026 PubMed DOI

Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. framing the question and deciding on important outcomes J Clin Epidemiol. (2011) 64:395–400. 10.1016/j.jclinepi.2010.09.012 PubMed DOI

Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. . GRADE guidelines 6. rating the quality of evidence—imprecision. J Clin Epidemiol. (2011) 64:1283–93. 10.1016/j.jclinepi.2011.01.012 PubMed DOI

Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, et al. . GRADE guidelines: 8. Rating the quality of evidence–indirectness. J Clin Epidemiol. (2011) 64:1303–10. 10.1016/j.jclinepi.2011.04.014 PubMed DOI

Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. . GRADE guidelines: 5. rating the quality of evidence–publication bias J Clin Epidemiol. (2011) 64:1277–82. 10.1016/j.jclinepi.2011.01.011 PubMed DOI

Guyatt GH, Oxman AD, Sultan S, Glasziou P, Akl EA, Alonso-Coello P, et al. . GRADE guidelines: 9. rating up the quality of evidence. J Clin Epidemiol. (2011) 64:1311–6. 10.1016/j.jclinepi.2011.06.004 PubMed DOI

Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. . GRADE guidelines: 4. rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol. (2011) 64:407–15. 10.1016/j.jclinepi.2010.07.017 PubMed DOI

Brunetti M, Shemilt I, Pregno S, Vale L, Oxman AD, Lord J, et al. . GRADE guidelines: 10. considering resource use and rating the quality of economic evidence. J Clin Epidemiol. (2013) 66:140–50. 10.1016/j.jclinepi.2012.04.012 PubMed DOI

Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso-Coello P, et al. . GRADE guidelines: 11. making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol. (2013) 66:151–7. 10.1016/j.jclinepi.2012.01.006 PubMed DOI

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. . GRADE guidelines: 12. preparing summary of findings tables-binary outcomes. J Clin Epidemiol. (2013) 66:158–72. 10.1016/j.jclinepi.2012.01.012 PubMed DOI

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. . GRADE guidelines: 13. preparing summary of findings tables and evidence profiles-continuous outcomes J Clin Epidemiol. (2013) 66:173–83. 10.1016/j.jclinepi.2012.08.001 PubMed DOI

Key TJ, Appleby PN, Spencer EA, Travis RC, Roddam AW, Allen NE. Mortality in British vegetarians: results from the European prospective investigation into cancer and nutrition (EPIC-Oxford). Am J Clin Nutr. (2009) 89:1613S−9S. 10.3945/ajcn.2009.26736L PubMed DOI

Crowe FL, Appleby PN, Travis RC, Key TJ. Risk of hospitalization or death from ischemic heart disease among British vegetarians and nonvegetarians: results from the EPIC-Oxford cohort study. Am J Clin Nutr. (2013) 97:597–603. 10.3945/ajcn.112.044073 PubMed DOI

Chang-Claude J, Hermann S, Eilber U, Steindorf K. Lifestyle determinants and mortality in German vegetarians and health-conscious persons: results of a 21-year follow-up. Cancer Epidemiol Biomarkers Prev. (2005) 14:963–8. 10.1158/1055-9965.EPI-04-0696 PubMed DOI

Orlich MJ, Singh PN, Sabate J, Jaceldo-Siegl K, Fan J, Knutsen S, et al. . Vegetarian dietary patterns and mortality in Adventist Health Study 2. JAMA Intern Med. (2013) 173:1230–8. 10.1001/jamainternmed.2013.6473 PubMed DOI PMC

Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, et al. . Mortality in vegetarians and non-vegetarians: a collaborative analysis of 8300 deaths among 76,000 men and women in five prospective studies. Public Health Nutr. (1998) 1:33–41. PubMed

Appleby PN, Key TJ, Thorogood M, Burr ML, Mann J. Mortality in British vegetarians. Public Health Nutr. (2002) 5:29–36. 10.1079/PHN2001248 PubMed DOI

Wang X, Lin X, Ouyang YY, Liu J, Zhao G, Pan A, et al. . Red and processed meat consumption and mortality: dose-response meta-analysis of prospective cohort studies. Public Health Nutr. (2016) 19:893–905. 10.1017/S1368980015002062 PubMed DOI PMC

Yang C, Pan L, Sun C, Xi Y, Wang L, Li D. Red meat consumption and the risk of stroke: a dose-response meta-analysis of prospective cohort studies. J Stroke Cerebrovasc Dis. (2016) 25:1177–86. 10.1016/j.jstrokecerebrovasdis.2016.01.040 PubMed DOI

Bechthold A, Boeing H, Schwedhelm C, Hoffmann G, Knuppel S, Iqbal K, et al. . Food groups and risk of coronary heart disease, stroke and heart failure: a systematic review and dose-response meta-analysis of prospective studies. Crit Rev Food Sci Nutr. (2019) 59:1071–90. 10.1080/10408398.2017.1392288 PubMed DOI

