Like thousands of other people with hemophilia A, 17-year-old Sean O’Connor lacks the genetic machinery to produce a working version of factor VIII. But O’Connor, a tall and lanky high school junior in Fruita, Colorado, has been protected by hemophilia prophylaxis since he was four years old. He is among a new generation who may be spared the devastating joint disease that is often a consequence of the disorder later in life.
“His joints are exceptional,” says his mother, Cindi Skalla. “Not one target joint.”
Skalla knows the consequences of hemophilia well. Her younger brother, Kurt, also has severe hemophilia. She grew up watching him cope with the disorder: the bleeds, the risk of infectious disease, joints ravaged by arthropathy (joint disease), surgery to fuse an ankle joint. She compares the experiences of her son and her brother, who is now 40 years old. “When I think of the life he’s had to live, and then you look at Sean, it’s beyond remarkable.”
For more than 40 years, doctors who care for people with hemophilia have known that therapy with replacement clotting factor can reduce bleeding into joints, lowering the risk of a common and troublesome complication of bleeding disorders—the joint deterioration that results from repeated bleeds.
Hemophilia is the oldest inherited bleeding disorder, recognized for centuries. However, it was not until the 1960s and the advancements in cryoprecipitate that clinicians could use and compare different approaches to manage the treatment of hemophilia and its complications.
Any remaining doubts about the value of prophylactic therapy were put to rest by a landmark study published by Marilyn J. Manco-Johnson, MD, and colleagues in the August 9, 2007, issue of The New England Journal of Medicine.
For the first time, a well-controlled, randomized clinical trial showed that regular prophylaxis with recombinant factor VIII can prevent joint disease in young boys with severe hemophilia A.
“The results will be very useful for people with hemophilia for a long, long time,” said Manco-Johnson, medical director of Mountain States Regional Hemophilia and Thrombosis Center, a hemophilia treatment center (HTC) in Denver, when presenting preliminary study findings at the National Hemophilia Foundation’s 58th Annual Meeting in Philadelphia in October 2006.
“This confirms what had been shown by retrospective data,” says collaborating hematologist W. Keith Hoots, MD, professor of pediatrics at the University of Texas in Houston and medical director of Gulf States Hemophilia & Thrombophilia Treatment Center. “This strengthens the argument for prophylaxis.”
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Although the benefits of hemophilia prophylaxis seemed increasingly apparent, other forces have worked against its wider practice in the US.
Hoots, Manco-Johnson and others familiar with the issue suggest several reasons for the lower prevalence of prophylaxis in the US compared with other developed countries:
- Regular factor infusions pose challenges for many parents of young children. “Prophylaxis can be stressful in its own way,” explains social worker Erin Stang, LCSW, of the Mountain States HTC. “This is not an easy chore. Prophylaxis requires a commitment of valuable and limited resources such as time, energy and finances. It can be too much to expect in a chaotic family system.”
- Prophylaxis, requiring greater quantities of factor, is more costly than on-demand therapy. In the past, some insurers and third-party payers balked at picking up the tab in the absence of concrete scientific evidence that prophylaxis was beneficial.
- Some parents are concerned about the risk of infection with the hepatitis C virus and the human immunodeficiency virus (HIV). These concerns have been mostly resolved by screening, testing and reducing viral load from blood products, as well as the introduction of recombinant factor products.
- There is uncertainty about possible links between the type of factor product and the timing of prophylaxis with the development of inhibiting antibodies.
According to Manco-Johnson, a review of data from the Universal Data Collection project compiled by the Centers for Disease Control and Prevention (CDC) shows that in 2003, only 33% of children under age six with severe hemophilia received prophylaxis; the proportion rose to 49% in 2005.
Momentum toward universal acceptance of prophylactic factor therapy hit a speed bump with the publication of an analysis by the Cochrane Collaborative. Based in Oxford, UK, the organization fosters evidence-based medicine. In April 2006, Cochrane Database of Systematic Reviews published a report on the role of clotting factor prophylaxis in preventing bleeding and bleeding-related complications in people with hemophilia.
The Cochrane team combed through electronic databases, journals and collections of abstracts to identify 29 studies related to prophylactic therapy. Four studies, with a total of only 37 participants, were judged eligible for inclusion in the analysis.
One study demonstrated that those on prophylaxis had a lower frequency of joint bleeds than people who received placebo. Another study found that people with hemophilia B had fewer bleeds when receiving weekly versus biweekly factor infusions. Two other studies compared prophylactic regimens among people with hemophilia A, finding no difference in terms of joint bleeds.
“There is insufficient evidence,” the Cochrane report authors concluded, “to determine whether prophylactic clotting factor concentrates decrease bleeding and bleeding-related complications in hemophilia A or B.”
The Cochrane analysis put the greatest weight on rigorously controlled double-blind clinical trials, in which participants were randomized to receive an active agent or placebo. “Cochrane holds in disdain anything that is not a randomized, controlled clinical trial,” says Paul Giangrande, MD, vice president of the World Hemophilia Foundation (WHF) and chairman of the organization’s medical advisory board.
Although considered the gold standard for clinical research, Giangrande says, randomized placebo-controlled clinical trials are difficult to conduct with conditions such as hemophilia. It would be unethical to give clotting factor to one group of people with hemophilia and inert placebo to another.
However, the case for prophylaxis had been made in other ways, Giangrande and other hematologists contend. The benefits of prophylaxis were seen in cohort studies and retrospective reviews—but had not been proven in a prospective, randomized clinical trial.
