Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial

Howard D Sesso, JoAnn E Manson, Aaron K Aragaki, Pamela M Rist, Lisa G Johnson, Georgina Friedenberg, Trisha Copeland, Allison Clar, Samia Mora, M Vinayaga Moorthy, Ara Sarkissian, William R Carrick, Garnet L Anderson, COSMOS Research Group, JoAnn E Manson, Howard D Sesso, Pamela M Rist, Susanne Rautiainen Lagerstrom, Shari S Bassuk, Lu Wang, Aditi Hazra, Heike Gibson, Meryl S LeBoff, Samia Mora, Olivia I Okereke, Deirdre K Tobias, Nancy R Cook, Paulette D Chandler, William Christen, Georgina Friedenberg, Trisha Copeland, Jasmah Hanna, Allison Clar, Denise D'Agostino, Manickavasagar Vinayagamoorthy, Heike Gibson, Eunjung Kim, Martin Van Denburgh, Gregory Kotler, Chunying Li, Vadim Bubes, Ara Sarkissian, Doug Smith, Eduardo C Pereira, Melvyn Okeke, Elise Roche, David Bates, Claire Ridge, Alexandra Phillips, Brielle Salvo, Annalee Wilson, Leah Hall, Jimaldy Baez, Young-Hwan Sim, Hayara Cardoso, Gabriel Senor, Connor Rudnicki, Hanh Huynh, Viviane Nguyen, Nicholas Terrell, Beth A Holman, Joseph Walter, Lisa Fields Johnson, Amy Casarella, Julia O'Connell, William Christen, Susanne Rautiainen Lagerstrom, Luc Djoussé, Paulette D Chandler, Aditi Hazra, Deidre K Tobias, Zareen M Farukhi, Lu Wang, Xuehong Zhang, Kenneth Breen, George V Menjin Jr, Rolando Rodriguez, Shamikhah Curry, Samia Mora, Leah Arsenault, Olubunmi Solano, Alison Weinberg, Jennifer Coates, Matthew Kilroe, Lincoln Zernicke, Katelyn Hasson, Karen Matthew, Samia Mora, Chris Pfeffer, Julie Duszlak, David Bates, Vincent Guzman, Josue Falcon, Alex Romero, Henry Kupets, Frank Cortez, James C LeSuer, Andrea Hrbek, Eileen Bowes, Philomena Quinn, Megan Mele, Garnet L Anderson, Lisa Johnson, Leslie F Tinker, Aaron K Aragaki, Megan Herndon, Sue L Mann, Mary Pettinger, Rebecca P Hunt, Bill Carrick, Kate Szyperski, Lori Proulx-Burns, Elizabeth Burrows, Marian Limacher, Judith Hsia, Ganesh Asaithambi, Muhib Khan, Nandakumar Nagaraja, Lenore C Ocava, Jana Wold, Brian Silver, Stephanie Connelly, Gretchen Van Lom, Cris Garvida, Kathy Hightower, Patricia Spaulding, Wei Lin, Jenny Schoenberg, Patti Olee, Lawrence S Cohen, Theodore Colton, I Craig Henderson, Stephen Hulley, Alice H Lichtenstein, Eugene R Passamani, Rebecca A Silliman, Nanette Wenger, Shari E Ludlam, Hagen Schroeter, Michael Fare, Javier Ottawani, Catherine Kwik-Uribe, Cassandra Arnaiz, Ann Costanza, John Greene, Paul Hennessey, Sarma Vadlamani, Mallik Karmsetty, Paul Martini, Jan-Willem van Klinken, Alpa Shah, Lori Stern, Howard D Sesso, JoAnn E Manson, Aaron K Aragaki, Pamela M Rist, Lisa G Johnson, Georgina Friedenberg, Trisha Copeland, Allison Clar, Samia Mora, M Vinayaga Moorthy, Ara Sarkissian, William R Carrick, Garnet L Anderson, COSMOS Research Group, JoAnn E Manson, Howard D Sesso, Pamela M Rist, Susanne Rautiainen Lagerstrom, Shari S Bassuk, Lu Wang, Aditi Hazra, Heike Gibson, Meryl S LeBoff, Samia Mora, Olivia I Okereke, Deirdre K Tobias, Nancy R Cook, Paulette D Chandler, William Christen, Georgina Friedenberg, Trisha Copeland, Jasmah Hanna, Allison Clar, Denise