In many studies of hemophilia A, only treated bleeds are reported. However, a significant proportion of bleeding events go untreated in this patient population, according to findings of a prospective cohort study.
“Annualized bleeding rate (ABR) is often used as the primary endpoint in clinical trials because the frequency and cumulative occurrence of bleeds is strongly correlated with long-term joint function,” according to Michael U. Callaghan, MD, of Central Michigan University in Detroit, and colleagues who published their findings in Research and Practice in Thrombosis and Haemostasis. “However, data collection on bleeds is often connected with treatment in clinical studies, potentially resulting in underestimated ABRs if only treated bleeds are documented, with untreated bleeds remaining unrecorded.”
To help establish a baseline of untreated bleeds in patients with hemophilia A on standard factor VIII (FVIII) or bypassing agent therapy, Dr. Callaghan and colleagues prospectively collected data using the Bleed and Medications Questionnaire from three patient groups: cohort A included patients ages 12 or older with FVIII inhibitors (n=103), cohort B included patients younger than 12 with FVIII inhibitors (n=24), and cohort C included patients ages 12 or older without FVIII inhibitors (n=94).
Data from this noninterventional study (NIS) were then compared with data in the same individuals after they transferred to one of the phase III HAVEN trials, open-label studies evaluating emicizumab prophylaxis.
Among the 221 enrolled patients in the NIS study, the incidence of untreated bleeds was about 40% of all bleeds in patients with FVIII inhibitors (39.8% in cohort A and 40.1% in cohort B) and 26.2% in patients without inhibitors. About half of the untreated bleeds that occurred in patients receiving prophylactic treatment were followed by a dose of coagulation factor within 24 hours.
For cohorts A and C, the majority of treated and untreated bleeds were in the joints. In the younger cohort B, only 7.1% of untreated bleeds were in the joints, most commonly the knee (63.6%).
Untreated muscle bleeds varied across cohorts. Adults and adolescents with FVIII inhibitors had a rate of 13.5% for untreated muscle bleeds versus a rate of 32.6% in those without inhibitors. The pediatric cohort B had a rate of 7.7%.
According to the researchers, among the pediatric cohort, the most common location for untreated bleeds was “other.” Bleed locations included the knee, mouth, back of knee, or shin.
Spontaneous bleeds accounted for the majority of untreated bleeds in adults and adolescents with inhibitors (63.0%), but a minority in those without FVIII inhibitors (35.8%).
In the HAVEN trials, all transferred patients received emicizumab 1.5 mg/kg every week. Comparison after enrollment in HAVEN showed reduced treated and untreated bleeds after initiation of emicizumab prophylaxis.
Dr. Callaghan and colleagues acknowledged that both the NIS and HAVEN studies were limited by the use of patient-reported bleeds, which could result in over- or under-reporting. In addition, “the finding that half of the participants who were on prophylaxis in the NIS administered a dose of factor concentrate within 24 [hours] after an untreated bleed adds further complexity to the interpretation of these data,” they wrote. Outside of a trial these patients may have instead adjusted their prophylaxis dosing schedule as needed.
“A significant proportion of subjectively perceived bleeds in people with hemophilia A remain untreated, suggesting that the full burden of the disease is not adequately captured in many clinical studies,” the researchers wrote. “An understanding of why some bleeding events remain untreated is needed, and capturing these events in clinical trials would provide a more comprehensive evaluation of therapies.”
Any conflicts of interest declared by the authors can be found in the original article.
Callaghan MU, Asikanius E, Lehle M, et al. Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3. Res Pract Thromb Haemost. 2022;6(6):e12782.