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: Brett E Skolnick, Magdy Shenouda, Naum M Khutoryansky, Anthony E Pusateri, Don Gabriel, Marcus E Carr
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 113 Issue 4 Pg. 703-10 (Oct 2011) ISSN: 1526-7598 [Electronic] United States
• PMID: 21890888 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Hemostatics
• Platelet Aggregation Inhibitors
• Recombinant Proteins
• Clopidogrel
• recombinant FVIIa
• Factor VIIa
• Ticlopidine

Topics

• Adult
• Biopsy
• Clopidogrel
• Double-Blind Method
• Factor VIIa (adverse effects, therapeutic use)
• Hemorrhage (chemically induced, drug therapy)
• Hemostasis (drug effects)
• Hemostatics (adverse effects, therapeutic use)
• Humans
• Male
• New Jersey
• Placebo Effect
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (adverse effects)
• Platelet Function Tests
• Recombinant Proteins (adverse effects, therapeutic use)
• Thrombelastography
• Ticlopidine (adverse effects, analogs & derivatives)
• Time Factors
• Treatment Outcome
• Young Adult