Download PDF
Thromb Haemost
DOI: 10.1055/a-2806-3554
Original Article: Stroke, Systemic or Venous Thromboembolism

Effects of Cocoa Extract and Multivitamin Supplementation on Venous Thromboembolism in the COSMOS Trial

Authors

  • Sarah Jaehwa Park 

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    2   Osher Center for Integrative Health, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

  • JoAnn E. Manson

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    3   Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States

  • Eunjung Kim

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States

  • Robert J. Glynn

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    4   Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States

  • Pamela M. Rist

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    3   Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States

  • Matthew A. Allison

    5   Department of Family Medicine, University of California, San Diego, California, United States

  • Howard D. Sesso

    1   Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    2   Osher Center for Integrative Health, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States
    3   Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States

Funding Information This publication was supported in part by the National Center for Complementary and Integrative Health of the National Institutes of Health (NIH), Bethesda, MD with training grant 5T32AT000051 (SJP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is supported by an investigator-initiated grant from Mars Edge (JEM, HDS), a segment of Mars dedicated to nutrition research and products, which included infrastructure support and the donation of study pills and packaging. Pfizer Consumer Healthcare (now Haleon) provided support through the partial provision of study pills and packaging (JEM, HDS). COSMOS is also supported in part by NIH grants AG050657, AG071611, EY025623, and HL157665. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005.
Further Information
   Permissions and Reprints


Graphical Abstract

Abstract

Background

Epidemiological and experimental studies suggest cocoa flavanols and multivitamin-multimineral (MVM) supplements may confer arterial vascular benefits. However, their effects on clinical venous thromboembolic events have been infrequently examined.

Objective

To evaluate whether cocoa extract (CE) or MVM supplementation reduces the risk of venous thromboembolism (VTE) among older adults.

Methods

We conducted an ancillary study analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), a completed randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of CE and MVM supplementation for the prevention of cardiovascular disease and cancer among 21,442 older US adults. Our primary outcome was self-reported incident VTE, defined as the first reported deep vein thrombosis (DVT) or pulmonary embolism (PE) event after randomization; secondary outcomes were the individual components.

Results

Over a median follow-up of 3.5 years, 379 participants reported an incident VTE event (including 277 DVT and 165 PE). In intention-to-treat analyses, neither CE (HR: 0.88; 95% CI: 0.72, 1.08) nor MVM (HR: 0.89; 95% CI: 0.73, 1.09) significantly reduced VTE risk, with similar findings for DVT and PE. Exploratory latency and per-protocol analyses suggested potential patterns of benefit that merit further evaluation.

Conclusion

In this large trial of older adults, neither CE nor MVM supplementation significantly reduced the risk of VTE or its component parts in intention-to-treat analyses. Additional research may help clarify whether these supplements influence VTE risk in other contexts or populations.

Keywords

cocoa extract - multivitamin - venous thromboembolism - deep vein thrombosis - pulmonary embolism

Data Availability Statement

The dataset(s) will be de-identified prior to release for sharing. We will make the data and associated documentation available to users only under a data-sharing agreement. Details on the availability of the study data to other investigators will be on our study Web site at https://cosmostrial.org/.


Contributors' Statement

H.D.S. 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; S.J.P. and H.D.S. conceptualized and designed the study; E.K. performed statistical analysis; S.J.P., J.E.M., E.K., R.J.G., P.M.R., M.A.A., and H.D.S. acquired, analyzed, or interpreted the data; S.J.P. drafted the manuscript; S.J.P., J.E.M., E.K., R.J.G., P.M.R., M.A.A., and H.D.S. provided critical edits to the manuscript. All the authors read and approved the final manuscript.


