{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T14:34:25Z","timestamp":1769783665735,"version":"3.49.0"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010525","name":"NHS Education for Scotland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010525","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["223499\/Z21\/Z"],"award-info":[{"award-number":["223499\/Z21\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["214588\/Z\/18\/Z"],"award-info":[{"award-number":["214588\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Evidence for the net benefit of aspirin for primary prevention of cardiovascular disease (CVD) is finely balanced, leading to variation in guideline recommendations internationally. External validity of randomised clinical trial (RCT) evidence may therefore be of particular importance. The aim of this study is to characterise real-world patients according to their eligibility for guideline-cited aspirin RCTs for primary CVD prevention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Eligibility criteria from 14 RCTs were applied to a linked primary care\/hospital discharge dataset of people\u2009\u2265\u200940 years without CVD. Proportions eligible for each trial were calculated, and characteristics of eligible and ineligible patients compared for each trial, including Cox regression analysis of event rates for major adverse cardiovascular events (MACE), major bleeding events, and non-cardiovascular mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 570,211 included patients (300,500 [52.7%] women, 336,877 [59%]\u2009&lt;\u200960 years), the median proportion ineligible for 14 RCTs was 90.7% (range 42.5\u201399.4%) and 24.0% of patients were ineligible for all RCTs. On average, trial-ineligible populations were younger (median age trial-ineligible 57.8 vs trial-eligible 62.6 years,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.008) and a lower proportion had hypertension (23.9% vs 50.9%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004), diabetes (6.4% vs 11.5%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.015), or a regular statin prescription (11.8% vs 26.7%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001). Trial-ineligible populations had a higher hazard of MACE compared to trial-eligible in four RCTs and lower in ten (hazard ratio [HR] range across all RCTs 0.45 [95%CI 0.40\u20130.51] to 2.78 [95%CI 2.61\u20132.96]). Hazards of bleeding events in the trial-ineligible were lower than the trial-eligible in eight RCTs and higher in four (HR range across all RCTs 0.63 [95%CI, 0.59\u20130.66] to 1.69 [95%CI, 1.53\u20131.86]), and time-varying hazards of non-CVD death were consistently lower in four RCTs and higher in five (HR range across all RCTs and time points 0.29 [95%CI 0.24\u20130.36] to 11.42 [95%CI 9.91\u201313.17]).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Compared with trial-ineligible populations within the same age and sex strata, RCTs recruited people of varying CVD risk but often excluded people at high risk of bleeding or non-CVD death, highlighting that many trials may overestimate the net benefit of aspirin for primary prevention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-026-04654-w","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:16:04Z","timestamp":1769490964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Eligibility of real-world patients for aspirin primary prevention trials in cardiovascular disease"],"prefix":"10.1186","volume":"24","author":[{"given":"Michael","family":"Holder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel R.","family":"Morales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Hanlon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A","family":"McAllister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Guthrie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"issue":"7650","key":"4654_CR1","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","volume":"336","author":"GH Guyatt","year":"2008","unstructured":"Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. Grade: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924\u20136.","journal-title":"BMJ"},{"issue":"1","key":"4654_CR2","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s13063-020-4139-0","volume":"21","author":"J He","year":"2020","unstructured":"He J, Morales DR, Guthrie B. Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review. Trials. 2020;21(1):228.","journal-title":"Trials"},{"issue":"25","key":"4654_CR3","doi-asserted-by":"publisher","first-page":"2982","DOI":"10.1016\/j.jacc.2020.11.010","volume":"76","author":"GA Roth","year":"2020","unstructured":"Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990\u20132019: update from the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982\u20133021.","journal-title":"J Am Coll Cardiol"},{"issue":"34","key":"4654_CR4","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1093\/eurheartj\/ehab484","volume":"42","author":"FLJ Visseren","year":"2021","unstructured":"Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227\u2013337.","journal-title":"Eur Heart J"},{"key":"4654_CR5","doi-asserted-by":"crossref","unstructured":"Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849\u201360.","DOI":"10.1016\/S0140-6736(09)60503-1"},{"issue":"23","key":"4654_CR6","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.1001\/jama.2014.15690","volume":"312","author":"Y Ikeda","year":"2014","unstructured":"Ikeda Y, Shimada K, Teramoto T, Uchiyama S, Yamazaki T, Oikawa S, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA. 2014;312(23):2510\u201320.","journal-title":"JAMA"},{"issue":"16","key":"4654_CR7","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1056\/NEJMoa1805819","volume":"379","author":"JJ McNeil","year":"2018","unstructured":"McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509\u201318.","journal-title":"N Engl J Med"},{"issue":"11","key":"4654_CR8","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1001\/jama.297.11.1233","volume":"297","author":"HG Van Spall","year":"2007","unstructured":"Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA. 2007;297(11):1233\u201340.","journal-title":"JAMA"},{"issue":"16","key":"4654_CR9","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1001\/jama.2022.4983","volume":"327","author":"US Preventive Services Task Force","year":"2022","unstructured":"US Preventive Services Task Force. Aspirin use to prevent cardiovascular disease: US preventive services task force recommendation statement. JAMA. 2022;327(16):1577\u201384.","journal-title":"JAMA"},{"issue":"12","key":"4654_CR10","doi-asserted-by":"publisher","first-page":"836","DOI":"10.7326\/M16-0577","volume":"164","author":"K Bibbins-Domingo","year":"2016","unstructured":"Bibbins-Domingo K. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. preventive services task force recommendation statement. Ann Intern Med. 2016;164(12):836\u201345.","journal-title":"Ann Intern Med"},{"issue":"16","key":"4654_CR11","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1001\/jama.2022.3337","volume":"327","author":"JM Guirguis-Blake","year":"2022","unstructured":"Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA. Aspirin use to prevent cardiovascular disease and colorectal cancer: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2022;327(16):1585\u201397.","journal-title":"JAMA"},{"issue":"16","key":"4654_CR12","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1056\/NEJMoa1804988","volume":"379","author":"L Bowman","year":"2018","unstructured":"Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529\u201339.","journal-title":"N Engl J Med"},{"issue":"10152","key":"4654_CR13","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/S0140-6736(18)31924-X","volume":"392","author":"JM Gaziano","year":"2018","unstructured":"Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392(10152):1036\u201346.","journal-title":"Lancet"},{"key":"4654_CR14","unstructured":"National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification. 2023. Available at: https:\/\/www.nice.org.uk\/guidance\/ng238. Accessed 31 Mar 2025."},{"key":"4654_CR15","unstructured":"Scottish Intercollegiate Guidelines Network (SIGN). SIGN 149 \u2022 Risk estimation and the prevention of cardiovascular disease. 2017. Available at: https:\/\/www.sign.ac.uk\/sign-149-risk-estimation-and-the-prevention-of-cardiovascular-disease. Accessed 31 Mar 2025."},{"issue":"2","key":"4654_CR16","doi-asserted-by":"publisher","first-page":"162","DOI":"10.12997\/jla.2019.8.2.162","volume":"8","author":"JH Kim","year":"2019","unstructured":"Kim JH, Shim MJ, Lee SY, Oh J, Kim SH. Aspirin for primary prevention of cardiovascular disease. J Lipid Atheroscler. 