Effects of Vorapaxar on Clot Characteristics, Coagulation, Inflammation, and Platelet and Endothelial Function in Patients Treated with Mono‐and Dual‐Antiplatelet Therapy

BACKGROUND: Vorapaxar is indicated with standard antiplatelet therapy (APT) in patients with a history of myocardial infarction (MI) or peripheral arterial disease (PAD). OBJECTIVES: To evaluate the comparative effects of vorapaxar on platelet-fibrin clot characteristics (PFCC), coagulation, inflammation, and platelet and endothelial function during treatment with daily 81 mg aspirin (A), 75 mg clopidogrel (C), both (C + A), or neither. METHODS: Thrombelastography, conventional platelet aggregation (PA), ex vivo endothelial function by ENDOPAT, coagulation, platelet activation/inflammation marked by urinary 11-dehydrothromboxane B2 (UTxB2 ) and safety were determined in patients who were APT naive (n = 21), on C (n = 8), on A (n = 29), and on A + C (n = 23) during 1 month of vorapaxar therapy and 1 month of offset. RESULTS: Vorapaxar had no effect on PFCC, ADP- or collagen-induced PA, thrombin time, fibrinogen, PT, PTT, von Willebrand factor (vWF), D-dimer, or endothelial function (P > .05 in all groups). Inhibition of SFLLRN (PAR-1 activating peptide)-stimulated PA by vorapaxar was accelerated by A + C at 2 hours (P < .05 versus other groups) with nearly complete inhibition by 30 days that persisted through 30 days after discontinuation in all groups (P < .001). SFLLRN-induced PA during offset was lower in APT patients versus APT-naive patients (P < .05). Inhibition of UTxB2 was observed in APT-naive patients treated with vorapaxar (P < .05). Minor bleeding was only observed in C-treated patients. CONCLUSION: Vorapaxar had no influence on PFCC measured by thrombelastography, coagulation, or endothelial function irrespective of APT. Inhibition of protease activated receptor (PAR)-1 mediated platelet aggregation by vorapaxar was accelerated by A + C and offset was prolonged by concomitant APT. Vorapaxar-induced anti-inflammatory effects were observed in non-aspirin-treated patients.