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Thromb Haemost 2019; 119(10): 1573-1582
DOI: 10.1055/s-0039-1694774
Theme Issue Article
Georg Thieme Verlag KG Stuttgart · New York

Aspirin and Primary Prevention in Patients with Diabetes—A Critical Evaluation of Available Randomized Trials and Meta-Analyses

Karsten Schrör
1   Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
,
Steen D. Kristensen
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
,
Robert F. Storey
3   Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
,
Freek W. A. Verheugt
4   Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
› Author Affiliations
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Publication History

28 March 2019

28 June 2019

Publication Date:
20 August 2019 (online)

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ErratumThromb Haemost 2019; 119(10): e1-e1
DOI: 10.1055/s-0040-1702204

Abstract

Primary prevention of cardiovascular events with aspirin in patients with elevated cardiovascular risk, including diabetics, is currently under intense discussion. Data from meta-analyses suggests that the efficacy of aspirin in these patients is low, whereas there is a significantly increased bleeding tendency. However, meta-analyses are based on trials that differ in many important aspects, including study selection. Fresh insights were expected from the ASCEND trial, by far the largest primary, randomized, placebo-controlled prevention trial in diabetics without known cardiovascular disease. There was a small but significant reduction in serious cardiovascular events by aspirin (8.6% vs. 9.6%) but also a significant increase in major bleeding: 4.1% versus 3.2%. Unfortunately, this trial did not meet the desired annual rate of elevated vascular risk of ≥ 2%. It was only 1.2 to 1.3%, and thus in the range of other primary prevention trials in low-risk patients. Apart from potential compliance problems, possible explanations for the small cardioprotective effect of antiplatelet treatment include a healthy lifestyle as well as improved vascular protection by comedication with vasoactive and anti-inflammatory drugs, such as statins or antihypertensive agents, as well as proton-pump inhibitors that might modify bleeding, specifically in the upper gastrointestinal tract—the most frequently affected site. Also, the introduction of new antidiabetic drugs with more favorable cardiovascular effects may in part explain the low event rate. ASCEND, similar to ARRIVE, did not study patients at elevated (as planned) but only at low vascular risk and, therefore, was largely confirmatory of earlier primary prevention trials.