D'Agostino, Manickavasagar Vinayagamoorthy, Heike Gibson, Eunjung Kim, Martin Van Denburgh, Gregory Kotler, Chunying Li, Vadim Bubes, Ara Sarkissian, Doug Smith, Eduardo C Pereira, Melvyn Okeke, Elise Roche, David Bates, Claire Ridge, Alexandra Phillips, Brielle Salvo, Annalee Wilson, Leah Hall, Jimaldy Baez, Young-Hwan Sim, Hayara Cardoso, Gabriel Senor, Connor Rudnicki, Hanh Huynh, Viviane Nguyen, Nicholas Terrell, Beth A Holman, Joseph Walter, Lisa Fields Johnson, Amy Casarella, Julia O'Connell, William Christen, Susanne Rautiainen Lagerstrom, Luc Djoussé, Paulette D Chandler, Aditi Hazra, Deidre K Tobias, Zareen M Farukhi, Lu Wang, Xuehong Zhang, Kenneth Breen, George V Menjin Jr, Rolando Rodriguez, Shamikhah Curry, Samia Mora, Leah Arsenault, Olubunmi Solano, Alison Weinberg, Jennifer Coates, Matthew Kilroe, Lincoln Zernicke, Katelyn Hasson, Karen Matthew, Samia Mora, Chris Pfeffer, Julie Duszlak, David Bates, Vincent Guzman, Josue Falcon, Alex Romero, Henry Kupets, Frank Cortez, James C LeSuer, Andrea Hrbek, Eileen Bowes, Philomena Quinn, Megan Mele, Garnet L Anderson, Lisa Johnson, Leslie F Tinker, Aaron K Aragaki, Megan Herndon, Sue L Mann, Mary Pettinger, Rebecca P Hunt, Bill Carrick, Kate Szyperski, Lori Proulx-Burns, Elizabeth Burrows, Marian Limacher, Judith Hsia, Ganesh Asaithambi, Muhib Khan, Nandakumar Nagaraja, Lenore C Ocava, Jana Wold, Brian Silver, Stephanie Connelly, Gretchen Van Lom, Cris Garvida, Kathy Hightower, Patricia Spaulding, Wei Lin, Jenny Schoenberg, Patti Olee, Lawrence S Cohen, Theodore Colton, I Craig Henderson, Stephen Hulley, Alice H Lichtenstein, Eugene R Passamani, Rebecca A Silliman, Nanette Wenger, Shari E Ludlam, Hagen Schroeter, Michael Fare, Javier Ottawani, Catherine Kwik-Uribe, Cassandra Arnaiz, Ann Costanza, John Greene, Paul Hennessey, Sarma Vadlamani, Mallik Karmsetty, Paul Martini, Jan-Willem van Klinken, Alpa Shah, Lori Stern

Abstract

Background: Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.

Objectives: We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.

Methods: We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.

Results: During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.

Conclusions: Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Keywords: cancer; cardiovascular disease; cocoa extract; flavanols; multivitamin; randomized clinical trial.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Screening, randomization, and follow-up of the participants. 1Eligibility was determined by medical history, age, and willingness to forego personal use of cocoa extract and multivitamin pills. 2Eligibility was determined by medical history, age, willingness to forego personal use of cocoa extract and multivitamin pills, caffeine sensitivity, and willingness to limit calcium and vitamin D supplement use. 3Included subjects who never completed the screening phase (n = 2914), eligibility could not be determined (n = 5), and enrollment goal already met (n = 55). 4Included subjects who never completed screening phase (n = 168) and enrollment goal already met (n = 54).