Supplementary Material



Publication History

Received: 26 June 2025

Accepted after revision: 04 February 2026

Accepted Manuscript online:
06 February 2026

Article published online:
16 February 2026

© 2026. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost 2014; 40 (07) 724-735
    Search in Google Scholar
  • 2 Anderson Jr FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107 (23, Suppl 1): I9-I16
    Search in Google Scholar
  • 3 Gregson J, Kaptoge S, Bolton T. et al; Emerging Risk Factors Collaboration. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol 2019; 4 (02) 163-173
    Search in Google Scholar
  • 4 Mahmoodi BK, Cushman M, Anne Næss I. et al. Association of traditional cardiovascular risk factors with venous thromboembolism. Circulation 2017; 135 (01) 7-16
    Search in Google Scholar
  • 5 Glynn RJ, Rosner B. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol 2005; 162 (10) 975-982
    Search in Google Scholar
  • 6 Prandoni P, Bilora F, Marchiori A. et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348 (15) 1435-1441
    Search in Google Scholar
  • 7 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162 (10) 1182-1189
    Search in Google Scholar
  • 8 Everett BM, Glynn RJ, Buring JE, Ridker PM. Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women. J Thromb Haemost 2009; 7 (04) 588-596
    Search in Google Scholar
  • 9 Erdman Jr JW, Carson L, Kwik-Uribe C, Evans EM, Allen RR. Effects of cocoa flavanols on risk factors for cardiovascular disease. Asia Pac J Clin Nutr 2008; 17 (1, Suppl 1): 284-287
    Search in Google Scholar
  • 10 Manach C, Mazur A, Scalbert A. Polyphenols and prevention of cardiovascular diseases. Curr Opin Lipidol 2005; 16 (01) 77-84
    Search in Google Scholar
  • 11 Kim Y, Je Y. Flavonoid intake and mortality from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies. Clin Nutr ESPEN 2017; 20: 68-77
    Search in Google Scholar
  • 12 Quintal Martínez JP, Segura Campos MR. Flavonoids as a therapeutical option for the treatment of thrombotic complications associated with COVID-19. Phytother Res 2023; 37 (03) 1092-1114
    Search in Google Scholar
  • 13 Vazhappilly CG, Ansari SA, Al-Jaleeli R. et al. Role of flavonoids in thrombotic, cardiovascular, and inflammatory diseases. Inflammopharmacology 2019; 27 (05) 863-869
    Search in Google Scholar
  • 14 Schroeter H, Heiss C, Balzer J. et al. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A 2006; 103 (04) 1024-1029
    Search in Google Scholar
  • 15 Sansone R, Rodriguez-Mateos A, Heuel J. et al; Flaviola Consortium, European Union 7th Framework Program. Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study. Br J Nutr 2015; 114 (08) 1246-1255
    Search in Google Scholar
  • 16 Sun Y, Zimmermann D, De Castro CA, Actis-Goretta L. Dose-response relationship between cocoa flavanols and human endothelial function: a systematic review and meta-analysis of randomized trials. Food Funct 2019; 10 (10) 6322-6330
    Search in Google Scholar
  • 17 Rein D, Paglieroni TG, Wun T. et al. Cocoa inhibits platelet activation and function. Am J Clin Nutr 2000; 72 (01) 30-35
    Search in Google Scholar
  • 18 Rein D, Paglieroni TG, Pearson DA. et al. Cocoa and wine polyphenols modulate platelet activation and function. J Nutr 2000; 130 (8S Suppl): 2120S-2126S
    Search in Google Scholar
  • 19 Grassi D, Necozione S, Lippi C. et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 2005; 46 (02) 398-405
    Search in Google Scholar
  • 20 Ried K, Fakler P, Stocks NP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev 2017; 4 (04) CD008893
    Search in Google Scholar
  • 21 Sesso HD, Manson JE, Aragaki AK. et al; COSMOS Research Group. Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. Am J Clin Nutr 2022; 115 (06) 1490-1500
    Search in Google Scholar
