Long-Term Analysis Identifies Encouraging Trends in Hemophilia A Care

From 1999 to 2010, bleeding events among U.S. patients with hemophilia A have dropped dramatically, coinciding with a marked increase in the use of bleeding prophylaxis, according to an analysis of a long-term surveillance project conducted by the Centers for Disease Control and Prevention (CDC) and the United States Hemophilia Treatment Center Network (USHTCN). The study authors, led by Marilyn J. Manco-Johnson, MD, director of the Hemophilia and Thrombosis Center at the University of Colorado in Denver, also identified several factors associated with increased risk of joint hemorrhage and arthropathy.

“Hemophilic arthropathy is caused by recurrent hemorrhage into joints and is related to most adverse hemophilia outcomes, including disability, chronic pain, and invasive surgeries,” Dr. Manco-Johnson and authors wrote. “Our data confirm prophylaxis was effective in reducing joint bleeding rates, total bleeding rates, and target joint bleeding in all age groups regardless of the age of initiation.”

The CDC and USHTCN surveillance project collected data from 6,196 male patients (≥2 years old) who had visited one of 134 USHTCN centers between 1999 and 2010. The prospective, cross-sectional analysis reported by Dr. Manco-Johnson and authors included data from 2,908 patients who had ≥2 visits during the 12-year follow-up period. Age at first visit ranged from 2 to 69 years old, with an average age at first visit of 17.7 years (median = 14 years).

During follow-up, the overall rate of prophylaxis use increased from 31 percent to 59 percent and, by 2010, 75 percent of patients ≤19 years old had been treated with prophylaxis. “The increases have been steady in all age groups, with younger participants adopting prophylaxis earlier than older participants,” the authors noted.

From 1999 to 2010, prophylaxis usage increased as follows (p values not reported):

  • Children (2 to ≤10 years old): 46% to 76%
  • Adolescents (10 to ≤19 years old): 30% to 75%
  • Young adults (20 to ≤29 years old): 11% to 51%

For patients receiving prophylaxis, the rates of joint and total bleeding events during the study period were approximately half the rates for patients not receiving prophylaxis (p<0.01 for each):

  • Total bleeding rate (prophylaxis vs. no prophylaxis): 17% decrease (4.91 events per 6 months in 1999 to 4.07 events per 6 months in 2010) vs. 30% decrease (14.2 to 9.87 events per 6 months)
  • Joint bleeding rate (prophylaxis vs. no prophylaxis): 22% decrease (3.03 events per 6 months in 1999 to 2.36 events per 6 months in 2010) vs. 23% decrease (9.52 to 7.25 events per 6 months)

Notably, target joint bleeding decreased 52 percent in patients using prophylaxis (0.33 [standard deviation = 0.58] to 0.16 [standard deviation = 0.55] target joints; p values not reported) and 65 percent in those not using prophylaxis (1.68 [standard deviation = 2.2] to 0.59 [standard deviation = 1.2] target joints; p values not reported). “The reasons why joint outcomes improved for participants not on prophylaxis is unknown,” the authors wrote.

The researchers also assessed whether rates of total and joint bleeding, number of target joints, proportion of total normal joint range of motion (ROM), race/ethnicity, or obesity predicted arthropathy. They found that, although prophylaxis predicted decreased bleeding at any age (p<0.001), only prophylaxis initiation prior to 4 years of age and non-obesity predicted preservation of joint motion (p<0.001 for each).

Other factors significantly associated with decreased overall joint ROM included advanced age, non-white race, and obesity. In addition, receiving an inhibitor was also negatively associated with decreased ROM, but this association was not statistically significant. See TABLE for more results from this analysis.

“This analysis suggests that continuous prophylaxis lowers the bleeding rate of participants with active joint bleeding but may have little to offer participants with advanced arthropathy and few acute hemarthroses in terms of reduction in bleeding,” the authors concluded. “However, individuals with advanced arthropathy treated with prophylaxis may have decreased pain and increased mobility, permitting physical therapy, increased exercise, improved fitness, and increased participation.”

The study is limited by its cross-sectional nature, which cannot causally relate declining trends in joint hemorrhage with trends of increasing prophylaxis use. In addition, patients’ self-reported bleeding rates could have led to reporting bias.


Reference

Manco-Johnson MJ, Soucie JM, and Gill JC. Prophylaxis usage, bleeding rates and joint outcomes of hemophilia 1999-2010: a surveillance project by the United States Hemophilia Treatment Network (USHTCN) and the Centers for Disease Control and Prevention (CDC). Blood. 2016;128:1405.

TABLE. Multivariate Analysis of the Effect of Prophylaxis on Overall Joint ROM*
Covariates Initial ROM Status Rate of ROM Change
Parameter Estimate p Value Parameter Estimate p Value
Age −0.85 <0.001
Race (white vs. other) 1.56 <0.001
Inhibitor (yes vs. no) −0.46 0.06
BMI (≥85th vs. <85th percentile) −1.07 0.003 −0.09 0.001
Primary prophylaxis <4 years (yes vs. no) 0.96 0.24 0.20 0.03
Primary prophylaxis 4 or 5 years (yes vs. no) 0.92 0.34 0.10 0.29
Secondary prophylaxis (yes vs. no) 0.54 0.46 0.04 0.36
*For 2,908 U.S. hemophilia patients (male; 2-19 years old)

ROM = range of motion; BMI = body mass index

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