Keywords

diabetes - aspirin - primary prevention - myocardial infarction - bleeding
 

  • References

  • 1 Lim HS, Blann AD, Lip GY. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention. Circulation 2004; 109 (21) 2524-2528
    CrossrefPubMedGoogle Scholar
  • 2 Rao Kondapally Seshasai S, Kaptoge S, Thompson A. , et al; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364 (09) 829-841
    CrossrefPubMedGoogle Scholar
  • 3 European Heart Network. European Cardiovascular Disease Statistics; 2017
    PubMed
  • 4 Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339 (04) 229-234
    CrossrefPubMedGoogle Scholar
  • 5 Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I. Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med 2009; 26 (02) 142-148
    CrossrefPubMedGoogle Scholar
  • 6 Schnell O, Erbach M, Hummel M. Primary and secondary prevention of cardiovascular disease in diabetes with aspirin. Diab Vasc Dis Res 2012; 9 (04) 245-255
    CrossrefPubMedGoogle Scholar
  • 7 Khan SU, Ul Abideen Asad Z, Khan MU. , et al. Aspirin for primary prevention of cardiovascular outcomes in diabetes mellitus: An updated systematic review and meta-analysis. Eur J Prev Cardiol 2019; 2047487319825510
    PubMedGoogle Scholar
  • 8 Ansa BE, Hoffman Z, Lewis N. , et al. Aspirin use among adults with cardiovascular disease in the United States: implications for an intervention approach. J Clin Med 2019; 8 (02) pii: E264
    CrossrefPubMedGoogle Scholar
  • 9 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 (03) 277-287
    CrossrefPubMedGoogle Scholar
  • 10 Zinman B, Wanner C, Lachin JM. , et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373 (22) 2117-2128
    CrossrefPubMedGoogle Scholar
  • 11 Chamberlain JJ, Johnson EL, Leal S, Rhinehart AS, Shubrook JH, Peterson L. Cardiovascular disease and risk management: review of the American Diabetes Association Standards of Medical Care in Diabetes 2018. Ann Intern Med 2018; 168 (09) 640-650
    CrossrefPubMedGoogle Scholar
  • 12 Schneider DJ. Factors contributing to increased platelet reactivity in people with diabetes. Diabetes Care 2009; 32 (04) 525-527
    CrossrefPubMedGoogle Scholar
  • 13 DiMinno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood 1986; 68 (04) 886-891
    CrossrefPubMedGoogle Scholar
  • 14 Guthikonda S, Lev EI, Patel R. , et al. Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin. J Thromb Haemost 2007; 5 (03) 490-496
    CrossrefPubMedGoogle Scholar
  • 15 Rocca B, Secchiero P, Ciabattoni G. , et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A 2002; 99 (11) 7634-7639
    CrossrefPubMedGoogle Scholar
  • 16 Lev EI. Immature platelets: clinical relevance and research perspectives. Circulation 2016; 134 (14) 987-988
    CrossrefPubMedGoogle Scholar
  • 17 Schrör K. Blood vessel wall interactions in diabetes. Diabetes 1997; 46 (Suppl. 02) S115-S118
    CrossrefPubMedGoogle Scholar
  • 18 Véricel E, Januel C, Carreras M, Moulin P, Lagarde M. Diabetic patients without vascular complications display enhanced basal platelet activation and decreased antioxidant status. Diabetes 2004; 53 (04) 1046-1051
    CrossrefPubMedGoogle Scholar
  • 19 Santilli F, Lapenna D, La Barba S, Davì G. Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus. Free Radic Biol Med 2015; 80: 101-110
    CrossrefPubMedGoogle Scholar
  • 20 Thaulow E, Erikssen J, Sandvik L, Stormorken H, Cohn PF. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 1991; 84 (02) 613-617
    CrossrefPubMedGoogle Scholar
  • 21 Ridker PM, Manson JE, Buring JE, Goldhaber SZ, Hennekens CH. The effect of chronic platelet inhibition with low-dose aspirin on atherosclerotic progression and acute thrombosis: clinical evidence from the Physicians' Health Study. Am Heart J 1991; 122 (06) 1588-1592
    CrossrefPubMedGoogle Scholar
  • 22 Manson JE, Grobbee DE, Stampfer MJ. , et al. Aspirin in the primary prevention of angina pectoris in a randomized trial of United States physicians. Am J Med 1990; 89 (06) 772-776
    CrossrefPubMedGoogle Scholar
  • 23 Rocca B, Santilli F, Pitocco D. , et al. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost 2012; 10 (07) 1220-1230
    CrossrefPubMedGoogle Scholar
  • 24 Giaretta A, Rocca B, Di Camillo B, Toffolo GM, Patrono C. In silico modeling of the antiplatelet pharmacodynamics of low-dose aspirin in health and disease. Clin Pharmacol Ther 2017; 102 (05) 823-831
