title: Reversal of clopidogrel-induced bleeding with rFVIIa in healthy subjects: a randomized, placebo-controlled, double-blind, exploratory study.
abstract: 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 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.
  
  
  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 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).
  
  
  CONCLUSIONS
  In this clinical study, rFVIIa (10 and 20 μg/kg) reversed the effect of clopidogrel on blood loss.
authors: Novo Nordisk, 100 College Rd. West, Princeton, NJ 08540, USA. BRES@novonordisk.com
authors: Brett E
authors: BE
authors: Skolnick
authors: Magdy
authors: M
authors: Shenouda
authors: Naum M
authors: NM
authors: Khutoryansky
authors: Anthony E
authors: AE
authors: Pusateri
authors: Don
authors: D
authors: Gabriel
authors: Marcus E
authors: ME
authors: Carr
mesh_terms: D000328:Adult; D001706:Biopsy; D000077144:Clopidogrel; D004311:Double-Blind Method; D015942:Factor VIIa / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy*; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009515:New Jersey; D015990:Placebo Effect; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D010979:Platelet Function Tests; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013916:Thrombelastography; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006490:Hemostatics; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D000077144:Clopidogrel; C103587:recombinant FVIIa; D015942:Factor VIIa; D013988:Ticlopidine