Kim K, Hyeon J, Lee SA, Kwon SO, Lee H, Keum N, et al. . Role of total, red, processed, and white meat consumption in stroke incidence and mortality: a systematic review and meta-analysis of prospective cohort Studies. J Am Heart Assoc. (2017) 6:5983. 10.1161/JAHA.117.005983 PubMed DOI PMC

Barnard ND, Levin SM, Yokoyama Y. A systematic review and meta-analysis of changes in body weight in clinical trials of vegetarian diets. J Acad Nutr Diet. (2015) 115:954–69. 10.1016/j.jand.2014.11.016 PubMed DOI

Li SS, Blanco Mejia S, Lytvyn L, Stewart SE, Viguiliouk E, Ha V, et al. . Effect of plant protein on blood lipids: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. (2017) 6:6659. 10.1161/JAHA.117.006659 PubMed DOI PMC

Satija A, Bhupathiraju SN, Spiegelman D, Chiuve SE, Manson JE, Willett W, et al. . Healthful and unhealthful plant-based diets and the risk of coronary heart disease in U.S. Adults. J Am Coll Cardiol. (2017) 70:411–22. 10.1016/j.jacc.2017.05.047 PubMed DOI PMC

Le LT, Sabate J. Beyond meatless, the health effects of vegan diets: findings from the Adventist cohorts. Nutrients. (2014) 6:2131–47. 10.3390/nu6062131 PubMed DOI PMC

Orlich MJ, Jaceldo-Siegl K, Sabate J, Fan J, Singh PN, Fraser GE. Patterns of food consumption among vegetarians and non-vegetarians. Br J Nutr. (2014) 112:1644–53. 10.1017/S000711451400261X PubMed DOI PMC

Jenkins DJ, Mirrahimi A, Srichaikul K, Berryman CE, Wang L, Carleton A, et al. . Soy protein reduces serum cholesterol by both intrinsic and food displacement mechanisms. J Nutr. (2010) 140:2302S−11S. 10.3945/jn.110.124958 PubMed DOI

Blanco Mejia S, Kendall CW, Viguiliouk E, Augustin LS, Ha V, Cozma AI, et al. . Effect of tree nuts on metabolic syndrome criteria: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. (2014) 4:e004660. 10.1136/bmjopen-2013-004660 PubMed DOI PMC

Ha V, Sievenpiper JL, de Souza RJ, Jayalath VH, Mirrahimi A, Agarwal A, et al. . Effect of dietary pulse intake on established therapeutic lipid targets for cardiovascular risk reduction: a systematic review and meta-analysis of randomized controlled trials. CMAJ. (2014) 186:E252–262. 10.1503/cmaj.131727 PubMed DOI PMC

Jayalath VH, de Souza RJ, Sievenpiper JL, Ha V, Chiavaroli L, Mirrahimi A, et al. . Effect of dietary pulses on blood pressure: a systematic review and meta-analysis of controlled feeding trials. Am J Hypertens. (2014) 27:56–64. 10.1093/ajh/hpt155 PubMed DOI PMC

Viguiliouk E, Blanco Mejia S, Kendall CW, Sievenpiper JL. Can pulses play a role in improving cardiometabolic health? Evidence from systematic reviews and meta-analyses. Ann N Y Acad Sci. (2017) 1392:43–57. 10.1111/nyas.13312 PubMed DOI PMC

Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr. (2010) 91:502–9. 10.3945/ajcn.2008.26285 PubMed DOI PMC

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. . Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. (2017) 38:2459–72. 10.1093/eurheartj/ehx144 PubMed DOI PMC

Ascherio A, Willett WC, Rimm EB, Giovannucci EL, Stampfer MJ. Dietary iron intake and risk of coronary disease among men. Circulation. (1994) 89:969–74. PubMed

Lee DH, Folsom AR, Jacobs DR Jr. Iron, zinc, and alcohol consumption and mortality from cardiovascular diseases: the Iowa Women's Health Study. Am J Clin Nutr. (2005) 81:787–91. 10.1093/ajcn/81.4.787 PubMed DOI

van der AD, Peeters PH, Grobbee DE, Marx JJ, van der Schouw YT. Dietary haem iron and coronary heart disease in women. Eur Heart J. (2005) 26, 257–62. 10.1093/eurheartj/ehi027 PubMed DOI

de Oliveira Otto MC, Alonso A, Lee DH, Delclos GL, Bertoni AG, Jiang R, et al. Dietary intakes of zinc and heme iron from red meat, but not from other sources, are associated with greater risk of metabolic syndrome and cardiovascular disease. J Nutr. (2012) 142:526–33. 10.3945/jn.111.149781 PubMed DOI PMC

Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J Am Heart Assoc. (2017) 6:4947. 10.1161/JAHA.116.004947 PubMed DOI PMC

Dhurandhar NV, Schoeller D, Brown AW, Heymsfield SB, Thomas D, Sorensen TI, et al. Energy balance measurement: when something is not better than nothing. Int J Obes. (2015) 39:1109–13. 10.1038/ijo.2014.199 PubMed DOI PMC

Willett W. Lessons from dietary studies in Adventists and questions for the future. Am J Clin Nutr. (2003) 78(Suppl. 3):539S−43S. 10.1093/ajcn/78.3.539S PubMed DOI

Haddad EH, Tanzman JS. What do vegetarians in the United States eat? Am J Clin Nutr. (2003) 78(Suppl. 3):626S−32S. 10.1093/ajcn/78.3.626S PubMed DOI

Ipsos Vegan Society Poll. Available online at: https://www.ipsos.com/ipsos-mori/en-uk/vegan-society-poll (accessed September 8, 2018).

Melina V, Craig W, Levin S. Position of the academy of nutrition and dietetics: vegetarian diets. J Acad Nutr Diet. (2016) 116:1970–80. 10.1016/j.jand.2016.09.025 PubMed DOI

Portal TS. Share of people who follow a vegetarian diet worldwide as of 2016, by region. (2016). Available online at: https://www.statista.com/statistics/597408/vegetarian-diet-followers-worldwide-by-region/ (accessed September 8, 2018).

Charlebois S. More Than 3 Million Canadians Vegetarian or Vegan: Study. CTV News. (2018). Available online at: https://www.ctvnews.ca/canada/more-than-3-million-canadians-vegetarian-or-vegan-study-1.4027606 (accessed September 8, 2018).

Nielsen Plant-Based Proteins are Gaining Dollar Share Among North Americans. (2017). Available online at: https://www.nielsen.com/us/en/insights/news/2017/plant-based-proteins-are-gaining-dollar-share-among-north-americans.html (accessed September 8, 2018).

Mintel 2018 Summer Food and Drink Trends. (2018). Available online at: https://www.mintel.com/summer-food-drink-trends (accessed September 8, 2018).

Lee V, McKay T, Ardern CI. Awareness and perception of plant-based diets for the treatment and management of type 2 diabetes in a community education clinic: a pilot study. J Nutr Metab. (2015) 2015:236234. 10.1155/2015/236234 PubMed DOI PMC

Barnard ND, Scialli AR, Turner-McGrievy G, Lanou AJ. Acceptability of a low-fat vegan diet compares favorably to a step II diet in a randomized, controlled trial. J Cardiopulm Rehabil. (2004) 24:229–35. 10.1097/00008483-200407000-00004 PubMed DOI

Barnard ND, Gloede L, Cohen J, Jenkins DJ, Turner-McGrievy G, Green AA, et al. . A low-fat vegan diet elicits greater macronutrient changes, but is comparable in adherence and acceptability, compared with a more conventional diabetes diet among individuals with type 2 diabetes. J Am Diet Assoc. (2009) 109:263–72. 10.1016/j.jada.2008.10.049 PubMed DOI PMC

Katcher HI, Ferdowsian HR, Hoover VJ, Cohen JL, Barnard ND. A worksite vegan nutrition program is well-accepted and improves health-related quality of life and work productivity. Ann Nutr Metab. (2010) 56:245–52. 10.1159/000288281 PubMed DOI

Fox N, Ward K. Health, ethics and environment: a qualitative study of vegetarian motivations. Appetite. (2008) 50:422–9. 10.1016/j.appet.2007.09.007. PubMed DOI

Tilman D, Clark M. Global diets link environmental sustainability and human health. Nature. (2014) 515:518–22. 10.1038/nature13959 PubMed DOI

Willett W, Rockstrom J, Loken B, Springmann M, Lang T, Vermeulen S, et al. . Food in the Anthropocene: the EAT-Lancet Commission on healthy diets from sustainable food systems. Lancet. (2019) 393:447–92. 10.1016/S0140-6736(18)31788-4 PubMed DOI

Rinaldi S, Campbell EE, Fournier J, O'Connor C, Madill J. A comprehensive review of the literature supporting recommendations from the Canadian diabetes association for the use of a plant-based diet for management of type 2 diabetes. Can J Diabetes. (2016) 40:471–7. 10.1016/j.jcjd.2016.02.011 PubMed DOI

Nordic dietary patterns and cardiometabolic outcomes: a systematic review and meta-analysis of prospective cohort studies and randomised controlled trials

Dietary Patterns and Cardiometabolic Outcomes in Diabetes: A Summary of Systematic Reviews and Meta-Analyses

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03610828