BACKGROUND: The role of aspirin in primary prevention of cardiovascular disease (CVD) remains unclear. We aimed to investigate the benefit-risk ratio of aspirin for primary prevention of CVD with a particular focus on subgroups. METHODS: Randomized controlled trials comparing the effects of aspirin for primary prevention of CVD versus control and including at least 1000 patients were eligible for this meta-analysis. The primary efficacy outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, major adverse cardiovascular events (MACE), myocardial infarction, ischemic stroke, and net clinical benefit. The primary safety outcome was major bleeding. Subgroup analyses involving sex, concomitant statin treatment, diabetes, and smoking were performed. RESULTS: Thirteen randomized controlled trials comprising 164,225 patients were included. The risk of all-cause and cardiovascular mortality was similar for aspirin and control groups (RR 0.98; 95% CI, 0.93-1.02; RR 0.99; 95% CI, 0.90-1.08; respectively). Aspirin reduced the relative risk (RRR) of major adverse cardiovascular events (MACE) by 9% (RR 0.91; 95% CI, 0.86-0.95), myocardial infarction by 14% (RR 0.86; 95% CI, 0.77-0.95), and ischemic stroke by 10% (RR 0.90; 95% CI, 0.82-0.99), but was associated with a 46% relative risk increase of major bleeding events (RR 1.46; 95% CI, 1.30-1.64) compared with controls. Aspirin use did not translate into a net clinical benefit adjusted for event-associated mortality risk (mean 0.034%; 95% CI, - 0.18 to 0.25%). There was an interaction for aspirin effect in three patient subgroups: (i) in patients under statin treatment, aspirin was associated with a 12% RRR of MACE (RR 0.88; 95% CI, 0.80-0.96), and this effect was lacking in the no-statin group; (ii) in non-smokers, aspirin was associated with a 10% RRR of MACE (RR 0.90; 95% CI, 0.82-0.99), and this effect was not present in smokers; and (iii) in males, aspirin use resulted in a 11% RRR of MACE (RR 0.89; 95% CI, 0.83-0.95), with a non-significant effect in females. CONCLUSIONS: Aspirin use does not reduce all-cause or cardiovascular mortality and results in an insufficient benefit-risk ratio for CVD primary prevention. Non-smokers, patients treated with statins, and males had the greatest risk reduction of MACE across subgroups. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019118474.

1st Department of Cardiology Poznan University of Medical Sciences Poznan Poland

Department of Cardiology Oslo University Hospital Oslo Norway

Department of Clinical Pharmacology Medical University of Vienna Vienna Austria

Department of Experimental and Clinical Pharmacology Centre for Preclinical Research and Technology Medical University of Warsaw Warsaw Poland

Division of Cardiology Department of Internal Medicine 2 Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Institute of Computer Science of Academy of Sciences of the Czech Republic Prague Czech Republic

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Pruller F, Milke OL, Bis L, Fruhwald F, Scherr D, Eller P, et al. Impaired aspirin-mediated platelet function inhibition in resuscitated patients with acute myocardial infarction treated with therapeutic hypothermia: a prospective, observational, non-randomized single-centre study. Ann Intensive Care. 2018;8(1):28. doi: 10.1186/s13613-018-0366-x. PubMed DOI PMC

Siller-Matula JM, Delle-Karth G, Christ G, Neunteufl T, Maurer G, Huber K, et al. Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin. Int J Cardiol. 2013;167(2):430–435. doi: 10.1016/j.ijcard.2012.01.016. PubMed DOI

Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol. 2010;159(3):502–517. doi: 10.1111/j.1476-5381.2009.00555.x. PubMed DOI PMC

Antithrombotic TC. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71–86. doi: 10.1136/bmj.324.7329.71. PubMed DOI PMC

Antithrombotic Trialists C, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, 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):1849–1860. doi: 10.1016/S0140-6736(09)60503-1. PubMed DOI PMC

Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med. 2008;121(1):43–49. doi: 10.1016/j.amjmed.2007.10.002. PubMed DOI

Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354–471. PubMed

Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81. PubMed PMC

Siller-Matula JM. Hemorrhagic complications associated with aspirin: an underestimated hazard in clinical practice? JAMA. 2012;307(21):2318–2320. doi: 10.1001/jama.2012.6152. PubMed DOI

Bartolucci AA, Tendera M, Howard G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol. 2011;107(12):1796–1801. doi: 10.1016/j.amjcard.2011.02.325. PubMed DOI

Guirguis-Blake JM, Evans CV, Senger CA, O'Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(12):804–813. doi: 10.7326/M15-2113. PubMed DOI

Raju N, Sobieraj-Teague M, Hirsh J, O'Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med. 2011;124(7):621–629. doi: 10.1016/j.amjmed.2011.01.018. PubMed DOI

Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(3):209–216. doi: 10.1001/archinternmed.2011.628. PubMed DOI

Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am Heart J. 2011;162(1):115–124. doi: 10.1016/j.ahj.2011.04.006. PubMed DOI

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019;2019:CIR0000000000000678. PubMed PMC

Bibbins-Domingo K, Force USPST 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):836–845. doi: 10.7326/M16-0577. PubMed DOI

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):1036–1046. doi: 10.1016/S0140-6736(18)31924-X. PubMed DOI PMC

Group ASC. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529–1539. doi: 10.1056/NEJMoa1804988. PubMed DOI

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):1509–1518. doi: 10.1056/NEJMoa1805819. PubMed DOI PMC

Gouya G, Arrich J, Wolzt M, Huber K, Verheugt FW, Gurbel PA, et al. Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis. Stroke. 2014;45(2):492–503. doi: 10.1161/STROKEAHA.113.002590. PubMed DOI

Navarese EP, De Luca G, Castriota F, Kozinski M, Gurbel PA, Gibson CM, et al. Low-molecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost. 2011;9(10):1902–1915. doi: 10.1111/j.1538-7836.2011.04445.x. PubMed DOI

Siller-Matula JM, Huber K, Christ G, Schror K, Kubica J, Herkner H, et al. Impact of clopidogrel loading dose on clinical outcome in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Heart. 2011;97(2):98–105. doi: 10.1136/hrt.2010.195438. PubMed DOI

Siller-Matula JM, Jilma B, Schror K, Christ G, Huber K. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemost. 2010;8(12):2624–2641. doi: 10.1111/j.1538-7836.2010.04049.x. PubMed DOI

Siller-Matula JM, Petre A, Delle-Karth G, Huber K, Ay C, Lordkipanidze M, et al. Impact of preoperative use of P2Y12 receptor inhibitors on clinical outcomes in cardiac and non-cardiac surgery: a systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care. 2017;6(8):753–770. doi: 10.1177/2048872615585516. PubMed DOI

The Medical Research Council's General Practice Research Framework 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):233–241. doi: 10.1016/S0140-6736(97)11475-1. PubMed DOI

de Gaetano G, Collaborative Group of the Primary Prevention P 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):89–95. doi: 10.1016/S0140-6736(00)03539-X. PubMed DOI

Hansson L, Zanchetti A, Carruthers SG, Dahlof 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. HOT Study Group Lancet. 1998;351(9118):1755–1762. PubMed

Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed) 1988;296(6618):313–316. doi: 10.1136/bmj.296.6618.313. PubMed DOI PMC

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):1293–1304. doi: 10.1056/NEJMoa050613. PubMed DOI

Steering Committee of the Physicians’ Health Study Research G Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989;321(3):129–135. doi: 10.1056/NEJM198907203210301. PubMed DOI

Eikelboom JW, Connolly SJ, Hart RG, Wallentin L, Reilly P, Oldgren J, et al. Balancing the benefits and risks of 2 doses of dabigatran compared with warfarin in atrial fibrillation. J Am Coll Cardiol. 2013;62(10):900–908. doi: 10.1016/j.jacc.2013.05.042. PubMed DOI

