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Thromb Haemost 2015; 114(05): 876-882
DOI: 10.1160/TH15-03-0202
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Schattauer GmbH

Aspirin for primary prevention in diabetes mellitus: from the calculation of cardiovascular risk and risk/benefit profile to personalised treatment

Francesca Santilli
1   Department of Medicine and Aging, Center of Excellence on Aging, University of Chieti, Chieti, Italy
,
Pasquale Pignatelli
2   I Clinica Medica, Sapienza University, Rome, Italy
,
Francesco Violi
2   I Clinica Medica, Sapienza University, Rome, Italy
,
Giovanni Davì
1   Department of Medicine and Aging, Center of Excellence on Aging, University of Chieti, Chieti, Italy
› Author Affiliations
Further Information

Publication History

Received: 05 March 2015

Accepted after major revision: 29 May 2015

Publication Date:
06 December 2017 (online)

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Summary

Type 2 diabetes mellitus is characterised by persistent thromboxane (TX)-dependent platelet activation, regardless of disease duration. Low-dose aspirin, that induces a permanent inactivation of platelet cyclooxygenase (COX)-1, thus inhibiting TXA2 biosynthesis, should be theoretically considered the drug of choice. The most up-to-date meta-analysis of aspirin prophylaxis in this setting, which includes three trials conducted in patients with diabetes and six other trials in which such patients represent a subgroup within a broader population, reported that aspirin is associated with a non-significant decrease in the risk of vascular events, although the limited amount of available data precludes a precise estimate of the effect size. An increasing body of evidence supports the concept that less-than-expected response to aspirin may underlie mechanisms related to residual platelet hyper-reactivity despite anti-platelet treatment, at least in a fraction of patients. Among the proposed mechanisms, the variable turnover rate of the drug target (platelet COX-1) appears to represent the most convincing determinant of the inter-individual variability in aspirin response. This review intends to develop the idea that the understanding of the determinants of less-than-adequate response to aspirin in certain individuals, although not changing the paradigm of the indication to low-dose aspirin prescription in primary prevention, may help identifying, in terms of easily detectable clinical or biochemical characteristics, individuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged.

