• Brett E Skolnick, Magdy Shenouda, Naum M Khutoryansky, Anthony E Pusateri, Don Gabriel, and Marcus E Carr.
• Novo Nordisk, 100 College Rd. West, Princeton, NJ 08540, USA. BRES@novonordisk.com
• Anesth. Analg.. 2011 Oct 1;113(4):703-10.

BackgroundClopidogrel (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.MethodsIn this single-center, randomized, placebo-controlled, double-blind, dose-escalation, exploratory phase I trial, we assessed the safety and effects of rFVIIa in reversing clopidogrel-enhanced 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.ResultsA 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 μg/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 μg/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).ConclusionsIn this clinical study, rFVIIa (10 and 20 μg/kg) reversed the effect of clopidogrel on blood loss.

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