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Introduction Ticagrelor is a more potent platelet inhibitor than clopidogrel but also has a more rapid offset of inhibitory effect. The optimal timing of discontinuation of ticagrelor prior to coronary artery bypass graft (CABG) surgery is unknown. In the ONSET/OFFSET study of patients with stable coronary artery disease, ticagrelor’s effects dissipated within 48–120 hours of discontinuation. However, there is evidence that the pharmacodynamics of antiplatelet therapy are significantly altered during an acute coronary syndrome (ACS) and the ONSET/OFFSET study results should not be extrapolated to ACS patients. Although the PLATO study suggested that it was safe to discontinue ticagrelor 48 hours prior to CABG, regulatory authorities recommended that ticagrelor should be discontinued 5 days prior to CABG. The PLATO study also showed that ticagrelor was associated with fewer deaths following pulmonary adverse events and sepsis compared to clopidogrel. It is unknown whether ticagrelor’s additional property of inhibiting cellular adenosine uptake might underlie this observation. The aim of this study was to characterise the offset of ticagrelor’s activity in inhibiting platelets and also in inhibiting cellular adenosine uptake in ACS patients. Methods Patients admitted with ACS, treated with ticagrelor and referred for CABG were recruited. Venous blood was drawn from patients at the following 6 timepoints: 2 hours (h), 24 hour, 48 hour, 72 hour, 96 hour, and 120 hour after the last dose of ticagrelor prior to CABG. Whole-blood aggregometry was carried out using the Multiplate analyzer with adenosine diphosphate 6.45 µM as agonist and the final value of area under the curve (AUC) (units, U) was recorded. Results were analysed using linear mixed models. A local protocol was referred to, where an AUC of >50U supports safe progression to surgery, while values 50U indicates need for re-testing 24–48 hours later. Inhibition of adenosine uptake was determined by measuring the adenosine plasma concentration using liquid chromatography. Results 13 patients were recruited, all of whom received ticagrelor prior to CABG surgery. At 96 hour post ticagrelor, the mean AUC was 82.8U, (95% confidence interval, 60.4, 105.2). Only at 96 hour was the lower limit of the confidence interval >50U. From the mixed model analysis, the comparison between 72 hour and 120 hour post ticagrelor showed a significant difference (p=0.007) while 96 hour and 120 hour showed no significant difference (p=1.000). Adenosine plasma concentration was measured in 7 patients who received ticagrelor and showed no significant difference in adenosine plasma concentration across all timepoints. Conclusion ACS patients might be safe to undergo CABG surgery 4 days after the cessation of ticagrelor. Ticagrelor might have no measurable effect on adenosine transport in ACS patients.

Introduction In the PLATO study, the novel platelet P2Y 12 inhibitor ticagrelor was unexpectedly associated with fewer deaths following pulmonary infections and sepsis than clopidogrel. The risk of myocardial infarction or stroke is greatly increased following bacteremia, which can create an inflammatory environment associated with thrombotic changes in the fibrin network. We therefore aimed to determine whether greater P2Y 12 inhibition by ticagrelor compared to clopidogrel would result in greater reduction in platelet-leukocyte interactions, thereby reducing inflammatory responses and the prothrombotic state associated with inflammation. Methods Thirty healthy volunteers were randomised to ticagrelor 90 mg bd (n = 10), clopidogrel 75 mg od (n = 10) or no antiplatelet medications (controls; n = 10) for one week. E. coli endotoxin (LPS) 2 ng/kg was then administered intravenously. Plasma fibrin clot density was assessed ex vivo using a validated turbidimetric assay and D-dimer was measured using the INNOVANCE assay. Fibrin clot structure was investigated ex vivo using scanning electron microscopy. Fibrin network density and fibrin diameter were determined using imageJ software. Informed consent was obtained. The study was approved by a medical ethics committee and funded by the Medical Research Council (UK). Results In the control group, fibrin clot maximum absorbance (an indicator of fibrin clot density), increased by 109 ± 37% at 6 h after LPS administration compared to baseline (p Conclusion To our knowledge, this is the first study to show that ticagrelor reduces prothrombotic changes in fibrin clot structure induced by bacterial endotoxaemia in vivo . The greater potency of the effects of ticagrelor compared to clopidogrel provides a potential mechanism for the reduced mortality following sepsis observed in the PLATO study.

Introduction In the PLATelet inhibition and patient Outcomes (PLATO) study, ticagrelor was associated with fewer pulmonary infection events and subsequent deaths but slightly higher inflammatory markers compared to clopidogrel. Ticagrelor and clopidogrel inhibit platelet P2Y12 receptors via different mechanisms and ticagrelor additionally is a weak inhibitor of reuptake of adenosine, which has numerous effects on innate immunity. We studied the effects of ticagrelor and clopidogrel on the innate immune responses of healthy volunteers. Methods 30 healthy volunteers were randomised to receive ticagrelor 90 mg bd (n = 10), clopidogrel 75 mg od (n = 10) or no antiplatelet medication (controls; n = 10) for one week. E. coli endotoxin (LPS, 2 ng/kg) was then administered intravenously. Blood was sampled pre-treatment, after treatment and over 24 h post LPS. Platelet aggregation induced by 30 µM ADP was assessed by optical aggregometry. Platelet P-selectin expression and platelet-leukocyte conjugate formation were determined by flow cytometry. Plasma levels of cytokines were determined using cytometric bead array. Results After treatment, maximal platelet aggregation responses to ADP in the ticagrelor, clopidogrel and control groups were 12 ± 6%, 31 ± 26% and 81 ± 24% respectively. After LPS exposure, ticagrelor and clopidogrel significantly reduced ADP-induced platelet P-selectin expression and platelet-monocyte conjugate formation compared to controls. LPS-induced increases in TNF were significantly attenuated by both ticagrelor (p = 0.025) and clopidogrel (p = 0.017), which reduced peak levels by 61% and 60% respectively compared to controls. Peak TNF levels correlated with indices of platelet reactivity (ADP-induced platelet aggregation [p = 0.0096], P-selectin expression [p = 0.026] and platelet-monocyte conjugate formation [p = 0.024]). Ticagrelor also significantly attenuated IL-6 release (p = 0.015), reducing peak levels by 43% compared to controls, whereas clopidogrel had a non-significant effect (p = 0.15), with peak levels 28% lower than controls. Conclusion Ticagrelor inhibited release of pro-inflammatory cytokines TNF and IL-6 in a model of human sepsis. The similar effect of ticagrelor and clopidogrel, as well as the correlation between levels of platelet reactivity and TNF release, suggest that P2Y12 contributes to innate immune response and demonstrates anti-inflammatory effects of P2Y12 inhibition.