Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder (clinically symptomatic prevalence rate ~1:10,000). Patients with VWD have impaired hemostasis due to a quantitative or qualitative deficit in von Willebrand Factor (VWF) that alters platelet adhesion and collagen binding and/or decreases FVIII concentrations. Most patients with VWD present with mild-to-moderate mucosal bleeding (epistaxis, menorrhagia), although life-threatening bleeding may also occur, especially in patients with VWD type 3 and some forms of VWD type 2. While bleeds associated with VWD have been well described in the literature, information on the burden associated with major bleeding events (MBE) is limited. Real-world data can be used to help understand the clinical and economic impact of these events.

Aims: To estimate the prevalence, healthcare resource utilization (HCRU), and costs associated with MBE among patients with VWD.

Methods: Patients with VWD with ≥1 year of continuous enrollment since the eligibility start date were identified from Truven databases (01/2008-12/2016). Patients with MBEs were identified using a medical claim associated with an ICD-9/10 CM diagnosis code for intracranial, GI, or eye bleed; or menorrhagia, epistaxis, and joint bleeds that required red blood cell transfusion in an inpatient (IP) setting or within 7 days of diagnosis in an outpatient (OP) setting. Prevalence was calculated as the proportion of eligible patients with ≥1 MBE during the observation period (from start to the end of continuous eligibility). To evaluate economic burden, patients with ≥1 MBE on or after the first diagnosis of VWD were compared with patients with no MBEs. HCRU and cost in the 12-month continuous enrollment period following the first MBE were compared with those from a similar 12-month period for patients without MBEs. Regression models were used, controlling for demographics, health plan, index year, Charlson Comorbidity Index (CCI), comorbidities, thrombotic events, and HCRU during the 12-month continuously enrolled baseline period. For patients with MBEs, the proportion of patients with comorbidities was compared between the 12-month baseline and study periods using McNemar test.

Results: 19,785 VWD patients were identified (mean age 34 years, 75% female) During a median observation of 4 years, 15.1% of patients experienced ≥1 MBE (mean rate: 0.11 ± 0.64 MBE/year). GI bleeding was the most prevalent MBE, occurring in 13.4% of all patients. Although not common, the prevalence of intracranial bleeds (1.1%) was slightly higher in males than females (1.7% vs 0.9%). In the sample to evaluate economic burden, 773 patients with ≥1 MBE (age 44.5 ± 20.1 years) and 4285 patients without MBEs (age 34.2 ± 19.5 years) were selected. Patients with MBEs were significantly (p<0.01) more likely to have an IP admission (OR, 4.1; 95% CI, 3.4-5.0), ER visit (1.8; 1.5-2.1), or OP visit (4.9; 1.8-13.4); they also had significantly longer IP stays (IRR, 3.9; 95% CI, 3.1-4.9) and more frequent IP admissions (3.2; 2.8-3.8), ER visits (2.0; 1.8-2.3), and OP visits (1.3; 1.2-1.3), compared to those without MBEs. Patients with MBEs incurred significantly (p<0.01) higher total healthcare costs (adjusted mean difference, $20,890; 95% CI, $15,524-$29,254) than those without MBEs. Among the 773 patients with MBEs, approximately 1 in 4 patients had a MBE (26.8%) diagnosed in the IP setting. The overall annual mean (± SD) IP length of stay (LOS) was 7.4 ± 19.4 days, with intracranial bleeds associated with the longest mean IP LOS (14.3 ± 19.4 days). The readmission rate was 3.1% for any MBE, and 2.5% for the same type of MBE as the initial bleed. The proportions of patients with anemia (24.2% vs 15.9%; p<0.01) and anxiety (18.6% vs 14.2%; p<0.01) were significantly higher after the MBE than before.

Conclusions: In this large retrospective analysis of data from a US commercial healthcare plan, ~15% of patients with VWD experienced MBEs, mostly GI bleeds. While our estimation of some MBEs may be conservative, this is the first study to use a large dataset with sound statistical methods to evaluate the burden associated with MBEs in this population. MBEs were associated with additional comorbidities and high HCRU and costs (driven by inpatient costs), so optimal therapy is essential to prevent MBEs in patients with VWD.


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Author notes


Asterisk with author names denotes non-ASH members.