- Correction(s) for this article:
- CorrectionsSep 2023
- CorrectionsSep 2023
Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia.
To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations.
Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583)
Primary/community care in Australia and the United States.
Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons).
100 mg of aspirin daily or placebo.
Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset.
19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results.
Hemoglobin was measured annually. No data were available on causes of anemia.
Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin.
Primary Funding Source:
National Institutes of Health and Australian National Health and Medical Research Council.
Garcia-Casal MN, Pasricha S-R, Sharma AJ, et al. Use and interpretation of hemoglobin concentrations for assessing anemia status in individuals and populations: results from a WHO technical meeting. Ann N Y Acad Sci. 2019;1450:5-14. [PMID: 31006883] doi:10.1111/nyas.14090 CrossrefMedlineGoogle Scholar
Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123:615-624. doi:10.1182/blood-2013-06-508325  CrossrefMedlineGoogle Scholar
Gaskell H, Derry S, Andrew Moore R, et al. Prevalence of anaemia in older persons: systematic review. BMC Geriatr. 2008;8:1. [PMID: 18194534] doi:10.1186/1471-2318-8-1 CrossrefMedlineGoogle Scholar
Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104:2263-2268. [PMID: 15238427] doi:10.1182/blood-2004-05-1812 CrossrefMedlineGoogle Scholar
Ferrucci L, Guralnik JM, Bandinelli S, et al. Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol. 2007;136:849-855. [PMID: 17341272] doi:10.1111/j.1365-2141.2007.06502.x CrossrefMedlineGoogle Scholar
Tettamanti M, Lucca U, Gandini F, et al. Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study. Haematologica. 2010;95:1849-1856. [PMID: 20534701] doi:10.3324/haematol.2010.023101 CrossrefMedlineGoogle Scholar
Artz AS, Thirman MJ. Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. J Gerontol A Biol Sci Med Sci. 2011;66:925-932. [PMID: 21659341] doi:10.1093/gerona/glr090 CrossrefMedlineGoogle Scholar
Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med. 2006;119:327-334. [PMID: 16564775] doi:10.1016/j.amjmed.2005.08.027 CrossrefMedlineGoogle Scholar
Chaves PHM, Ashar B, Guralnik JM, et al. Looking at the relationship between hemoglobin concentration and prevalent mobility difficulty in older women. Should the criteria currently used to define anemia in older people be reevaluated? J Am Geriatr Soc. 2002;50:1257-1264. [PMID: 12133021] doi:10.1046/j.1532-5415.2002.50313.x CrossrefMedlineGoogle Scholar
Thein M, Ershler WB, Artz AS, et al. Diminished quality of life and physical function in community-dwelling elderly with anemia. Medicine (Baltimore). 2009;88:107-114. [PMID: 19282701] doi:10.1097/MD.0b013e31819d89d5 CrossrefMedlineGoogle Scholar
Lucca U, Tettamanti M, Mosconi P, et al. Association of mild anemia with cognitive, functional, mood and quality of life outcomes in the elderly: the "Health and Anemia" study. PLoS One. 2008;3:e1920. [PMID: 18382689] doi:10.1371/journal.pone.0001920 CrossrefMedlineGoogle Scholar
Corona LP, Andrade FCD, da Silva Alexandre T, et al. Higher hemoglobin levels are associated with better physical performance among older adults without anemia: a longitudinal analysis. BMC Geriatr. 2022;22:233. [PMID: 35313814] doi:10.1186/s12877-022-02937-4 CrossrefMedlineGoogle Scholar
Milman N, Pedersen AN, Ovesen L, et al. Hemoglobin concentrations in 358 apparently healthy 80-year-old Danish men and women. Should the reference interval be adjusted for age? Aging Clin Exp Res. 2008;20:8-14. [PMID: 18283222] doi:10.1007/BF03324741 CrossrefMedlineGoogle Scholar
