Interactions between aspirin and ticagrelor during experimental human endotoxaemia

Abstract

Abstract Introduction Dual antiplatelet therapy (DAPT) with aspirin 75-100mg once daily (OD) and the P2Y12 inhibitor ticagrelor is a standard treatment for acute coronary syndromes. De-escalating DAPT to ticagrelor monotherapy reduces bleeding risk yet appears to have minimal ischaemic penalty in most groups. The reason for this is unclear. P2Y12 inhibition can inhibit inflammatory processes relevant to atherothrombosis but aspirin may hypothetically counter these via platelet PGE2 inhibition. We studied the regimen-dependent effects of aspirin +/- ticagrelor in a human model of endotoxaemia. Endotoxin activates toll-like receptor 4, a key damage receptor in atherogenesis. Methods 72 healthy volunteers were randomised to receive either no aspirin or aspirin 20mg twice daily (BD), 75mg OD or 300mg OD for 10 days +/- a loading dose of ticagrelor on the last day prior to receiving intravenous endotoxin administration (2ng/kg). Blood was collected at 9 timepoints from 1h pre to 6h post endotoxin. Key cytokines and prostanoids in the blood/urine were measured by ELISA, platelet function by light transmittance aggregometry and platelet-leukocyte interaction by flow cytometry. Bleeding time was measured pre and 3h post endotoxin. After >5 weeks, in a 2nd period they received the same dose of aspirin as the 1st but received ticagrelor if they had not already, and vice versa, undergoing a 2nd endotoxin challenge at the end of the period. The primary endpoint was plasma tumour necrosis factor (TNF)-α. Results 72 participants were randomised (median 22.5yrs [range 18-59], 6F:66M). A total of 128 endotoxin challenges were performed. Endotoxaemia was associated with flu-like symptoms, pyrexia, tachycardia and relative hypotension but was safe. In those not receiving aspirin, plasma TNF-α was significantly lower when receiving ticagrelor vs. no ticagrelor, but in those receiving any dose of aspirin the significant effect of ticagrelor was abolished (Fig 1). All doses of aspirin fully suppressed arachidonic acid-induced PA with or without ticagrelor despite the thromboinflammatory stimulus of endotoxaemia (Fig 2A), and significantly augmented the inhibitory effect of ticagrelor on collagen-induced PA (2B). Aspirin 75mg OD and 300mg OD, but not 20mg BD, significantly prolonged bleeding time from baseline (2C). Ticagrelor significantly prolonged bleeding time in combination with any dose of aspirin or no aspirin. Aspirin dose-dependently inhibited PGE2 release. Conclusions All doses of aspirin tested prevented the ability of ticagrelor to significantly inhibit cytokine release during experimental endotoxaemia. Aspirin 20mg BD may offer improved bleeding risk with maintained antiplatelet effect compared to standard regimens. Where ticagrelor monotherapy is an option, dropping aspirin may allow ticagrelor to exert greater beneficial effect on inflammatory pathways relevant to atherothrombosis, potentially reducing ischaemic risk whilst also reducing bleeding risk.Figure 1Figure 2