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Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Bench to Clinic Symposia EDITORIAL REVIEW Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and Future Directions DOMINICK J. ANGIOLILLO, MD, PHD of low-dose aspirin (75–162 mg/day) as a primary prevention strategy in patients with type 1 or type 2 diabetes at increased Ͼ ardiovascular disease is the leading patients undergoing percutaneous coro- cardiovascular risk, including those 40 cause of morbidity and mortality in nary interventions (PCI) (4). However, years of age or who have additional risk C patients with diabetes (1). The con- these agents are available only for paren- factors (family history of cardiovascular comitant presence of multiple classical teral use and have a short duration of ac- disease, hypertension, smoking, dyslipi- cardiovascular risk factors in diabetic tion, which impedes their use for long- demia, or albuminuria) (8). However, subjects contributes to enhanced athero- term protection. The need for alternative aspirin therapy should not be recom- thrombotic risk (2). However, other risk antiplatelet treatment strategies led to the mended for patients aged Ͻ21 years be- factors may be important such as abnor- evaluation of effects obtained from a com- cause this may increase the risk of Reye’s mal platelet function (3). Platelets, in fact, bination of oral antiplatelet agents inhib- syndrome. The role of aspirin in diabetic play a key role in atherogenesis, and its iting other platelet-activating pathways. patients aged Ͻ30 years remains unclear thrombotic complications and measures, Ticlopidine is a first-generation thienopy- because it has not been investigated. which lead to blockade of one or multiple ridine, which irreversibly blocks the Several clinical trials have evaluated the efficacy of aspirin in diabetic patients pathways modulating platelet activation platelet ADP P2Y12 receptor (6). Its com- and aggregation processes, are pivotal in bination with aspirin is associated with a (9–12). Most of these studies showed a reducing ischemic risk in diabetic sub- more enhanced inhibition of platelet benefit of aspirin in diabetic patients (9– jects (4). This article reviews currently function and better clinical outcomes in 11). However, these outcomes were based available antiplatelet agents on ischemic patients undergoing coronary stenting on post hoc analyses because these trials events in diabetic patients, limitations of compared with aspirin monotherapy or were not specifically designed for diabetic currently available treatment strategies, aspirin plus warfarin (6). However, the patients. In addition, the obtained results and antiplatelet agents currently under limited safety profile of ticlopidine and its were based on small numbers of subjects, clinical development that may potentially inability to achieve antiplatelet effects which may explain why aspirin was not overcome these limitations. rapidly have led clopidogrel, a second- always shown to be beneficial in the pri- generation thienopyridine, to become the mary prevention setting in diabetic pa- Antiplatelet therapy ADP P2Y12 receptor antagonist of choice tients (12). There are three different classes of plate- (6–7). The Japanese Primary Prevention of let-inhibiting drugs: cyclooxygenase-1 Aspirin. Aspirin selectively acetylates Atherosclerosis With Aspirin for Diabetes (COX-1) inhibitors (aspirin), ADP P2Y12 the COX-1 enzyme, thereby blocking the (JPAD) trial (clinical trial reg. no. receptor antagonists (thienopyridines), formation of thromboxane A2 in platelets NCT00110448) was the first prospec- and platelet glycoprotein (GP) IIb/IIIa in- (5). This effect is irreversible because tively designed trial to evaluate the use of hibitors, which are mostly used for the platelets are enucleate and, thus, unable aspirin (81 mg or 100 mg) in the primary prevention and treatment of athero- to resynthesize COX-1. In addition to be- prevention of cardiovascular events in pa- thrombotic disorders (4) (Fig. 1). Aspirin ing the antiplatelet agent of choice for sec- tients with type 2 diabetes (n ϭ 2,539) inhibits the COX-1 enzyme and therefore ondary prevention of ischemic events in aged 30–85 years in Japan (13). After a blocks platelet thromboxane A2 synthesis patients with atherosclerotic disease, as- median follow-up of 4.37 years, there was (5). However, patients on aspirin therapy, pirin may also be used for primary pre- a 20% difference between the aspirin and particularly those at high risk, may con- vention of ischemic events. In fact, nonaspirin arms in the primary end point tinue to have recurrent thrombotic although this indication in the