Heavy menstrual bleeding overlooked in many VWD clinical trial designs
Review highlights gaps in eligibility criteria and outcome measures
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Heavy menstrual bleeding — a frequently reported symptom in women with von Willebrand disease (VWD) — is often overlooked in clinical trial design, eligibility criteria, and outcome measures, a review study finds.
For example, traditional clinical trial outcomes for bleeding disorders, such as the annualized bleed rate, failed to capture the duration and severity of heavy menstrual bleeding, according to researchers.
“Until we address this issue, we will lack clarity on optimal treatment, including the role of [preventive treatment] for the management of [heavy menstrual bleeding] in females with VWD,” the scientists wrote in the study, “Menstrual outcomes are frequently overlooked in von Willebrand disease trials,” published in Research and Practice in Thrombosis and Haemostasis.
Heavy menstrual bleeding is common in VWD
VWD occurs when the body does not have enough von Willebrand factor (VWF), a protein needed for blood clotting, or when the VWF it has does not work properly. This impairs the body’s ability to form blood clots, leading to abnormally heavy and prolonged bleeding.
According to a previous study, about two-thirds of women with VWD experience heavy menstrual bleeding, many of them with low levels of ferritin, a protein that stores iron inside cells. Such excessive bleeding can lead to anemia (low red blood cell counts) and fatigue, significantly disrupting daily life.
Because heavy menstrual bleeding is common in women with VWD, researchers examined the inclusion of menstrual and female-specific outcomes in clinical trials that assessed prophylaxis, or preventive treatment, for VWD.
“We sought to provide an evidence base, if possible, regarding the role of prophylaxis on menstrual outcomes from which guidance could be developed,” wrote researchers who conducted the review as part of the European Association for Haemophilia and Allied Disorders’ Women and Girls+ with Bleeding Disorders Working Group.
The team searched three clinical trial databases (U.S., Canadian, and European) for studies open to female VWD patients older than 12 between 2014 and 2024. A total of 10 studies were selected: two focused specifically on menstrual bleeding and enrolled only female patients, while the other eight enrolled both male and female patients.
Trial criteria often missed menstrual bleeding
According to the analysis, menstrual-related criteria were rarely included in the eligibility requirements for these trials. Five of the general studies with male and female patients required participants to have had treated bleeds in the previous six to 12 months as a condition of enrollment. Still, four of those studies specifically excluded treated menstrual bleeds.
Most studies required females to use effective contraception, while no such requirement existed for males. One study listed male partner sterilization as an acceptable contraceptive option.
Some studies also restricted the use of hormonal therapies. One study excluded female patients who had used combined oral contraceptives or contraceptive implants within three months of the study start. Another excluded those expected to start hormonal contraceptives or an intrauterine device (IUD) during the study period.
The outcome measures used in the general studies largely mirrored those used for people with hemophilia, an inherited bleeding disorder where blood does not clot properly due to low levels of working clotting proteins. The annualized bleed rate (ABR), the number of bleeding episodes per year, was used in eight of the 10 studies, but was not used in the two menstrual bleeding-focused studies.
“Annualised bleed rate was originally developed to record predominantly joint and muscle bleeding in a haemophilia population, but ABR provides no indication of bleed duration or severity,” the researchers wrote.
The team also found that heavy menstrual bleeding requiring treatment was listed as an outcome in four of the eight general studies, and menstrual blood loss or duration was measured in two. No general study included heavy menstrual bleeding requiring blood transfusion as an outcome. Two of the eight general studies reported on quality of life.
Trial reports often lacked key details
Enrollment data were available for seven of the 10 studies. Of the 185 people with VWD enrolled across those studies, 65 female participants older than 12 (35%) could be identified. In many cases, this required extrapolation from the data rather than being clearly stated.
The sex of participants was not reported in one study. In three others, sex and age were reported separately, making it difficult to determine how many female patients were of menstrual age. Because menopausal status was also not reported, these numbers may not fully reflect the number of menstruating participants, the scientists noted.
In the general studies, one reported on menstrual bleeding and the effect of treatment on menstrual outcomes among the enrolled women. In another study reporting on the first recombinant VWF replacement therapy, female patients accounted for nearly half (48%) of enrolled participants but were listed only in the demographics table.
The researchers noted that these studies were conducted predominantly in high-income settings, where females represent 62% of those registered with VWD.
“Disappointingly, this review of clinical trials of prophylaxis for [VWD patients] from 2014-2024 identified little recorded or published data relating to menstrual bleeding in females with VWD,” the researchers concluded. “Future studies should aim to more clearly delineate their study population and ensure equity in both their eligibility criteria and outcomes for all types of bleeding and persons enrolled.”