  • 22 Bailey RL, Gahche JJ, Lentino CV. et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011; 141 (02) 261-266
    Search in Google Scholar
  • 23 Rautiainen S, Åkesson A, Levitan EB, Morgenstern R, Mittleman MA, Wolk A. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. Am J Clin Nutr 2010; 92 (05) 1251-1256
    Search in Google Scholar
  • 24 Holmquist C, Larsson S, Wolk A, de Faire U. Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women—Stockholm Heart Epidemiology Program (SHEEP). J Nutr 2003; 133 (08) 2650-2654
    Search in Google Scholar
  • 25 Bailey RL, Fakhouri TH, Park Y. et al. Multivitamin-mineral use is associated with reduced risk of cardiovascular disease mortality among women in the United States. J Nutr 2015; 145 (03) 572-578
    Search in Google Scholar
  • 26 Rimm EB, Willett WC, Hu FB. et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998; 279 (05) 359-364
    Search in Google Scholar
  • 27 Rautiainen S, Rist PM, Glynn RJ, Buring JE, Gaziano JM, Sesso HD. Multivitamin use and the risk of cardiovascular disease in men. J Nutr 2016; 146 (06) 1235-1240
    Search in Google Scholar
  • 28 Glynn RJ, Ridker PM, Goldhaber SZ, Zee RYL, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women's Health Study. Circulation 2007; 116 (13) 1497-1503
    Search in Google Scholar
  • 29 Blondon M, Rodabough RJ, Budrys N. et al; From the Women's Health Initiative Randomized Controlled Trial. The effect of calcium plus vitamin D supplementation on the risk of venous thromboembolism. Thromb Haemost 2015; 113 (05) 999-1009
    Search in Google Scholar
  • 30 Sesso HD, Rist PM, Aragaki AK. et al; COSMOS Research Group. Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. Am J Clin Nutr 2022; 115 (06) 1501-1510
    Search in Google Scholar
  • 31 Sesso HD, Christen WG, Bubes V. et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 2012; 308 (17) 1751-1760
    Search in Google Scholar
  • 32 Rist PM, Sesso HD, Johnson LG. et al; COSMOS Research Group. Design and baseline characteristics of participants in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Contemp Clin Trials 2022; 116: 106728
    Search in Google Scholar
  • 33 Cauley JA, Crandall C. The Women's Health Initiative: a landmark resource for skeletal research since 1992. J Bone Miner Res 2020; 35 (05) 845-860
    Search in Google Scholar
  • 34 Bassuk SS, Manson JE, Lee IM. et al. Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). Contemp Clin Trials 2016; 47: 235-243
    Search in Google Scholar
  • 35 Willett WC, Sampson L, Stampfer MJ. et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985; 122 (01) 51-65
    Search in Google Scholar
  • 36 Feskanich D, Rimm EB, Giovannucci EL. et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc 1993; 93 (07) 790-796
    Search in Google Scholar
  • 37 Chiuve SE, Fung TT, Rimm EB. et al. Alternative dietary indices both strongly predict risk of chronic disease. J Nutr 2012; 142 (06) 1009-1018
    Search in Google Scholar
  • 38 Ottaviani JI, Borges G, Momma TY. et al. The metabolome of [2–14C](-)-epicatechin in humans: implications for the assessment of efficacy, safety, and mechanisms of action of polyphenolic bioactives. Sci Rep 2016; 6:29034
    Search in Google Scholar
  • 39 Cox DR. Regression models and life-tables. J R Stat Soc B 1972; 34 (02) 187-202
    Search in Google Scholar
  • 40 Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics 2000; 56 (03) 779-788
    Search in Google Scholar
  • 41 Willems S, Schat A, van Noorden MS, Fiocco M. Correcting for dependent censoring in routine outcome monitoring data by applying the inverse probability censoring weighted estimator. Stat Methods Med Res 2018; 27 (02) 323-335
    Search in Google Scholar