Keywords

Antiplatelet agents - diabetes mellitus - aspirin response - prevention
 

  • References

  • 1 Gregg EW, Li Y, Wang J. et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med 2014; 17: 1514-1523.
    PubMedSearch in Google Scholar
  • 2 American Diabetes Association. Cardiovascular disease and risk management. Sec. 8. In Standards of Medical Care in Diabetes-2015. Diabetes Care 2015; 38 (Suppl 1) S49-S57.
    CrossrefPubMedSearch in Google Scholar
  • 3 Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chaemo-prevention, both, or neither?. Eur Heart J 2013; 34: 3403-3411.
    CrossrefPubMedSearch in Google Scholar
  • 4 Antithrombotic Trialists' (ATT) Collaboration. Baigent C, Blackwell L. 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: 1849-1860.
    CrossrefPubMedSearch in Google Scholar
  • 5 Raju N, Sobieraj-Teague M, Hirsh J. et al. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med 2011; 124: 62-69.
    PubMedSearch in Google Scholar
  • 6 Bartolucci AA, Tendera M, Howard G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2011; 107: 1796-1801.
    CrossrefPubMedSearch in Google Scholar
  • 7 Belch J, MacCuish A, Campbell I. 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. Br Med J 2008; 337: 1030-1036.
    CrossrefPubMedSearch in Google Scholar
  • 8 Ogawa H, Nakayama M, Morimoto T. et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes. A randomised controlled trial. J Am Med Assoc 2008; 300: 2134-2141.
    CrossrefPubMedSearch in Google Scholar
  • 9 Fowkes FGR, Price JF, Stewart MCW. et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomised controlled trial. J Am Med Assoc 2010; 303: 841-848.
    CrossrefPubMedSearch in Google Scholar
  • 10 The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Authors/Task Force Members: Ryde'n Lars. (ESC Chairperson) (Sweden) Grant Peter J.. (EASD Chairperson) (UK) Anker Stefan D.. (Germany) et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2013; 34: 3035-3087.
    CrossrefPubMedSearch in Google Scholar
  • 11 Vandvik PO, Lincoff AM, Gore JM. et al. Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e637S-e668S.
    CrossrefPubMedSearch in Google Scholar
  • 12 Sarwar N, Gao P, Seshasai SR. et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375: 2215-2222.
    CrossrefPubMedSearch in Google Scholar
  • 13 Haffner SM, Lehto S, Ronnemaa T. et al. 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: 229-234.
    CrossrefPubMedSearch in Google Scholar
  • 14 Davi G, Catalano I, Averna M. et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 1769-1774.
    CrossrefPubMedSearch in Google Scholar
  • 15 Davi G, Ciabattoni G, Consoli A. et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation 1999; 99: 224-229.
    CrossrefPubMedSearch in Google Scholar
  • 16 Davi G, Santilli F, Vazzana N. Platelets. Third Edition. Chapter 35: Diabetes mellitus Edited by Michelson Alan D.. Elsevier/Academic Press; 2013. pp. 711-732.
    CrossrefSearch in Google Scholar
  • 17 Patrono C, Garcia Rodriguez LA, Landolfi R. et al. Low-dose aspirin for the prevention of atherothrombosis. N Eng J Med 2005; 353: 2373-2383.
    CrossrefPubMedSearch in Google Scholar
  • 18 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
    CrossrefPubMedSearch in Google Scholar
  • 19 Pignone M, Alberts MJ, Colwell JA. et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol 2010; 55: 2878-2886.
    CrossrefPubMedSearch in Google Scholar
  • 20 Perk J, De Backer G, Gohlke H. et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2012; 33: 1635-1701.
    CrossrefPubMedSearch in Google Scholar
  • 21 Hennekens CH, Baigent C. Aspirin in primary prevention-good news and bad news. Nat Rev Cardiol 2012; 9: 262-263.
    CrossrefPubMedSearch in Google Scholar
  • 22 Giovannucci E, Harlan DM, Archer MC. et al. Diabetes and cancer: a consensus report. Diabetes Care 2010; 33: 1674-1685.
    CrossrefPubMedSearch in Google Scholar
  • 23 Rothwell PM, Fowkes FGR, Belch JFF. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patients data from randomised trials. Lancet 2011; 377: 31-41.
    CrossrefPubMedSearch in Google Scholar
  • 24 Rothwell PM, Price JF, Fowkes FGR. et al. Short-term effects of daily aspirin on cancer incidence, mortality and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012; 379: 1602-1612.
    CrossrefPubMedSearch in Google Scholar
  • 25 De Berardis G, Lucisano G, D'Ettorre A. et al. Association of aspirin use with major bleeding in patients with and without diabetes. J Am Med Assoc 2012; 307: 2286-2294.
    PubMedSearch in Google Scholar
  • 26 Patrono C. Diabetes: Does aspirin increase the risk of major bleeds?. Nat Rev Cardiol 2012; 9: 495-496.
    CrossrefPubMedSearch in Google Scholar
  • 27 A Study of Cardiovascular Events iN Diabetes (ASCEND). University of Oxford. Clinical Trial Service Unit Website. Available from: http://www.ctsu.ox.ac.uk/ascend/ Accessed February 18 2015
    PubMedSearch in Google Scholar
