© Schattauer 2015 Thrombosis and Haemostasis 114.5/2015 876 Aspirin for primary prevention in diabetes mellitus: from the calculation of cardiovascular risk and risk/benefit profile to personalised treatment Francesca Santilli 1 ; Pasquale Pignatelli 2 ; Francesco Violi 2 ; Giovanni Davì 1 1 Department of Medicine and Aging, Center of Excellence on Aging, University of Chieti, Chieti, Italy; 2 I Clinica Medica, Sapienza University, Rome, Italy 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 TXA 2 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, re- ported 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 as- pirin may underlie mechanisms related to residual platelet hyper-reac- tivity 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 de- terminants of less-than-adequate response to aspirin in certain indi- viduals, 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, in- dividuals who would attain inadequate protection from aspirin, and for whom different strategies should be challenged. Keywords Antiplatelet agents, diabetes mellitus, aspirin response, prevention Correspondence to: Giovanni Davì Center of Excellence on Aging “G. D’Annunzio” University Foundation Via Luigi Polacchi 11, 66013 Chieti, Italy Tel: +39 0871 541312, Fax: +39 0871 541261 E-mail: gdavi@unich.it Received: March 5, 2015 Accepted after major revision: May 29, 2015 Epub ahead of print: August 6, 2015 http://dx.doi.org/10.1160/TH15-03-0202 Thromb Haemost 2015; 114: 876–882 Viewpoint Article Search strategy This document is based on a comprehensive review of the avail- able literature. PubMed database was searched through February 2015 for articles in English reporting aspirin use for primary pre- vention in diabetes mellitus. The following search terms were used: ‘aspirin’, ‘diabetes’, ‘primary prevention, ‘antiplatelet therapy’, ‘cardiovascular diseases’, ‘prophylaxis’, ‘cardiovascular risk’ and ‘guidelines’. Identified references were hand-searched to locate other potentially useful references. Clinical randomised trials, prospective cohort studies and retrospective analyses were in- cluded, as well as meta-analyses; abstracts were excluded. In the past two decades, preventive care for adults with diabetes de- clined substantially the rates of diabetes-related complications (acute myocardial infarction (MI), stroke, end-stage renal disease, lower-ex- tremity amputation). However, a large burden of disease persists be- cause of the continued increase in the prevalence of diabetes (1). The latest American Diabetes Association (ADA) guidelines for prevention and management of diabetes complications, suggest considering aspirin therapy (75–162 mg/day) as a primary preven- tion strategy in those with diabetes at increased cardiovascular risk (10-year risk > 10 %). This includes most men aged > 50 years or women aged > 60 years who have at least one additional major risk factor (2). Aspirin to prevent initial cardiovascular events in diabetes mellitus: where do we stand? In general populations without previous cardiovascular disease (CVD), the absolute benefits of antiplatelet prophylaxis are of un- certain value in primary prevention (3), because the balance be- tween vascular events avoided and major bleeds caused by aspirin is substantially uncertain. In a systematic review of six trials in- cluding 95,000 individuals, a 12 % risk reduction (4) was found, mainly due to a reduction in non-fatal MI, with a non statistically significant net effect on stroke (a reduction in ischaemic stroke and a slight increase in haemorrhagic stroke). Moreover, vascular mortality was not changed by aspirin treatment. Major bleeding (gastrointestinal and extracranial) increased by 0.03 % per year. Two updated meta-analyses (5, 6), including three more recent trials POPAPAD (7), JPAD (8), and AAA (9), demonstrated a For personal or educational use only. No other uses without permission. All rights reserved. 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