  • 42 Zhong GC, Hu TY, Yang PF. et al. Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial. Aging (Albany NY) 2021; 13 (14) 18564-18585
    Search in Google Scholar
  • 43 Kwok CS, Boekholdt SM, Lentjes MAH. et al. Habitual chocolate consumption and risk of cardiovascular disease among healthy men and women. Heart 2015; 101 (16) 1279-1287
    Search in Google Scholar
  • 44 Greenberg JA, Manson JE, Neuhouser ML. et al. Chocolate intake and heart disease and stroke in the Women's Health Initiative: a prospective analysis. Am J Clin Nutr 2018; 108 (01) 41-48
    Search in Google Scholar
  • 45 Buijsse B, Weikert C, Drogan D, Bergmann M, Boeing H. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur Heart J 2010; 31 (13) 1616-1623
    Search in Google Scholar
  • 46 Morze J, Schwedhelm C, Bencic A. et al. Chocolate and risk of chronic disease: a systematic review and dose-response meta-analysis. Eur J Nutr 2020; 59 (01) 389-397
    Search in Google Scholar
  • 47 McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012; 95 (02) 454-464
    Search in Google Scholar
  • 48 Mursu J, Voutilainen S, Nurmi T, Tuomainen TP, Kurl S, Salonen JT. Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2008; 100 (04) 890-895
    Search in Google Scholar
  • 49 Mursu J, Nurmi T, Tuomainen TP, Ruusunen A, Salonen JT, Voutilainen S. The intake of flavonoids and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2007; 98 (04) 814-818
    Search in Google Scholar
  • 50 Cassidy A, O'Reilly EJ, Kay C. et al. Habitual intake of flavonoid subclasses and incident hypertension in adults. Am J Clin Nutr 2011; 93 (02) 338-347
    Search in Google Scholar
  • 51 van Dam RM, Naidoo N, Landberg R. Dietary flavonoids and the development of type 2 diabetes and cardiovascular diseases: review of recent findings. Curr Opin Lipidol 2013; 24 (01) 25-33
    Search in Google Scholar
  • 52 Xu X, Shi Z, Liu G. et al. Article the joint effects of diet and dietary supplements in relation to obesity and cardiovascular disease over a 10-year follow-up: a longitudinal study of 69,990 participants in australia. Nutrients 2021; 13 (03) 944
    Search in Google Scholar
  • 53 Rautiainen S, Lee IM, Rist PM. et al. Multivitamin use and cardiovascular disease in a prospective study of women. Am J Clin Nutr 2015; 101 (01) 144-152
    Search in Google Scholar
  • 54 Neuhouser ML, Wassertheil-Smoller S, Thomson C. et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts. Arch Intern Med 2009; 169 (03) 294-304
    Search in Google Scholar
  • 55 Zhou K, Zhao R, Geng Z. et al. Association between B-group vitamins and venous thrombosis: systematic review and meta-analysis of epidemiological studies. J Thromb Thrombolysis 2012; 34 (04) 459-467
    Search in Google Scholar
  • 56 Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158 (19) 2101-2106
    Search in Google Scholar
  • 57 Hung KC, Yang SH, Chang CY. et al. Is circulating vitamin D status associated with the risk of venous thromboembolism? A meta-analysis of observational studies. Nutrients 2023; 15 (05) 1113
    Search in Google Scholar
  • 58 Wan J, Yuan J, Li X. et al. Association between serum vitamin D levels and venous thromboembolism (VTE): a systematic review and meta-analysis of observational studies. Complement Ther Med 2020; 54: 102579
    Search in Google Scholar
  • 59 Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E. Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med 2007; 146 (11) 761-767
    Search in Google Scholar
  • 60 den Heijer M, Willems HPJ, Blom HJ. et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood 2007; 109 (01) 139-144
    Search in Google Scholar
  • 61 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
    Search in Google Scholar
  • 62 Cushman M, Tsai AW, White RH. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117 (01) 19-25
    Search in Google Scholar