The National Hemophilia Foundation and its Medical and Scientific Advisory Council (MASAC) has endorsed prophylaxis since 1994. On the heels of the Cochrane report, in April 2006 MASAC revised a recommendation advising that prophylaxis begin at a young age for people with severe hemophilia A or B.
Joint Health Study
With support from the CDC and the National Institutes of Health, and recombinant factor VIII provided by Bayer HealthCare, Manco-Johnson and a group of researchers from more than 20 HTCs launched a five-year longitudinal study in 1996 to compare prophylaxis to episodic on-demand factor therapy.
“At the time we started our study, very few children—or adults—were being treated with prophylaxis,” Manco-Johnson says.
Sixty-five boys with severe hemophilia who were younger than two and a half years old were randomly assigned to receive regular prophylactic infusions of factor VIII, or an enhanced episodic schedule of infusions at the time of a joint bleed. All of the participants were followed until they were six years old, when their joints were evaluated by clinical exam and magnetic resonance imaging (MRI).
By the time they turned six years old, the boys who received episodic therapy were more than six times more likely to have joint damage detected by MRI than those who had prophylaxis. Of those on prophylaxis, 93% were considered to have normal joints, compared with 55% in the group receiving episodic treatment.
The study settles any uncertainty that may remain about the clinical value of prophylactic factor therapy for people with severe hemophilia. “If there were any insurer or third-party payer that was reluctant to pay for prophylaxis because of doubts about efficacy, this has put that to rest,” says Hoots.
Observers say that the results of the joint health study are so clear and compelling that it is unlikely that a study like it could be conducted today. Now that prophylaxis is indisputably the standard of care for people with severe hemophilia in the US, withholding it in a clinical trial would be out of the question.
Most insurers and third-party payers have, for the most part, now accepted prophylactic factor therapy as a reasonable and essential benefit. “There aren’t a lot of barriers preventing patients from getting prophylaxis,” says David Linney, hemophilia financial services project coordinator at the Great Lakes Hemophilia Foundation in Milwaukee, Wisconsin.
Some financial issues were raised, however, in an editorial accompanying the Joint Outcomes Study in the August 9, 2007, issue of The New England Journal of Medicine. Gloris Roosendaal, MD, and Floris Lafeber, PhD, both of the University Medical Center Urtecht, the Netherlands, drew attention to the $300,000 average annual cost of prophylaxis and posed the question of costs versus benefits.
The Joint Outcomes Study establishes a benchmark for comparing new treatments and regimens, and will likely spur research into whether prophylaxis helps people with severe hemophilia avoid costly complications in the future. The focus on economic issues will increase the need for economic analyses and quality-of-life studies, Giangrande says.
While the Joint Outcomes Study is a welcome addition to the medical literature and provides key information, several issues related to prophylaxis remain unresolved. Clinical researchers continue to discuss when to initiate prophylaxis, an ideal dosing regimen and choice of venous access.
Still unknown is how long a person should remain on prophylactic therapy, and what the drawbacks could be to its discontinuation. Some clinicians believe that when a person reaches adulthood, factor may be able to be dialed back as the body experiences less stress. MASAC recommendation #179, “Concerning Prophylaxis,” recommends that prophylaxis be continued throughout life.
“The efficacy of prophylaxis has not been proven in adults,” Hoots says. However, he still stands firmly by it. “There seems to be a price on stopping prophylaxis. You’ll always have better joints if you’ve had prophylaxis.”
“In the old days, we didn’t know if you had to take prophylaxis for your whole life,” says Brenda Riske, RN, clinic and research director at the Mountain States HTC. “Now we’re of the opinion that this joint disease will occur, and it won’t go away if you don’t address it.”
The joint health study group continues to follow participants, who return for MRI scans when they are 10, 14 and 18 years old. Investigators will track the health of the participants’ joints over an extended time period.
Like the 31 children who were in the prophylaxis group of the Joint Outcomes Study, O’Connor will probably infuse factor regularly for the rest of his life. “He doesn’t see himself going off prophylaxis,” his mother reports. “He says he feels better when he infuses.”
“Prophylaxis wasn’t a mode of therapy when I started on factor in 1971,” says John Reed, a 48-year-old pharmacist in Cyril, Oklahoma, who has severe hemophilia A. Reed says that the damage to his joints seems to have halted 13 years ago, when he began prophylactic therapy, while others he knows with hemophilia have continued to deteriorate. “I’m in excellent health compared to other people my age who have been on episodic treatment their entire life,” he says. “A lot of these guys keep getting worse, walking with crutches one year and in a wheelchair when I see them again.”
For Stang, the social worker, the joint health study provides assurance that, thanks to prophylaxis, children with hemophilia will have the opportunity to avoid the complications that affected previous generations, and grow up with a healthy self-image as well. “When I look at a group of boys at hemophilia summer camp, I can rarely tell who has hemophilia and who does not,” she says. “All the boys are active and able to participate in camp activities. For these boys, prophylactic treatment has been a real gift.”
Aside from helping to avoid the devastating joint damage that results from repeated bleeds, people on prophylaxis tend to miss less school and work, and are more engaged in activities and their community, says Stang.
Boys with healthy joints tend to be active and enthusiastic, and have the opportunity to explore interests and participate in a variety of activities, Stang says. “They are treated as normal boys and not labeled as ‘different.’ All of these experiences increase the chances of children growing up feeling good about themselves.”