FIGURE 2
FIGURE 2
HRs and 95% CIs1 for the primary and secondary CVD outcomes, according to randomized assignment, in intention-to-treat analyses. 1Summary statistics were from Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort. CIs were not adjusted for multiple comparisons. 2This outcome was a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. 3This outcome was a composite of myocardial infarction, stroke, and CVD death. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.
FIGURE 3
FIGURE 3
Cumulative incidence rates of total cardiovascular events1 and CVD death, according to year of follow-up, in the cocoa extract group and placebo group. 1Primary outcome (left panel): a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. Secondary outcome (right panel): CVD death. Summary statistics were from Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort (intention-to-treat analyses). P value was for the effect of randomization group, based on a stratified score (log-rank) test. Rates (%) were annualized. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.
FIGURE 4
FIGURE 4
HRs and 95% CIs1 for the primary and secondary CVD outcomes, according to randomized assignment, where follow-up of noncompliant participants was censored. 1Summary statistics were from weighted Cox regression models that stratified baseline hazard functions by multivitamin trial randomization group, age, sex, and recruitment cohort, and used the robust sandwich estimator for variance. Time-dependent weights were calculated as the inverse probability of compliance, where probabilities were estimated from a Cox regression model with baseline hazard functions stratified by age, sex, recruitment source, multivitamin-trial arm and cocoa extract trial arm, and included baseline history of CVD and hypertension status (time-dependent) as covariates. CIs were not adjusted for multiple comparisons. 2A participant's follow-up was censored at the first time they reported having missed >8 d of cocoa extract study pills per month, took personal nonstudy cocoa extract, or did not respond to a semiannual questionnaire. 3Total cardiovascular event was a composite of myocardial infarction, stroke, CVD death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery. 4Major cardiovascular event was a composite of myocardial infarction, stroke, and CVD death. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.

References

    1. Dillinger TL, Barriga P, Escarcega S, Jimenez M, Salazar Lowe D, Grivetti LE. Food of the gods: cure for humanity? A cultural history of the medicinal and ritual use of chocolate. J Nutr. 2000;130(8):2057S–72S.
    1. Aron PM, Kennedy JA. Flavan-3-ols: nature, occurrence and biological activity. Mol Nutr Food Res. 2008;52(1):79–104.
    1. Onatibia-Astibia A, Franco R, Martinez-Pinilla E. Health benefits of methylxanthines in neurodegenerative diseases. Mol Nutr Food Res. 2017;61(6):2001600670–201600884.. doi:10.1002/mnfr.201600670.
    1. Sansone R, Ottaviani JI, Rodriguez-Mateos A, Heinen Y, Noske D, Spencer JP, Crozier A, Merx MW, Kelm M, Schroeter Het al. . Methylxanthines enhance the effects of cocoa flavanols on cardiovascular function: randomized, double-masked controlled studies. Am J Clin Nutr. 2017;105(2):352–60.
    1. 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):1616–23.
    1. Greenberg JA, Manson JE, Neuhouser ML, Tinker L, Eaton C, Johnson KC, Shikany JM. Chocolate intake and heart disease and stroke in the Women's Health Initiative: a prospective analysis. Am J Clin Nutr. 2018;108(1):41–8.
    1. Kwok CS, Boekholdt SM, Lentjes MAH, Loke YK, Luben RN, Yeong JK, Wareham NJ, Myint PK, Khaw K-T. Habitual chocolate consumption and risk of cardiovascular disease among healthy men and women. Heart. 2015;101(16):1279–87.
    1. Zhong GC, Hu TY, Yang PF, Peng Y, Wu JJ, Sun WP, Cheng L, Wang CR. Chocolate consumption and all-cause and cause-specific mortality in a US population: a post hoc analysis of the PLCO cancer screening trial. Aging. 2021;13(14):18564–85.
