Reversal of Clopidogrel-Induced Bleeding with rFVIIa in Healthy Subjects: A Randomized, Placebo-Controlled, Double-Blind, Exploratory Study

BACKGROUND: Clopidogrel (Plavix) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven) induces hemostasis in hemophilia patients with inhibitors (alloantibodies) and has been proposed as potential treatment for mitigating clopidogrel therapy–mediated bleeding. METHODS: In this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrelenhanced bleeding in an experimentally induced punch biopsy in healthy subjects. Efficacy assessments included the reversal of bleeding characteristics (bleed duration [BD], the primary end point and blood loss volume [BV] induced by punch biopsy, and thromboelastograph [TEG] parameters) with rFVIIa or placebo after clopidogrel treatment. RESULTS: A significant number of subjects (56%) had limited response to clopidogrel (defined as 30% platelet aggregation inhibition) and were discontinued from study. The remaining subjects continued and had 4 biopsies. Of 40 subjects randomized, 37 were evaluated for efficacy. Clopidogrel treatment increased BD and BV compared with the baseline biopsy. Recombinant FVIIa (10 and 20 g/kg) significantly mitigated the clopidogrel-induced effects on BV (P 0.007 and P 0.001, respectively). Early trial termination limited the evaluation of effects of higher rFVIIa doses. Subgroup analyses of subjects biopsied by the same physician demonstrated significant reduction of clopidogrel-induced BD with 20 g/kg rFVIIa (P 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG-R) and clot angle (TEG-A) (P 0.005). CONCLUSIONS: In this clinical study, rFVIIa (10 and 20 g/kg) reversed the effect of clopidogrel on blood loss. (Anesth Analg 2011;113:703–10)