A comparison of the pharmacological profiles of prasugrel and ticagrelor assessed by platelet aggregation, thrombus formation and haemostasis in rats

Abstract

BACKGROUND AND PURPOSEPrasugrel is a third-generation thienopyridine prodrug and ticagrelor is a non-competitive P2Y12 receptor antagonist. In their phase 3 studies, both agents reduced rates of ischemic events relative to treatment with clopidogrel. EXPERIMENTAL APPROACHThe pharmacodynamic profile of anti-platelet effects of prasugrel was compared with that of ticagrelor in rats. KEY RESULTSThe active metabolite of prasugrel was less potent than ticagrelor and its active metabolite on platelet aggregation in vitro. In contrast, prasugrel was a more potent antiplatelet agent than ticagrelor on ex vivo platelet aggregation: their ED50 values at peak for ADP 20 mmol·L -1 were 1.9 and 8.0 mg·kg, respectively. Prasugrel's inhibition of platelet aggregation was maintained for up to 24 h after administration, but ticagrelor's duration of action was substantially shorter. Prasugrel and ticagrelor significantly inhibited thrombus formation with ED50 values of 1.8 and 7.7 mg·kg -1 , respectively. Both agents also prolonged bleeding times (ED200 values of 3.0 and 13 mg·kg -1 respectively) suggesting that at equivalent levels of inhibition of platelet aggregation, the agents would show comparable antithrombotic activity with similar bleeding risk. Platelet transfusion significantly increased blood platelet numbers similarly in prasugrel-and ticagrelor-treated rats. In the prasugrel-treated group, platelet transfusion caused significant shortening of bleeding time, while in the ticagrelor-treated group, platelet transfusion showed no influence on bleeding time under the experimental conditions employed. CONCLUSIONS AND IMPLICATIONSPrasugrel and ticagrelor showed several differences in their pharmacological profiles and these disparities may reflect their differing reversibility and/or pharmacokinetic profiles. AbbreviationsACS, acute coronary syndrome; PCI, percutaneous coronary intervention; PRP, platelet-rich plasma

Comparison of patient intake of ticagrelor, prasugrel, or clopidogrel on restoring platelet function by donor platelets

“…Thereby our data confirm and extend in vivo data obtained in animal experiments: Sugidachi and colleagues 16 recently showed that PLT transfusion in rats receiving prasugrel reduced bleeding time, while PLT transfusion did not shorten bleeding time in ticagrelortreated rats.…”

Correction of prasugrel‐related bleeding by prophylactic transfusion of human platelets in a rabbit model

“…Because of the profound inhibition of platelet aggregation induced by prasugrel, a high platelet transfusion dose also would be required to overcome the effects of prasugrel. Only a single in vivo animal study performed in rats demonstrated that a fixed high dose of allogeneic platelets (increasing the platelet count by 1.6, with no more information regarding platelet count) could shorten but not normalize the bleeding duration after tail transection 4 hours after a loading dose of prasugrel . The result reported herein demonstrates a dose‐effect relationship between the platelet transfusion dose and the reduction of prasugrel‐related bleeding.…”

Oral antiplatelet therapy: impact for transfusion medicine

“…There is no direct comparison of dual antiplatelet treatment with aspirin and prasugrel vs. aspirin and ticagrelor in humans, so far. In rats, however, prasugrel and ticagrelor appear to have an equivalent antithrombotic efficacy .…”