    PubMedGoogle Scholar
  • 25 Goto S, Goto S. Selection of a suitable patient population for new antiplatelet therapy from the large clinical trial database of the thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events-thrombolysis in myocardial infarction 50 (TRA-2P-TIMI50) trial. Circulation 2015; 131 (12) 1041-1043
    CrossrefPubMedGoogle Scholar
  • 26 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22 (09) 1381-1389
    CrossrefPubMedGoogle Scholar
  • 27 Roth GJ, Siok CJ. Acetylation of the NH2-terminal serine of prostaglandin synthetase by aspirin. J Biol Chem 1978; 253 (11) 3782-3784
    CrossrefPubMedGoogle Scholar
  • 28 Hohlfeld T, Schrör K. Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions?. Thromb Haemost 2015; 114 (03) 469-477
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 DiChiara J, Bliden KP, Tantry US. , et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes 2007; 56 (12) 3014-3019
    CrossrefPubMedGoogle Scholar
  • 30 Pulcinelli FM, Biasucci LM, Riondino S. , et al. COX-1 sensitivity and thromboxane A2 production in type 1 and type 2 diabetic patients under chronic aspirin treatment. Eur Heart J 2009; 30 (10) 1279-1286
    CrossrefPubMedGoogle Scholar
  • 31 Di Minno MN, Lupoli R, Palmieri NM, Russolillo A, Buonauro A, Di Minno G. Aspirin resistance, platelet turnover, and diabetic angiopathy: a 2011 update. Thromb Res 2012; 129 (03) 341-344
    CrossrefPubMedGoogle Scholar
  • 32 Gurbel PA, Bliden KP, DiChiara J. , et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation 2007; 115 (25) 3156-3164
    CrossrefPubMedGoogle Scholar
  • 33 Henry P, Vermillet A, Boval B. , et al. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2011; 105 (02) 336-344
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 ATT. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994; 308 (6921): 81-106
    CrossrefPubMedGoogle Scholar
  • 35 Antithrombotic Trialists' Collaboration. 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
    CrossrefPubMedGoogle Scholar
  • 36 Baigent C, Blackwell L, Collins R. , et al; Antithrombotic Trialists' (ATT) Collaboration. 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
    CrossrefPubMedGoogle Scholar
  • 37 De Berardis G, Sacco M, Strippoli GF. , et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339: b4531
    CrossrefPubMedGoogle Scholar
  • 38 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; >pii: ehz224
    PubMedGoogle Scholar
  • 39 Tzoulaki I, Siontis KC, Evangelou E, Ioannidis JP. Bias in associations of emerging biomarkers with cardiovascular disease. JAMA Intern Med 2013; 173 (08) 664-671
    CrossrefPubMedGoogle Scholar
  • 40 ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992; 268 (10) 1292-1300
    CrossrefPubMedGoogle Scholar
  • 41 Belch J, MacCuish A, Campbell I. , et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. 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
    CrossrefPubMedGoogle Scholar
  • 42 Ogawa H, Nakayama M, Morimoto T. , et al; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. 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
    CrossrefPubMedGoogle Scholar
  • 43 Saito Y, Okada S, Ogawa H. , et al; JPAD Trial Investigators. 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 (07) 659-670
    CrossrefPubMedGoogle Scholar
  • 44 Hebert PR, Schneider WR, Hennekens CH. Use of aspirin among diabetics in the primary prevention of cardiovascular disease: need for reliable randomized evidence and astute clinical judgment. J Gen Intern Med 2009; 24 (11) 1248-1250
    CrossrefPubMedGoogle Scholar
  • 45 Elwood P. POPADAD trial. Don't stop taking aspirin. BMJ 2008; 337: a2581
    CrossrefPubMedGoogle Scholar
  • 46 Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol 2005; 25 (07) 1463-1469
    CrossrefPubMedGoogle Scholar
  • 47 Diehm C, Lange S, Darius H. , et al. Association of low ankle brachial index with high mortality in primary care. Eur Heart J 2006; 27 (14) 1743-1749
    CrossrefPubMedGoogle Scholar
  • 48 Chaudhary R, Bliden KP, Garg J. , et al. Statin therapy and inflammation in patients with diabetes treated with high dose aspirin. J Diabetes Complications 2016; 30 (07) 1365-1370
    CrossrefPubMedGoogle Scholar
  • 49 Ridker PM, Manson JE, Gaziano JM, Buring JE, Hennekens CH. Low-dose aspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial. Ann Intern Med 1991; 114 (10) 835-839