    1. 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):814–8.
    1. Cassidy A, O'Reilly EJ, Kay C, Sampson L, Franz M, Forman JP, Curhan G, Rimm EB. Habitual intake of flavonoid subclasses and incident hypertension in adults. Am J Clin Nutr. 2011;93(2):338–47.
    1. 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(4):890–5.
    1. 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(2):454–64.
    1. Morze J, Schwedhelm C, Bencic A, Hoffmann G, Boeing H, Przybylowicz K, Schwingshackl L. Chocolate and risk of chronic disease: a systematic review and dose-response meta-analysis. Eur J Nutr. 2020;59(1):389–97.
    1. 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(1):25–33.
    1. Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1):230S–42S.
    1. Heiss C, Keen CL, Kelm M. Flavanols and cardiovascular disease prevention. Eur Heart J. 2010;31(21):2583–92.
    1. Raman G, Avendano EE, Chen S, Wang J, Matson J, Gayer B, Novotny JA, Cassidy A. Dietary intakes of flavan-3-ols and cardiometabolic health: systematic review and meta-analysis of randomized trials and prospective cohort studies. Am J Clin Nutr. 2019;110(5):1067–78.
    1. Ottaviani JI, Heiss C, Spencer JPE, Kelm M, Schroeter H. Recommending flavanols and procyanidins for cardiovascular health: revisited. Mol Aspects Med. 2018;61:63–75.
    1. Hooper L, Kay C, Abdelhamid A, Kroon PA, Cohn JS, Rimm EB, Cassidy A. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2012;95(3):740–51.
    1. Lin X, Zhang I, Li A, Manson JE, Sesso HD, Wang L, Liu S. Cocoa flavanol intake and biomarkers for cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials. J Nutr. 2016;146(11):2325–33.
    1. Sansone R, Rodriguez-Mateos A, Heuel J, Falk D, Schuler D, Wagstaff R, Kuhnle GGC, Spencer JPE, Schroeter H, Merx MWet al. . 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(8):1246–55.
    1. Rodriguez-Mateos A, Weber T, Skene SS, Ottaviani JI, Crozier A, Kelm M, Schroeter H, Heiss C. Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial. Am J Clin Nutr. 2018;108(6):1229–37.
    1. 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):6322–30.
    1. Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH, Kelm M. (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci. 2006;103(4):1024–9.
    1. Ried K, Fakler P, Stocks NP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev. 2017;(5). doi:10.1002/14651858.cd008893.pub3.
    1. Davison K, Berry NM, Misan G, Coates AM, Buckley JD, Howe PR. Dose-related effects of flavanol-rich cocoa on blood pressure. J Hum Hypertens. 2010;24(9):568–76.
    1. Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, Desideri G, Blumberg JB, Ferri C. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46(2):398–405.
    1. Kuebler U, Arpagaus A, Meister RE, von Kanel R, Huber S, Ehlert U, Wirtz PH. Dark chocolate attenuates intracellular pro-inflammatory reactivity to acute psychosocial stress in men: a randomized controlled trial. Brain Behav Immun. 2016;57:200–8.
    1. Dower JI, Geleijnse JM, Gijsbers L, Schalkwijk C, Kromhout D, Hollman PC. Supplementation of the pure flavonoids epicatechin and quercetin affects some biomarkers of endothelial dysfunction and inflammation in (pre)hypertensive adults: a randomized double-blind, placebo-controlled, crossover trial. J Nutr. 2015;145(7):1459–63.
    1. Rein D, Paglieroni TG, Pearson DA, Wun T, Schmitz HH, Gosselin R, Keen CL. Cocoa and wine polyphenols modulate platelet activation and function. J Nutr. 2000;130(8):2120S–6S.
    1. Rein D, Paglieroni TG, Wun T, Pearson DA, Schmitz HH, Gosselin R, Keen CL. Cocoa inhibits platelet activation and function. Am J Clin Nutr. 2000;72(1):30–5.
