Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3

Abstract

Background Bleeding in people with hemophilia A can be life threatening, and intra‐articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported. Objectives We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice. Patients/Methods Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial. Results In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra‐individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis. Conclusion A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies.

Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies

“…This may reflect concerns about the predictability of hemostasis provided by BPAs, which is in agreement with the high proportion of untreated bleeds seen in the HAVEN 1 and 2 studies in PwHA with FVIII inhibitors compared with HAVEN 3, which was in PwHA without FVIII inhibitors. 25 The number of treated bleeds was low in PwHA both with or without FVIII inhibitors across both the major and minor procedures, suggesting that emicizumab provides hemostatic benefits for patients with or without FVIII inhibitors.…”

Defining success in haemophilia care – Are we doing it right?

“…While untreated bleeds may be a possibility in clinical practice depending on local protocols, 29 that should surely not be allowed to extend into clinical trials. It is good that a very recent report of data from a clinical trial of a non-CFC product has reported all joint bleeds and not just the treated ones.…”

Untreated bleeds: Unveiling the subtleties and challenges of bleeding event counts and patient experience in clinical trials for bleeding disorders

“…Now consider a similar situation with joint bleeding. Fortunately, joint bleeding has a published definition, which was used in the HAVEN studies 5 . The 2014 ISTH guidelines define joint bleeding as a joint “aura” in combination with swelling/warmth, pain, and loss of range of motion of the joint, and note that improvement of symptoms with administration of clotting factor and rest can help distinguish arthropathy pain from bleeding 6 .…”

“…The HAVEN studies, 1 , 2 , 3 , 4 which have demonstrated the efficacy and safety of emicizumab, differed from most previous hemophilia studies not only in prophylaxis mechanism; they presented bleeding event data for both treated and untreated bleeds. In this issue of RPTH , Callaghan et al 5 present all available details of the untreated bleeds in HAVEN studies 1–3, including adults with HA and inhibitors (HAVEN 1), children with HA and inhibitors (HAVEN 2), and adults with HA without inhibitors (HAVEN 3).…”

“…Fortunately, joint bleeding has a published definition, which was used in the HAVEN studies. 5 The 2014 ISTH guidelines define joint bleeding as a joint "aura" in combination with swelling/warmth, pain, and loss of range of motion of the joint, and note that improvement of symptoms with administration of clotting factor and rest can help distinguish arthropathy pain from bleeding. 6 A new musculoskeletal bleed is defined as bleeding occurring more than 72 h after an Bleeding event identification is likely to get even more challenging as prophylaxis continues to improve and bleeding rates continue to decrease (Figure 1).…”