Addressing Underreported and Untreated Bleeds in Hemophilia A Patients

Patients’ daily bleed diaries helped investigators understand why some bleeds are treated, and some are not, as well as their causes, according to research presented at the 60th ASH Annual Meeting & Exposition in San Diego, California, this past weekend.

An international team of investigators conducted a prospective, noninterventional study that recruited 221 male hemophilia A patients aged 12 years or older to understand the differences between treated and untreated bleeds. They also monitored any differences between inhibitor and noninhibitor populations. Other papers on this topic often can be compromised because of the differing definitions of “bleeds” that are used, according to the study authors, although rate of bleeds is often the primary endpoint of clinical studies that involve hemophilia A.

“In contrast to most prior studies that collected data only about treatment events, this tool asked about bleeds and treatment separately,” study author Michael Callaghan, MD, clinical associate professor of pediatrics at Wayne State University School of Medicine in Detroit, Michigan, told Rare Disease Report®. “Prior studies therefore only captured and reported the treated bleeds and there was an assumption that all bleeds were treated. We know that some bleeds are not treated but [we] were surprised by the high number and type of untreated bleeds, including many joint bleeds.”

Study participants were invited to complete a daily bleed and medication questionnaire (developed by a sponsor, the investigators noted) on a handheld device. This provided them with data about all bleeds, including location, whether they were treated or untreated, medications used, and the reasons for use, including if factor VIII or bypassing agents were involved. The investigators said that this unique perspective allowed for an “exploratory examination” of differences between the treated and untreated bleeds.

“These data became very important because many of these participants went on the HAVEN trials of emicizumab which used the same tool to collect data and allowed for intrapatient comparison of treatment on standard of care before emicizumab to emicizumab,” Dr. Callaghan added.

There were 103 patients in the inhibitor cohort and 93 in the noninhibitor group, for a median efficacy period of 25.4 and 27.7 weeks, respectively. The inhibitor group had 1562 total bleeds, with 60% treated and 40% untreated, the investigators observed. In the patient group without inhibitors, there were 1183 bleeds, of which 86.5% were treated and 13.5% were untreated.

In both groups, the most common type of bleed was joint, at 71% in each group, followed by muscle (15% in both groups). The patients with inhibitors also had few soft tissue, bruise/hematoma, or miscellaneous bleeds, while in the noninhibitor group the bleeds were categorized as “other.”

The cause of the treated bleeds among both groups was relatively evenly split between spontaneous or traumatic reasons. No bleeds were reported with surgery or procedural causes in either group; however, causes of untreated bleeds were a different story. Spontaneous bleeds made up two-thirds of the causes for inhibitor patients, but only one-third for noninhibitor patients. Traumatic causes were responsible for about one-third of inhibitor patients but two-thirds of noninhibitor patients.

“We think this type of data collection is important and provides a more granular picture of the effectiveness of therapies and should be utilized going forward,” Dr. Callaghan concluded. “It would also be beneficial to investigate the decision process regarding treatment of bleeds to better understand what bleeds are not treated and why as well as the long-term sequelae of these bleeds.”

The abstract, “Untreated Bleeds May Βe Historically Under-Reported and More Prevalent in People with Hemophilia Α with Inhibitors,” was published online.