2019;8(2):162\u201372.","journal-title":"J Lipid Atheroscler"},{"issue":"10","key":"4654_CR17","doi-asserted-by":"publisher","first-page":"e177","DOI":"10.1016\/j.jacc.2019.03.010","volume":"74","author":"DK Arnett","year":"2019","unstructured":"Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC\/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;74(10):e177\u2013232.","journal-title":"J Am Coll Cardiol"},{"issue":"Suppl 1","key":"4654_CR18","doi-asserted-by":"publisher","first-page":"S111","DOI":"10.2337\/dc20-S010","volume":"43","author":"American Diabetes Association","year":"2020","unstructured":"American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S111-134.","journal-title":"Diabetes Care"},{"issue":"3","key":"4654_CR19","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1093\/ije\/dyv098","volume":"44","author":"E Herrett","year":"2015","unstructured":"Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, et al. Data resource profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44(3):827\u201336.","journal-title":"Int J Epidemiol"},{"key":"4654_CR20","unstructured":"Clinical Practice Research Datalink. CPRD Gold primary care database. 2018. Available at: https:\/\/www.cprd.com. Accessed Jan 7 2026."},{"issue":"1","key":"4654_CR21","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s10654-018-0442-4","volume":"34","author":"S Padmanabhan","year":"2019","unstructured":"Padmanabhan S, Carty L, Cameron E, Ghosh RE, Williams R, Strongman H. Approach to record linkage of primary care data from Clinical Practice Research Datalink to other health-related patient data: overview and implications. Eur J Epidemiol. 2019;34(1):91\u20139.","journal-title":"Eur J Epidemiol"},{"issue":"5","key":"4654_CR22","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","volume":"40","author":"ME Charlson","year":"1987","unstructured":"Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373\u201383.","journal-title":"J Chronic Dis"},{"issue":"1","key":"4654_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-019-0753-5","volume":"19","author":"D Metcalfe","year":"2019","unstructured":"Metcalfe D, Masters J, Delmestri A, Judge A, Perry D, Zogg C, et al. Coding algorithms for defining Charlson and Elixhauser co-morbidities in Read-coded databases. BMC Med Res Methodol. 2019;19(1):115.","journal-title":"BMC Med Res Methodol"},{"issue":"3","key":"4654_CR24","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1093\/ageing\/afw039","volume":"45","author":"A Clegg","year":"2016","unstructured":"Clegg A, Bates C, Young J, Ryan R, Nichols L, Ann Teale E, et al. Development and validation of an electronic frailty index using routine primary care electronic health record data. Age Ageing. 2016;45(3):353\u201360.","journal-title":"Age Ageing"},{"key":"4654_CR25","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j2099","volume":"357","author":"J Hippisley-Cox","year":"2017","unstructured":"Hippisley-Cox J, Coupland C, Brindle P. Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study. BMJ. 2017;357:j2099.","journal-title":"BMJ"},{"issue":"2","key":"4654_CR26","doi-asserted-by":"publisher","first-page":"e63","DOI":"10.1016\/S2589-7500(19)30012-3","volume":"1","author":"V Kuan","year":"2019","unstructured":"Kuan V, Denaxas S, Gonzalez-Izquierdo A, Direk K, Bhatti O, Husain S, et al. A chronological map of 308 physical and mental health conditions from 4 million individuals in the English National Health Service. Lancet Digit Health. 2019;1(2):e63\u201377.","journal-title":"Lancet Digit Health"},{"issue":"6618","key":"4654_CR27","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1136\/bmj.296.6618.313","volume":"296","author":"R Peto","year":"1988","unstructured":"Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ. 1988;296(6618):313\u20136.","journal-title":"BMJ"},{"issue":"3","key":"4654_CR28","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1056\/NEJM198907203210301","volume":"321","author":"Steering Committee of the Physicians\u2019 Health Study Research Group","year":"1989","unstructured":"Steering Committee of the Physicians\u2019 Health Study Research Group. Final report on the aspirin component of the ongoing Physicians\u2019 Health Study. N Engl J Med. 1989;321(3):129\u201335.","journal-title":"N Engl J Med"},{"issue":"10","key":"4654_CR29","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1001\/jama.1992.03490100090033","volume":"268","author":"ETDRS Study Group","year":"1992","unstructured":"ETDRS Study Group. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 14. ETDRS investigators. JAMA. 1992;268(10):1292\u2013300.","journal-title":"JAMA"},{"issue":"9098","key":"4654_CR30","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0140-6736(97)11475-1","volume":"351","author":"TW Meade","year":"1998","unstructured":"Meade TW, Wilkes HC, Kelleher CC, Roderick PJ, Brennan PJ, Wilson CW, et al. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet. 1998;351(9098):233\u201341.","journal-title":"Lancet"},{"issue":"9118","key":"4654_CR31","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1016\/S0140-6736(98)04311-6","volume":"351","author":"L Hansson","year":"1998","unstructured":"Hansson L, Zanchetti A, Carruthers SG, Dahl\u00f6f B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755\u201362.","journal-title":"Lancet"},{"issue":"9250","key":"4654_CR32","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0140-6736(00)03539-X","volume":"357","author":"G de Gaetano","year":"2001","unstructured":"de Gaetano G, Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative group of the primary prevention project. Lancet. 2001;357(9250):89\u201395.","journal-title":"Lancet"},{"issue":"13","key":"4654_CR33","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1056\/NEJMoa050613","volume":"352","author":"PM Ridker","year":"2005","unstructured":"Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293\u2013304.","journal-title":"N Engl J Med"},{"issue":"7677","key":"4654_CR34","first-page":"1030","volume":"337","author":"J Belch","year":"2008","unstructured":"Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337(7677):1030\u20134.","journal-title":"BMJ"},{"key":"4654_CR35","doi-asserted-by":"crossref","unstructured":"Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300(18):2134\u20132141.","DOI":"10.1001\/jama.2008.623"},{"issue":"9","key":"4654_CR36","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1001\/jama.2010.221","volume":"303","author":"FGR Fowkes","year":"2010","unstructured":"Fowkes FGR, Price JF, Stewart MCW, Butcher I, Leng GC, Pell ACH, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841\u20138.","journal-title":"JAMA"},{"key":"4654_CR37","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djw129","author":"S Zhang","year":"2016","unstructured":"Zhang S, Liang F, Li W, Tannock I. Comparison of eligibility criteria between protocols, registries, and publications of cancer clinical trials. J Natl Cancer Inst. 2016. https:\/\/doi.org\/10.1093\/jnci\/djw129.","journal-title":"J Natl Cancer Inst"},{"key":"4654_CR38","unstructured":"NHS England. NHS staff earnings estimates. 2025. Available at: https:\/\/digital.nhs.uk\/data-and-information\/publications\/statistical\/nhs-staff-earnings-estimates. Accessed Mar 31 2025."},{"key":"#cr-split#-4654_CR39.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Jun 23 -. Identifier NCT00000500, Physicians' Health Study"},{"key":"#cr-split#-4654_CR39.2","unstructured":"1981 [cited 2025 Mar 31];[about 4 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00000500."},{"issue":"4","key":"4654_CR40","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1056\/NEJM198801283180431","volume":"318","author":"Steering Committee of the Physicians\u2019 Health Study Research Group","year":"1988","unstructured":"Steering Committee of the Physicians\u2019 Health Study Research Group. Preliminary report: findings from the Aspirin Component of the Ongoing Physicians\u2019 Health Study. N Engl J Med. 1988;318(4):262\u20134.","journal-title":"N Engl J Med"},{"key":"4654_CR41","unstructured":"US Bureau of Labor Statistics. Occupational employment and wage statistics. 2023. Available at: https:\/\/www.bls.gov\/oes\/. Accessed Mar 31 2025."},{"key":"#cr-split#-4654_CR42.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Jun 23 -. Identifier NCT00000151, Early Treatment Diabetic Retinopathy Study (ETDRS)"},{"key":"#cr-split#-4654_CR42.2","unstructured":"1979 [cited 2025 Mar 31];[about screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00000151."},{"issue":"5 Suppl","key":"4654_CR43","first-page":"741","volume":"98","author":"ETDRS Study Group","year":"1991","unstructured":"ETDRS Study Group. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology. 