  • 28 De Berardis G, Sacco M, Evangelista V. et al. ACCEPT-D Study Group. Aspirin and Simvastatin Combination for Cardiovascular Events PreventionTrial in Diabetes (ACCEPT-D): design of a randomised 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: 21-29.
    CrossrefPubMedSearch in Google Scholar
  • 29 Davi G, Santilli F. Aspirin as antiplatelet agent in diabetes. Eur J Intern Med 2010; 21: 149-153.
    CrossrefPubMedSearch in Google Scholar
  • 30 Rocca B, Patrono C. Determinants of the interindividual variability in response to antiplatelet drugs. J Thromb Haemost 2005; 3: 1597-1602.
    CrossrefPubMedSearch in Google Scholar
  • 31 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin “resistance.”. J Am Coll Cardiol 2009; 53: 667-677.
    CrossrefPubMedSearch in Google Scholar
  • 32 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
    CrossrefPubMedSearch in Google Scholar
  • 33 Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009; 103: 20A-26A.
    CrossrefPubMedSearch in Google Scholar
  • 34 Lordkipanidze M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
    CrossrefPubMedSearch in Google Scholar
  • 35 Pettinella C, Romano M, Stuppia L. et al. Cyclooxygenase-1 haplotype C50T/A-842G does not affect platelet response to aspirin. Thromb Haemost 2009; 101: 687-690.
    Thieme ConnectPubMedSearch in Google Scholar
  • 36 Mateo JF, Gil-Guillen VF, Mateo E. et al. Multifactorial approach and adherence to prescribed oral medications in patients with type 2 diabetes. Int J Clin Pract 2006; 60: 422-428.
    CrossrefPubMedSearch in Google Scholar
  • 37 Grosser T, Fries S, Lawson JA. et al. Drug resistance and pseudo-resistance: an unintended consequence of enteric coating aspirin. Circulation 2013; 127: 377-385.
    CrossrefPubMedSearch in Google Scholar
  • 38 Ciabattoni G, Boss AH, Daffonchio l. et al. Radioimmunoassay measurement of 2,3— dinor metabolites of prostacyclin and thromboxane in human urine. Adv Prostaglandin Thromboxane Leukot Res 1987; 17B: 598-602.
    PubMedSearch in Google Scholar
  • 39 Santilli F, Davi G, Basili S. et al. Thromboxane and prostacyclin biosynthesis in heart failure of ischemic origin: effects of disease severity and aspirin treatment. J Thromb Haemost 2010; 8: 914-922.
    PubMedSearch in Google Scholar
  • 40 Santilli F, Lapenna D, La Barba S, Davi G. Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus. Free Radic Biol Med 2014; 80C: 101-110.
    PubMedSearch in Google Scholar
  • 41 Cangemi R, Pignatelli P, Carnevale R. et al. Platelet isoprostane overproduction in diabetic patients treated with aspirin. Diabetes 2012; 61: 1626-1632.
    CrossrefPubMedSearch in Google Scholar
  • 42 Carnevale R, Iuliano L, Nocella C. et al. Relationship Between Platelet and Urinary 8-Iso-PGF2alpha Levels in Subjects With Different Degrees of NOX2 Regulation. J Am Heart Assoc 2013; 2: e000198
    PubMedSearch in Google Scholar
  • 43 Lemkes BA, Bahler L, Kamphuisen PW. et al. The influence of aspirin dose and glycaemic control on platelet inhibition in patients with type 2 diabetes mellitus. J Thromb Haemost 2012; 10: 639-646.
    CrossrefPubMedSearch in Google Scholar
  • 44 Watala C, Pluta J, Golanski J. et al. Increased protein glycation in diabetes melli- tus is associated with decreased aspirin-mediated protein acetylation and reduced sensitivity of blood platelets to aspirin. J Mol Med 2005; 83: 148-158.
    CrossrefPubMedSearch in Google Scholar
  • 45 Smith JP, Haddad EV, Taylor MB. Suboptimal inhibition of platelet cyclooxygenase-1 by aspirin in metabolic syndrome. Hypertension 2012; 59: 719-725.
    CrossrefPubMedSearch in Google Scholar
  • 46 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998; 352: 837-853.
    CrossrefPubMedSearch in Google Scholar
  • 47 Rao AK, Chouhan V, Chen X. et al. Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycaemia in young healthy men. Diabetes 1999; 48: 1156-1161.
    CrossrefPubMedSearch in Google Scholar
  • 48 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: 1220-1230.
    CrossrefPubMedSearch in Google Scholar
  • 49 Capodanno D, Patel A, Dharmashankar K. et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv 2011; 4: 180-187.
    CrossrefPubMedSearch in Google Scholar
  • 50 Moukarbel GV, Bhatt DL. Antiplatelet therapy and proton pump inhibition: clinician update. Circulation 2012; 125: 375-380.
    CrossrefPubMedSearch in Google Scholar
  • 51 Cleland JGF. Is aspirin useful in primary prevention?. Eur Heart J 2013; 34: 3412-3418.
    PubMedSearch in Google Scholar
  • 52 ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): A randomised control trial. Contemp Clin Trials 2013; 36: 555-564.
    CrossrefPubMedSearch in Google Scholar
  • 53 De Backer G, Graham I, Cooney MT. Do novel biomarkers add to existing scores of total cardiovascular risk?. Eur J Prev Cardiol 2012; 19: 14-17.
    CrossrefPubMedSearch in Google Scholar
  • 54 Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE). Available at: http://www.arrive-study.com/EN/ Accessed February 18 2015
    PubMedSearch in Google Scholar