general (5.4 vs. 6.7%, respectively) that failed to events. GP IIb/IIIa inhibitors are very po- population is controversial, there is an ex- achieve statistical significance (P ϭ 0.16). tent antiplatelet agents, which exert ef- pert consensus for aspirin usage in the Among patients aged Ͼ65 years (n ϭ fects through inhibition of the final primary prevention setting in diabetic 1,363), aspirin was associated with a 32% common pathway that mediates platelet patients. reduction in the risk of the primary end aggregation processes, and have been Aspirin as a primary prevention strat- point (6.3 vs. 9.2%; P ϭ 0.047). Further- shown to be effective in preventing egy in diabetes. The American Diabetes more, in aspirin-treated patients, the thrombotic complications in high-risk Association (ADA) recommends the use incidence of fatal coronary and cerebro- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● vascular events (a secondary end point) From the Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida. was significantly lower by 90% (0.08 vs. Corresponding author: Dominick J. Angiolillo, [email protected]fl.edu. 0.8%; P ϭ 0.0037); however, there were Received 16 November 2008 and accepted 10 December 2008. no differences in nonfatal coronary and DOI: 10.2337/dc08-2064 © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cerebrovascular events. Aspirin was well cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. tolerated, with no significant increase in org/licenses/by-nc-nd/3.0/ for details. the composite of hemorrhagic stroke and DIABETES CARE, VOLUME 32, NUMBER 4, APRIL 2009 531 Antiplatelet therapy in diabetes diovascular disease, including those with diabetes (15–16). The meta-analyses in- cluded 287 secondary prevention trials involving 212,000 high-risk patients with acute or prior vascular disease or another condition that increased their risk of vas- cular disease. Aspirin in doses ranging from 75 to 325 mg/day was the most fre- quently used antiplatelet agent. In the ma- jor high-risk groups (acute myocardial infarction, past history of myocardial in- farction, past history of stroke or transient ischemic attack, acute stroke, and any other relevant history of vascular disease), antiplatelet therapy reduced the inci- dence of vascular events by 23%. Of note, a low dose of aspirin (75–150 mg/day) was found to be at least as effective as higher daily doses. Furthermore, bleed- ing complications were reduced with the lower doses. In more than 4,500 diabetic patients studied in the ATC, the incidence of vascular events was also reduced from Figure 1— Mechanisms of action of antiplatelet agents. Aspirin inhibits thromboxane A2 (TXA2) 23.5 in the control group to 19.3% in the synthase through blockade of the COX-1 enzyme. Picotamide, ramatroban, and ridogrel inhibit group treated with antiplatelet therapy both TXA2 synthase and TXA2 receptors. Thienopyridines, ticlopidine, and clopidogrel are inhib- (P Ͻ 0.01) and from 17.2 to 13.7% in the itors of ADP P2Y12 receptor and block intracellular pathways leading to platelet activation. ϳ42,000 nondiabetic patients (P Ͻ Prasugrel, ticagrelor, cangrelor, and elinogrel are P2Y receptor antagonists currently under 12 0.00001). Although the overall incidence 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, of vascular events was much higher in di- which may be directly inhibited by intravenous GP IIb/IIIa receptor antagonists. Cilostazol is an abetic patients, the benefit of antiplatelet inhibitor of phosphodiesterase (PDE) III, which inhibits platelets through an increase in in- therapy in both diabetic and nondiabetic traplatelet cAMP levels. E5555 and SCH 530348 are thrombin receptor antagonists that block the patients was consistent (42 vascular PAR-1 subtype. (Adapted from Schafer AI: Antiplatelet therapy. Am J Med 101:199–209, 1996.) events were prevented for every 1,000 di- abetic patients and 35 events for every 1,000 nondiabetic patients). severe gastrointestinal bleeding. Limita- sure index Յ0.99 but no symptomatic tions of this trial include the open-label cardiovascular disease were randomized P2Y12 receptor antagonists assignment to aspirin and the low event to aspirin (100 mg) and antioxidants in a Clopidogrel is currently the thienopyri- rate. Therefore, the study may have been double-blind, 2 ϫ 2 factorial, placebo- dine of choice because it has a more favor- underpowered to demonstrate a signifi- controlled fashion. This trial failed to able safety profile compared with that of cant effect of aspirin on the primary end show any benefit with aspirin or antioxi- ticlopidine (6–7). The Clopidogrel versus point. The results
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