Variability in the Recovery Rate of Platelet Cyclooxygenase Activity During Chronic Therapy With Low-Dose Aspirin in Type 2 Diabetes.

Aspirin is currently recommended for cardiovascular prevention in type 2 diabetes (T2DM). However, two primary prevention trials failed to substantiate its efficacy in T2DM and incomplete platelet inhibition has been reported. We hypothesized that faster recovery of platelet cyclooxygenase (COX)-1 activity may explain incomplete thromboxane (TX) A2 inhibition by low-dose aspirin during the 24-hour dosing interval. One-hundred T2DM patients on chronic therapy with aspirin 100 mg daily were studied. Serum TXB2, an index of platelet COX-1 activity, was measured every 3 hours, between 12 and 24 hours after a witnessed aspirin administration, to characterize the kinetics of platelet COX-1 recovery (phase 1). Thirty-three patients with the steepest COX-1 recovery slopes were randomized to receive aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily for 28 days (phase 2). On day 29, COX-1 recovery was reassessed over the 12 to 24 hour dosing interval. COX-1 activity displayed linear kinetics with large interindividual variability in recovery slope, ranging from 0.001 to 0.46 ng/ml/hr. Multiple linear regression analysis showed that mean platelet volume (β=0.42, SEM=0.005, p<0.0001), higher body-mass index quartiles (β=0.26, SEM=0.022, p=0.007), and age (β=–0.18, SEM=0.002, p=0.049) predicted serum TXB2 recovery slope, independently of other variables. A twice daily aspirin regimen, but not a doubling of the dose, completely corrected the abnormal recovery slope of platelet COX-1 activity: absolute values were 0.11 (0.1–0.14), 0.06 (0.05–0.08), 0.01 (0.002–0.02) ng/ml/hr (medians, IQR), for 100 mg once daily, 200 mg once daily and 100 mg twice daily, respectively; the median (IQR) changes versus phase 1 slopes were –33.3 (0–50.5, p=0.08), –55.5 (40–60.9, p=0.02) and –87.5 (69.1–99.7, p<0.0001) %, respectively. We conclude that interindividual variability in the recovery rate of platelet COX-1 activity during the aspirin dosing interval most likely reflects abnormal megakaryopoiesis associated with T2DM; inadequate thromboxane inhibition can be overcome by a twice daily regimen; the clinical efficacy and safety of a tailored regimen of aspirin therapy remain to be tested.