Journal article
Reversal of Clopidogrel-Induced Bleeding with rFVIIa in Healthy Subjects: A Randomized, Placebo-Controlled, Double-Blind, Exploratory Study
Anesthesia and analgesia, v 113(4), pp 703-710
01 Oct 2011
PMID: 21890888
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
BACKGROUND: Clopidogrel (Plavix (R)) therapy, although effective for minimizing risk of thrombotic events, is also associated with potential bleeding risk. Recombinant activated FVII (rFVIIa, NovoSeven (R)) 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 (R)] 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 mu 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 mu g/kg rFVIIa (P = 0.048). Ex vivo analysis of rFVIIa demonstrated clotting dynamics presented by parameters time to clot onset (TEG (R)-R) and clot angle (TEG (R)-A) (P < 0.005).
CONCLUSIONS: In this clinical study, rFVIIa (10 and 20 mu g/kg) reversed the effect of clopidogrel on blood loss. (Anesth Analg 2011;113:703-10)
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Details
- Title
- Reversal of Clopidogrel-Induced Bleeding with rFVIIa in Healthy Subjects: A Randomized, Placebo-Controlled, Double-Blind, Exploratory Study
- Creators
- Brett E. Skolnick - Novo Nordisk, 100 College Rd. West, Princeton, NJ 08540, USA.Magdy Shenouda - MDS Pharma ServicesNaum M. Khutoryansky - NOVO NORDISK ASAnthony E. Pusateri - NOVO NORDISK ASDon Gabriel - College Station Medical CenterMarcus E. Carr - Novo Nordisk (United States)
- Publication Details
- Anesthesia and analgesia, v 113(4), pp 703-710
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 8
- Grant note
- Novo Nordisk Inc., Princeton, NJ; Novo Nordisk
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Engineering Technology
- Web of Science ID
- WOS:000295215100008
- Scopus ID
- 2-s2.0-80053327833
- Other Identifier
- 991019335225104721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Anesthesiology