1991;98(5 Suppl):741\u201356.","journal-title":"Ophthalmology"},{"issue":"1","key":"4654_CR44","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3109\/08037059309077529","volume":"2","author":"The HOT Study Group","year":"1993","unstructured":"The HOT Study Group. The Hypertension Optimal Treatment Study (The HOT Study): the HOT Study Group. Blood Press. 1993;2(1):62\u20138.","journal-title":"Blood Press"},{"key":"4654_CR45","doi-asserted-by":"publisher","unstructured":"ISRCTN. London: BioMed Central: 2005 Sep 7 -. Identifier ISRCTN63594484, Thrombosis Prevention Trial; 2005 [cited 2025 Mar 31];[about 3 screens]. Available from: https:\/\/doi.org\/10.1186\/ISRCTN63594484.","DOI":"10.1186\/ISRCTN63594484"},{"issue":"8","key":"4654_CR46","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1093\/oxfordjournals.eurheartj.a062576","volume":"9","author":"TW Meade","year":"1988","unstructured":"Meade TW, Wilkes HC, Stirling Y, Brennan PJ, Kelleher C, Browne W. Randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study. Eur Heart J. 1988;9(8):836\u201343.","journal-title":"Eur Heart J"},{"key":"4654_CR47","unstructured":"Framingham Heart Study. Cardiovascular disease (10-year risk). 2018. Available at: https:\/\/www.framinghamheartstudy.org\/fhs-risk-functions\/cardiovascular-disease-10-year-risk\/. Accessed Mar 31 2025."},{"issue":"2","key":"4654_CR48","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1177\/174182679500200209","volume":"2","author":"Primary Prevention Project","year":"1995","unstructured":"Primary Prevention Project. Epidemiological feasibility of cardiovascular primary prevention in general practice: a trial of vitamin E and aspirin. Eur J Cardiovasc Prev Rehabil. 1995;2(2):137\u201342.","journal-title":"Eur J Cardiovasc Prev Rehabil"},{"key":"#cr-split#-4654_CR49.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Jun 23 -. Identifier NCT00000479, Women's Health Study (WHS): a randomized trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer"},{"key":"#cr-split#-4654_CR49.2","unstructured":"1992 [cited 2025 Mar 31];[about 3 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00000479."},{"issue":"1","key":"4654_CR50","first-page":"19","volume":"9","author":"KM Rexrode","year":"2000","unstructured":"Rexrode KM, Lee IM, Cook NR, Hennekens CH, Buring JE. Baseline characteristics of participants in the Women\u2019s Health Study. J Womens Health. 2000;9(1):19\u201327.","journal-title":"J Womens Health"},{"key":"4654_CR51","doi-asserted-by":"publisher","unstructured":"ISRCTN. London: BioMed Central: 2000 Oct 17 -. Identifier ISRCTN53295293, The Prevention Of Progression of Asymptomatic Diabetic Arterial Disease (a multicentre study); 1997 [cited 2025 Mar 31];[about 4 screens]. Available from: https:\/\/doi.org\/10.1186\/ISRCTN53295293.","DOI":"10.1186\/ISRCTN53295293"},{"key":"#cr-split#-4654_CR52.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Jun 23 -. Identifier NCT00110448, Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial"},{"key":"#cr-split#-4654_CR52.2","unstructured":"2002 [cited 2025 Mar 31];[about 2 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00110448."},{"key":"4654_CR53","doi-asserted-by":"publisher","unstructured":"ISRCTN. London: BioMed Central: 2002 Jan 31 -. Identifier ISRCTN66587262, Tackling heart disease: the Scottish aspirin trial; 1998 [cited 2025 Mar 31];[about 5 screens]. Available from: https:\/\/doi.org\/10.1186\/ISRCTN66587262.","DOI":"10.1186\/ISRCTN66587262"},{"key":"#cr-split#-4654_CR54.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Sep 22 -. Identifier NCT00225849, Japanese Primary Prevention Project With Aspirin"},{"key":"#cr-split#-4654_CR54.2","unstructured":"2005 [cited 2025 Mar 31];[about 2 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00225849."},{"key":"#cr-split#-4654_CR55.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2007 Jul 12 -. Identifier NCT00501059, A study to assess the efficacy and safety of enteric-coated acetylsalicylic acid in patients at moderate risk of cardiovascular disease (ARRIVE)"},{"key":"#cr-split#-4654_CR55.2","unstructured":"2007 [cited 2025 Mar 31];[about 3 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00501059."},{"key":"#cr-split#-4654_CR56.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2005 Aug 24 -. Identifier NCT00135226, ASCEND: A Study of Cardiovascular Events iN Diabetes"},{"key":"#cr-split#-4654_CR56.2","unstructured":"2005 [cited 2025 Mar 31];[about 3 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT00135226."