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Despite expectations to the contrary, treatment with recombinant von Willebrand factor (VWF) was not superior to tranexamic acid (TXA) for managing heavy menstrual bleeding in women with mild or moderate von Willebrand disease, a small randomized crossover trial found.

Over two treatment cycles, menstrual blood loss measured by pictorial blood assessment chart (PBAC) scores was significantly lower with TXA than with recombinant VWF (mean 225 vs 272, respectively, P=0.39). But while both treatments showed some effect, neither corrected PBAC scores to the normal range of under 100, reported researchers led by Margaret Ragni, MD, MPH, of the University of Pittsburgh.

Given the antifibrinolytic agent's lower costs than recombinant VWF, and the fact that no differences in quality of life or healthcare utilization were identified between study groups, TXA "appears to be a more effective approach to heavy menstrual bleeding," the researchers wrote in .

Roughly four in five women with von Willebrand disease experience heavy menstrual bleeding, and effective treatments remain a major unmet need, according to the study authors. While hormonal and nonhormonal options (including TXA) provide some relief, many patients continue to experience significant menstrual blood loss that affects their medical, social, and psychological well-being, and reduces quality of life.

"Although VWF concentrate (plasma-derived VWF or recombinant VWF) safely reduces bleeding events in patients with von Willebrand disease, it is costly, requires intravenous infusion, and few data are available regarding its use for heavy menstrual bleeding," wrote Ragni and co-authors, explaining the rationale for their trial.

Their open-label phase III study -- -- was conducted at 13 U.S. centers and randomized 36 female patients with mild to moderate (type 1 and 2) disease. The initial assigned treatment -- 1 day of recombinant VWF or oral TXA for 5 days -- was given for two menstrual cycles, and then patients switched to the opposite treatment for their subsequent two cycles. Slow recruitment led to early termination of the trial.

In an accompanying , Frank Leebeek, MD, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands, highlighted that patients with more severe disease (type 3) were excluded from enrollment and emphasized that "the conclusion that recombinant VWF is not superior to tranexamic acid should be confined to patients with moderate or mild von Willebrand disease."

Moreover, he said, the trial's early end meant it failed to reach the planned 60 participants, limiting the validity of the results, "especially given the well-known variability in PBAC scores over time" in this patient population.

Use of oral contraceptives were not allowed in the trial, Leebeek noted, due to concerns over the potential risk for venous thrombosis.

But "in general practice, this is the first line of treatment for heavy menstrual bleeding for women with von Willebrand disease," he wrote. "In many patients for whom oral contraceptives are not effective for reducing bleeding, tranexamic acid is prescribed, sometimes in combination with oral contraceptives."

Ragni and her fellow study authors acknowledged that recombinant VWF could still play a role in this patient population.

"Although recombinant VWF was not superior to tranexamic acid, it did reduce PBAC score for blood loss and might provide another approach to management of heavy menstrual bleeding in those for whom tranexamic acid, hormones, or desmopressin are ineffective or poorly tolerated," they wrote. "These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience."

VWDMin enrolled 39 females ages 13 to 45 years with mild or moderate von Willebrand disease (historical VWF ristocetin cofactor less than 0.50 IU/mL) with heavy menstrual bleeding, defined as a PBAC score over 100 in one of their past two menstrual cycles.

Ultimately, 36 patients were randomly assigned 1:1 to either the 1-day initial treatment with recombinant VWF concentrate or TXA given three times daily for 5 days for two menstrual cycles, and then the reverse treatment. Median follow-up was 24 weeks.

Most participants were adults (89%), more than two-thirds were white, and 8% were Black. The vast majority had type 1 von Willebrand disease (89%), with the remaining having type 2/2A/2M disease.

The study's primary endpoint tested whether VWF would lead to a 40-point improvement in PBAC score after two cycles of treatment, though neither arm met this endpoint. Secondary outcomes included safety, cycle severity and length, and quality-of-life -- assessed by multiple measures, including the Ruta Menorrhagia severity score; the Center for Epidemiologic Studies Depression Scale; the CDC's Health-Related Quality of Life instrument, for physical and mental measures; and the Short-Form-36.

Researchers found less frequent flooding with TXA versus VWF (44% vs 60%, P=0.014), "but no difference in cycle severity or cycle length" between treatments. Furthermore, no differences were observed when it came to days lost from school or work, need for iron infusion, or emergency visits for heavy bleeding.

Ragni and colleagues reported no serious adverse events (AEs), no grade 3/4 AEs, and no treatment-related deaths. The most common AEs were mucosal bleeding in 6% of patients during TXA treatment compared with no cases during recombinant VWF treatment, and a higher rate of "other bleeding" with TXA (8% vs 4%, respectively).

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