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CONFLICTS OF INTEREST: Dr. Gurbel reports serving as a consultant fees/receiving honoraria from Daiichi Sankyo, Bayer, AstraZeneca, Merck, Boehringer, Janssen, and CSL; receiving grants from the National Institutes of Health, Daiichi Sankyo, CSL, AstraZeneca, Harvard Clinical Research Institute, Bayer, Haemonetics, Duke Clinical Research Institute, Sinnowa, an Coramed. Dr. Jeong has received honoraria for lectures from AstraZeneca, Sanofi-Aventis, Daiichi Sankyo/Lilly, Haemonetics, Otsuka and Yuhan Pharmaceuticals; and research grants or support from AstraZeneca, Korean Society of Interventional Cardiology, Han-mi Pharmaceuticals, and Haemonetics.
Fig. 1Proposed mechanism of atherothrombosis in diabetes mellitus [4,5]. PKC, protein kinase C; RAGE, receptor for advanced glycation endproducts; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PAI-1, plasminogen activator inhibitor-1; VSMC, vascular smooth muscle cell.
Fig. 2Antiplatelet agents currently available or under development [9,10]. PAR, protease-activated receptor; TXA, thromboxane; COX-1, cyclooxygenase-1; PDE, phosphodiesterase; AC, adenylyl cyclase; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; 5-HT2A, 5-hydroxytryptamine (serotonin) receptor 2A; VASP-P, vasodilator-stimulated phosphoprotein-phosphorylation; PKA, protein kinase A; GP, glycoprotein; TNF, tumor necrosis factor.
Fig. 3Relationship between clinical benefit and bleeding risk according to absolute cardiovascular risk in primary prevention trials of aspirin. Adapted from Halvorsen et al. [13]. To examine the association between treatment effects of aspirin on cardiovascular events, major gastrointestinal bleeding, and total major bleeding according to the level of cardiovascular risk (per 100 person-years in the control arm), univariate inverse variance-weighted linear regressions of the risk difference was fitted for the outcome events per 100 person-years between the two experimental arms. The size of circles is proportional to the inverse of variance of the risk difference. Red arrow denotes the area where benefit likely equals risk, yellow area denotes area of prescription uncertainty, and green arrow denotes the area where benefit most likely exceeds risk. Continuous line=linear regression; dotted line=lower and higher 95% confidence interval. CV, cardiovascular; GI, gastrointestinal; SAPAT, Swedish Angina Pectoris Aspirin Trial; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; PPP, Primary Prevention Project; HOT, Hypertension Optimal Treatment; WHS, Women's Health Study; BDT, British Doctors Trial; PHS, Physicians Health Study; AAA, Aspirin for Asymptomatic Atherosclerosis; TPT, Thrombosis Prevention Trial; POPAPDAD, prevention of progression of arterial disease and diabetes.
Fig. 4Metabolic pathway of P2Y12 receptor inhibitors. Adapted from Levine et al., with permission from Nature Publishing Group [23]. MDR1, multidrug resistance protein 1; hCE, human carboxylesterase; CYP, cytochrome P450; ADP, adenosine diphosphate; GP, glycoprotein.
Fig. 5Randomized clinical trials evaluating primary efficacy of intensified antiplatelet regimen versus clopidogrel in diabetic patients with acute coronary syndrome [22,37,39,56]. CI, confidence interval; CURRENT-OASIS 7, Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent EveNTs-Optimal Antiplatelet Strategy for InterventionS; PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; TRITON-TIMI 38, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; PLATO, platelet inhibition and patient outcomes.
Table 1Clinical trials of aspirin in primary prevention for diabetes
Table 2Main outcomes of randomized clinical trials investigating clinical efficacy of oral antiplatelet treatment in diabetic patients with acute coronary syndrome or undergoing percutaneous coronary intervention