Prophylaxis effective at preventing joint bleeds and preserving joint function and structure in young boys with hemophilia A

According to a new landmark study published in The New England Journal of Medicine, infusions of clotting factor VIII used preventively can significantly reduce the risk of developing joint damage associated with joint bleeding in young children with hemophilia A.

The multi-center study involved 15 academic and major treatment institutions throughout the United States, including University of Colorado at Denver and Health Sciences Center, as well as collaboration with the Centers for Disease Control and Prevention and the National Institutes of Health.

The study is the first and only randomized, prospective trial comparing the progression of joint disease in boys with hemophilia A who were treated either with prophylactic or regular, continuous infusions to prevent bleeding, or treated at the time of and in response to bleeding known as episodic on-demand treatment. The findings showed that 93 percent of boys who received prophylactic treatment had normal joints at the age of six compared to only 55 percent in the episodic treatment group. This trial provides the strongest medical evidence to date comparing joint outcomes associated with prophylactic and episodic treatment approaches.

“Our results show for the first time that prophylaxis, initiated between six and 30 months of age, is effective at preventing joint bleeds and preserving joint function and structure in young boys with hemophilia A,” said Marilyn Manco-Johnson, MD, principal investigator of the study and director of the Mountain States Regional Hemophilia and Thrombosis Center at the UCDHSC School of Medicine. “These results provide health care professionals – as well as parents of children with hemophilia A – with solid information to guide optimum treatment.”

Joint damage caused by repeated bleeding into the joints – often referred to as hemophilic arthropathy – is one of the most debilitating and costly consequences of hemophilia A. It can result in long-term inflammation and deterioration of the joint, and ultimately lead to loss of mobility. However, previous retrospective patient studies have suggested that regular, prophylactic infusions of the clotting factor that is deficient given to young patients before they develop permanent joint damage may reduce the risk of hemophilic arthropathy.

“Results from the study indicate the importance of initiating prophylaxis before recurrent bleeding has occurred in individual joints in young boys with severe hemophilia,” said Keith Hoots, MD, study investigator, professor of pediatrics and division head/pediatric hematology, University of Texas Medical School at Houston.

A subset of patients in the study were identified with joint damage despite an absence or low occurrence of overt bleeds into these joints. The investigators suggest that subclinical bleeds – bleeds that are asymptomatic and often go unnoticed – play a role in the development of joint damage. It is speculated that subclinical bleeds may be prevented through prophylactic infusion.

Early signs of joint damage were detected in the study using state-of-the-art magnetic resonance imaging (MRI) techniques. By the time the patients completed the study at six years of age, joint and cartilage damage was significantly greater in the episodic group compared to the prophylaxis group.

Participants in the five-year clinical trial, known as the Joint Outcome Study, used the Kogenate® Bayer product line, a recombinant factor VIII therapy for the treatment of hemophilia A.

The University of Colorado at Denver and Health Sciences Center is one of three universities in the University of Colorado System. Located in Denver, on the Auraria Campus, at Ninth & Colorado Blvd. and on the Anschutz Medical Campus in Aurora, Colo., UCDHSC is Colorado's premier research university offering more than 100 degrees and programs in 12 schools and colleges and serving more than 28,000 students in Metro Denver and online.

The five-year prospective, multi-center, randomized study was conducted at 15 hemophilia treatment centers in the United States, and enrolled 65 boys with hemophilia A between the ages of six months and 30 months. The study was supported by a grant from the Centers for Disease Control and Prevention and the National Institutes of Health. The Hemophilia and Thrombosis Research Society contributed through the recruitment of participating sites. Bayer HealthCare donated a total of 17 million units of recombinant Factor VIII to treat children for the duration of the trial. The children were randomized to receive either a prophylaxis regimen consisting of 25 IU/kg rFVIII every other day (n=32) or enhanced episodic treatment consisting of at least three doses of rFVIII totaling a minimum of 80 U/kg at the time of a joint bleed (n=33). The children were followed until the age of six years, when they were assessed for bone or cartilage damage using X-ray and MRI of damage-prone joints (elbows, knees and ankles). The study also assessed joint function, number of joint hemorrhages and amount of product consumed.

Prophylaxis patients had significantly fewer joint hemorrhages per year and overall number of bleeds per year compared to patients on episodic treatment (mean joint bleeds 0.63 vs. 4.89, respectively; mean total bleeds 3.27 vs. 17.69, respectively; P< 0.001 for both). When evaluated by MRI at the age of six years, 93 percent of children in the prophylaxis group had joints that appeared normal, compared to 55 percent of patients who received episodic treatment (P= 0.002). This translated to an 84 percent reduction in the risk for joint damage in patients who received prophylaxis from an early age. The correlation of hemarthroses with joint scores as measured with MRI was weak (r=0.22 with P<0.001).

Based on MRI, bone or cartilage damage was confirmed in 7 percent of children in the prophylaxis group compared to 45 percent of those in the episodic group (P= 0.002).

Hemophilia A, also known as factor VIII deficiency or classic hemophilia, is largely an inherited bleeding disorder in which one of the proteins needed to form blood clots in the body is missing or reduced. Hemophilia A, the most common type of hemophilia, is caused by deficient or defective blood coagulation proteins, known as factor VIII. Hemophilia A is characterized by prolonged or spontaneous bleeding, especially into the muscles, joints or internal organs. Approximately 400,000 people around the world have hemophilia A.

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