Multivitamins in the prevention of cancer and cardiovascular disease: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial

Howard D Sesso, Pamela M Rist, Aaron K Aragaki, Susanne Rautiainen, Lisa G Johnson, Georgina Friedenberg, Trisha Copeland, Allison Clar, Samia Mora, M Vinayaga Moorthy, Ara Sarkissian, Jean Wactawski-Wende, Lesley F Tinker, William R Carrick, Garnet L Anderson, JoAnn E Manson, 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, Pamela M Rist, Aaron K Aragaki, Susanne Rautiainen, Lisa G Johnson, Georgina Friedenberg, Trisha Copeland, Allison Clar, Samia Mora, M Vinayaga Moorthy, Ara Sarkissian, Jean Wactawski-Wende, Lesley F Tinker, William R Carrick, Garnet L Anderson, JoAnn E Manson, 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: Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited.

Objectives: The study objective was to determine if a daily MVM decreases total invasive cancer among older adults.

Methods: We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) 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 from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer.

Results: During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns.

Conclusions: A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. 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 cancer outcomes, according to randomized assignment, in intention-to-treat analyses. 1Summary statistics were from Cox regression models that stratified baseline hazard functions by cocoa extract trial randomization group, age, sex, and recruitment cohort. Analyses were not adjusted for multiple comparisons. 2This outcome was a composite of invasive cancers of any site other than nonmelanoma skin cancer.
FIGURE 3
FIGURE 3
Cumulative incidence rates of invasive cancer events,1 according to year of follow-up, in multivitamin group and placebo group. 1Primary outcome: a composite of invasive cancers of any site other than nonmelanoma skin cancer. Summary statistics were from Cox regression models that stratified baseline hazard functions by cocoa extract 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.
FIGURE 4
FIGURE 4
HRs and 95% CIs1 for secondary cardiovascular disease outcomes, according to randomized assignment, in intention-to-treat analyses. 1Summary statistics were from Cox regression models that stratified baseline hazard functions by cocoa extract trial randomization group, age, sex, and recruitment cohort. Analyses were not adjusted for multiple comparisons. 2This outcome was a composite of myocardial infarction, stroke, cardiovascular death, CABG/PCI, unstable angina including hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty. 3This outcome was a composite of myocardial infarction, stroke, and cardiovascular death. CABG/PCI, coronary artery bypass graft and percutaneous coronary intervention; CVD, cardiovascular disease.

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