Untreated bleeds often go undocumented during clinical trials, but reporting these bleeding events could provide additional insight into therapy efficacy.
A significant portion of bleeding events go untreated and unreported in patients with hemophilia A, a noninterventional study published in Research and Practice in Thrombosis and Haemostasis found. The study highlights a need for recording untreated bleeds in clinical trials and identifying why they go untreated.
Coagulation factor VIII (FVIII) deficiency causes hemophilia A, which can lead to life-threatening bleeds in patients with the condition. Hemophilia A is often managed with prophylactic treatment, but there is still a possibility of breakthrough bleeds occurring in patients on FVIII or bypassing agent prophylaxis. In clinical trials, the primary end point is often annualized bleeding rate (ABR), but untreated bleeds often go undocumented during trials in which data collection on bleeding is connected to treatment. When bleeds go untreated, they can contribute to arthropathy and disease burden.
“A baseline of treated and untreated bleeds in individuals on standard FVIII or bypassing agent therapy (taken on demand or prophylactically) needs to be established to serve as a comparator for treatment-related outcomes with nonfactor therapies, such as emicizumab, a bispecific, humanized, monoclonal antibody, which demonstrated highly efficacious bleed protection across the HAVEN clinical study program,” the authors wrote.
The observational, noninterventional study explored bleeding rates in adolescents and adults with hemophilia A with or without FVIII inhibitors, as well as children with hemophilia A with FVIII inhibitors. The Bleed and Medication Questionnaire (BMQ) was used to collect data from patients on all bleeds, regardless of treatment or non-treatment.
A total of 221 participants were included in the study and stratified into 3 cohorts. Cohort A included 102 adults and adolescents with FVIII inhibitors monitored for a median of 26 weeks; cohort B included 24 children with FVIII inhibitors monitored for a median of 23.4 weeks; and cohort C included 94 adults and adolescents without FVIII inhibitors monitored for a median of 29.8 weeks.
Out of 1656 total bleeds recorded in cohort A, 659 (39.8%) were untreated, with 74 patients (71.8%) reporting untreated bleeds. In cohort B, 156 bleeds out of 389 (40.1%) were untreated, with 13 patients (54.2%) reporting untreated bleeds. Of 1653 recorded bleeds in cohort C, 433 (26.2%) were untreated, with 45 patients (47.9%) reporting untreated bleeds. Model-based ABRs for untreated bleeds in cohorts A, B, and C were 13.6, 15, and 7, respectively. The ABR for patients in cohort C on prophylactic therapy was 1.5, while the ABR for patients receiving episodic therapy was 12.9.
The majority of untreated bleeds in cohorts A and C were reported in joints, including the knee, elbow, ankle, and others. In cohort B, joint bleeds only accounted for 7.1% of untreated bleeds and were most often in the knee. Across the cohorts, proportions of treated muscle bleeds were similar while the proportions of untreated muscle bleeds varied. In adults and adolescents with FVIII inhibitors, 63% of untreated bleeds were spontaneous, versus 35.8% in patients without FVIII inhibitors.
The study also included an analysis of patients who enrolled in interventional studies of emicizumab as prophylaxis for hemophilia A. Of the 221 participants in the noninterventional study, 24 adults and adolescents joined the HAVEN 1 study (NCT02622321), 14 children with FVIII inhibitors entered the HAVEN 2 study (NCT02795767), and 48 adults and adolescents without FVIII inhibitors entered the HAVEN 3 study (NCT02847637).
The ABR for untreated bleeds decreased from 8.5 on bypassing agent prophylaxis to 2.3 in emicizumab prophylaxis in adults and adolescents with FVIII inhibitors enrolled in HAVEN 1. In pediatric patients, the ABR for untreated bleeds decreased from 14.8 during the noninterventional study to 4 in HAVEN 2. In adults and adolescents without FVIII inhibitors, there was no significant change between ABRs during the noninterventional study and during HAVEN 3. Untreated bleed proportions were higher in the HAVEN studies versus their corresponding cohorts in the noninterventional study. Proportions of spontaneous bleeds, however, decreased on emicizumab versus standard prophylaxis.
While both the noninterventional study and the HAVEN studies were limited by their reliance on patient reporting via the BMQ, the findings show that a high proportion of bleeds in patients with hemophilia A go untreated.
“The decision to treat a bleed or not is complex and may be influenced by patient-specific factors such as age and the presence of an inhibitor, as well as bleed and treatment characteristics,” the authors concluded. “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.”
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. Published online September 13, 2022. doi:10.1002/rth2.12782