The term resistance derives from a laboratory finding consisting in failure of an antiplatelet agent to adequately block its specific target on the platelet (33). A2 synthesis (5). However, patients on aspirin therapy, particularly those at high risk, may continue to have recurrent thrombotic events. GP IIb/IIIa inhibitors Itraconazole (Sporanox) are very potent antiplatelet agents, which exert effects through inhibition of the final common pathway that mediates platelet aggregation processes, and have been shown to be effective in preventing thrombotic complications in high-risk patients undergoing percutaneous coronary interventions (PCI) (4). However, these agents are available only for parenteral use and have a short duration of action, which impedes their use for long-term protection. The need for alternative antiplatelet treatment strategies led to the evaluation of effects obtained from a combination of oral antiplatelet agents inhibiting other platelet-activating pathways. Ticlopidine is a first-generation thienopyridine, which irreversibly blocks the platelet ADP P2Y12 receptor (6). Its combination with aspirin is associated with a more enhanced inhibition of platelet function and better clinical outcomes in patients undergoing coronary stenting compared with aspirin monotherapy or aspirin plus warfarin (6). However, the limited safety profile of ticlopidine and its inability to achieve antiplatelet effects rapidly have led clopidogrel, a second-generation thienopyridine, to become the ADP P2Y12 receptor antagonist of choice (6C7). Open in a separate window Figure 1 Mechanisms of action of antiplatelet agents. Aspirin inhibits thromboxane A2 (TXA2) synthase through blockade of the COX-1 enzyme. Picotamide, ramatroban, and ridogrel inhibit both Itraconazole (Sporanox) TXA2 synthase and TXA2 receptors. Thienopyridines, ticlopidine, Itraconazole (Sporanox) ERK1 and clopidogrel are inhibitors of ADP P2Y12 receptor and block intracellular pathways leading to platelet activation. Prasugrel, ticagrelor, cangrelor, and elinogrel are P2Y12 receptor antagonists currently under clinical investigation. Aspirin and P2Y12 receptor antagonists have synergistic effects in blocking the final common pathway leading to platelet aggregation represented by GP IIb/IIIa receptor, which may be directly inhibited by intravenous GP IIb/IIIa receptor antagonists. Cilostazol is an inhibitor of phosphodiesterase (PDE) III, which inhibits platelets through an increase in intraplatelet cAMP levels. E5555 and SCH 530348 are thrombin receptor antagonists that block the PAR-1 subtype. (Adapted from Schafer AI: Antiplatelet therapy. 101:199C209, 1996.) Aspirin. Aspirin selectively acetylates the COX-1 enzyme, thereby blocking the formation of thromboxane A2 in platelets (5). This effect is irreversible because platelets are enucleate and, thus, unable to resynthesize COX-1. In addition to being the antiplatelet agent of choice for secondary prevention of ischemic events in patients with atherosclerotic disease, aspirin may also be used for primary prevention of ischemic events. In fact, although this indication in the general population is controversial, there is an expert consensus for aspirin usage in the primary prevention setting in diabetic patients. Aspirin as a primary prevention strategy in diabetes. The American Diabetes Association (ADA) recommends the use of low-dose aspirin (75C162 mg/day) as a primary prevention strategy in patients with type 1 or type 2 diabetes at increased cardiovascular risk, including those 40 years of age or who have additional risk factors (family history of cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria) (8). However, aspirin therapy should not be recommended for patients aged 21 years because this may increase the risk of Reye’s syndrome. The role of aspirin in diabetic patients aged 30 years remains unclear because it has not been investigated. Several clinical trials have evaluated the efficacy of aspirin in diabetic patients (9C12). Most of these studies showed a benefit of aspirin in diabetic patients (9C11). However, these outcomes were based on post hoc analyses because these trials were not.