Patti G, Lucerna M, Pecen L, Siller-Matula JM, Cavallari I, Kirchhof P, et al. Thromboembolic risk, bleeding outcomes and effect of different antithrombotic strategies in very elderly patients with atrial fibrillation: a sub-analysis from the PREFER in AF (PREvention oF Thromboembolic Events-European Registry in Atrial Fibrillation). J Am Heart Assoc. 2017;6(7):e005657. 10.1161/JAHA.117.005657. PubMed PMC

Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA. 1992;268(10):1292–300. PubMed

Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, 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):841–848. doi: 10.1001/jama.2010.221. PubMed DOI

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):2510–2520. doi: 10.1001/jama.2014.15690. PubMed DOI

Saito Y, Okada S, Ogawa H, Soejima H, Sakuma M, Nakayama M, et al. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow-up of a randomized controlled trial. Circulation. 2017;135(7):659–670. doi: 10.1161/CIRCULATIONAHA.116.025760. PubMed DOI

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:a1840. doi: 10.1136/bmj.a1840. PubMed DOI PMC

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):2134–2141. doi: 10.1001/jama.2008.623. PubMed DOI

Mahmoud AN, Gad MM, Elgendy AY, Elgendy IY, Bavry AA. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40(7):607–617. doi: 10.1093/eurheartj/ehy813. PubMed DOI

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(3):277–287. doi: 10.1001/jama.2018.20578. PubMed DOI PMC

Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321(7270):1183–1187. doi: 10.1136/bmj.321.7270.1183. PubMed DOI PMC

Lanas A, Carrera-Lasfuentes P, Arguedas Y, Garcia S, Bujanda L, Calvet X, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015;13(5):906–912. doi: 10.1016/j.cgh.2014.11.007. PubMed DOI

Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol. 2011;9(9):762–768. doi: 10.1016/j.cgh.2011.05.020. PubMed DOI

Siller-Matula JM, Delle-Karth G. Addition of omeprazole to dual antiplatelet therapy with clopidogrel plus aspirin lowers the risk of upper gastrointestinal bleeding. Evid Based Med. 2011;16(5):144–145. doi: 10.1136/ebm1304. PubMed DOI

Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol. 2017;14(12):697–710. doi: 10.1038/nrgastro.2017.117. PubMed DOI

Islam MM, Poly TN, Walther BA, Dubey NK, Anggraini Ningrum DN, Shabbir SA, et al. Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018;30(12):1395–1405. doi: 10.1097/MEG.0000000000001198. PubMed DOI

Postula M, Rosiak M, Kaplon-Cieslicka A, Kondracka A, Trzepla E, Filipiak KJ, et al. Do statins influence platelet reactivity on acetylsalicylic acid therapy in patients with type 2 diabetes? Cardiol J. 2012;19(5):494–500. doi: 10.5603/CJ.2012.0090. PubMed DOI

Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015;11(1):115–121. doi: 10.5114/aoms.2015.49216. PubMed DOI PMC

Barale C, Frascaroli C, Senkeev R, Cavalot F, Russo I. Simvastatin effects on inflammation and platelet activation markers in hypercholesterolemia. Biomed Res Int. 2018;2018:6508709. doi: 10.1155/2018/6508709. PubMed DOI PMC

Godino C, Pavon AG, Mangieri A, Salerno A, Cera M, Monello A, et al. Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: the STATIPLAT randomized study. Clin Cardiol. 2017;40(8):605–611. doi: 10.1002/clc.22709. PubMed DOI PMC

Toso A, De Servi S, Leoncini M, Angiolillo DJ, Calabro P, Piscione F, et al. Effects of statin therapy on platelet reactivity after percutaneous coronary revascularization in patients with acute coronary syndrome. J Thromb Thrombolysis. 2017;44(3):355–361. doi: 10.1007/s11239-017-1541-x. PubMed DOI

Verdoia M, Pergolini P, Rolla R, Nardin M, Schaffer A, Barbieri L, et al. Impact of high-dose statins on vitamin D levels and platelet function in patients with coronary artery disease. Thromb Res. 2017;150:90–95. doi: 10.1016/j.thromres.2016.12.019. PubMed DOI