    1. Ottaviani JI, Borges G, Momma TY, Spencer JPE, Keen CL, Crozier A, Schroeter H. 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(1):29034.
    1. Actis-Goretta L, Leveques A, Rein M, Teml A, Schafer C, Hofmann U, Li H, Schwab M, Eichelbaum M, Williamson G. Intestinal absorption, metabolism, and excretion of (-)-epicatechin in healthy humans assessed by using an intestinal perfusion technique. Am J Clin Nutr. 2013;98(4):924–33.
    1. Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, Mena P, Del Rio D, Crozier A. Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update. Arch Toxicol. 2014;88(10):1803–53.
    1. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD. Pure dietary flavonoids quercetin and (−)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr. 2008;88(4):1018–25.
    1. Rist PM, Sesso HD, Johnson LG, Aragaki AK, Wang L, Rautiainen S, Hazra A, Tobias DK, LeBoff MS, Schroeter Het al. . Design and baseline characteristics of participants in the COcoa Supplement and Multivitamins Outcomes Study (COSMOS). Contemp Clin Trials. 2022;116:106728. doi:10.1016/j.cct.2022.106728.
    1. Cauley JA, Crandall C. The Women's Health Initiative: a landmark resource for skeletal research since 1992. J Bone Miner Res. 2020;35(5):845–60.
    1. Bassuk SS, Manson JE, Lee IM, Cook NR, Christen WG, Bubes VY, Gordon DS, Copeland T, Friedenberg G, D'Agostino DMet al. . Baseline characteristics of participants in the VITamin D and Omega-3 TriaL (VITAL). Contemp Clin Trials. 2016;47:235–43.
    1. Lang JM, Buring JE, Rosner B, Cook N, Hennekens CH. Estimating the effect of the run-in on the power of the Physicians' Health Study. Stat Med. 1991;10(10):1585–93.
    1. Feskanich D, Rimm EB, Giovannucci EL, Colditz GA, Stampfer MJ, Litin LB, Willett WC. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc. 1993;93(7):790–6.
    1. Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Britten A, Lucarelli D, Luben R, Grace PB, Mawson DH, Tym Aet al. . Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies. Sci Rep. 2018;8(1):9859.
    1. Curb JD, McTiernan A, Heckbert SR, Kooperberg C, Stanford J, Nevitt M, Johnson KC, Proulx-Burns L, Pastore L, Criqui Met al. . Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol. 2003;13(9):S122–8.
    1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Joint EoMI, Katus HA, Lindahl B, Morrow DAet al. . Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020–35.
    1. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.
    1. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet North Am Ed. 1991;337(8756):1521–6.
    1. Cox DR. Regression models and life-tables. J Royal Statist Soc B. 1972;34:187–220.
    1. Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. New York: Springer; 2000.
    1. 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(3):779–88.
    1. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra Jet al. . Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;378(25):e34. doi:10.1056/NEJMoa1800389.
    1. Jafari Azad B, Daneshzad E, Meysamie AP, Koohdani F. Chronic and acute effects of cocoa products intake on arterial stiffness and platelet count and function: a systematic review and dose-response meta-analysis of randomized clinical trials. Crit Rev Food Sci Nutr. 2021;61(3):357–79.
    1. Schroeter H, Heiss C, Spencer JPE, Keen CL, Lupton JR, Schmitz HH. Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. Mol Aspects Med. 2010;31(6):546–57.
    1. Kuhnle GGC. Nutrition epidemiology of flavan-3-ols: the known unknowns. Mol Aspects Med. 2018;61:2–11.
    1. Kwok CS, Loke YK, Welch AA, Luben RN, Lentjes MA, Boekholdt SM, Pfister R, Mamas MA, Wareham NJ, Khaw KTet al. . Habitual chocolate consumption and the risk of incident heart failure among healthy men and women. Nutr Metab Cardiovasc Dis. 2016;26(8):722–34.
