Further Ex Vivo Evidence Supporting Higher Aspirin Dosing in Patients With Coronary Artery Disease and Diabetes

Abstract

A spirin remains the cornerstone antiplatelet agent for primary and secondary prevention in patients with diabetes mellitus (DM), a disease associated with heightened platelet reactivity, endothelial dysfunction, and inflammation. 1,2 Patients with DM are at a greater risk of death, myocardial infarction, and stroke resulting from thrombotic event occurrence than are patients without diabetes. Because reactive platelets play a central role in the genesis of thrombotic events, the antiplatelet effects of various antiplatelet therapy regimens have been a focus of ex vivo investigations in this high-risk population. The current guidelines recommend aspirin (75 to 162 mg QD) for primary prevention in men aged Ͼ50 years and women aged Ͼ60 years with diabetes at increased cardiovascular risk (10-year risk Ͼ10%). Despite these recommendations, the clinical efficacy of the widely used low-dose aspirin regimen (75 to 81 mg QD) to treat the patient with diabetes remains a major source of controversy, and the optimal dose is unknown. 3 Article see p 180Previous investigations have examined the dose-related effects of aspirin on platelet reactivity. In stable patients with coronary artery disease (CAD), low-dose aspirin did not inhibit platelet function in a significant number, despite highly effective blockade of its primary platelet target cyclooxygenase-1 (COX-1). 4,5 The ASPECT (Aspirin-Induced Platelet Effect) study, a double-blind, double-crossover, William design investigation of 81, 162, and 325 mg QD aspirin administered as single doses for 4 weeks, each over a 12-week period, was the largest serial pharmacodynamic investigation of the dose-related effects of aspirin on platelet function in patients with CAD. 4 It was clearly demonstrated in the ASPECT study that aspirin inhibited platelet aggregation stimulated by agonists other than arachidonic acid in a dose-dependent manner; significant effects were observed for collagen-and shear-induced aggregation and 11-dehydrothromboxane B 2 production. Dose-related inhibition of platelet aggregation was hypothesized to be due to effects of aspirin beyond inhibition of its primary target COX-1 by acetylation and was termed a non-COX-1 effect. 4 In a post hoc analysis of ASPECT, patients with and without DM were compared. Greater platelet reactivity and a higher prevalence of aspirin resistance were present in the patients with DM. Aspirin doses of Ͼ81 mg QD (162 to 325 mg QD) were associated with similar rates of resistance and platelet function in patients with and without DM. It was hypothesized, therefore, that a higher aspirin dosing strategy than 81 mg QD in patients with diabetes may be associated with enhanced platelet inhibition and better protection against atherothrombotic event occurrence. 6 Various mechanisms have been proposed to explain the attenuated antiplatelet effect of aspirin therapy in DM, such as reduced drug bioavailability, accelerated platelet turnover, and glycosylation of platelet membrane proteins. 5 When platelet turnover is heightened, an incr...

Effects of low-dose aspirin and fish oil on platelet function and NF-kappaB in adults with diabetes mellitus

“…Clinical trial data have supported that the most optimal dose for patients with known coronary artery disease when weighing risks and benefits is between 75 and 100 mg [46]. The ASPECT clinical trial [23,47], the largest serial pharmacodynamic investigation of dose-dependent effects of aspirin on platelet aggregation in individuals with known coronary artery disease, has shown that aspirin effects on arachidonic acid-induced platelet aggregation are an important means of determining aspirin insensitivity in those with known coronary artery disease, but that ADP- and collagen-induced aggregation are also potentially important factors in determining whether aspirin is exerting its antiplatelet effects. Our data regarding effects of ADP and collagen at low dose on aggregation suggest that it may be that aspirin + fish oil exert a greater effect than aspirin alone 4 hours after ingestion.…”