PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies

被引：6

作者：

Nash, Jennifer ^{[1
,2
]}

Meah, Mohammed N. ^{[2
]}

Whittington, Beth ^{[2
,6
]}

Debono, Samuel ^{[2
]}

Raftis, Jennifer ^{[2
]}

Miller, Mark R. ^{[2
]}

Sorbie, Andrew ^{[2
]}

Mills, Nicholas L. ^{[2
]}

Nespoux, Josselin ^{[2
]}

Bruce, Lorraine ^{[2
]}

Duffin, Rodger ^{[2
]}

Dhaun, Neeraj ^{[2
]}

Brittan, Mairi ^{[2
]}

Chao, Longfei ^{[3
]}

Merali, Samira ^{[3
]}

Kim, Minji ^{[4
,7
]}

Wang, Zhaoqing ^{[4
]}

Zhang, Yue ^{[5
]}

Jin, Shiqiang ^{[5
]}

Wang, Beqing ^{[1
]}

Kozinn, Marc ^{[3
]}

Newby, David E. ^{[2
]}

机构：

[1] Univ Edinburgh, Room SU305,Chancellors Bldg,49 Little France Cresc, Edinburgh EH16 4SB, Scotland

[2] Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Scotland

[3] Clin Pharmacol & Pharmacometr, Bristol Myers Squibb, Lawrenceville, NJ USA

[4] Bristol Myers Squibb, Translat Med, Lawrenceville, NJ USA

[5] Global Biometr & Data Sci, Bristol Myers Squibb, Lawrenceville, NJ USA

[6] WorldWide Patient Safety, Bristol Myers Squibb, Lawrenceville, NJ USA

[7] Early Cardiovasc Clin Dev, R&D, Bristol Myers Squibb, Lawrenceville, NJ USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2024年 / 44卷 / 04期

关键词：

aspirin; coronary artery disease; platelet activation; platelet aggregation; thrombosis; ticagrelor; THROMBUS FORMATION; MYOCARDIAL-INFARCTION; TASK-FORCE; MODEL; INTERVENTION; METAANALYSIS; HEMOSTASIS; GUIDELINES; MANAGEMENT; ELEVATION;

D O I：

10.1161/ATVBAHA.123.320448

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND:BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. 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 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 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-AP (agonist peptide)-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).CONCLUSIONS:PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

引用

页码：987 / 996

页数：10

共 33 条

[1] Sex Differences in Ischemic Heart Disease Advances, Obstacles, and Next Steps [J].

Aggarwal, Niti R. ;

Patel, Hena N. ;

Mehta, Laxmi S. ;

Sanghani, Rupa M. ;

Lundberg, Gina P. ;

Lewis, Sandra J. ;

Mendelson, Marla A. ;

Wood, Malissa J. ;

Volgman, Annabelle S. ;

Mieres, Jennifer H. .

CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES, 2018, 11 (02)

[2]

Amsterdam EA, 2014, J AM COLL CARDIOL, V64, P2645, DOI [10.1016/j.jacc.2014.09.017, 10.1016/j.jacc.2014.09.016, 10.1016/j.jacc.2014.10.011, 10.1161/CIR.0000000000000134]

[3] 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation (vol 42, pg 1289, 2020) [J].