PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies

Jennifer Nash, Mohammed N. Meah, Beth Whittington, Samuel Debono, Jennifer Raftis, Mark R. Miller, Andrew Sorbie, Nicholas L. Mills, Josselin Nespoux, Lorraine Bruce, Rodger Duffin, Neeraj Dhaun, Mairi Brittan, Longfei Chao, Samira Merali, Minji Kim, Zhaoqing Wang, Yue Zhang, Shiqiang Jin, Beqing WangMarc Kozinn, David E. Newby

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background: BMS-986141 is a novel potent highly selective antagonist of protease-activated receptor type 4 (PAR4). PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy.
Methods: Forty-five patients with stable coronary heart disease and ten healthy volunteers completed a phase 2a open-label four-arm single-centre study. Patients were allocated to one of three treatment arms for seven days: (i) ticagrelor (90 mg twice daily), (ii) aspirin (75 mg once daily) or (iii) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before, 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants.
Results: BMS-986141 demonstrated highly selective inhibition of PAR4-agonist peptide (AP) induced platelet aggregation, p-selectin expression, and platelet-monocyte aggregate expression (p≤0.001 for all) which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%, p=0.001) and in patients receiving ticagrelor alone (-28%, p=0.001), aspirin alone (-23%, p=0.018), or both in combination (-24%, p≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (p≤0.001 for all) and total thrombus area under high shear stress conditions (p≤0.01 for all).
Conclusion: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin or their combination, in patients with stable coronary heart disease.
Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
DOIs
Publication statusPublished - 15 Feb 2024

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