Boncler M, Gresner P, Nocun M, Rywaniak J, Dolnik M, Rysz J, et al. Elevated cholesterol reduces acetylsalicylic acid-mediated platelet acetylation. Biochim Biophys Acta. 2007;1770(12):1651–1659. doi: 10.1016/j.bbagen.2007.09.002. PubMed DOI

Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation. 2013;127(2):251–257. doi: 10.1161/CIRCULATIONAHA.112.145334. PubMed DOI

Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012;126(1):92–103. doi: 10.1161/CIRCULATIONAHA.112.095554. PubMed DOI

Seidu S, Kunutsor SK, Sesso HD, Gaziano JM, Buring JE, Roncaglioni MC, et al. Aspirin has potential benefits for primary prevention of cardiovascular outcomes in diabetes: updated literature-based and individual participant data meta-analyses of randomized controlled trials. Cardiovasc Diabetol. 2019;18(1):70. doi: 10.1186/s12933-019-0875-4. PubMed DOI PMC

Larsen SB, Grove EL, Neergaard-Petersen S, Wurtz M, Hvas AM, Kristensen SD. Determinants of reduced antiplatelet effect of aspirin in patients with stable coronary artery disease. PLoS One. 2015;10(5):e0126767. doi: 10.1371/journal.pone.0126767. PubMed DOI PMC

Li WJ, Zhang HY, Miao CL, Tang RB, Du X, Shi JH, et al. Cigarette smoking inhibits the anti-platelet activity of aspirin in patients with coronary heart disease. Chin Med J. 2011;124(10):1569–1572. PubMed

Ikonomidis I, Lekakis J, Vamvakou G, Andreotti F, Nihoyannopoulos P. Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease: effects of aspirin treatment. Am Heart J. 2005;149(5):832–839. doi: 10.1016/j.ahj.2004.08.030. PubMed DOI

Bliden KP, Dichiara J, Lawal L, Singla A, Antonino MJ, Baker BA, et al. The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol. 2008;52(7):531–533. doi: 10.1016/j.jacc.2008.04.045. PubMed DOI

Desai NR, Mega JL, Jiang S, Cannon CP, Sabatine MS. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol. 2009;53(15):1273–1278. doi: 10.1016/j.jacc.2008.12.044. PubMed DOI PMC

Berger JS, Bhatt DL, Steinhubl SR, Shao M, Steg PG, Montalescot G, et al. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009;120(23):2337–2344. doi: 10.1161/CIRCULATIONAHA.109.866533. PubMed DOI PMC

Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295(3):306–313. doi: 10.1001/jama.295.3.306. PubMed DOI

De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009;339:b4531. doi: 10.1136/bmj.b4531. PubMed DOI PMC

Kunutsor SK, Seidu S, Khunti K. Aspirin for primary prevention of cardiovascular and all-cause mortality events in diabetes: updated meta-analysis of randomized controlled trials. Diabet Med. 2017;34(3):316–327. doi: 10.1111/dme.13133. PubMed DOI

Fox CS, Golden SH, Anderson C, Bray GA, Burke LE, de Boer IH, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777–1803. doi: 10.2337/dci15-0012. PubMed DOI PMC

Pignone M, Williams CD. Aspirin for primary prevention of cardiovascular disease in diabetes mellitus. Nat Rev Endocrinol. 2010;6(11):619–628. doi: 10.1038/nrendo.2010.169. PubMed DOI PMC

Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2019:ehz486. 10.1093/eurheartj/ehz486. PubMed

Pignone M, Earnshaw S, Pletcher MJ, Tice JA. Aspirin for the primary prevention of cardiovascular disease in women: a cost-utility analysis. Arch Intern Med. 2007;167(3):290–295. doi: 10.1001/archinte.167.3.290. PubMed DOI

Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med. 2006;144(5):326–336. doi: 10.7326/0003-4819-144-5-200603070-00007. PubMed DOI