Anti-Inhibitor Coagulant Complex Prophylaxis in Hemophilia with Inhibitors
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.
N Engl J Med 2011; 365:1684-1692November 3, 2011
Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established.
We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period.
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.
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.)
Supported by a research grant from Baxter BioScience.
Dr. Leissinger reports serving on advisory boards and receiving lecture fees from Baxter and Novo Nordisk, and receiving grant support from Baxter and fees for the development of educational presentations from Novo Nordisk; Dr. Gringeri, serving on advisory boards for and receiving lecture fees and travel fees from Baxter; Dr. Berntorp, serving on advisory boards for and receiving lecture fees and grant support from Baxter; Dr. Carpenter, receiving grant support from Baxter; Ms. Jo, receiving consulting fees from Baxter; Dr. Kavakli, receiving grant support, lecture fees, and travel expenses from Baxter and Novo Nordisk; Dr. Lassila, providing expert testimony for Baxter and Novo Nordisk and receiving lecture fees and travel expenses from Baxter; Dr. Négrier, serving on advisory boards for and receiving consulting fees, grant support, lecture fees, and fees for development of educational presentations from Baxter; Dr. Rocino, serving on advisory boards for Baxter and receiving consulting fees from Baxter, Novo Nordisk, Bayer, and Pfizer, and receiving lecture fees from Baxter, Novo Nordisk, and Bayer; Dr. Schramm, serving on advisory boards for Wyeth and Pfizer; Dr. Uscatescu, serving on advisory boards for and receiving consulting fees from Baxter; Dr. Zülfikar, receiving consulting fees from Baxter; and Dr Windyga, serving on advisory boards and receiving consulting fees from Baxter.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
Drs. Leissinger and Gringeri contributed equally to this article.
We thank Dr. Louis Aledort for serving as the data safety monitor and Michele Grygotis for providing editorial assistance with an earlier version of the manuscript.