    1. Nishiumi S, Miyamoto S, Kawabata K, Ohnishi K, Mukai R, Murakami A, Ashida H, Terao J. Dietary flavonoids as cancer-preventive and therapeutic biofactors. Front Biosci. 2011;S3(1):1332–62.
    1. Maskarinec G. Cancer protective properties of cocoa: a review of the epidemiologic evidence. Nutr Cancer. 2009;61(5):573–9.
    1. Mogollon JA, Boivin C, Lemieux S, Blanchet C, Claveau J, Dodin S. Chocolate flavanols and skin photoprotection: a parallel, double-blind, randomized clinical trial. Nutr J. 2014;13(1):66. doi:10.1186/1475-2891-13-66.
    1. Ávila-Gálvez MÁ, García-Villalba R, Martínez-Díaz F, Ocaña-Castillo B, Monedero-Saiz T, Torrecillas-Sánchez A, Abellán B, González-Sarrías A, Espín JC. Metabolic profiling of dietary polyphenols and methylxanthines in normal and malignant mammary tissues from breast cancer patients. Mol Nutr Food Res. 2019;63(9):1801239.
    1. Jin H, Leng Q, Li C. Dietary flavonoid for preventing colorectal neoplasms. Cochrane Database Syst Rev. 2012;8:CD009350. doi:10.1002/14651858.CD009350.pub2.
    1. Zamora-Ros R, Agudo A, Lujan-Barroso L, Romieu I, Ferrari P, Knaze V, Bueno-de-Mesquita HB, Leenders M, Travis RC, Navarro Cet al. . Dietary flavonoid and lignan intake and gastric adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr. 2012;96(6):1398–408.
    1. Vogiatzoglou A, Mulligan AA, Luben RN, Lentjes MAH, Heiss C, Kelm M, Merx MW, Spencer JPE, Schroeter H, Kuhnle GGC. Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union. Br J Nutr. 2014;111(8):1463–73.
    1. Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev. 2012;8:CD008893. doi:10.1002/14651858.CD008893.pub2.
    1. Montagna MT, Diella G, Triggiano F, Caponio GR, De Giglio O, Caggiano G, Di Ciaula A, Portincasa P. Chocolate, “Food of the Gods”: history, science, and human health. Int J Environ Res Public Health. 2019;16(24):4960. doi:10.3390/ijerph16244960.
    1. Valverde García D, Pérez Esteve É, Barat Baviera JM. Changes in cocoa properties induced by the alkalization process: a review. Compr Rev Food Sci Food Saf. 2020;19(4):2200–21.
    1. Taş NG, Gökmen V. Effect of alkalization on the Maillard reaction products formed in cocoa during roasting. Food Res Int. 2016;89:930–6.
    1. Todorovic V, Milenkovic M, Vidovic B, Todorovic Z, Sobajic S. Correlation between antimicrobial, antioxidant activity, and polyphenols of alkalized/nonalkalized cocoa powders. J Food Sci. 2017;82(4):1020–7.
    1. Li Y, Feng Y, Zhu S, Luo C, Ma J, Zhong F. The effect of alkalization on the bioactive and flavor related components in commercial cocoa powder. J Food Compos Anal. 2012;25(1):17–23.
    1. Marsh CE, Green DJ, Naylor LH, Guelfi KJ. Consumption of dark chocolate attenuates subsequent food intake compared with milk and white chocolate in postmenopausal women. Appetite. 2017;116:544–51.
    1. Ottaviani JI, Balz M, Kimball J, Ensunsa JL, Fong R, Momma TY, Kwik-Uribe C, Schroeter H, Keen CL. Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. Am J Clin Nutr. 2015;102(6):1425–35.
    1. Liu S, Sesso HD. Flavonoid consumption and cardiometabolic health: potential benefits due to foods, supplements, or biomarkers?. Am J Clin Nutr. 2021;114(1):9–11.

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