Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia

Marilyn J. Manco-Johnson, M.D., Thomas C. Abshire, M.D., Amy D. Shapiro, M.D., Brenda Riske, M.S., M.B.A., M.P.A., Michele R. Hacker, Sc.D., Ray Kilcoyne, M.D., J. David Ingram, M.D., Michael L. Manco-Johnson, M.D., Sharon Funk, B.Sc., P.T., Linda Jacobson, B.S., Leonard A. Valentino, M.D., W. Keith Hoots, M.D., George R. Buchanan, M.D., Donna DiMichele, M.D., Michael Recht, M.D., Ph.D., Deborah Brown, M.D., Cindy Leissinger, M.D., Shirley Bleak, M.S.N., Alan Cohen, M.D., Prasad Mathew, M.D., Alison Matsunaga, M.D., Desiree Medeiros, M.D., Diane Nugent, M.D., Gregory A. Thomas, M.D., Alexis A. Thompson, M.D., Kevin McRedmond, M.D., J. Michael Soucie, Ph.D., Harlan Austin, Ph.D., and Bruce L. Evatt, M.D.

ABSTRACT

Background Effective ways to prevent arthropathy in severe hemophilia are unknown.

Methods We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).

Results Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.

Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov] .)