Patel KV, Harris TB, Faulhaber M, et al. Racial variation in the relationship of anemia with mortality and mobility disability among older adults. Blood. 2007;109:4663-4670. [PMID: 17284526] doi:10.1182/blood-2006-10-055384 CrossrefMedlineGoogle Scholar
Chaves PHM, Xue Q-L, Guralnik JM, et al. What constitutes normal hemoglobin concentration in community-dwelling disabled older women? J Am Geriatr Soc. 2004;52:1811-1816. doi:10.1111/j.1532-5415.2004.52502.x  CrossrefMedlineGoogle Scholar
Riva E, Tettamanti M, Mosconi P, et al. Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study. Haematologica. 2009;94:22-28. doi:10.3324/haematol.13449  CrossrefMedlineGoogle Scholar
Karoopongse E, Srinonprasert V, Chalermsri C, et al. Prevalence of anemia and association with mortality in community-dwelling elderly in Thailand. Sci Rep. 2022;12:7084. [PMID: 35490162] doi:10.1038/s41598-022-10990-7 CrossrefMedlineGoogle Scholar
Jacobsen AP, Raber I, McCarthy CP, et al. Lifelong aspirin for all in the secondary prevention of chronic coronary syndrome: still sacrosanct or is reappraisal warranted? Circulation. 2020;142:1579-1590. [PMID: 32886529] doi:10.1161/CIRCULATIONAHA.120.045695 CrossrefMedlineGoogle Scholar
Liu EY, Al-Sofiani ME, Yeh HC, et al. Use of preventive aspirin among older US adults with and without diabetes. JAMA Netw Open. 2021;4:e2112210. [PMID: 34152419] doi:10.1001/jamanetworkopen.2021.12210 CrossrefMedlineGoogle Scholar
US Preventive Services Task Force; Davidson KW, Barry MJ, Mangione CM, et al. Aspirin use to prevent cardiovascular disease: US Preventive Services Task Force recommendation statement. JAMA. 2022;327:1577-1584. [PMID: 35471505] doi:10.1001/jama.2022.4983 CrossrefMedlineGoogle Scholar
Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA. 2019;321:277-287. [PMID: 30667501] doi:10.1001/jama.2018.20578 CrossrefMedlineGoogle Scholar
Whitlock EP, Burda BU, Williams SB, et al. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:826-835. [PMID: 27064261] doi:10.7326/M15-2112 LinkGoogle Scholar
Chen Y-g, Xu F, Zhang Y, et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl). 2006;119:32-36. [PMID: 16454979] CrossrefMedlineGoogle Scholar
Fisher M, Cushman M, Knappertz V, et al. An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration. Am Heart J. 2008;156:106-111. [PMID: 18585504] doi:10.1016/j.ahj.2007.12.035 CrossrefMedlineGoogle Scholar
Wolfe R, Murray AM, Woods RL, et al. The aspirin in reducing events in the elderly trial: statistical analysis plan. Int J Stroke. 2018;13:335-338. [PMID: 29111960] doi:10.1177/1747493017741383 CrossrefMedlineGoogle Scholar
McNeil JJ, Woods RL, Nelson MR, et al; ASPREE Investigator Group. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017;72:1586-1593. [PMID: 28329340] doi:10.1093/gerona/glw342 CrossrefMedlineGoogle Scholar
McNeil JJ, Nelson MR, Woods RL, et al; ASPREE Investigator Group. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379:1519-1528. [PMID: 30221595] doi:10.1056/NEJMoa1803955 CrossrefMedlineGoogle Scholar
McNeil JJ, Wolfe R, Woods RL, et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509-1518. [PMID: 30221597] doi:10.1056/NEJMoa1805819 CrossrefMedlineGoogle Scholar
McNeil JJ, Woods RL, Nelson MR, et al; ASPREE Investigator Group. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499-1508. [PMID: 30221596] doi:10.1056/NEJMoa1800722 CrossrefMedlineGoogle Scholar
Margolis KL, Mahady SE, Nelson MR, et al. Development of a standardized definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Contemp Clin Trials Commun. 2018;11:30-36. doi:10.1016/j.conctc.2018.05.015  CrossrefMedlineGoogle Scholar
Sonoda K. Iron deficiency anemia: guidelines from the American Gastroenterological Association. Am Fam Physician. 2021;104:211-212. [PMID: 34383429] MedlineGoogle Scholar
Anker SD, Comin Colet J, Filippatos G, et al; Fair-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436-2448. [PMID: 19920054] doi:10.1056/NEJMoa0908355 CrossrefMedlineGoogle Scholar
