Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease

Abstract

Background-Patients with type 2 diabetes mellitus (T2DM) have reduced aspirin-induced pharmacodynamic effects. This may be attributed to increased platelet turnover rates resulting in an increased proportion of non-aspirin-inhibited platelets during the daily dosing interval. The hypothesis of this study was that an increase in the frequency of drug administration [twice daily (bid) versus once daily (od)] may provide more effective platelet inhibition in T2DM patients. Methods and Results-T2DM patients with stable coronary artery disease were prospectively recruited. Patients modified their aspirin regimen on a weekly basis according to the following scheme: 81 mg/od, 81 mg/bid, 162 mg/od, 162 mg/bid, and 325 mg/od. Pharmacodynamic assessments included light-transmittance aggregometry after arachidonic acid, collagen and adenosine diphosphate stimuli; VerifyNow-Aspirin assay; and serum thromboxane B 2 (TXB 2 ) levels. Twenty patients were analyzed. All patients were sensitive and compliant to aspirin irrespective of dose, as assessed by arachidonic acid-induced aggregation. When aspirin was administered once daily, there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays (collagen-induced aggregation and VerifyNow-Aspirin). An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid (PϽ0.05 for both assays) and between 81 mg/od and 162 mg/bid (PϽ0.05 for both assays). There was no impact of aspirin dosing regimens on adenosine diphosphate-induced aggregation. A dose-dependent effect of aspirin was observed on serum TXB 2 levels (Pϭ0.003). Conclusions-Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease, with a twice-daily, low-dose aspirin administration resulting in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB 2 levels. The clinical implications of a modified aspirin regimen tailored to T2DM patients warrant further investigation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01201785.

Association of plasma concentrations of salicylic acid and high on ASA platelet reactivity in type 2 diabetes patients

“…Once-daily administration of low-dose ASA may be associated with incomplete inhibition of platelet COX-1 activity and thromboxane-dependent function in diabetics [3,4,23,26]. In the present study, despite the lack of simple linear relationship between plasma concentrations of SA and the S-TxB 2 , we found lower concentrations of SA in several groups of patients selected based on empirical cut-off points for S-TxB 2 .…”

“…Based on these considerations, we calculated ASA dose in mg/kg of body weight, and we found that lower dose of ASA based on the ASA dose per kg of body weight can predict higher S-TxB 2 concentrations. As it was suggested by others, the higher doses or twice daily dosing of ASA may overcome the reduced platelet response to ASA, thus increased platelet reactivity, observed in diabetic patients [3,26].…”

Aspirin Resistance: Current Status and Role of Tailored Therapy

“…34 Based on the above data, it has been proposed that certain high-risk patient populations might benefit from diagnostic screening for tailored antiplatelet therapy. In a small study conducted by Capodanno et al, 75 30 patients with type 2 diabetes mellitus and coronary artery disease underwent a weekly aspirin dose and/or frequency escalation scheme followed by platelet functional testing using the VerifyNow assay. Platelet function was tested in each patient after 1 week of either daily aspirin at a dose of 81 mg, 162 mg, or 325 mg, or twice-daily aspirin at a dose of 81 mg or 162 mg.…”

“…Similar to the findings of Rocca et al, 34 twice-daily aspirin was associated with more platelet inhibition than once-daily aspirin. 75 Neubauer et al 76 recently studied a dose escalation and subsequent therapeutic substitution algorithm in aspirin and clopidogrel nonresponders in patients undergoing PCI for ACS or stable angina. Patients underwent whole-blood aggregometry to both ADP and arachidonic acid.…”

Effect of ASA dose doubling versus switching to clopidogrel on plasma inflammatory markers concentration in patients with type 2 diabetes and high platelet reactivity: The AVOCADO study

“…75 mg per day). Previous studies demonstrated that T2DM patients treated with 162 mg ASA had lower incidence of HPR than those receiving 81 mg, however increasing the dose to 325 mg had not resulted in further improvement in terms of platelet reactivity [14,15]. Also in the AVOCADO study switching to higher dose of ASA reduced platelet reactivity in T2DM patients with HPR initially treated with 75 mg of ASA per day [16].…”