An approach to target joint bleeding in hemophilia: Prophylaxis for all or individualized treatment?
Article Outline
MASAC, Medical and Scientific Advisory Council
Ten years ago, the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation recommended prophylaxis as optimal therapy for severe hemophilia (MASAC Medical Bulletin #193). Oddly, this important but expensive treatment modality was fully embraced without the debate and scrutiny usually reserved for costly diseases. And why not? Hemophilia, the “royal disease,” has usually commanded a larger medical focus than the approximately 18,000 current US hemophilia patients would seem to dictate. Hemophilia can indeed “hold court” because of its association with the lineage of Queen Victoria and, more important, the cost of treatment. In this issue of The Journal, the role of prophylaxis in preventing joint disease has resurfaced for a novel fiscal analysis. Kern and colleagues thoughtfully weigh the financial impact of joint disease on hemophilia treatment.1 There are no studies that focus on the cost implication surrounding the development of a target joint in this population.
Kern et al1 studied 16 boys, over a 20-year period, in order to assess the financial impact of the development of a target joint. These patients were managed similarly, both for treatment of a joint bleed (2 infusions/bleed) and for management of persistent target joint bleeding (prophylaxis followed by surgical synovectomy). Fifteen of the patients developed a target joint, defined as 3 bleeds over a 3-month time frame. The results were not unexpected. The cost of treating a patient after development of a target joint increased by more than twofold, and the vast majority of this expenditure was related to factor concentrate (90%). The median age at which these children developed a target joint was just under 4 years, with the youngest child being 15 months of age. These 15 patients developed an average of three target joints over the course of observation. The number of bleeding episodes after establishment of a target joint tripled from baseline (3 bleeds before target joint development; 10 bleeds after). Patients underwent surgery for persistent synovitis approximately 2 years after initiating prophylaxis. The conclusion from this study seems firm; that treatment of target joint bleeding is expensive. Yet the implications of these findings, that prophylaxis is the best means to reduce target joint bleeding, may be less certain. Whether the authors are correct in their assertion first requires a brief retrospective of hemophilic joint disease as well as what is known about prophylaxis.
Joint disease remains the hallmark of hemophilia, and its spectrum is best characterized by the landmark study of Aledort and colleagues, who defined a 90% joint disease prevalence in severe hemophilia.2 Patients with severe hemophilia in the study usually experienced a mean of 15 bleeds/year, and this arthropathy caused restriction of activity in at least 50% of affected patients. More recent prevalence data regarding target joint bleeding (defined as 4 bleeds/6 months) is best provided by information within the Uniform Data Collection of the Centers for Disease Control. Their data suggests that 37% of patients with hemophilia will eventually manifest a target joint (Uniform Data Collection, October 2003).
Because severe hemophiliacs (<1% FVIII/FIX levels) are the most likely to manifest joint disease, it seemed appealing to early investigators that raising factor levels above this threshold by the use of regular or prophylactic infusions of factor concentrate might limit joint disease. Indeed, Hirschman and colleagues demonstrated that maintaining trough FVIII/FIX levels of 2% was associated with reduced bleeding.3 Prophylaxis to raise FVIII/IX levels with plasma was first attempted in the early 1940s, but volume considerations precluded widespread use. In 1976, Aronstam et al performed the only known randomized, blinded, crossover trial to assess the efficacy of weekly prophylaxis with FVIII concentrate. In this small study of 9 school-age boys with target joint bleeding, they demonstrated a 15% (13.6 to 11.6 bleeds/100 days) reduction in bleeding compared with a placebo control.4
It would appear that prophylaxis is effective in reducing joint bleeding, but can it also limit joint damage? Data from Aldedort and colleagues1 and from Fischer et al5 would suggest that it does not. Although the patient populations from these two studies were different in terms of age and extent of joint disease, both groups continued to have bleeding while on prophylaxis (5.7 and 3.7 bleeds/year; respectively) while also demonstrating radiographic progression.