Aalen OO, Johansen S. An empirical transition matrix for non-homogeneous markov chains based on censored observations. Scand J Stat. 1978;5:141-150. Google Scholar
Gaskell H, Derry S, Moore RA. Is there an association between low dose aspirin and anemia (without overt bleeding)? Narrative review. BMC Geriatr. 2010;10:71. [PMID: 20920233] doi:10.1186/1471-2318-10-71 CrossrefMedlineGoogle Scholar
Silagy CA, McNeil JJ, Donnan GA, et al. Adverse effects of low-dose aspirin in a healthy elderly population. Clin Pharmacol Ther. 1993;54:84-89. [PMID: 8330469] doi:10.1038/clpt.1993.115 CrossrefMedlineGoogle Scholar
Nelson MR, Reid CM, Ames DA, et al. Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study. Med J Aust. 2008;189:105-109. [PMID: 18637782] doi:10.5694/j.1326-5377.2008.tb01932.x CrossrefMedlineGoogle Scholar
Sostres C, Lanas A. Gastrointestinal effects of aspirin. Nat Rev Gastroenterol Hepatol. 2011;8:385-394. [PMID: 21647198] doi:10.1038/nrgastro.2011.97 CrossrefMedlineGoogle Scholar
Greenberg PD, Cello JP, Rockey DC. Asymptomatic chronic gastrointestinal blood loss in patients taking aspirin or warfarin for cardiovascular disease. Am J Med. 1996;100:598-604. [PMID: 8678078] doi:10.1016/s0002-9343(96)00009-5 CrossrefMedlineGoogle Scholar
Blackshear JL, Baker VS, Holland A, et al. Fecal hemoglobin excretion in elderly patients with atrial fibrillation: combined aspirin and low-dose warfarin vs conventional warfarin therapy. Arch Intern Med. 1996;156:658-660. [PMID: 8629878] CrossrefMedlineGoogle Scholar
Rockey DC. Occult and obscure gastrointestinal bleeding: causes and clinical management. Nat Rev Gastroenterol Hepatol. 2010;7:265-279. [PMID: 20351759] doi:10.1038/nrgastro.2010.42 CrossrefMedlineGoogle Scholar
Boakye E, Uddin SMI, Obisesan OH, et al. Aspirin for cardiovascular disease prevention among adults in the United States: trends, prevalence, and participant characteristics associated with use. Am J Prev Cardiol. 2021;8:100256. [PMID: 34632437] doi:10.1016/j.ajpc.2021.100256 CrossrefMedlineGoogle Scholar
Pasricha SR, Tye-Din J, Muckenthaler MU, et al. Iron deficiency. Lancet. 2021;397:233-248. [PMID: 33285139] doi:10.1016/S0140-6736(20)32594-0 CrossrefMedlineGoogle Scholar
Zakai NA, French B, Arnold AM, et al. Hemoglobin decline, function, and mortality in the elderly: the cardiovascular health study. Am J Hematol. 2013;88:5-9. [PMID: 23044913] doi:10.1002/ajh.23336 CrossrefMedlineGoogle Scholar
Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc. 2005;53:1360-1365. [PMID: 16078962] doi:10.1111/j.1532-5415.2005.53416.x CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
Zoe K. McQuilten,
School of Public Health and Preventive Medicine, Monash University; Department of Haematology, Monash Health; and Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia (Z.K.M.)
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia (L.T.P.T., R.W., R.L.W., J.J.M.)
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, Victoria; Diagnostic Haematology, The Royal Melbourne Hospital, Parkville, Victoria; and Clinical Haematology, The Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, Victoria; and Department of Medical Biology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia (S.-R.P.)
City of Hope National Medical Center, Duarte, California (A.S.A.)
Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia (M.B.)
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts (A.T.C.)
Center for the Study of Aging and Human Development, Duke University, Durham, North Carolina (H.J.C.)
Cancer, Ageing and Vaccines Research Group, School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia (J.E.L.)
Berman Center for Outcomes and Clinical Research and Department of Medicine, Geriatrics Division, Hennepin Healthcare Research Institute, Minneapolis, Minnesota (A.M.M.)
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia (M.R.N.)