},{"key":"#cr-split#-4654_CR57.1","unstructured":"Clinicaltrials.gov. Bethesda (MD): National Library of Medicine (US): 2009 Dec 23 -. Identifier NCT01038583, Aspirin in Reducing Events in the Elderly (ASPREE)"},{"key":"#cr-split#-4654_CR57.2","unstructured":"2010 [cited 2025 Mar 31];[about 3 screens]. Available from: https:\/\/ClinicalTrials.gov\/show\/NCT01038583."},{"issue":"9","key":"4654_CR58","doi-asserted-by":"publisher","first-page":"e369","DOI":"10.1016\/j.clon.2022.05.011","volume":"34","author":"AG Abraham","year":"2022","unstructured":"Abraham AG, Joseph K, Spratlin JL, Zebak S, Alba V, Iafolla M, et al. Does loosening the inclusion criteria of the CROSS trial impact outcomes in the curative-intent trimodality treatment of oesophageal and gastroesophageal cancer patients? Clin Oncol (R Coll Radiol). 2022;34(9):e369-376.","journal-title":"Clin Oncol (R Coll Radiol)"},{"issue":"3","key":"4654_CR59","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1007\/s12350-021-02679-7","volume":"29","author":"MH Al-Mallah","year":"2022","unstructured":"Al-Mallah MH, Ahmed AI, Nabi F, Chang SM, Kleiman NS, Chamsi-Pasha MA, et al. Outcomes of patients with moderate-to-severe ischemia excluded from the ischemia trial. J Nucl Cardiol. 2022;29(3):1100\u20135.","journal-title":"J Nucl Cardiol"},{"issue":"3","key":"4654_CR60","first-page":"333","volume":"9","author":"WD Hall","year":"1999","unstructured":"Hall WD. Representation of blacks, women, and the very elderly (aged > or = 80) in 28 major randomized clinical trials. Ethn Dis. 1999;9(3):333\u201340.","journal-title":"Ethn Dis"},{"issue":"2","key":"4654_CR61","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.ejvs.2021.10.026","volume":"63","author":"M Sogaard","year":"2022","unstructured":"Sogaard M, Nielsen PB, Skjoth F, Larsen TB, Eldrup N. Revascularisation for symptomatic peripheral artery disease: external applicability of the VOYAGER PAD trial. Eur J Vasc Endovasc Surg. 2022;63(2):285\u201394.","journal-title":"Eur J Vasc Endovasc Surg"},{"key":"4654_CR62","doi-asserted-by":"crossref","unstructured":"Maasland L, van Oostenbrugge RJ, Franke CF, Scholte Op Reimer WJ, Koudstaal PJ, Dippel DW. Patients enrolled in large randomized clinical trials of antiplatelet treatment for prevention after transient ischemic attack or ischemic stroke are not representative of patients in clinical practice: the Netherlands Stroke Survey. Stroke. 2009;40(8):2662\u20132668.","DOI":"10.1161\/STROKEAHA.109.551812"},{"issue":"7","key":"4654_CR63","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1001\/archinte.161.7.949","volume":"161","author":"DM Lloyd-Jones","year":"2001","unstructured":"Lloyd-Jones DM, O\u2019Donnell CJ, D\u2019Agostino RB, Massaro J, Silbershatz H, Wilson PW. Applicability of cholesterol-lowering primary prevention trials to a general population: the Framingham Heart Study. Arch Intern Med. 2001;161(7):949\u201354.","journal-title":"Arch Intern Med"},{"issue":"4","key":"4654_CR64","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1177\/2047487317743352","volume":"25","author":"J Pavlovi\u0107","year":"2020","unstructured":"Pavlovi\u0107 J, Greenland P, Deckers JW, Kavousi M, Hofman A, Ikram MA, et al. Assessing gaps in cholesterol treatment guidelines for primary prevention of cardiovascular disease based on available randomised clinical trial evidence: the Rotterdam Study. Eur J Prev Cardiol. 2020;25(4):420\u201331.","journal-title":"Eur J Prev Cardiol"},{"key":"4654_CR65","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.atherosclerosis.2021.12.002","volume":"341","author":"MB Mortensen","year":"2022","unstructured":"Mortensen MB, Nordestgaard BG. Guidelines versus trial-evidence for statin use in primary prevention: the Copenhagen General Population Study. Atherosclerosis. 2022;341:20\u20136.","journal-title":"Atherosclerosis"},{"issue":"3","key":"4654_CR66","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1007\/s11239-018-1698-y","volume":"46","author":"AB Hughey","year":"2018","unstructured":"Hughey AB, Gu X, Haymart B, Kline-Rogers E, Almany S, Kozlowski J, et al. Warfarin for prevention of thromboembolism in atrial fibrillation: comparison of patient characteristics and outcomes of the \u201cReal-World\u201d Michigan Anticoagulation Quality Improvement Initiative (MAQI(2)) registry to the RE-LY, ROCKET-AF, and ARISTOTLE trials. J Thromb Thrombolysis. 