New England Journal of Medicine Publishes Results of Study on Anti-Inhibitor Coagulant Prophylaxis in Hemophilia Patients with Inhibitors

After exposure to factor VIII, alloantibodies (inhibitors) that neutralize factor VIII clotting function develop in approximately 30% of patients with severe hemophilia A.1 The development of high-titer factor VIII inhibitors (>5 Bethesda units [BU]) complicates treatment because bleeding no longer responds to standard factor VIII replacement. Alternative forms of clotting-factor concentrates, known as bypassing agents, are used to treat bleeding in these patients.
Two bypassing agents are currently available: anti-inhibitor coagulant complex (AICC) and recombinant activated factor VII (rFVIIa). Both agents control approximately 80% of bleeding episodes in patients with hemophilia and inhibitors.4 Nonetheless, their hemostatic efficacy is difficult to predict and does not result in the success rates obtained with factor VIII replacement in patients who have hemophilia without inhibitors.5 Consequently, patients with inhibitors are at increased risk for bleeding that is difficult to control.6 Poorly controlled hemarthroses result in the early onset of chronic joint disease and physical disability, which can substantially impair the quality of life.
Prophylaxis, the routine scheduled replacement of factor VIII, is standard care for patients who have severe hemophilia A without inhibitors, because of its ability to prevent bleeding. However, for patients with inhibitors who have refractory bleeding with serious consequences and who could derive an even greater benefit from prevention of bleeding, factor VIII prophylaxis is ineffective.
Although anecdotal reports13-16 have suggested that regular administration of AICC may prevent bleeding in patients with hemophilia A and factor VIII inhibitors, the efficacy of this therapeutic regimen has been unproved. The Prophylaxis with Factor Eight Inhibitor Bypassing Activity (Pro-FEIBA) study was designed to compare the efficacy and safety of AICC prophylaxis with on-demand therapy in this patient population.

Results

Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug.

Conclusions

AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.)
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Medical professionals cited in this article:

Cindy Leissinger, M.D., Alessandro Gringeri, M.D., Bülent Antmen, M.D., Erik Berntorp, M.D., Chiara Biasoli, M.D., Shannon Carpenter, M.D., Paolo Cortesi, M.Sc., Hyejin Jo, M.S., Kaan Kavakli, M.D., Riitta Lassila, M.D., Massimo Morfini, M.D., Claude Négrier, M.D., Angiola Rocino, M.D., Wolfgang Schramm, M.D., Margit Serban, M.D., Marusia Valentina Uscatescu, M.D., Jerzy Windyga, M.D., Bülent Zülfikar, M.D., and Lorenzo Mantovani, D.Sc.