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On top of standard antiplatelet therapy, vorapaxar reduces the risk of ischemic events or cardiovascular death in patients with stable coronary artery disease (CAD).1 Vorapaxar is a selective antagonist of protease-activated receptor-1 (PAR-1), thereby blocking thrombin-mediated platelet activation.2,3 However, other actions of thrombin, such as fibrin formation and protein-C activation, are not inhibited by blocking PAR-1. Although vorapaxar probably does not affect the coagulation process directly, platelet inhibition leading to reduced availability of a procoagulant surface for the assembly of coagulation factors might lower the rate of thrombin formation indirectly. Therefore, the aim of this study is to assess whether the beneficial effect of vorapaxar on top of standard antiplatelet therapy in stable CADpatients can only be ascribed to more potent platelet inhibition or to an additional effect on thrombin generation. To study whether vorapaxar reduces thrombin generation indirectly,weselectedtwoupstreambiomarkersofcoagulation activity, factor IXa-antithrombin (FIXa-AT) and factor Xa-antithrombin (FXa-AT). As a marker of downstream coagulation activity, we measured thrombin–antithrombin (TAT) complexes. Finally, to study the additional effect onplatelet activity, soluble P-selectin was assessed as a plasma biomarker of αgranule release induced by platelet activation.4–6 The study was performed on plasma samples obtained from patients from three Norwegian centers participating in the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events—Thrombolysis in Myocardial Infarction 50-trial (TRA2°P-TIMI-50).1 The institutional review board approved the study protocol and all patients gave written informed consent. Patients with a previous history of myocardial infarction were randomly assigned to receive either vorapaxar (2.5mgdaily) or placebo in a blinded fashion, on top of standard antiplatelet agents, as managed by the treating physicians according to standards of care.1,7 Patients using anticoagulant medication during follow-up were excluded. A total of 135 patients with stable CAD were randomized to vorapaxar (n1⁄4 73) or placebo (n1⁄4 62). Baseline characteristics including age, comorbidity, and co-medication were well balanced between both groups (►Table 1). To study the effects of long-term treatment, blood samples were taken after amean study drug exposure of 904 ( 149) days. The use of concomitant antiplatelet agents was comparable between both groups; at the time of blood sampling, 92.6 and 22.2% were treated with aspirin and clopidogrel, respectively. According to solubleP-selectin levels, platelet activationwas reduced in vorapaxar-treated patients compared with the placebo group (24.9 ng/mL [interquartile range, IQR: 20.0– 31.5] vs. 29.3 [IQR: 22.3–32.5]; p1⁄4 0.027). No difference was found in FIXa-AT levels (94.0 27.1 vs. 94.5 34.0; p1⁄4 0.93), FXa-AT levels (282.0 57.4 vs. 296.4 54.6; p1⁄4 0.14), and TAT levels (4.0 [IQR: 3.1–5.0] vs. 3.8 [IQR: 3.0–4.9]; p1⁄4 0.71) between the vorapaxar-group and placebo-group (►Fig. 1). No differences in platelet or coagulation biomarker levels were found when comparing patients on single or dual antiplatelet therapy for both treatment groups (►Appendix A). Our data suggest that, on top of aspirin and/or clopidogrel, vorapaxar further reduces platelet activation in patients with stable CAD. This fits with the observed reduction in

Effects of the PAR-1 Antagonist Vorapaxar on Platelet Activation and Coagulation Biomarkers in Patients with Stable Coronary Artery Disease