The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low‐dose aspirin in patients with and without diabetes

Abstract

See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX‐1 at bay. This issue, pp 1217–9. Summary Background. Interindividual variability in response to aspirin has been popularized as ‘resistance’. We hypothesized that faster recovery of platelet cyclooxygenase‐1 activity may explain incomplete thromboxane (TX) inhibition during the 24‐h dosing interval. Objective. To characterize the kinetics and determinants of platelet cyclooxygenase‐1 recovery in aspirin‐treated diabetic and non‐diabetic patients. Patients/Methods. One hundred type 2 diabetic and 73 non‐diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB2 was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase‐1 recovery. Patients with the fastest TXB2 recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB2 recovery was reassessed. Results and Conclusions. Platelet TXB2 production was profoundly suppressed at 12 h in both groups. Serum TXB2 recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL−1 h−1) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non‐diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB2 recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low‐dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.

In Vivo Platelet Activation and Aspirin Responsiveness in Type 1 Diabetes

“…The rate of in vivo TXA 2 biosynthesis was assessed by the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB 2 (TXM), as previously described (9,11). In vivo oxidant stress was assessed by the urinary excretion of the F 2 -isoprostane 8-iso-PGF 2a (12), as previously described (9); the major urinary prostacyclin metabolite (PGIM) 2,3-dinor-6-keto-PGF 1a was measured as previously described (13) (Supplementary Data).…”

“…However, the duration of the antiplatelet effect of low-dose aspirin may be reduced in patients with T2DM, and a twice-daily dosing improves inhibition of T2DM platelets versus the standard oncedaily regimen (9,10). Whether this applies to T1DM remains unexplored.…”

The prognostic utility of tests of platelet function for the detection of ‘aspirin resistance’ in patients with established cardiovascular or cerebrovascular disease: a systematic review and economic evaluation

“…[66][67][68][69][70] Increasing the frequency of aspirin administration to twice daily has been shown to effectively improve the inhibition of platelet function by aspirin in these settings, although the clinical benefit of this therapy modification remains unknown. 63,64,[71][72][73] Although the characteristics associated with poor response have been explored in detail, 74 it is noteworthy that the different studies have used different platelet function methodologies to explore the determinants of platelet responses. In parallel, a number of different studies have shown platelet function assay results to lack correlation and agreement among themselves, thus identifying different patients as poor responders to aspirin and having different determinants of response.…”

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD – Summary

“…180 There is emerging evidence of sustained efficacy using twice-daily aspirin in subjects with DM and CVD. 180,181 Secondary prevention. The first collaborative overview of the Antiplatelet Trialists' Collaboration found that antiplatelet therapy (mostly with aspirin) is similarly effective among patients with pre-existing symptomatic CVD, regardless of the presence of DM.…”