So what data are available concerning the efficacy of prophylaxis in preventing joint disease? The pivotal study in defining the effectiveness of this form of therapy is from the work of Nilsson and colleagues, who demonstrated that prophylaxis, initiated between 1 and 2 years of age, utilizing FVIII or FIX concentrates at a frequency of 2 to 3 times per week to keep trough factor levels >1%, would allow for pristine joints, by both physical and radiographic examination, into early adult life.6 Despite these remarkable results, there remains some criticism of this investigation. First, patient numbers were small (n
=15) and the study was retrospective and not controlled. Second, the prophylactic schedule demanded a high level of parental and patient commitment with frequent visits to the outpatient clinic for the very young children. Finally, cost was not factored prominently into the treatment schema. Nonetheless, it was this work that prompted MASAC to recommend prophylaxis as standard therapy for children with severe hemophilia.
Although agreeing with the concept of prophylaxis, other investigators have argued for a different approach. The Canadian group has demonstrated the utility of initiating prophylaxis early and on a weekly basis.7 They showed that half of their patients (n=12) had normal joints, maintained on once weekly FVIII dosing (50 IU/kg).7 Similarly, Dutch clinicians wait until the first joint bleed (median 2.2 years) and then start with a lower dosing schedule (30 IU/kg/week).5 Investigators from Sweden currently initiate therapy, often once weekly and always at an early age (<3 years).8 In this study, age at initiating prophylaxis was more important to maintaining joint health than the factor dose utilized or the dosing interval.
The lack of randomized trials to discern the role and effectiveness of prophylaxis in hemophilia is troubling. Most consider the benefit of prophylaxis to be a foregone conclusion and that all children with severe hemophilia should be utilizing regular infusions of factor. This is more likely to be true in Europe and in Canada, but it is not the case in the United States, where only 47% of hemophilia A patients are on regular, at least weekly, FVIII infusions.9 Thankfully, there are two trials near completion, one from Italy and the other from the United States, which should answer in a controlled, prospective way, whether prophylaxis is more effective than aggressive (2-3 infusions/bleed) replacement therapy for prevention of joint disease. These results should be balanced with consideration of potential adverse events and cost. The most troubling side effects of prophylaxis in small children are the potential complications of central venous access. Infection is a well-known complication as is the growing concern of silent thrombosis, approaching 80% in one small prospective series.10
So how can one manage or prevent development of a target joint? One approach is to consider prophylaxis of all children with severe hemophilia at an early age, before joint bleeding, perhaps individualizing therapy to once weekly infusions. For this option, in the United States at least, one must consider use of a central venous catheter with its attendant risks. Additionally, this approach would unnecessarily treat the 10% to 15% of severe hemophiliacs who do not manifest joint bleeding. A second option would be to individualize prophylactic therapy based on the patient's bleeding pattern, starting before 3 years of age and escalating therapy from once weekly treatment as needed. A third option would be to initiate short term prophylaxis (3 months) after an early target joint is established (2 bleeds into a joint) and, if bleeding recurs, then consider a synovectomy (arthroscopic or radionuclide) or continued prophylaxis. This option would first need to be tested in the scrutiny of a clinical trial but has the potential advantage of removing the thickened synovium with resultant decreased bleeding and the opportunity to avoid the cost of long-term prophylaxis with its potential venous access complications.11
Kern and colleagues have presented data to suggest that the cost of treating an established target joint is quite high. They argue that maintenance of long-term prophylaxis before joint disease is established appears a viable option. However, this retrospective study probably did not capture some joint bleeds, and patients with established joint disease who failed prophylaxis waited almost 2 years before a synovectomy was performed. Additionally, only patients with clinical synovitis underwent a surgical procedure. All of these considerations suggest that the extent of joint damage in this group of patients may have been greater than realized. Accordingly, the fiscal impact may have been less if intervention (prophylaxis or synovectomy) were sooner.
Assuming that the randomized trials currently in progress support the efficacy of prophylaxis, this author would advocate for an individualized prophylactic schedule based on the patient's bleeding pattern. And, hopefully, clinical trials addressing surgical/radionuclide intervention in early target joint bleeding may support the role of synovectomy in the management of hemophilic arthropathy.
References
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PII: S0022-3476(04)00759-0
doi:10.1016/j.jpeds.2004.08.040
© 2004 Elsevier Inc. All rights reserved.
Refers to article:
- Clinical and cost implications of target joints in Canadian boys with severe hemophilia A
