355Effects of the PAR-1 receptor antagonist vorapaxar on platelet activation and coagulation biomarkers in patients with stable coronary artery disease

Abstract

Introduction: Vorapaxar is a selective antagonist of protease‐activated receptor 1 (PAR‐1), thereby blocking thrombin‐mediated platelet activation. Although vorapaxar is likely not to affect the coagulation process directly, inhibition of platelet activation and thereby reducing the availability of a procoagulant platelet surface for the assembly of coagulation factors, might reduce the formation of thrombin and fibrin indirectly. While standard coagulation tests, like prothrombin time (PT) and activated partial thromboplastin time (aPTT), are not influenced by vorapaxar use, the effect on more specific biomarkers of coagulation is currently unknown. A reduction in platelet activation can be measured by soluble P‐selectin, a plasma biomarker of in vivo platelet activation. Next to thrombin‐antithrombin (TAT) complex levels, the complexes of factor IXa‐antithrombin (IXa‐AT) and factor Xa‐antithrombin (Xa‐AT) are new biomarkers of upstream coagulation activity. Purpose: To investigate the effect of vorapaxar on biomarkers of platelet activation and coagulation activity in patients with stable coronary artery disease (CAD). Methods: Soluble P‐selectin and TAT were measured following manufacturer's instructions. Factor IXa‐AT and factor Xa‐AT were determined with in‐house developed enzyme‐linked immunosorbent assays (ELISAs). Samples were taken while on long‐term treatment in a subgroup of patients with stable CAD randomized to vorapaxar or placebo on top of standard antiplatelet therapy participating in the TRA2°P‐TIMI‐50 trial. For this analysis, we excluded patients using anticoagulant medication during follow‐up. Student's t‐test and Mann‐Whitney U test were used for comparison of biomarker levels between groups. Results:. Baseline characteristics including comorbidity, prior cardiovascular disease, concomitant aspirin and clopidogrel use (99.3% and 56.3%, respectively), and other concomitant medication were well balanced between the vorapaxargroup (n=73) and placebo‐group (n=62). Samples were taken after a mean study drug exposure of 904 (± 149) days. As anticipated, platelet activation was reduced in the vorapaxar‐group, according to soluble P‐selectin levels (ng/mL) (mean ± SD); 26.12±7.81 in the vorapaxar‐group vs. 29.39±9.16 in the placebo‐group (p=0.027). However, coagulation activity as measured by TAT, IXa‐AT and Xa‐ AT was comparable in vorapaxar vs placebo group: TAT (μg/L) (median, [IQR]) 4.08 [3.20‐5.01] vs. 3.88 [3.26‐4.92], p=0.71; IXa‐AT (pM) (median, [IQR]) 86,7 [77.2‐101.3] vs. 85,5 [77.7‐97.6], p=0.95; X‐AT (pM) (mean ± SD) 282.1±57.4 vs. 296.4±54.6, p=0.14. Conclusion: On top of standard antiplatelet therapy, vorapaxar reduced platelet activation as measured by a reduction in soluble P‐selectin levels. We did not find an additional effect of vorapaxar on TAT, IXa‐AT and Xa‐AT levels in patients with stable CAD, indicating that vorapaxar does not further reduce thrombin generation via intensified platelet inhibition.