    PubMedGoogle Scholar
  • 50 ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379 (16) 1529-1539
    CrossrefPubMedGoogle Scholar
  • 51 Hennekens CH, Schneider WR, Hebert PR, Tantry US, Gurbel PA. Hypothesis formulation from subgroup analyses: nonadherence or nonsteroidal anti-inflammatory drug use explains the lack of clinical benefit of aspirin on first myocardial infarction attributed to “aspirin resistance”. Am Heart J 2010; 159 (05) 744-748
    CrossrefPubMedGoogle Scholar
  • 52 Aung T, Buck GAN, Parish S. , et al. Once daily low-dose aspirin reduces urinary thromboxane B2 effectively even at 12–24 hours from dosing in the ASCEND (A study on cardiovascular events in diabetes) trial. Eur Heart J Suppl 2017; 38: 426 (P2088)
    PubMedGoogle Scholar
  • 53 Schrör K, Nitschmann S. Importance of acetylsalicylic acid in primary prevention: ASCEND, ARRIVE and ASPREE as well as a meta-analysis by Rothwell et al. [in German]. Internist (Berl) 2019; 60 (02) 209-216
    CrossrefPubMedGoogle Scholar
  • 54 Patti G, Cavallari I, Andreotti F. , et al. Prevention of atherothrombotic events in patients with diabetes mellitus: from atherothrombotic therapies to new-generation glucose-lowering drugs. Nat Rev Cardiol 2019; 16 (02) 113-130
    CrossrefPubMedGoogle Scholar
  • 55 Marso SP, Daniels GH, Brown-Frandsen K. , et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375 (04) 311-322
    Google Scholar
  • 56 Mahaffey KW, Neal B, Perkovic V. , et al; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018; 137 (04) 323-334
    CrossrefPubMedGoogle Scholar
  • 57 Randriamboavonjy V, Fleming I. Insulin, insulin resistance, and platelet signaling in diabetes. Diabetes Care 2009; 32 (04) 528-530
    CrossrefPubMedGoogle Scholar
  • 58 Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011; 123 (07) 798-813
    CrossrefPubMedGoogle Scholar
  • 59 Olesen KKW, Madsen M, Egholm G. , et al. Patients with diabetes without significant angiographic coronary artery disease have the same risk of myocardial infarction as patients without diabetes in a real-world population receiving appropriate prophylactic treatment. Diabetes Care 2017; 40 (08) 1103-1110
    CrossrefPubMedGoogle Scholar
  • 60 Schrör K, Löbel P, Steinhagen-Thiessen E. Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia. Eicosanoids 1989; 2 (01) 39-45
    PubMedGoogle Scholar
  • 61 Serebruany VL, Miller M, Pokov AN. , et al. Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). Am J Cardiol 2006; 97 (09) 1332-1336
    CrossrefPubMedGoogle Scholar
  • 62 Fisher M, Cushman M, Knappertz V, Howard G. An assessment of the joint associations of aspirin and statin use with C-reactive protein concentration. Am Heart J 2008; 156 (01) 106-111
    CrossrefPubMedGoogle Scholar
  • 63 Bhatt DL, Cryer BL, Contant CF. , et al; COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363 (20) 1909-1917
    CrossrefPubMedGoogle Scholar
  • 64 Dahal K, Sharma SP, Kaur J, Anderson BJ, Singh G. Efficacy and safety of proton pump inhibitors in the long-term aspirin users: a meta-analysis of randomized controlled trials. Am J Ther 2017; 24 (05) e559-e569
    CrossrefPubMedGoogle Scholar
  • 65 Kyrle PA, Westwick J, Scully MF, Kakkar VV, Lewis GP. Investigation of the interaction of blood platelets with the coagulation system at the site of plug formation in vivo in man--effect of low-dose aspirin. Thromb Haemost 1987; 57 (01) 62-66
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Undas A, Brummel K, Musial J, Mann KG, Szczeklik A. Blood coagulation at the site of microvascular injury: effects of low-dose aspirin. Blood 2001; 98 (08) 2423-2431
    CrossrefPubMedGoogle Scholar
  • 67 Parker WAE, Orme RC, Hanson J. , et al. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome. Platelets 2019; 30 (02) 148-157
    CrossrefPubMedGoogle Scholar
  • 68 Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991; 77 (12) 2547-2552
    CrossrefPubMedGoogle Scholar
  • 69 Elwood PC, Pickering J, Yarnell J, O'Brien JR, Ben Shlomo Y, Bath P. Bleeding time, stroke and myocardial infarction: the Caerphilly prospective study. Platelets 2003; 14 (03) 139-141
    CrossrefPubMedGoogle Scholar
  • 70 Harker LA, Slichter SJ. The bleeding time as a screening test for evaluation of platelet function. N Engl J Med 1972; 287 (04) 155-159
    CrossrefPubMedGoogle Scholar