School of Public Health and Preventive Medicine, Monash University; and Clinical Biochemistry Unit, Alfred Pathology Service, Alfred Health, Melbourne, Victoria, Australia (H.G.S.)
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria; and Department of Haematology, Monash Health, Melbourne, Victoria, Australia (E.M.W.).
Acknowledgment: Dr. McQuilten is supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leader Investigator grant (GNT1194811). Drs. Wood and McNeil are supported by NHMRC Leadership Fellow Investigator grants (GNT1177784 and GNT1173690). Dr. Pasricha is supported by an NHMRC Career Development Fellowship (GNT2009047). Dr. Chan is an American Cancer Society Clinical Research Professor. Serum samples were retrieved and prepared for analysis by the ASPREE Biobank staff at Monash University.
Grant Support: ASPREE was funded by grants (U01AG029824 and U19AG062682) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. The ASPREE-Anemia analysis was supported by a grant from the Alfred Health Trust. Ferritin measurements were supported by reagent contributions from Abbott Diagnostics and research funds of the Alfred Pathology Service. Drs. Artz and Cohen were supported by a grant from the National Institutes of Health (U01AG034661).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0675.
Data Sharing Statement: The following data will be made available with publication: Deidentified participant data. Requests for data access will be via the ASPREE Principal Investigators with details for applications provided through the web site, www.ASPREE.org, and in accord with the NIH policy on data sharing, details available at https://grants.nih.gov/grants/policy/data_sharing. These data will be made available to: Investigators whose proposed use of the data has been approved by a review committee identified for this purpose. Types of Analysis: Analyses required to achieve aims in the approved proposal. Mechanisms: Through the web-based data portal Safe Haven, based at Monash University, Australia.
Corresponding Author: Zoe K. McQuilten, MB, BS, PhD, School of Public Health and Preventive Medicine, Monash University, 553 St. Kilda Road, Melbourne, VIC 3004, Australia; e-mail, Zoe.
Correction: This article was amended on 25 July 2023 to add information to the grant support section. A correction has been published (doi:10.7326/L23-0274).
Author Contributions: Conception and design: H.J. Cohen, J.E. Lockery, J.J. McNeil, Z.K. McQuilten, M.R. Nelson, S.-R. Pasricha, E.M. Wood, R.L. Woods.
Analysis and interpretation of the data: A.S. Artz, M. Bailey, A.T. Chan, H.J. Cohen, J.J. McNeil, Z.K. McQuilten, M.R. Nelson, S.-R. Pasricha, H.G. Schneider, L.T.P. Thao, R. Wolfe, E.M. Wood, R.L. Woods.
Drafting of the article: J.J. McNeil, Z.K. McQuilten, M.R. Nelson, H.G. Schneider, L.T.P. Thao, E.M. Wood.
Critical revision of the article for important intellectual content: A.S. Artz, M. Bailey, A.T. Chan, H.J. Cohen, J.J. McNeil, Z.K. McQuilten, A.M. Murray, M.R. Nelson, S.-R. Pasricha, H.G. Schneider, L.T.P. Thao, R. Wolfe, E.M. Wood, R.L. Woods.
Final approval of the article: A.S. Artz, M. Bailey, A.T. Chan, H.J. Cohen, J.E. Lockery, J.J. McNeil, Z.K. McQuilten, A.M. Murray, M.R. Nelson, S.-R. Pasricha, H.G. Schneider, L.T.P. Thao, R. Wolfe, E.M. Wood, R.L. Woods.
Provision of study materials or patients: M.R. Nelson, H.G. Schneider.
Statistical expertise: M. Bailey, L.T.P. Thao, R. Wolfe.
Obtaining of funding: A.T. Chan, J.J. McNeil, Z.K. McQuilten, M.R. Nelson, H.G. Schneider, R. Wolfe, E.M. Wood, R.L. Woods.
Administrative, technical, or logistic support: A.T. Chan, J.E. Lockery, Z.K. McQuilten, H.G. Schneider.
Collection and assembly of data: J.E. Lockery, M.R. Nelson, H.G. Schneider, R. Wolfe, R.L. Woods.
This article was published at Annals.org on 20 June 2023.
* Drs. Wood and McNeil are co–senior authors.