2018;46(3):316\u201324.","journal-title":"J Thromb Thrombolysis"},{"issue":"7","key":"4654_CR67","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1016\/j.cardfail.2022.04.011","volume":"28","author":"T Thorvaldsen","year":"2022","unstructured":"Thorvaldsen T, Ferrannini G, Mellbin L, Benson L, Cosentino F, McMurray JJV, et al. Eligibility for dapagliflozin and empagliflozin in a real-world heart failure population. J Card Fail. 2022;28(7):1050\u201362.","journal-title":"J Card Fail"},{"issue":"12","key":"4654_CR68","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1093\/eurjpc\/zwad092","volume":"30","author":"AMD Kristensen","year":"2023","unstructured":"Kristensen AMD, Pareek M, Kragholm KH, Torp-Pedersen C, McEvoy JW, Prescott EB. Temporal trends in low-dose aspirin therapy for primary prevention of cardiovascular disease in European adults with and without diabetes. Eur J Prev Cardiol. 2023;30(12):1172\u201381.","journal-title":"Eur J Prev Cardiol"},{"issue":"10","key":"4654_CR69","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1001\/jama.2024.27333","volume":"333","author":"LM Wilson","year":"2025","unstructured":"Wilson LM, Anderson TS. Trends in preventive aspirin use by atherosclerotic cardiovascular risk. JAMA. 2025;333(10):904\u20137.","journal-title":"JAMA"},{"key":"4654_CR70","doi-asserted-by":"crossref","unstructured":"Gupta M, Gulati S, Nasir K, Sarraju A. Aspirin use prevalence for cardiovascular disease prevention among U.S. adults from 2012 to 2021. Ann Intern Med. 2024;177(8):1139\u20131141.","DOI":"10.7326\/M24-0427"},{"issue":"3","key":"4654_CR71","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.033562","volume":"13","author":"HS Bhatia","year":"2024","unstructured":"Bhatia HS, Trainor P, Carlisle S, Tsai MY, Criqui MH, DeFilippis A, et al. Aspirin and cardiovascular risk in individuals with elevated lipoprotein(a): the multi-ethnic study of atherosclerosis. J Am Heart Assoc. 2024;13(3):e033562.","journal-title":"J Am Heart Assoc"},{"issue":"10","key":"4654_CR72","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1161\/ATVBAHA.122.318020","volume":"42","author":"LB Cofer","year":"2022","unstructured":"Cofer LB, Barrett TJ, Berger JS. Aspirin for the primary prevention of cardiovascular disease: time for a platelet-guided approach. Arterioscler Thromb Vasc Biol. 2022;42(10):1207\u201316.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"2","key":"4654_CR73","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.120.003304","volume":"14","author":"F Riveros-Mckay","year":"2021","unstructured":"Riveros-Mckay F, Weale ME, Moore R, Selzam S, Krapohl E, Sivley RM, et al. Integrated polygenic tool substantially enhances coronary artery disease prediction. Circ Genom Precis Med. 2021;14(2):e003304.","journal-title":"Circ Genom Precis Med"},{"issue":"9","key":"4654_CR74","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.jcmg.2024.05.016","volume":"17","author":"M McDermott","year":"2024","unstructured":"McDermott M, Meah MN, Khaing P, Wang KL, Ramsay J, Scott G, et al. Rationale and design of SCOT-HEART 2 trial: CT angiography for the prevention of myocardial infarction. JACC Cardiovasc Imaging. 2024;17(9):1101\u201312.","journal-title":"JACC Cardiovasc Imaging"}],"container-title":["BMC Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12916-026-04654-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04654-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12916-026-04654-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:02:38Z","timestamp":1769731358000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12916-026-04654-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4654"],"URL":"https:\/\/doi.org\/10.1186\/s12916-026-04654-w","relation":{},"ISSN":["1741-7015"],"issn-type":[{"value":"1741-7015","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"14 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The Clinical Practice Research Datalink (CPRD) Independent Scientific Advisory Committee (ISAC) approved access to the data for this study (protocol 20_018). CPRD have ethical approval from the Health Research Authority to provide anonymised patient data to researchers (East Midlands-Derby National Health Service Research Ethics Committee reference 21\/EM\/0265).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"57"}}