  • 71 Szczeklik A, Krzanowski M, Góra P, Radwan J. Antiplatelet drugs and generation of thrombin in clotting blood. Blood 1992; 80 (08) 2006-2011
    CrossrefPubMedGoogle Scholar
  • 72 Ng JC, Yeomans ND. Helicobacter pylori infection and the risk of upper gastrointestinal bleeding in low dose aspirin users: systematic review and meta-analysis. Med J Aust 2018; 209 (07) 306-311
    CrossrefPubMedGoogle Scholar
  • 73 Cryer B, Redfern JS, Goldschmiedt M, Lee E, Feldman M. Effect of aging on gastric and duodenal mucosal prostaglandin concentrations in humans. Gastroenterology 1992; 102 (4 Pt 1): 1118-1123
    CrossrefPubMedGoogle Scholar
  • 74 Goto H, Sugiyama S, Ohara A. , et al. Age-associated decreases in prostaglandin contents in human gastric mucosa. Biochem Biophys Res Commun 1992; 186 (03) 1443-1448
    CrossrefPubMedGoogle Scholar
  • 75 Ogawa E, Kanazawa M, Yamamoto S. , et al. Expression analysis of two mutations in carnitine palmitoyltransferase IA deficiency. J Hum Genet 2002; 47 (07) 342-347
    CrossrefPubMedGoogle Scholar
  • 76 Li L, Geraghty OC, Mehta Z, Rothwell PM. ; Oxford Vascular Study. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017; 390 (10093): 490-499
    CrossrefPubMedGoogle Scholar
  • 77 Vaduganathan M, Bhatt DL, Cryer BL. , et al; COGENT Investigators. Proton-pump inhibitors reduce gastrointestinal events regardless of aspirin dose in patients requiring dual antiplatelet therapy. J Am Coll Cardiol 2016; 67 (14) 1661-1671
    PubMedGoogle Scholar
  • 78 Whellan DJ, Goldstein JL, Cryer BL. , et al. PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies. Am Heart J 2014; 168 (04) 495-502.e4
    CrossrefPubMedGoogle Scholar
  • 79 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
    CrossrefPubMedGoogle Scholar
  • 80 Gaziano JM, Brotons C, Coppolecchia R. , et al; ARRIVE Executive Committee. 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
    CrossrefPubMedGoogle Scholar
  • 81 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 (16) 1509-1518
    CrossrefPubMedGoogle Scholar
  • 82 Arnett DK, Blumenthal RS, Albert MA. , et al. 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; pii:S0735-1097(19)33876-8
    PubMedGoogle Scholar
  • 83 Aimo A, De Caterina R. Aspirin for primary cardiovascular prevention: is there a need for risk stratification?. Eur Heart J 2019; ehz223
    PubMedGoogle Scholar
  • 84 Raber I, McCarthy CP, Vaduganathan M. , et al. The rise and fall of aspirin in the primary prevention of cardiovascular disease. Lancet 2019; 393 (10186): 2155-2167
    CrossrefPubMedGoogle Scholar
  • 85 Hennekens CH, Sacks FM, Tonkin A. , et al. Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their meta-analyses. Arch Intern Med 2004; 164 (01) 40-44
    CrossrefPubMedGoogle Scholar
  • 86 Byrne P, Cullinan J, Smith A, Smith SM. Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews. BMJ Open 2019; 9 (04) e023085
    CrossrefPubMedGoogle Scholar
  • 87 De Berardis G, Sacco M, Evangelista V. , et al; ACCEPT-D Study Group. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials 2007; 8: 21
    CrossrefPubMedGoogle Scholar
  • 88 Sundström J, Hedberg J, Thuresson M, Aarskog P, Johannesen KM, Oldgren J. Low-dose aspirin discontinuation and risk of cardiovascular events: a Swedish Nationwide, Population-Based Cohort Study. Circulation 2017; 136 (13) 1183-1192
    CrossrefPubMedGoogle Scholar
  • 89 Capodanno D, Mehran R, Valgimigli M. , et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol 2018; 15 (08) 480-496
    CrossrefPubMedGoogle Scholar
  • 90 Simpson SH, Abdelmoneim AS, Omran D, Featherstone TR. Prevalence of high on-treatment platelet reactivity in diabetic patients treated with aspirin. Am J Med 2014; 127 (01) 95.e1-95.e9
    CrossrefPubMedGoogle Scholar
  • 91 Dillinger JG, Drissa A, Sideris G. , et al. Biological efficacy of twice daily aspirin in type 2 diabetic patients with coronary artery disease. Am Heart J 2012; 164 (04) 600-606.e1
    CrossrefPubMedGoogle Scholar
  • 92 Bhatt DL, Grosser T, Dong JF. , et al. Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus. J Am Coll Cardiol 2017; 69 (06) 603-612
    CrossrefPubMedGoogle Scholar
  • 93 Gurbel PA, Bliden KP, Chaudhary R. , et al. Antiplatelet effect durability of a novel, 24-hour, extended-release prescription formulation of acetylsalicylic acid in patients with type 2 diabetes mellitus. Am J Cardiol 2016; 118 (12) 1941-1947
    CrossrefPubMedGoogle Scholar